The Alkaloids Chemistry and Pharmacology, Volume 31 - (1987)

THE ALKALOIDS

Chemistry and Pharmacology

Volume 31

THE ALKALOIDS

Chemistry and Pharmacology

A list of contents of volumes in this treatise is available from the publisher on request

THE ALKALOIDS Chemistry and Pharmacology

Edited by Arnold Brossi

National Institutes of Health Bethesda, Maryland

VOLUME 31

ACADEMIC PRESS, INC. Harcourt Brace Jovanovich, Publishers

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87 88 89 YO 9 8 7 6 5 4 3 2 I

CONTENTS

PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 1 . Reissert Synthesis of Isoquinoline and Indole Alkaloids

GABOR BLASKO. PETER KEREKES. AND SANDOR MAKLEIT

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1 . Synthesis of Isoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111 . Synthesis of Indole Alkaloid Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 2 . Aristolochia Alkaloids

ZHONG-LIANG CHEN AND DA-YUAN ZHU

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1 . Structural Relations and Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I11 . Spectroscopic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Chemical Reactions and Structural Determination . . . . . . . . . . . . . . . . . . . . . . . . . V . Chemical Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

VI . Pharmacology and Clinical Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII . Summary of Physical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 3 . Chromone Alkaloids

PETER J . HOUGHTON

I . Introduction . . . . . . . . . . I1 . Botanical Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I11 . The Flavonoidal Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Noreugenin-Related Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ix

1 5

24 21 27

29 30 36 43 47 54 62 62

67 68 15 87 99

V

vi CONTENTS

Chapter 4 . Dibenzopyrrocoline Alkaloids

I . W . ELLIOTT

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1 . History . . . . . . .

111 . Cryptaustoline and Cryptowoline . . . . . . . . . . . . . . . . . . . . . . . . .

V . Pharmacology . . IV . Synthesis and Reactions of Dibenzopyrrocolines ..........................

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 5 . Lupine Alkaloids

KH . A . ASLANOV, Yu . K . KUSHMURADOV, AND A . S . SADYKOV

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111 . X-Ray Structural Investigation of Quinolizidine Alkaloids . . . . . . . . . . . . . . . . . . IV . Bicyclic Quinolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . Tricyclic Quinolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

VI . Tetracyclic Quinolizidine Alkaloids of the Sparteine Group . . . . . . . . . . . . . . . . .

I1 . 13C-NMR Spectroscopy of Quinolizidine Alkaloids .......................

VII . Tetracyclic Alkaloids of the Leontidine Group (Quinolizidine-Indolizidine Alkaloids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

VIII . Tetracyclic Alkaloids of the Aloperine Group ............................ IX . Tetracyclic Alkaloids of the Matrine Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 6 . Alkaloids from Ants and Other Insects

ATSUSHI NUMATA AND TOSHIRO IBUKA

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1 . Occurrence and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111 . Structure and Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ..............................................

Chapter 7 . Pavine and Isopavine Alkaloids

BELKIS GOZLER

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1 . Occurrence and Structure Elucidation . . . . . . . . . . . . . . . . . . . . . . . . .

111 . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Unnatural Pavines and Isopavines . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . Spectral Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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i01 103 106 108 114 115

118 132 134 140 146 155

164 167 169 184

194 194 238 302

317 319 330 356 362

CONTENTS

VI. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Chemotaxonomic Considerations . . . . . . . . . . . .

VIII. Homopavines and Homoisopavines . . . . . . . . . . . IX. Aporphine-Pavine Dimers . . . . . . . . . . . . . . . . . . X. Pharmacology ............................

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

......................... 312

......................... 316

......................... 378

......................... 381

......................... 383

......................... 384

......................... 39 1

This Page Intentionally Left Blank

PREFACE

Discussion of the Reissert synthesis in connection with isoquinoline and indole alkaloid synthesis follows a suggestion that important methods in alkaloid chemistry be reviewed. “Aristolochia Alkaloids” refers to a group of alkaloids casu- ally discussed under “Aporphine Alkaloids,” now taken out of this context and presented here for the first time as an independent group of alkaloids. Also for the first time ‘‘Chromone Alkaloids” and ‘ ‘Dibenzopyrrocoline Alkaloids” are presented, many of them having interesting pharmacological properties, The “Lupine Alkaloids” were discussed in Vols. 3, 7, and 9 of this treatise. This classical group of alkaloids is updated here and presented by experts in the field. “Alkaloids from Ants and Other Insects” presents compounds discussed earlier under ‘ ‘Piperidine Alkaloids,’ ’ ‘‘Pyrrolizidine Alkaloids ,” “Simple Indo- lizidine and Quinolizidine Alkaloids, ’ ’ and “Pyrrolidine Alkaloids, ’ ’ now condensed in one chapter summarizing these interesting natural products. “Pavine and Isopavine Alkaloids, ” discussed under the heading ‘‘Isoquinoline Al- kaloids” in Vols. 12 and 17 of this treatise, now comprises more than two dozen alkaloids, justifying their presentation as a separate group of isoquinoline alkaloids. Occurrence, spectral properties, structures, and synthesis and biosynthesis are professionally covered, and pharmacological properties included whenever known.

Arnold Brossi

ix


- CHAPTER 1 -

REISSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS*

GABOR BLASKO

Central Research Institute for Chemistry The Hungarian Academy of Sciences

Budapest, H-1525 Hungary

~ T E R KEREKESI.

AND

SANDOR MAKLEIT

Department of Organic Chemistry Kossuth Lajos University of Debrecen

Debrecen, H-4010 Hungary

I. Introduction A. Preparation of Reissert Compounds B. Reaction of Reissert Compounds

A. Synthesis of 1-Benzylisoquinolines B. Synthesis of Cularines and Quettamines C. Synthesis of Pavinanes D. Synthesis of Aporphines and Oxoaporphines E. Synthesis of Protoberberines F. Synthesis of Phthalideisoquipoline Alkaloids G. Synthesis of Emetine Analogs

111. Synthesis of Indole Alkaloid Analogs A. Synthesis and Reactions of 3,4-Dihydro-P-carboline Reissert Compounds B . Synthesis of Ellipticine Analogs

IV. Conclusion References

11. Synthesis of Isoquinoline Alkaloids

I. Introduction

In 1905 Arnold Reissert discovered ( I , 2) that quinoline (1) or isoquinoline (2) could react with benzoyl chloride in the presence of aqueous potassium cyanide,

* This chapter is dedicated to the memory of Dr. Wter Kerekes, who died in Bethesda, Maryland, on August 1, 1984.

t Deceased.

1 THE ALKALOIDS, VOL. 31 Copyright 0 1987 by Academic Press, Inc.

All rights of reproduction in any fonn reserved.

2 GABOR BLASKO, PETER KEREKES, AND SANDOR MAKLEIT

I F-0 !a

3

H‘ ’CN

SCHEME 1

resulting in 1,2-dihydro- 1 -benzoyl-2-cyanoquinoline (3) or 1,2-dihydr0-2-benzoyl-1-cyanoisoquinoline (4), respectively (Scheme 1). The latter type of compounds, later named “Reissert compounds,’ ’ became versatile tools for different synthetic applications.

The chemistry of Reissert compounds has been the subject of numerous general reviews (3-10). In 1973 Popp gave a summary on the use of Reissert compounds in the synthesis of isoquinoline alkaloids and related compounds (3. We now wish to summarize new results that have appeared from 1973 to the end of 1985 for the application of Reissert compounds in the synthesis of isoquinoline as well as indole alkaloids.

A. PREPARATION OF REISERT COMPOUNDS

The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became domi- nant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide.

I . REISSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS 3

10 I I

SCHEME 2

B. REACTION OF REISSERT COMPOUNDS

Acid-catalyzed hydrolysis of Reissert compounds results in an aldehyde, a formal reduction product of the acyl halide utilized in the Reissert compound formation (11). The mechanism of the reaction according to McEwen and Cobb (3), is shown in Scheme 2.

Isoquinoline Reissert compounds of type 12 could be easily converted to the corresponding 1 -cyanoisoquinolines (13) by simple base treatment ( 4 3 (Scheme 3 ) . This transformation also takes place with high yields when type 12 compounds are oxidized with molecular oxygen in a two-phase system in the presence of phase-transfer catalysts (12-14). It should be mentioned that similar oxidation of dihydro Reissert compounds of type 14 afforded the corresponding dihydroisocarbostyril derivatives (15) (12-14). Base treatment of isoquinoline Reissert compounds followed by intramolecular rearrangement, due to the absence of a proper intermolecular reaction partner, results in 1 -acylisoquinoline derivatives (18) (3).

The formation of a “Reissert anion” (intermediate of type 16) is usually the introductory step in a great number of synthetic routes leading to isoquinoline as well as indole alkaloids and related compounds. On the one hand, the alkylation of a Reissert anion with alkyl halide followed by alkaline hydrolysis is the most frequently used method for the synthesis of 1 -alkyl- or 1 -arylalkylisoquinolines (20) (Scheme 4). On the other hand, Reissert anions react with aldehydes to form


I CN

12 13

1 2 5 R W N $ $ , - R q - RWN c t G-

C N d CN $=O R’

16 17 18 R’

SCHEME 3

R q N _ e _ f i . RW 8 - KOH

2 9 R”-X N-C-R’ E ~ O H H CN CN R”

19 12

16 k“

21

‘ W N 0

CH-OC-R’

R 23

22

SCHEME 4

1. REISSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS 5

first an alkoxide intermediate (21), in which the negatively charged oxygen could attack the amide carbonyl to yield oxazolidine 22, and this on rearomatization affords the final product, a secondary alcohol ester (23). In the following section we discuss the utilization of the above reactions of Reissert compounds for the purpose of alkaloid synthesis.

11. Synthesis of Isoquinoline Alkaloids

A. SYNTHESIS OF ~-BENZYLISOQUINOLINES

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. (15) starting from isoquinoline and benzyl chloride (Scheme 5) . The preparation of Reissert compound N-benzyl- 1-cyano- 1,2-dihydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply l-benzylisoquinoline (25) in an overall yield of 75-84%.

Skiles and Cava have investigated the alkylation method of isoquinoline Reis- sert compounds (16), performing a comparative study on the alkylation of

R'

$QN&

H CN

4 R1=R2=R3=H

26 R1=H, R2=R3=OCH3

27 R~=R~=R'=oc%

28 R1=H, R2+R3=OCH20

SCHEME 5


TABLE I Comparison of Yields of Alkylation Reactions

~

Method, % yield

Reissert compound Product A B C

4 24 46 95 91 26 29 38 92 94 27 30 52 94 96 28 31 51 93 92

compounds 4, 26,27, and 28 with both benzyl chloride and o-nitrobenzyl chloride, using three different reaction conditions:

A. Lithium diisopropylamide in THF/HMPA B. Potassium hydroxide with benzene in the presence of dicyclohexyl- 18-

C . 50% aqueous sodium hydroxide with benzene or acetonitrile in the pres-

According to measured yields, conditions B and C have been found to be much more advantageous than method A (see Table I).

Several 1 -benzylisoquinoline alkaloids have been synthesized utilizing the above reaction sequence. For example, takatonine (34) has been obtained from Reissert compound 27 via alkylation with p-methoxybenzyl chloride and subsequent hydrolysis and quatemarization with methyl iodide (17). Similarly, escholamine (37) has been prepared from N-benzoyl- l-cyano-6,7-methylenedioxy- 1,2-dihydroisoquinoline (28) and 3,4-methylenedioxybenzyl chloride (17) as shown in Scheme 6.

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7 ) (18). 6- Methoxy-7-benzyloxyisoquinoline (39), prepared from 0-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to (*)-reticuline (38) in about 25% overall yield from 39.

Two similar pathways have been reported (19) for the total synthesis of a pseudobenzylisoquinoline-type alkaloid, rugosinone (43), isolated as a minor component of Thalictrum rugosum. As shown in Scheme 8 the anion of N- benzoyl- l-cyano-6,7-methylenedioxy-l,2-dihydroisoquinoline (28) was reacted

crown-6

ence of phase-transfer catalyst (cetrimonium bromide)

1 . REISSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS 7

H C N CH$ c H 3 0 3 c N Q N-C-g __ - 27 + CH,CI

/

CH,O \

OCH, 32

33 34 l a k a t o n i n e

O V \-0

35

36 37 Escholamine

SCHEME 6

with either 2-benzyloxy-3,4-dimethoxybenzaldehyde or 2,3,4-trimethoxy- benzaldehyde to produce the corresponding 1 -alkylated Reissert compound 44 or 45, respectively. Alkaline hydrolysis of these intermediates followed by oxidation of the benzylic alcohol moiety resulted in 1-acylisoquinolines 48 and 49, respectively. Removal of the benzyl protecting group of 48 with trimethylsilyl iodide gave rugosinone (43). The final step of the other pathway is a regioselective demethylation at position 2 ' , which could be achieved with boron trichloride, and the participation of the neighboring carbonyl group is regarded to ensure the high selectivity in supplying rugosinone (43).

8 GABOR BLASKO, PI~TER KEREKES, AND SANDOR MAKLEIT

- CH,O

38 Reticuline

SCHEME 7

C H , O V O R CH,O

OCH, 44 R=CH2$?

45 R=CH3

46 R=CH20 48 R=CH2@ 43 Rugosincne

47 R=CHJ 49 R=CH3

SCHEME 8


R' R' O'COCl - KCN

R' R'

1, NaOCH3

2 , HC1 CH,OH

CH,O

NaH, DMF

57 R ~ = H , R ~ = O H 59 RLH, $=OH

58 R ~ = O H , R ~ = H 60 R~=CH, R ~ = H

- CH,O CH,O

51 R ~ = H , $=OH 50 Trlmethoqulnol

52 FAOH, R ~ = H

SCHEME 9

In work aimed at developing a long-acting bronchodilator agent, analogs of trimethoquinol (50), containing a saligenine moiety (compounds 51 and 52) instead of the catechol nucleus, have been synthesized via a Reissert route (20), as shown in Scheme 9. Experiments have been made (21) for the synthesis of bisbenzylisoquinoline-type alkaloids by alkylation of the anion of isoquinoline Reissert compounds (4, 26, and 28) with bifunctional diaryl ethers such as 61, 62, and 63. 0-Methyldauricine (64) has been prepared by this route (Scheme lo), via condensation of Reissert compound 26 with diaryl ether 62 to give dialkylated product 65 followed by alkaline hydrolysis to afford bisbenzylisoquinoline 66. Quaternarization of 66 with methyl iodide and subsequent sodium borohydride reduction gave 0-methyldauricine (64) in racemic form (21).

B. SYNTHESIS OF CULARINES AND QUETTAMINES

Cularine (67) and related alkaloids constitute a small group of l-benzylisoquinoline-related alkaloids, which are distinguished from the main group by

10 GABOR BLASKO, PETER KEREKES, AND SANDOR MAKLEJT

CHJL B r - C H z o o -02 CH,- Br Q o y H 2 C I

61 OCH,

62

OCH, CH,-Br

CH30QO @ CH,-Br OCH,

63

66

64 O-Methyldauricine

SCHEME 10

possession of an intramolecular ether linkage between the isoquinoline nucleus and the l-benzyl portion. Cularines might be formed in nature by phenolic oxidative coupling of the corresponding 1 -benzylisoquinolines; therefore, their biomimetic total synthesis involves the construction of a 1 -benzylisoquinoline system with proper substitution pattern.

Jackson et al. (22) reported the biomimetic total synthesis of (+)-cularine (67) itself (Scheme 11). Benzyolation of isoquinoline 68 in the presence of potassium cyanide gave Reissert compound 69, the anion of which was alkylated with 3- benzyloxy-4-methoxybenzyl chloride, resulting in intermediate 70. After al-


CH,O CH,O ,0-CH20 $-CH,O H C N

68 69

OCH,

72 67 R=CX3 Cularine

73 R=H

SCHEME 11

kaline hydrolysis the required 1-benzylisoquinoline 71 was obtained. N-Meth- ylation of 71 followed by sodium borohydride reduction and acidic cleavage of the benzyl ether groups supplied 1,2,3,4,-tetrahydro- 1-(3-hydroxy-4-methoxybenzyl)-7-methoxy-2-methylisoquinolin-8-ol (72). Compound 72 was oxidized with potassium ferricyanide in an aqueous ammonium acetate-chloroform two- phase system to 0-demethylcularine (73), which could be converted to (?)- cularine (67) by methylation with diazomethane.

Oxocularine (74) and oxocompostelline (75) have also been synthesized (Scheme 12), with a novel cyclization in the key reaction step which leads to the cularine skeleton. 2’-Bromo- 1 -benzylisoquinolines 78 and 79, obtained by the Reissert method from 69, were dehydrohalogenated with dimsyl sodium, giving rise to a benzyne intermediate which could be attacked by either the nitrogen or oxygen nucleophile present in the molecule. The nitrogen attack generates dibenzopyrrocoline derivatives 80 and 81, respectively. At the same time, the intramolecular reaction of the phenoxide with the benzyne system resulted in cularines 82 and 83. The last two compounds could be oxidized in air or by Fremy’s salt to the target natural products oxocularine (74jand oxocompostelline (75), respectively (23).


CH,O @-CH,O H CN

69

R'O OR'

76 R ~ = Z = C H ~ 77 R1tRz=CH2

4

74 R ~ = R ~ = c H ~ Oxocularine

7 5 R I + R ~ = c H ~ Oxocompostelline

SCHEME 12

Quettamine (84) is an isoquinoline alkaloid incorporating a furan moiety condensed with both rings of the isoquinoline nucleus (24), and it is closely related biogenetically to cularine-type alkaloids. The total synthesis of quettamine (84) (Scheme 13) has been performed by the utilization of the known Reissert compound 69. Treatment of the anion generated from 69 with 4-benzyloxy- benzaldehyde yielded benzoate ester 85, which was hydrolyzed to the corresponding alcohol 86. N-Methylation of 86 followed by sodium borohydride reduction resulted in 1 -benzylisoquinoline derivative 87 in high yield. Cycliza- tion of the dihydrofuran ring was carried out with trifluoroacetic acid through a


1, C R j I CH30 0-CH20 H C N 2, NaBH4

69

@-CH,O 85 R=CO#

86 R=H

- c H 3 0 3 0 : H 3 pl-CH,O - TFA

pl-CH,O ' 87

ul OH uOH

88 84 Buettairine

SCHEME 13

benzylic cation derived from 87 to produce stereoselectively tetracycle 88 with a trans relationship between H-1 and H-a. Finally, quaternarization of 88 with methyl iodide gave (*I-quettamine (84) iodide (25).

C. SYNTHESIS OF PAVINANES

The total synthesis of pavinane alkaloid platycerine (89) (Scheme 14) has been accomplished successfully (26) via 1-benzylisoquinoline derivative 91 obtained from Reissert intermediate 90. Quaternarization of 91 with methyl iodide followed by lithium aluminum hydride reduction supplied 1,2-dihydroisoquinoline 92, which on treatment with a 7 : 5 mixture of formic acid and phosphorous acid gave (*)-platycerine (89) in 60-70% yield.

D. SYNTHESIS OF APORPHINES AND OXOAPORPHINES

The aporphines constitute one of the largest groups of isoquinoline alkaloids and have a wide range of physiological activity. For example, bulbocapinine (93) (see Scheme 15) affects the central nervous system and causes catatonia, boldine

14 G ~ O R BLASKO, PETER KEREKES, AND SANDOR MAKLEIT

89 Pla tycer ine

SCHEME 14

(94) has a mild sedative and diuretic activity, and glaucine (95) has covulsive as well as antitussive properties. Apomorphine (96), a.semisynthetic derivative of morphine, proved to be a promising drug for the treatment of Parkinson's and related neurological diseases, owing to its ability to stimulate the central dopamine receptors. Isothebaine (97) depresses the central nervous system, apocodeine (98) has emetic activity, and the quaternary laurifoline chloride (99) has hypotensive activity.

Neumeyer and co-workers have performed a thorough investigation (27) on structure-activity relationships of aporphines closely related to the dopaminergic apomorphine (96), which contains a virtually conformationally fixed dopamine moiety. Working toward the synthesis of a great number of mono-, di-, and trihydroxyaporphine derivatives, they frequently utilized the Reissert alkylation method (Scheme 16). For example, in the case of the syntheses of racemic apomorphine (96) (28), 8-hydroxyaporphine (100) (29), 10-hydroxyaporphine (101) (30), and 1 1-hydroxyaporphine (102) (31), the N-benzoyl-l-cyano-l,2- dihydroisoquinoline (4) was used as starting material together with a properly substituted 2-nitrobenzyl chloride. Reissert alkylation followed by alkaline hydrolysis gave l-(2-nitrobenzyl)isoquinoline derivatives 107, 108, 109, and 110, respectively. Quaternarization of these compounds with methyl iodide followed by potassium borohydride and catalytic reduction resulted in N-methyl- 1,2,3,4-


93 Bulbocapnine

HO F X C H 3

RO

96 R=H Apomorphine

98 R=CH3 Apocodeine

CH,

OR

94 R=H Boldine

95 R=CX3 Glaucine

97 Isothebaine

r ,

99 I au r i fo l ine

SCHEME 15

tetrahydro- l-(2-aminobenzyl)isoquinolines 111, 112, 113, and 114. Pschorr cyclization of these latter compounds followed by methoxy cleavage with hydro- iodic acid yielded racemic apomorphine (96), or 8-hydroxy-, 10-hydroxy-, and 1 1-hydroxyaporphines (100, 101, and 102), respectively. Similarly to the above reaction sequence N-alkyl analogs of bulbocapnine (93) have been prepared via the above Reissert alkylation-Pschorr cyclization route (32).

A novel and efficient synthesis of aporphinic alkaloids has been developed by Kupchan and O'Brien (33) via oxidative photocyclization of I-(or-hydroxy-2- iodobenzyl)d-hydroxy-7-rnethoxyisoquinolines such as 120, 121, or 122, all prepared by the Reissert method shown in Scheme 17. N-Methylation of oxoaporphines 124 and 125 yielded corunnine (127) and nandazurine (128), respectively. Reduction of 124 with Zn-AcOH resulted in thalicmidine (130), and similar reduction of 125 gave domesticine (131) in racemic form. Caaverine (129) has also been prepared by this route (33).

Reissert alkylation and Pschorr cyclization have frequently been utilized for the synthesis of oxoaporphine alkaloids by Cava and co-workers. Their synthetic

16 GABOR BLASKO, PETER KEREKES, AND S h O R MAKLEIT

111 R1=R2=OH, R3=H

112 R~=R'=H, $=OH

113 R1=R3=H, R2=OH

114 R1=OH, R2=R3=H

96 R~=R'=oH, R ~ = H

100 R~=R'=H, $=OH

101 R ~ = R ~ = H , $=OH

I02 $=OH, R2=R3=H

SCHEME 16

work comprising the synthesis of phenolic oxoaporphine alkaloid antheroline (132) (34 , the structure revision and synthesis of subsessiline (133) ( 3 3 , as well as the total synthesis of imenine (134) (36) are shown in Schemes 18-20.

E. SYNTHESIS OF PROTOBERBERINES

The Reissert alkylation method was also utilized for synthesizing the basic skeleton of protoberberine alkaloids (Scheme 21). Reaction of 3,4-dihydroisoquinoline derivatives 149, 150, and 151 with 2-chloromethylbenzoy1 chloride and trimethylsilyl cyanide in methylene chloride gave the corresponding 2- chloromethylbenzoyl- 1,2,3,4-tetrahydroisoquinaldonitriles (152, 153, and 154,


n ILO R ~ = R ~ = H

126 RW=H 127 R1=R2=OCH3 Oorunnine

128 R1+Rz=OCH20 Nandazurine

123 R~=P=H

129 R ~ = R ~ = R = H Caaverine

130 R1=R2=OCH3, R=CH3 Thalicnidine

131 R1+R2=OCH20, R=C? Donesticine

SCHEME 17

respectively). Reaction of these Reissert compounds with sodium hydride in dimethylformamide led directly to 8-oxoprotoberberine derivatives 158, 159, and 160 respectively, in high yields (37,38). The reaction could be extended successfully to the synthesis of 5,6-didehydro-8-oxoprotoberberine derivatives 167 and 168 as well (38,39).

The synthesis of 168 has also been completed by using other reaction conditions (Scheme 22). 6,7-Dimethoxyisoquinoline (162) was reacted with potassium cyanide and 2-chloromethylbenzoy1 chloride in the presence of a catalytic amount of benzyltriethylammonium chloride, resulting in 164 which on treatment with lithium diisopropylamide in hexamethylphosphoramide-tetrahydro- furan solvent mixture afforded the cyclized product 168 in high yield (40).


CH30 C H 3 0 F I / ::@

CH,O '

4 P

CH,O \

OR 0 C H,-$ I38 139 R=CH20

132 R=H Antheroline

SCHEME 18

c H 3 0 T CH,O \ - CH30@: CH,O \

N H, - \ \

OCH,-$ OR

142 143 R=CH2@

133 R=H Subsessiline

SCHEME 19


145

148 134 Imenine

SCHEME 20

In 198 1 multistep syntheses of (2)-mecambridine (169) and orientalidine (170) (Scheme 23) were accomplished by Kerekes (41), starting from a properly substituted Reissert compound. 2-Benzoyl- 1 -cyano- 1 ,2-dihydro-8-methoxy-6,7- methylenedioxyisoquinoline (171), obtained from cotarnine, was reacted with potassium cyanide and 3-benzyloxy-4-methoxybenzyl chloride; intermediate 172 was hydrolyzed to l-(3-benzyloxy-4-methoxybenzyl)-8-methoxy-6,7-methylenedioxyisoquinoline (173) without purification. 1-Benzylisoquinoline 173 on debenzylation and catalytic hydrogenation gave the corresponding 1,2,3,4- tetrahydroisoquinoline derivative 174. The internal Mannich reaction of 174 in neutral medium gave the 10,ll-disubstituted protoberberine derivative 175 as major product in addition to the 9,lO-disubstituted isomer 176. Treatment of compound 175 with formaldehyde in methanolic sodium hydroxide gave 11-0- demethylmecambridine (177) as a crystalline product. 1 1 -0-Demethylmecambri- dine (177) was finally converted to (+-)-mecambridine (169) on methylath with diazomethane, and into (*)-orientalidhe (170) on treatment with sodium hydride and dichloromethane in dry dimethylformamide.

20

- :z%

GABOR BLASKO, PETER KEREKES, AND SANDOR MAKLEIT

- ;:1$;; 1

149 R~=R‘=H

150 F ? = R ~ = O C H ~

151 R~+R’=OCH~O 152 R~=R’=H

154 R ~ + R ~ = O C H ~ O

153 R ~ = R ~ = O C R ~

SCHEME 22

1. RElSSERT SYNTHESIS OF ISOQUINOLINE AND INDOLE ALKALOIDS 21

NaOH

DI@

171’

172 OCH,

HCHo - -

173 I74

- c%R, CH30 - ECHO (:% CH30 , NaOH

\ OCH, \ OCH,

HO OH R‘

17s AH, OH 176 $=OH, R ~ = H C H p 2 F2 1 DlIF

OCH, OCH,

I69 Fkec ambri d ine 170 Orientalidine

SCHEME 23

F. SYNTHESIS OF PHTHALIDEISOQUINOLINE ALKALOIDS

Among the great number of different approaches for the synthesis of phthalideisoquinoline alkaloids the application of Reissert compounds, developed first by Kerekes et al. (42,43), proved to be one of the most efficient and suitable methods (Scheme 24). Treatment of isoquinoline Reissert compounds 26 or 28 with sodium hydride in dimethylformamide resulted in the formation of the corresponding “Reissert anions,” which were reacted with dimethoxy- or methylenedioxy-substituted o-forrnylbenzoic acid ester derivatives 178 and 179, respectively. The presumed mechanism of this reaction involves an initial reaction


178 R3=R4=CCHj

179 R3+R4=OCHz0

Q - CH-OC-g by". Rk

I82 R1+R2=R3+R4 =OCH20

I83 R'+R' =0CB2 0 , R3 =R4 =CCH3

184 R1=R2=OCH3, R7+R4=OCHz0

185 R1=Rz =R3=R4 =OCH3

186 R1+R2=R3+R4=OCHz0

187 R1+Rz=OCH20, R3=R4=OCH 3 188 R1=R2=OCH3, R7+R4=OCHZC

189 R1=R2 ,R3=R4 E O C S


198 R1+R2=R3+R4=OCH2C 20 2 R1+Rz =R3 +R4 =OC% 0

199 R1+R2=OCH20, R3=R4=OCK, 203 R1+Rz=OCH20, R3=R4=OCH 3

200 R1=R2=OCItj, R3+R4=OCHz0

201 R1=Rz=R3=R4=OC~ 205 R1=Rz=R3 =R4=OCH3

204 R1=Rz=CCHj, R3+R4=OCH;10

SCHEME 24 (Continued)

96 NaOH o \ o \

206 207

r 1

210

SCHEME 25

of the Reissert anion with the aldehyde carbonyl to form an alkoxide type intermediate (180), whose negatively charged oxygen attacks the amide carbonyl to yield an oxazolidine of type 181, which on rearomatization affords O-benzoyl- 1 -benzylisoquinoline derivatives 182-185. Saponification of the latter compounds with potassium hydroxide in aqueous alcoholic solution and subsequent lactonization by treatment with hydrochloric acid results in the phthalideisoquinoline skeleton with proper substitution patterns at rings A and D.

The aromatic phthalideisoquinolines (186-189) obtained were hydrogenated in the presence of a PtO, catalyst to obtain a nearly 1 : 1 mixture of erythro and threo norphthalideisoquinolines (190-193 and 194-197, respectively). The mixtures of erythro and threo diastereomer pairs were separated by preparative thin- layer chromatography, and finally Eschweiler-Clark N-methylation was performed on each norphthalideisoquinoline derivative, yielding (-+)-bicuculline (198), (?)-corlumine (199), (k)-P-hydrastine (200), and (+)-cordrastine I1 (201) all with erythro relative configuration and, on the other hand, (+)- adlumidine (202), (+)-adlumine (203), (+)-a-hydrastine (204), and (+-)-~or- drastine I (205) with the threo relative configuration of their C-1, C-9 stereo centers (42-44). The fact that pairs of diastereomeric N-norphthalideiso-


c H 3 0 w N - F - g CH,O \ CN H + :$% H - ’.C,H,

CHO 26

212

211

SCHEME 26

quinolines and phthalideisoquinolines were thus available has allowed a structure-activity relationship investigation on their y-aminobutyric acid (GABA, the inhibitory neurotransmitter agent of the mammalian central nervous system) antagonist activity (45).

Reaction of 2-(o-formylbenzoyl)-1,2-dihydroisoquinaldonitrile (206) with base followed by an intramolecular acylmigration gave the unsubstituted phthalideisoquinoline skeleton 210 as shown in Scheme 25 (40).

G. SYNTHESIS OF EMETINE ANALOGS

Successful attempts have been made for the preparation of different emetine analogs (46). For example, 211 has been synthesized by the reaction of Reissert compound 26 with the protoemetine analog 212 (Scheme 26).

111. Synthesis of Indole Alkaloid Analogs

A. SYNTHESIS AND REACTIONS OF

3,4-DIHYDRO-P-CARBOLINE REISSERT COMPOUNDS

The Reissert reaction of 3,4-dihydro-P-carboline (213) has also been studied (47,48). It has been shown that 3,Qdihydro-P-carboline (213) afforded 1- cyano-2,9-dibenzoyl-l,2,3,4-tetrahydro-~-carboline (214) with a phase-transfer catalyst and trimethylsilyl cyanide (Scheme 27). However, the “normal” Reis- sert product 2-benzoyl-1-cyano- 1,2,3,4-tetrahydro-P-carboline (215) was obtained when a catalytic amount of anhydrous aluminum chloride was used in addition to the trimethylsilyl cyanide reagent. Reaction of 214 with sodium


218

SCHEME 21

219 R=CHz@

220 R=H

221 R=cH~!$

222 R=H

223 224

SCHEME 28

hydride and excess of methyl iodide gave l-cyano-2,9-dimethyl-1,2,3,4- tetrahydro-P-carboline (216), while the use of 1,3-dibromopropane instead of methyl iodide led to the tetracyclic compound 217, which represents the skeleton of the canthin-6-one-type alkaloids. Similar reaction of 215 with a,a-dibromo-o- xylene supplied the benzoazepino-P-carboline 218 (47). It is interesting to mention that the hydrolysis was not accompanied by the elimination of the CN group.

Treatment of 4-chlorobutanoyl Reissert compounds 219 and 220 with sodium hydride in dimethylfomamide afforded indolo[2,3-a]quinolizine derivatives 221 and 222, respectively, in an intramolecular alkylation process (Scheme 28).


Similarly, intramolecular cyclization of the 2-chloromethylbenzoy1 Reissert derivative 223 resulted in N-benzyldemethoxycarbonyl-oxogambirtannine (224) (47).

B. SYNTHESIS OF ELLIPTICINE ANALOGS

The formation of Reissert derivatives of the antineoplastic agent ellipticine (225) (Scheme 29) and their reactions have been extensively studied by Popp and co-workers (39,49-51). The ellipticine Reissert compound 226 could be prepared either with benzoyl chloride and potassium cyanide in a dichloromethane- water system or, better, with benzoyl chloride and trimethylsilyl cyanide in dichloromethane. In similar manner 9-methoxyellipticine and a number of 6- substituted ellipticines have also been converted to the corresponding Reissert compounds.

Reaction of 2-benzoyl-6-benzyl- l-cyano-l,2-dihydroellipticine (227) with alkyl halides in dimethylfonnamide in the presence of sodium hydride gave the

225 Ellipticine 226 RL=H

227 R1=CH2g

CH R CN

M 228 X2=C$

229 R2=CH,0

P 230 R2=CH3

231 R2=C%0

232

SCHEME 29


alkylated Reissert derivatives 228 or 229, which could be hydrolyzed to 1- alkyl-6-benzylellipticines 230 and 231, respectively. The ellipticine Reissert compound 226 has also been converted to its cyclic fluorobrate salt 232 on treatment with fluoroboric acid in glacial acetic acid.

IV. Conclusion

Although a number of effective synthetic methods have been developed for the synthesis of isoquinoline as well as indole alkaloids (Bischler-Napieralski, Pictet-Spengler, Pomerantz-Fritsch syntheses, etc.), there is still a need to improve the existing methods and to develop new ones. It can be stated that the synthetic approach via Reissert compounds proved to be one of the most efficient routes to the alkaloids in question in the 1970s and 1980s. First, the preparation of 1-benzylisoquinoline alkaloids received much attention. More recently, the synthesis of aporphines, phthalideisoquinolines, and ellipticines, all of them possessing different valuable pharmacological properties, became the target of organic chemists. The Reissert approach has proved to be a good synthetic tool with general applicability to the synthesis of these type of alkaloids.

REFERENCES

1. A. Reissert, Chem. Ber. 38, 1603 (1905). 2. A. Reissert, Chem. Ber. 38, 3415 (1905). 3. W. E. McEwen, and R. L. Cobb, Chem. Rev. 55, 511 (1955). 4. F. D. Popp, Adv. Heterocyclic Chem. 9, 1 (1968). 5. F. D. Popp, Adv. Heterocyclic Chem. 24, 187 (1979). 6. F. D. Popp, Bull. SOC. Chim. Belg. 90, 609 (1981). 7. F. D. Popp, Heterocycles 1, 165 (1973). 8. F. D. Popp, Heterocycles 14, 1033 (1980). 9. F. D. Popp and B. C. Uff, Heterocycles 23, 731 (1985).

10. J. V. Cooney, J . Heterocyclic Chem. 20, 823 (1983). 11. E. Mosettig, Org. React. 8, 218 (1954). 12. M. D. Rozwadowska and D. Brbzda, Tetrahedron Lett., 589 (1978). 13. M. D. Rozwadowska, and D. Brbzda, Can. J . Chem. 58, 1239 (1980). 14. S . Ruchirawat and M. Chuankamnerdkam, Heterocycles 9, 1345 (1978). 15. B. C. Uff, J . R. Kershaw, and J. L. Neumeyer, Org. Synth. 54, 1892 (1974). 16. J . W. Skiles and M. P. Cava, Heterocycles 9, 653 (1978). 17. A. J . Birch, A. H. Jackson, and P. V. R. Shamnon, J . Chem. SOC. Perkin Trans I , 2190 (1974). 18. P. Kerekes, S. Makleit, and R. Bognfu, Acta Chim. Hung. 98, 491 (1978). 19. H. Y. Cheng and R. W. Doskotch, J . Nut. Prod. 43, 151 (1980). 20. S . F. Dyke, A. W. C. White, and D. Hartley, Tetrahedron 29, 857 (1973). 21. D. C. Smith and F. D. Popp, J . Heterocyclic Chem. 13, 573 (1976). 22. A. H. Jackson, G . W. Stewart, G . A. Chamock, and J. A . Martin, J . Chem. SOC. Perkin Trans

I , 1911 (1974).

28 GABOR BLASKO, PETER KEREKES, AND SANDOR MAKLEF

23. I. M. Boente, L. Castedo, A. Rodriguez, J. M. Saa, R. Suau, and M. C. Vidal, Tetruhedron

24. M. H. Abu Zarga, G. A. Miana, and M. Shamma, Tetrahedron Lett. 22, 541 (1981). 25. S. Chattopadhyay and M. Shamma, Heterocycles 19, 697 (1982). 26. F. R. Stermitz and D. K. Williams, J. Org. Chem. 38, 1761 (1973). 27. .I. L. Neumeyer, in “The Chemistry and Biology of Isoquinoline Alkaloids” (J. D. Phillipson,

M. F. Roberts, and M. H. Zenk, eds.), pp. 146-170, and references cited therein. Spnnger- Verlag, Berlin, Heidelberg, 1985.

Lett. 24, 2295 (1983).

28. 1. L. Neumeyer, B. R. Neustadt, and K. K. Weinhardt, J. Phurm. Sci. 59, 1850 (1970). 29. J. L. Neumeyer, W. P. Dafeldecker, B. Costall, and R. J. Naylor, J. Med. Chem. 20, 190

30. J. L. Neumeyer, J. F. Reinhard, W. P. Dafeldecker, J. Guarino, D. S. Kosersky, K. Fuxe, and

31. J. L. Neumeyer, F. E. Granchelli, K. Fuxe, U. Ungerstedt, and H. Corrodi, J. Med. Chem. 17,

32. D. R. Elmaleh, F. E. Granchelli, and J. L. Neumeyer, J. Heterocycl. Chem. 16, 87 (1979). 33. S. M. Kupchan and P. F. O’Brien, J . Chem. SOC., Chem. Commun., 915 (1973). 34. M. P. Cava and I. Noguchi, J. Org. Chem. 37, 2936 (1972). 35. J. W. Skiles and M. P. Cava, J . Org. Chem. 44, 409 (1979). 36. M. P. Cava and I. Noguchi, J. Org. Chem. 38, 60 (1973). 37. S. Ruchirawat, N. Phadungkul, M. Chuankamnerdkam, and C. Thebtaranonth, Heterocycles 6 ,

38. S. Ruchirawat, W. Lertwanawatana, and P. Thepchumne, Tetrahedron Lett. 21, 189 (1980). 39. S. Veeraraghavan and F. D. Popp, J. Heterocyclic Chem. 18, 17 (1981). 40. J. A. Tyrell and W. E. McEwen, J . Org. Chem. 46, 2476 (1981). 41. P. Kerekes, Acta Chim. Hung. 106, 303 (1981). 42. P. Kerekes, G. Horvith, Gy. Gail, and R. Bognh, Actu Chim. Hung. 97, 353 (1978). 43. P. Kerekes, Gy. Gail, R. Bognhr, T. Tor6, and B. Costisella, Actu Chim. Hung. 105, 283

44. P. Kerekes, unpublished results. 45. J. Kardos, G. Blask6, P. Kerekes, I. Kovics, and M. Simonyi, Biochern. Pharmucol. 33,3537

46. R. F. Watts and F. D. Popp, J. Heterocyclic Chem. 15, 1267 (1978). 47. S. Veeraraghavan and F. D. Popp, J. Heterocyclic Chem. 18, 909 (1981). 48. F. D. Popp and S. Veeraraghavan, Heterocycles 15, 481 (1981). 49. S. Veeraraghavan and F. D. Popp, Synthesis, 384 (1980). 50. F. D. Popp and S. Veeraraghavan, J. Heterocyclic Chem. 19, 1275 (1982). 51. F. D. Popp, Heterocycles 14, 1033 (1980).

(1977).

L. Aganati, J . Med. Chem. 19, 25 (1976).

1090 (1974).

43 (1977).

( 1980).

(1984).

- CHAPTER 2 -

ARISTOLOCHIA ALKALOIDS

ZHONG-LIANG CHEN AND DA-YUAN ZHU

Shanghai Institute of Materia Medica Academia Sinica

Shanghai, Peoples Republic of China

I. Introduction 11. Structural Relationships and Biosynthesis

A. Chemical Types B. Biosynthetic Studies

111. Spectroscopic Properties A. Mass Spectra B. Nuclear Magnetic Resonance

A. Structure of Aristolochic Acid I B. Other Aristolochic Acids C. Miscellaneous Reactions

A. Synthesis of Aristolochic Acids and Aristolactams B. Synthesis of 4,s-Dioxoaprophines

VI. Pharmacology and Clinical Use A. Antitumor Activity B . Immunomodulating Activity C. Antifertility Activity D. Miscellaneous E. Clinical Use F. Toxicity

References

IV. Chemical Reactions and Structural Determination

V. Chemical Synthesis

VII. Summary of Physical Properties

I. Introduction

Aristolochia is regarded as a genus of the family Aristolochiaceae; they are climbing and twining vines, distributed in the tropic and temperate zones. There are about 200 species worldwide ( I ) , and more than 40 of them have been studied chemically: A . acuminata, A . argentina, A . badamae, A . baetica, A . bambusifolia, A . bracteata, A . championii, A . chilensis, A . clematitis, A . cucurbitoides, A . debilis, A. elegans, A . esperanzae, A . fangchi, A . fimbriata, A . grifithii, A . heterophylla, A . indica, A . italica, A . kaempferi, A . kwangsiensis, A .


All rights of reproduction in any form reserved.

30 ZHONG-LIANG CHEN AND DA-YUAN ZHU

longa, A . macedonica, A . manshuriensis, A . maurorum, A . maxima, A . mollissima, A . moupinensis, A . ornithocephala, A . pallida, A . pendurata, A . reticulata, A . rotunda, A . serpentaria, A . sipho, A . tagala, A . taliscana, A . taliscula, A . tomentosa, A . triangularis, A . tuberosa, A . watsonii, A . westandii, and A. zenkeri, etc. (see Table 11). Some species of Aristolochia plant have been extensively used in folk medicine (2-4). The purpose of this chapter is to review the chemistry, spectroscopic properties, biosynthesis, pharmacology, and clinical use of Aristolochia N-containing substances. Early studies on the nitrophenanthrenic acids were summarized by Pailer in 1960 (3, and more recently by Mix et al. (6) and Ding and Lou (7). In 1971, Horrisberger reviewed the chemistry, pharmacology, and medical use in chronic infections of aristolochic acid (8).

Several reasons can be given for the strongly increasing interest in this group of natural products: first, the structural and biosynthetic relationships between aristolochic acids, aristolactams, 4,5-dioxoaporphines, and other isoquinoline alkaloids; second, the various biological activities of a number of compounds such as aristolochic acid I (1). Aristolochic acid I was reported as a potential tumor inhibitor. It inhibited the experimental tumor growth in animals and de- stroyed malignant human tumor cell growth in tissue cultures at low concentration (9-11). Aristolochic acid I has been widely used as a phagocyte stimulant in western Europe for some years. Recently, however, it has been sho.wn to be a potential carcinogen (12), and the denitro compound, aristolic acid (3,4-methylenedioxy-8-methoxyphenanthrenic acid, 70) was reported as an antifertility active substance (13,14).

Aristolochic acids are very easily soluble in alkali and form sodium salts that are recovered by acidification (15). The aristolochic acids and methyl esters were separated by column chromatography as usual, and thin-layer chromatography (TLC) (16), high-performance liquid chromatography (I 7 ) , and ion-exchange chromatography (18) have been used for separation and purification. Some in- dustrial-scale methods have been also reported (19-22). Most aristolochic acids and aristolactams in the pure state are sparingly soluble in ether, alcohol, chloroform, and acetone and readily soluble in DMSO, pyridine, and other alkaline solvents. For recrystalization of these compounds sometimes a Soxletor is used.

11. Structural Relationships and Biosynthesis

A. CHEMICAL TYPES

The natural Aristolochia N-containing substances may be divided into three structural types: nitrophenanthrenic acids, phenanthrene lactams, and isoquinoline alkaloids.

2. ARISTOLOCHIA ALKALOIDS 31

1. Nitrophenanthrenic Acids

Aristolochic acids, representatives of the substituted 10-nitrophenanthrene- 1 - acids, have been known since 1943, when Rosenmund and Reichstein first isolated aristolochic acid I (1) from A. clematitis (23) [this compound was named aristolochic acid A by Tomita and Sasagawa (24)] . Its structure was elucidated by Pailer et al. in 1956 by means of chemical reactions (25), and when several aristolochic acids-aristolochic acids I1 (2) (aristolochic acid B by Tomita), I11 (3) IIIa (4) (aristolochic acid C by Tomita), IV (5), and IVa (6)-were isolated from the root of A. clematitis by Pailer and his co-workers (26) and in the meantime from A. debilis and A. fangchi by Sasagawa (27).

1 3 1 R = H ,

2 R1= H ,

4 R1= O H , R 2 = H

5 R1= OCH ,R2= OCH3 3 3 6 R1= OH, R2= OCH

3

R 2 = OCH

R = H * 3 R1= OCH3,R 2 = H

10 R ~ = G ~ U , R ~ = OCH

R1 11 R1= OCH3,R2= N H 2 1 7 R = OH , Rz= OCH3

9 R1= H , R 2 = OCH 3 COOCHg

CH I 3 8 R1= OCH 3 ,R2= OCH 3 12 ~1: H , R*,NH-CH I

C - 1 -CH2-COOH

A general structural feature of these aristolochic acids is that the oxygenated functions are usually substituted at the C-6 and/or C-8 position. Chen et al. have isolated 7-hydroxy-8-methoxy-3 ,Cmethylenedioxy- 1 0-nitrophenanthrenic- 1 -acid (7), 7,8-dimethoxy-3 ,Cmethylenedioxy- 1 0-nitrophenanthrenic- 1 -acid (8) (28), which are oxygenated at both C-7 and C-8. Tseng and Ku isolated an unusual species, debilic acid (9), a nitrophenanthrenyl acetic acid derivative (29). Re- cently, a glucoside of aristolochic acid, aristoloside (lo), was isolated from A. manshuriensis by Nakanishi et al. (30) and developed by the Otsuka Phar- maceutical Co. group as an antitumor agent (31). Aristolochic amides 11 (32) and 12 (33) have been also reported.

Aristolochic acid derivatives have been found only among plants of the family Aristolochiaceae (Aristolochia spp. and Asarum canadense var. refexum (34)] and in Bragantia wallichii (35,36). In all derivatives, substitution of nitro group is present at C-10, the carboxy group is present at C-1, and a methylenedioxy is substituted at C-3 and C-4 only. This general structure will be very interesting in biosynthesis and plant biochemistry.

32 ZHONG-LIANG CHEN AND DA-YUAN ZHL

2. Phenanthrenic Lactams

Aristolactam (13) (in some papers, aristololactam) was first prepared by catalytic hydrogenation or zinc reduction in acetic acid from aristolochic acid I (25). It has been isolated from several Aristolochia plants, including A. debilis and A. fangchi (24). Kupchan and Merianos isolated the first aristolactam N-glucoside (19) from A. indica (37).

Maldonado et al. isolated taliscanine (aristolactam BI, 21) from the root of A. taliscana (38). Other aristolactams were subsequently discovered in Stephania cepharantha (Menispennaceae) (39), Schefferomitra subaequalis (Annonaceae) (40), and Doryphora sassafras (Monimiaceae) (41) . Priestap and co-workers systematically analyzed the aristolactams from rhizomes of A. agentina and isolated 13 aristolactams: aristolactams I (13), I1 (14), I11 (15), IV (16), Ia (17), I11 (18), A11 (24), A111 (25), AIa (26), AIIIa (27), B1(21), BII (22), and BIII (23) (42, 43) .

3. Isoquinoline Alkaloids

Some isoquinoline alkaloids have been isolated from Aristolochia plants. Magnoflorine (28) was first isolated from several plants of this genus: A . argentina, A. baetica, A . clematitis, A . debilis, A. fangchi, A . heterophylla, A. kaempferi, A . macedonica, and A. moupinensis. Asimilobine (29) (25), cyclanoline (30) (24), and hydrastine (31) (44) were also isolated. Priestap et al. isolated a phenanthrene amine, argentinine (32), from the root of A . argentina (45). Zhu et al. separated two new 4,5-dioxoaporphine alkaloids, tuberosinone (33) and tuberosinone-N-P-glucoside (34), from A. tuberosa (46).


J

CH 3 28

0

33 R=H

34 R=Glu 35

Govindachari and Viswanathan identified the aristolochine which was isolated by Krishnaswamy et al. 1935 (35) as 1-curine by 'H NMR, MS, and direct comparison with authentic sample of 1-curine to establish its identity (48,49). El- Sebakhy and Waterman reported the results of an examination of the leaves of A. elegans in which a bisbenzyl isoquinoline alkaloid, (-)-(R,R)-7'-O-methyl cuspidaline (39 , was isolated. This study failed to show the presence of any other nitro compounds in the leaves of A. elegans (50).

B. BIOSYNTHETIC STUDIES

The biosynthesis of aristolochic acids is considered to begin with l-benzyltetrahydroisoquinoline precursors and to proceed via aporphine intermediates (5). In radioactive labeling studies, Spenser and Tiwari infused dl-tyrosine-2-14C into the stem ofA. sipho. The 14C-labeled aristolochic acid I formed lost more than 60% of its radioactivity when it was decarboxylated to the corresponding nitro phenanthrene derivative. Administration of dl-dihydroxyphenylalanine-2-14C re-


HO \

HO #- OH

----, c H 3 0 7 - C € 1 3 HO A c H F - C H 3 /

/

\ 0

OCH3 CH 3 313

36 37

HO

4

- C H 3 fjpCH3 - 1

41 OCH3 39 40

SCHEME 1

sulted in the formation of radioactive aristolochic acid I, which did not lose radioactivity during decarboxylation. Decarboxylation of the acid derived from dihydro~yphenylethylamine-2-'~C resulted in the formation of an inactive nitrophenanthrene derivative. The aristolochic acid I derived from dl-noradrenaline-2-14C was labeled exclusively at the carboxy C atom. These results indicated that the norlaudanosoline derivative 36 was an intermediate in biosynthesis of aristolochic acid (51). Schuette etal. confirmed this hypothesis. They found that supplying tetrahydropapaverine-4- 14C hydrochloride to A. sipho gave no radioactive aristolochic acid I, but feeding norlaudanosoline-4- 14C HC1 yielded 14C-labeled aristolochic acid I with the carboxy group containing 60% of the radioactivity (52).

Comer et al. conducted studies in which tyrosine, dopa, dopamine, or noradrenaline served as the specific precursor. Feeding of doubly labeled (3-14C and 15N) tyrosine demonstrated that the nitro group of aristolochic acid I originates from the amino group of tyrosine (53). The incorporation of tyrosine, 3,4- dihydroxyphenylalanine, orientaline (37), prestephanine (40), and stephanine (41) into aristolochic acid in A. bracteata was studied by Sharma et al. in 1982. The evidence strongly supported the sequence shown in Scheme 1 for the biosynthesis of aristolochic acid I. Oxidative coupling of orientatline (37) gives prestephanine (40), which is cyclized to stephanine (41); oxidative cleavage of stephanine funished aristolochic acid I (1) (54). Parallel feeding with (--)-(R)- and (+)-(S)-orientaline showed that the sterospecificity is maintained in the biosynthesis route (54) and that the methylenedioxy group in aristolochic acid originates from an 0-methoxyphenol precursor.


Until relatively recently the aristolochic acids were known to occur in only the family Aristolochiaceae, but aristolactams and 4,5-dioxoaporphine alkaloids have been isolated from Menispermaceae, Annonaceae, Papaveraceae, and Piperaceae. Akasu et al. isolated cepharanone A (aristolactam 11, 14), cepharanone B (aristolactam BII, 22), cepharadione A (42), and cepharadione B (43) from Stephania cepharentha (Menispermaceae) (39). Cepharanone A has also been found in Piper saneturn (Piperaceae) (56). From the bark of SchefSero- rnitra subaequalis Duke and Gellert isolated alkaloid Y whose spectral properties are very similar to those reported for aristolactam BII (22) (40). Braz Fo et al. have isolated a monooxoaporphine alkaloid, fuseine (44), from another An- nonaceae plant Fusea longifolia, and its structural features closely resemble reduced debilic acid (58).

The cooccurrence of aristolactams and dioxoaporphines in these families is a very interesting problem from a chemotaxonomical point of view and supports the view that the Aristolochiales is related to Magnoliales and Ranunculales (43). Castedo et al. isolated pontevedrine (46), a 4,5-dioxoaporphine from Glaucium jlavurn (Papaveraceae) . The conversion of pontevedrine to the related aristolactam (48) takes place in vitro and can be regarded as a benzilic acid rearrangement followed by loss of one carbon. They proposed the 4,5-dioxoaporphines as possible intermediates and the biosynthetic pathway as shown in Scheme 2 (59).

Priestap has isolated a total of 12 aristolactams from A . argentina. These compounds all show a substitution pattern similar to that of the accompanying

OH n

I 6 C H 3 OCH3

-CH3

SCHEME 2

36 WONG-LIANG CHEN AND DA-YUAN ZHU

aristolochic acids, and Priestap suggested that the aristolochic acids are derived from aristolactams rather than directly from quaternary aporphine alkaloids (43).

The structural relationships between plants and insects have become very highly regarded (60). Euw and co-workers isolated aristolochic acid I from the swallowtail butterfly; 51 butterflies gave 5-6 mg aristolochic acid I (61). Aristolochic acid Ia has been also found by Rothschild et al. to occur in Zerynthia polyxena, a butterfly whose larvae feed on Aristolochia clematitis (62). Urzua er al. investigated the papilionoid butterfly living in Chile. The larval stages of the butterfly feed on the aboveground parts of A . chilensis, the food material contains aristolochic acid, and the insects retain these compounds after metamorphosis. Aristolochic acids I and Ia are major components of the tender stems and the leaves of A . chilensis, but aristolochic acids I and IVa appear to be the main acid components of this butterfly. The difference in composition was explained by metabolic transformation by the insect. From a biological point of view, the phenomenon has been interpreted as a result of an ancestral butterfly larva with the ability to store these poisonous metabolites, thus obtaining immediate protection from predators (63).

111. Spectroscopic Properties

Spectroscopic methods are widely used for the structural determination of Aristolochia alkaloids. These compounds all show a substituted phenanthrene chromophore in UV spectra. The UV spectrum of aristolochic acid I is characterized as follows: 223 (30000), 250 (30600), 318 (11500), 390 (5700) (24). The other aristolochic acid analogs are similar, for instance, aristolochic acid IV: 220 (4.41), 242 (4.53), 253 (4.53), 292 (4.17), 330 (4.02), 402 (4.00) (26); aristolochic acid Ia: 221, 255, 283, 321, 389 (63); aristolactam: 241 (4.50), 250 (4.47), 259 (4.56), 291 (4.16), 300 (4.15) (24); tuberosinone: 228 (4.57), 277

berosinone-N-D-glucoside: 227 (4.59), 240 (4.63), 285 (4.08), 330 (4.09), 370 (3.72), 388 (3.72), 477 (4.14) (46).

The phenolic derivatives of this series, such as aristolochic acid Ia and 4 3 - dioxoaporphine, suffered considerable bathochromic shifts, and further shifts toward the longer wavelength region are observed on addition of alkali. For instance, the UV spectrum of 4,5dioxoaporphine (49), 246 (4.70), 292 (4.14), 305 (4.26), 318 (4.28), 459 (4.23), shifts to 241 (4.71), 256 (4.67), 305 (4.21), 331 (4.25), 510 (4.30) in alkaline solution (64). This bathochromic shift was also found in aristolochic acid Ia (50) (63, 65). The UV spectroscopic method has been used for the quantitative analysis of aristolochic acids from plants or pharmaceutical products (66-68,71).

(4.12), 286 (4.15), 318 (4.05), 330 (4.16), 372 (3.91), 390 (3.94); tu-


The IR spectra are useful for detecting functional groups of Aristolochia alkaloids. Aristolochic acids show two characteristic bands at 1550 and 1350 cm- due to the absorption of nitro group, and the carboxy OH group appears at 3000-2500 .cm- as a broad continuous absorption. Hydroxy derivatives of aristolochic acids or aristolactams show OH and NH absorptions at 3300-3500 and 3200-3400 cm- l . The carboxy or lactam carbonyl is present at 1690 cm- l .

In general, the aromatic ring system shows stretches at 1625-1575 and 1525- 1475 cm- as usual, and observation of the 900-700 cm- region is often used for analysis of substitution type in aromatic derivatives (28).

A. MASS SPECTRA

The mass spectra of Aristolochia N-containing compounds were first reported by Pailer et al., who studied the electron impact-induced fragmentation of the esters of aristolochic acids. They found that the nitro radical is very easily split off from the molecular ion, giving the base peak (M - 46) + , and then the CH,, CO, etc. were removed. Pailer et al. concluded the fragmentation was as shown in Scheme 3 (26).

High-resolution mass spectroscopy is a very useful tool for the identification of Aristolochia alkaloids, for the analysis of mixtures, or for detection of trace impurities. Eckhardt et al. found that the primary clevage of aristolochic acid I occurs in the condensed aromatic system, which has a carboxy and a nitro functional group in pen position, with the elimination of NO,. This cleavage is usually observed in aristolochic acids and closely related compounds, in nitro naphthalenic compounds in general. The molecular ion of aristolochic acid, mlz 341, was determined as C,,Hl,NO,. The primary fragmentation of molecular ion consists of the elimination of a nitro group to yield the base peak at mlz 295 and then further fragments due to consecutive loss of small units, such as H, CH, CO, and CHO, at the ions C,,Hl0O5 294 (M - 47), C16H,0, 280 (M - 61), C16H1104 267 (M - 74), C1&04 252 (M - 89), C15Hl10, 239 (M - 102), C14H,0, 224 (M - 117), and C,,H,O, 196 (M- 145). The main fragmentation peaks are quite similar to the aristolochic esters (69).

Debilic acid (9) was the minor constituent of the Chinese medicinal plant A .


cq-&cH3 \o" I c43-&o;H3 c4p 0

c(x&:Q* \ 1 (Mi:llo R2 c 4 3 t.?.:

- go2 Z2EL N02

\ \ \

R2 2

(M-46) R1 R2 R1 R

(M-61) - OCH3

i (M-89)

I

(M-59)

R1 R2 (M-117)

SCHEME 3

debilis (29). Riicker and Chung recorded the mass spectrum of methyl ester of debilic acid. It showed a strong molecular peak and fragments at mlz 338 (M - 31), 323 (M - 46), 308 (M - 46 - 30), 293 (308 - 15); the fragmentation is shown in Scheme 4 (70).

The mass spectra of 4,5-oxoaporphine alkaloids are characterized by a direct loss of CO (M - 28) from the molecular ion (base peak) leading to a prominent peak at mlz 265 (27%). Subsequent loss of a methyl group accounted for the other significant peak at mlz 250 (51%) (64).

Terasa et al. have reported mass spectrum of 2-(phenanthro[3,4-6]-1,3-dioxole-6-nitro-5-carboxamido)propanoic acid methyl ester (12), a new aristolochic

m/z 308

(M-46-70)

SCHEME 4


m/e 396 (8%)

(M-16) 380 (1%) bH

a. 365 ( 3 % ) C .

d.

e .

SCHEME 5

290 (36%) 263 (20%)

248 ( 5 % ) 220 (10%)

acid derivative which was isolated from A . longu. Compound 12 shows an amino acid joined to the main structure by means of an amido linkage, and the main fragmentation is loss of the nitro group to form a base peak at m/z 350 and/or cleavage of the side chain (Scheme 5 ) (33).

B . NUCLEAR MAGNETIC RESONANCE

'H-NMR spectroscopy is the most commonly used technique in the structural elucidation of Aristolochiu alkaloids. 'H-NMR spectral data of aristolochic acids, aristolactams, and other related compounds are compiled in Table I. A comparison of chemical shifts and coupling constants indicates certain correla- tions which may be of diagnostic value. The aristolochic acids and aristolactams present a C-2 aromatic proton (6 7.50-7.90) and C-3, C-4 hydroxy (6 lo), methoxy (6 3.90-4.10), or methylenedioxy (6 6.35-6.55) substitution on ring A. There is only one proton on ring B (H-9). It is also to be noted that the presence of a strongly deshielding nitro group results in a downfield shift about 0.9 ppm of the H-9 to form a chemical shift at 6 8.40-8.70 in aristolochic acids, but in aristolactams H-9 appears rather upfield at 6 7.05-7.40; these signals are very easy to assign.

The analysis of proton signals on ring C is very useful in elucidating the structure of compounds in this series. The chemical shift of H-5, which can be recognized by its downfield position, is the same as in the phenanthrene nucleus. The most aristolochic acids and aristolactams have one or two substitutions in the form of hydroxy and/or methoxy groups on ring C; therefore, interpretation of coupling constants is useful to determine the ortho (J = 7-9) or meta (J = 1-3) H-H splitting and thus the position of substitutions.

Aristoloside, an aristolochic acid derivative, was isolated from a stem of A.

TABLE I 'H-NMR Spectral Data of Aristolochia Alkaloids

H- 1 H-2 H-3

Aristolochic acids Aristolochic acid - 7.76 s O-CH2--0

Aristolochic acid - 1.72 s O - C H 2 4

Aristolochic acid - 7.72 s M H 2 4

Aristolochic acid _. 7.78 s M H 2 4

Aristolochic acid - 1.72 s M H z 4

U (2)

la (50)

UIa (4)

I ( 1 )

UI (3)

7-Hydroxy- - 7.76 s M H 2 4 aristolochic P

0 acid 1(7) Aristolochic acid - 7.85 s M H 2 4

7-Methoxy- - 7.70 s M H 2 4 IVa (6)

aristolochic acid I (8)

N (5)

I methyl ester

IV methyl ester

Aristolochic acid - 7.72 s G-CH,--O

Aristolochic acid COOCH, 3.76 s 7.70 s M H 2 - - 0

Aristolochic acid COOCH, 3.68 s 7.73 s O-€H2-0

Aristoloside (10) - 7.78 s M H 2 4

Aristolochic acid COOCH, 3.88 s 7.76 s M H 2 - - 0

Compound 12 CORY 7.53 s M H Z - - O I1 methyl ester

H-4 H-5 H-6 H-7 H-8 H-9

6.44 s

(w) 6.44 s (w) 6.45 s (w) 6.43 s

(w) 6.44 s (w)

6.42 s (w)

8.98m

8.46d (J = 8) 8.44 s

8.58 dd (J = 9, 1.5) 8.48 d (J = 2)

8.66 d (J = 9)

7.76m

7.66 dd (J = 8, 8) OH 10.55 s

1.78 dd (J = 9, 9) ow 3 3.92 s

(3H) 7.46 d (J = 9)

7.16m

7.20 d (J = 8) 8.06 d (J = 9) 7.30 dd (J = 9, 1.5) 7.42 dd (J = 8, 2)

OH 10.33 s

8.20m 8.50 s

OH 8.48 s

7.25 d 8.44 s (J = 9) OCH, 4.00 s 8.50 s

(3H) 8.16 d 8.50 s (J = 8)

OCH, 3.91 s 8.40 s

(3H)

6.55 s 8.11 d OH 8.50 bn 6.88 d OCH, 4.06 s 8.55 s

(w) (J = 2) (J = 2) (3H) 6.41 s 8.66 d 7.72 d OCH, 4.00 s OCH, 4.00 s 8.43 s

(w) (J = 9) (J = 9) (3H) (3H)

6.44 s 8.06 d OCH, 3.92 s 6.92 d (w) (J = 1.5) ( 3 ~ ) (J = 1.5) 6.48 s 8.62 d 1.78 dd 7.32 d (w) (J = 8) (J = 8, 8) (J = 8) 6.33 s 8.11 dd OCH, 3.98 s 6.70 d (w) (J = 2.1, 0.7) (3H) (J = 2.1) 6.44 s 8.35 d - 7.13 d 6.49 s (J = 2) (J = 2) 6.39 s 9.12 d 7.75 m 7.75 m (w) (J = 7.5) 6.35 s 9.03 d 7.70 m 7.70 m (w) (J = 7)

OCH, 4.00 s 8.44 s

(3H) OCH, 4.06 s 8.61 s (3H) OCH, 4.01 s 8.73 d (3H) (J = 0.7) OCH, 4.07 s 8.50 s

(3H) 1.19 d 8.50 s (J = 7.5) 7.93 d 8.22 s (J = 7)

H-10 Ref.

28 -

37

28

-

-

Aristolactams Aristolactam Il -

(14) (cepharanone A)

Aristolactam (13) -

Aristolochic acid IVa lactam methyl ether

Aristolactam UIa (18)

Aristolactam Ia

Aristolactam IIIa N-p-D- glucoside (20)

N-@-D-

(17)

Aristolactam I

2 glucoside (19) Aristolactam AII (2)

Aristolactam A111 __ (25)

Aristolactam - AIIIa (27)

Aristolactam BU -

(22) (cepharanone B)

Doryflavine -

Aristolactam BIII -

(23)

7.64 s M H 2 4 6.48 s 8.48 m 7.55 m 7.55 m 7.91 rn 7.11 s (w)

7.53 s M H 2 4 6.43 s 7.99 d 1.42 dd 7.11 d OCH, 4.00 s 7.27 s

7.52 s M H 2 4 6.40s 7.60 d OCH, 3.91 s 6.77 d OCH, 3.98 s 7.27 s (w) (J = 8) (J = 8, 8) (J = 8) (3H)

(w) (J = 2) (3H) (J = 2) (3H)

7.60 s M H , + 6.46 s 7.96 d OH - 7.14 dd 7.78 d 7.35 s (2H) (J = 2.5)

(2H)

(w) (J = 2) (J = 8, 2) (J = 8)

(J = 8.5, 2.5) (J = 8.5)

(J = 8.5, 2.5) (J = 8.5, 8.5) (J = 8.5, 2.5) 7.62 s W H 2 4 6.46 s 8.04 dd 7.38 dd 7.08 dd OH - 7.38 s

7.89 s O-CH,--O 6.40 s 7.23 d OH 9.80 sbr 7.03 dd 7.75 d 7.69 s

7.80 s M H 2 4 6.52 s 8.23 d 7.62 dd 7.30 d OCH, 4.07 s 7.80 s (w) (J = 8) (J = 8, 8) (J = 8) (3H)

7.62 s OH 10.22 s

7.65 s OH 10.22 s

7.63 s OH -

7.85 s OCH, 4.06 s

(3H)

7.22 s OCH, 3.96 s

7.81 s OCH, 4.05 s

(3H)

OCH, 9.13 m 4.08 s

(3H) OCH, 8.67 d 4.08 s (J = 3.5) (3H) OCH, 8.57 d 4.02 s (J = 2.5) (3H) OCH, 9.12 m 4.03 s (3H) OH - 8.22 d

OCH, 8.86 d 4.05 s (J = 2.5) (3H)

(J = 2)

7.54 m 7.54 m 7.93 m 7.08 s

OCH, 3.95 s 7.25 dd 7.89 d 7.08 s (3H) (J = 9, 3.5) (J = 9)

OH - 7.99 d 7.76 d 7.03 s (J = 8.5, 2.5)

7.55 m 7.55 m 7.93 m 7.13 s

OH - 7.48 dd 7.84 d 7.11 s (J = 8)

OCH, 3.92 s 7.22 dd 7.84 d 7.07 s (3H) (J = 9, 2.5) (J = 9)

(J = 8, 2)

NH 43 10.78 s

NH 43 10.68 s

NH 43 10.68 s

NH 43 10.68 s NH 43 10.69 s

89 -

- 37

NH 43 10.77 s

43 __

NH 43 10.62 s

NH 43 10.78 s

6 -

Nn 43 10.70 s

(continued)

TABLE I (Continued)

H-10 Ref. H- 1 H-2 H-3 H-4 H-5 H-6 H-7 H-8 H-9

Aristolactam BI - 7.85 s OCH, 4.04 s OCH, 8.72 dd 7.55 dd 7.18 dd OCH, 4.04 s 7.43 s Nn 43 (21) (3H) 4.04 s 10.73 s

(3H)

4,5-Dioxoaporphine Tuberosinone 33

Tuberosinone-P-D -glucoside (34)

ComDound 49

and other alkaloids - 7.63 C+CH,-O 6.50 s 8.12 d OH 10 s 7.14 dd 7.74 d 8.05 s NH 46

- 7.89 s M H 2 4 6.54 s 8.28 d OH 10 s 7.16 dd 7.78 d 8.27 s - 46 (J = 8, 2) (J = 8) 12 s (w) (J = 2)

(w) (J = 2) (J = 8, 2) (J = 8) OCH, 9.46 dd 7.66 dt 7.66 dt 7 93 dd 7.50 s - 64 - 8.10 s OH - 4.06 s

(3H) 50

(-)-(R,R)-7’-O-Methylcuspidaline (35) 6.47s 6.56s

J=8.2,

(J=8)

1 . 5 6 d CH3 ( J = 7 ) I


manshuriensis. Nakanishi et al. illustrated the structure as ~-O-@-D- glucopyranoside of aristolochic acid D. They found that both H-5 (6 8.45) and H-7 (6 6.99) showed respective NOE enhancements of 20 and 9%) on irradiation of the anomeric proton (6 5.15), indicating the presence of a 6-O-glucoside linkage in aristoloside (30).

IV. Chemical Reactions and Structural Determination

A. STRUCTURE OF ARISTOLOCHIC ACID I

The structural determination of aristolochic acid I (1) was first accomplished by Pailer et al. Aristolochic acid I(C,,H,,O,N) is easily soluble in alkali as well as sodium bicarbonate. It was esterified with diazomethane in dioxane to give a methyl ester (C,,H,,O,N), and the methyl ester was readily saponified to re- cover aristolochic acid I. Zinc distillation of 1 gave a phenanthrene (Scheme 6). Aristolochic acid I was decarboxylated with copper powder in quinoline to yield a nitro phenanthrene derivative (O,,H, ,O,N,51).

Aristolochic acid I showed only one methoxy group. Catalytic hydrogenation of 1 or its methyl ester with PtO, or Pd-C in HOAc or reduction by zinc powder in acetic acid yielded a corresponding amino acid, which easily underwent ring closure to a lactam (C17H,,0,N,13). When distilled with 80% H,PO,, Aristolochic acid I underwent cleavage; formaldehyde was detected. The other functional group must be a methylenedioxy; therefore, the partial structure of aristolochic acid I is C,,H,(OCH,)(COOH)(NO,)(-O-CH,-O-) (72).

The decarboxylated compound 51 was oxidized with H,O, to give a carboxylic acid (C,,H,,O,, 52). This nitrogen-free substance was treated with concentrated HC1 to form a lactone (CI3HSO4, 53). It could be methylated to a dimethyl derivative and was further oxidized with KMnO, to a methoxy phthalic acid (54) (25). Pailer et al. synthesized the lactone 53 by the route of 1,5,6-trimethoxy- phenanthrenequinone-(9,lO) (56): The 1,5,6-&imethoxyphenanthrene carboxylic acid-( 10) (55) was oxidized with Na,Cr,O, to 56 and then further oxidized with H,O, to give a dicarboxylic acid (57). Compound 57 was cleaved with HC1 and gave a lactone which was identical with the degradation product of natural aristolochic acid I. Therefore, Pailer and co-workers deduced the structure of aristolochic acid I as 1 (25). Sasagawa reduced 51 with zinc powder and NH,OH to an amino compound (58) and then removed the amino group through the diazotization method to give a phenanthrene compound (60), which had previously been obtained from the Hofmann degradation of stephanine (41) ( 2 7 ) .


13

P CH ‘:

59 R=Ac

c

41 61

SCHEME 6

B . OTHER ARISTOLOCHIC ACIDS

The structure of aristolochic acid I1 (2) was determined by Pailer and Schlep- pnik in the same way as aristolochic acid I. Decarboxylation of aristolochic acid I1 gave a nitro compound (62). Oxidation of 62 and cleavage with HCl formed


Br v

COOH CH

67 65 66

62 L

64 68

SCHEME 7

3,4-benzo-8-hydroxycoumarin (63). Compound 62 was also reduced by catalytic hydrogenation to 3,4-methylenedioxy-l0-aminophenanthrene (64) (Scheme 7) (73). The Pailer-Schleppnik synthesis of 64 employed the condensation of 65 and o-nitrobenzaldehyde for the formation of the phenanthrene ring and then proceeded with Curtius rearrangement (74).

After the elucidation of the structure of aristolochic acid I, several related compounds, such as aristolochic acids 111, IIIa, IV, and debilic acid, were determined in the same way by Pailer (26), Pailer and Bergthaller (73 , Tomita and Sasagawa (24), and Tseng and Ku (29,76,77).

C . MISCELLANEOUS REACTIONS

Reduction of aristolochic acid I with NaBH, was investigated by It0 et al. They found that aristolochic acid I was reduced to 9,lO-dihydroaristolochic acid I (69) at room temperature (85% yield), and they also isolated a nitrogen-free product, aristolic acid (70) (Scheme 8) (5% yield). When this reaction takes place at 90-100°C for 3 hr, however, the main product obtained was aristolic acid. Decarboxylation of 9,lO-dihydroaristolochic acid I with copper powder in


Quinoline &

69 (85%) 71 UOiHj

70 (75%) ’ 1

12 hr c@*+ 0

W O W 3 73 (41%)

72 j.

78

SCHEME 8

quinoline gave a mixture of 71 and 72, and 9,lO-dehydrogenation occurred simultaneously (78).

In a program of search for the antifertility principle of aristolic acid, Mukhopadhyay et al. modified the NaBH, reduction procedure to get sufficient amounts for the purpose of biological testing. They reduced aristolochic acid I in 1% aq. NH,OH solution at 25°C for 4 hr and obtained a high yield of aristolic acid (90%) (79). Pakrashi et al. isolated 6-methoxyaristolic acid (78) from A. indica, and they prepared 78 by means of denitration of aristolochic acid IV (5) with NaBH, in the same manner (32) .

The structural determination of N-glycosides of Aristulochia alkaloids was also conducted. Some aristolactams and 4,5-dioxoaporphine alkaloids occur in nature as N-glycosides. For instance, aristolactam-P-D-glucoside (19) was ex- ceedingly resistant to mineral acid hydrolysis, but reduction of 19 with LiAlH, in THF yielded 74, which was readily hydrolyzed to the aglycone 75 and glucose (Scheme 9). This property paralleled the behavior of an N-glycoside of a pyrimidine nucleoside. The aglycone 75 can be directly prepared by LiAlH, reduction of aristolactam (13) (37). The N-glucoside of 4,5-dioxoaporphine alkaloids can also be hydrolyzed by the same method (46). Achari et al. found that


SCHEME 9

such glycosides effected the hydrolysis in one step, by heating with 85% formic acid at 175°C for 2 hr, rather than by the two-stage process of LiAlH, reduction followed by mild acid treatment (80).

Maldonado and co-workers isolated an aristolactam taliscanine (21) from A. tuliscunu. Methylation of taliscanine was carried out by treatment with dimethyl sulfate and K,CO, in acetone and yielded N-methyltaliscanine (76). Compound 76 was ozonized to give 77 and then further oxidized with CrO,-AcOH to give a carboxylic acid (79) (38).

CH CH ?O ' 3 : R c.Fi CH :gi -0 -.CH CH30 'Ii ' O F -CH

/ CHO , COOH ' OCH3 ' OCH3

\

OCH3

21 R=H 77

76 R=CH 79 3

V. Chemical Synthesis

A. SYNTHESIS OF ARISTOLOCHIC ACIDS AND ARISTOLOLACTAMS

1. Partial Synthesis

3,4,6,7-Tetramethoxy aristolochic acid (80) was obtained by nitration from the corresponding 3,4,6,7-tetramethoxy-phenanthrene-l-carbo~ylic acid (81), which was obtained from glaucine (82) via exhaustive Hofmann degradation (twice) followed by oxidation. Catalytic hydrogenation with Pd-C afforded the relevant aristolactam (83) (Scheme 10) (82).

Kunitomo et al. reported that air oxidation of dehydroaporphines , including 2,lO-dimethoxydehydroaporphine (84a), dehydronuciferine (85a), and dehydronantenine (86a), with tert-BuOK in DMSO gave corresponding N-meth-


n

'2/ Pd

CH ?O-

CH,N2 ' O 2

Nitratio: I J I 80

CH 3O

SCHEME 10

ylaristolactam-type substances. N-Methyl-3,4-methylenedioxy-7,8-dimethoxy- aristolactam (87b) was also obtained by the same method from dehydrocrebanine (87a) (Scheme 11) (83,84). 3,4-Methylenedioxy-6-methoxyaristolactam (91) was prepared from the meth-

yl ester of aristolochic acid IIIa (4) by Zn-AcOH reduction, and it was also obtained by treatment of the methyl ether of tuberosinone (33) with sodium hydroxide (46,85). Similarly, 3,4-methylenedioxy-6-methoxyaristolactam-N-~- D-glucoside (92) can be obtained from tuberosinone-N-P-D-glucoside (86).

2. Total Synthesis

Kupchan and Worrnser achieved the first total synthesis of aristolochic acid involving photocyclization of substituted 2-iodostilbenes. Piperonal (93) provided a suitable skeleton to build ling A of aristolochic acid (Scheme 12). Compound 93 was reduced to the piperonyl alcohol (94) with LiAlH,. Bromina- tion of 94 afforded 6-bromopiperonyl bromide (95). The benzyl bromide 95 was then hydrogenated to the corresponding 2-bromo-4,5-methylenedioxytoluene (96), using the n-butyllithium carbonation method. The toluic acid 97 was prepared and converted to the acid chloride 98 by the action of oxalyl chloride, and bromination of 98 produced 99 by radiation with a 200-W tungsten lamp. Meth- anolysis of 99 afforded the crystalline ester 100. Treatment of 100 with silver nitrate produced methylester (101).

Synthesis of ring C of aristolochic acid involved a sequence of 11 steps from 102 to 113 (Scheme 13). 2-Nitro-6-methoxytoluene (105) was oxidized to the nitroaldehyde 109 by the Kronhke reaction. Conversion of 109 to the oxime 110


SCHEME 11

and via Sandmeyer reaction to the iodaldehyde 112 was effected by the general method of Mayer. The condensation of 101 with the n-propylidene base 113 was effected in glacial acetic acid; 2-carbomethoxy-4,5-methylenedioxy-2'-iodo- methoxy-a-nitro-cis-stilbene (114) was obtained. Photolysis of this stilbene afforded aristolochic acid I methyl ester (115) (86).

Similarly, photolysis of 2-carbomethoxy-4,5-methylenedioxy-2'-iodo-a-nitro-cis-stilbene (117), which was prepared by condensation of 116 with 101, gave


C H 2 N 0 2 I

0 I J? OocH3

C H r O 101

SCHEME 12

aristolochic acid I1 methyl ester (118) (87,88). Aristolochic acids I and I1 were prepared by hydrolysis of their respective esters according to the method of Pailer and Schleppnik (73).

Cohare and co-workers reported that aristolactam BII (22) was prepared, following Kupchen’s method, by Perkin condensation of 6-bromo-3,4-dimethoxy phenyl acetic acid (119) and o-nitrobenzaldehyde (120) (Scheme 14). The 2-bromo-4,5-dimethoxy-2’-nitro-cis-stilbene-ol-carboxylic acid (121) was obtained. The nitro group of 121 was reduced with ferrous sulfate and ammonium hydroxide, and the resulting 2-bromo-4,5-dimethoxy-2’-amino-cis- stilbene-a-carboxylic acid (122) without purification was submitted to the Pschorr phenanthrene synthesis to yield 1 -bromo-3,4-dimethoxyphen- anthrene- 10-carboxylic acid (123). The phenanthrylamine 124 was prepared from 123 via a Schmidt reaction, and, by treatment with n-butyllithium and CO,, 124, afforded 22 (42).

B. SYNTHESIS OF 4,5-DIOXOAPORPHINES

1. Partial Synthesis

The partial synthesis of 4,5-dioxoaporphine has been achieved. Preparation of cepharadione B (43), 2,10-dimethoxy-4,5-dioxodehydroaporphine (84d), 4 3 - dioxodehydronantenine (86d), and 4,5-dioxodehydrocrebanine (87d) was achieved in DMSO by air oxidation of the corresponding dehydroaporphines with an alkali catalyst as described above (Section V,A,1). Oxidation of nan-

02 1 611


0

SCHEME 15

tenine (125) or dehydronantenine (86a) with an excess of KMnO, in acetone afforded corydione (126) along with oxonantenine (127) and nandazurine (128) (Scheme 15) (21,92).

Pontevedrine (46) and cepharadione B (43) were also obtained by photooxidation of corresponding dehydroaporphines (Scheme 16). Pontevedrine was obtained by irradiation of an ethanol solution of dehydropontevednne with a mercu-

CH 3O

CH 3O -CH3 hV O2

R I V 130 R 1 2 =R =OCH 3 1 2 ’* 131 R =R =H

SCHEME 16


-CH3 I;, o r

* DDQ

0

3

CH30 46

SCHEME 17

ry lamp under argon or nitrogen, while cepharadione B was prepared using a Hanovia 450-W lamp in a stream of oxygen (93,94). Castedo and co-workers reported that pontavedrine (46) was prepared from 4-hydroxyglaucine (catatine, 45) by oxidation with iodine or dichlorodicyanoquinone (DDQ) (Scheme 17) (59).

2. Total Synthesis Castedo et al. reported the total synthesis of pontevedrine (46) (Scheme 18).

The starting bromolactam 132, prepared by a known method ( 9 9 , was oxidized by oxygen in 0.1% methanolic sodium hydroxide to afford 1-(3’,4’-dimethoxy-6’-bromobenzyl)- 1,6,7-trimethoxyisoquinoline-3 ,4-dione (133). Com- pound 133 was transformed to 1-(E,E)-3‘,4’-dimethoxy-6’-bromobenzylid- ene-6,7-dimethoxyisoquinoline-3,4-dione (134). Subsquently, UV irradiation of

1 0 CH 3O - c

CH 3O

OCH3

OCH3 Br

134 133 132

CH30

CH $ 135

SCHEME 18

0

CHgO 46


134 in ethanolic alkali solution under an argon atmosphere afforded norpontevedrine (135) in 43% yield; thus, treatment of 135 with sodium hydride in dry DMF, to prevent the decarbonylation, followed by addition of methylfluosulfo- nate gave pontevedrine (46) in 76% yield.

A “one-pot’’ conversion of 132 to norpontevedrine (135) was also carried out by irradiation of 132 in ethanolic alkali solution under an oxygen atmosphere in 33% yield. It may be stated that this method of synthesis of 4,5-dioxoaporphine seems to be of wide scope and therefore that different alkaloids of this type may be synthesized in a similar manner (96).

VI. Pharmacology and Clinical Use

The genus Aristolochia comprises approximately 200 species, many of which have played important roles in folk medicine for treating sore throat, venomous snakebites, wounds, fevers, and tuberculosis. The chemistry and pharmacology of aristolochic acid, the main active principle, was researched by many scientists. Many worthy achievements in the pharmacology of aristolochic acid have been published.

A. ANTITUMOR ACTIVITY

Kupchan and Doskotsch (9) found that an alcoholic extract of A . indica possessed reproducible activity against the adenocarcinoma 755 test system. The active principle, aristolochic acid I, was isolated and characterized. Kamatsh and co-workers (97) reported that growth of mouse sarcoma-37 cells incubated with aristolochic acid at concentration of 100-200 pg/ml for 3 hr was completely inhibited. Treatment of mice with aristolochic acid (1.25-5 mg/kg ip per day) for 3 days after subcutaneous implantation of sarcoma-37 cells inhibited tumor growth in 40-50%. A dose of 2.5-5 mg/kg ip per day for 5 days remarkably prolonged survival. The cytotoxic effect on HeLa cells in culture was observed at a concentration of 25 pg/ml.

Aristolochic acid I was used in clinical trials in cancer therapy; however, it was abandoned due to liver and kidney toxicity (98). It is interesting that the cytotoxicity of aristolochic acid, not only previously observed in animal cells, has also been confirmed for plant cells (99). Aristoloside (lo), isolated from A. manshuriensis, possessed antitumor activity (31).

B . IMMUNOMODULATING ACTIVITY

Experiments performed in rabbits and guinea pigs showed marked stimulation of leukocyte phagocytosis following application of various dilutions of


Aristolochia extracts. Aristolochic acid I was characterized as the active principle. The acid was capable of offsetting chloramphenicol- and prednisone-impaired phagocytic activity. When phagocytosis was impaired by prednisone, the effect of the acid depended on the dose of prednisone: from 2.5 mglkg prednisone upwards its lesional activity could not be influenced, but for doses under 1 mg/kg values were clearly normalized by treatment with aristolochic acid I. Offsetting of damage by cyclophosphamide to phagocytosis was seen even after higher drug doses. As expected, the number of leukocytes was not influenced by aristolochic acid I.

Further investigation of the effects of aristolochic acid I found that it has a protection activating effect on the phagocytosis of leukocytes. This effect was also noted in cold-blooded animals including carps, Aesculopius snake, and Elaphe Zongssima (100). Aristolochic acid I stimulated the reticuloendothelial system (REiS) and abolished the RES-depressing effect of chloramphenicol in mice and rats, using the carbon-clearance test.

In mice infections with pneumococci were influenced very satisfactorily by aristolochic acid I. Rats with wounds infected with Staphylococcus aureus were treated intraperitoneally or orally with aristolochic acid I; compared to controls, the treated animals recovered much faster. Rabbits after intravenous application of aristolochic acid I showed an increased antibactericial action of serum (97). Mice infected with bacteria including Staphylococcus aureus, Diphococcus pneumoniae, and Streptococcus pyogenes could be protected by treatment with 50 Fg/kg ip of aristolochic acid I (97).

Treatment with aristolochic acid I increased the oxygen consumption and thus the metabolic activity in mice liver cells and splenocytes (102). Aristolochic acid is not a new antibiotic. It acts not on the invading pathogens but on the naturally existing endogenous defense of the diseased organism, via vigorous stimulation of the phagocytic activity of host leukocytes (100).

C . ANTIFERTILITY ACTIVITY

The roots of Aristolochia indica, commonly known as an “Indian birthwort,” are reputedly used in Indian folk medicine as an emmenagogue and as an abor- tifacient. Aristolochic acid and its methyl ester, sesquiterpene (12S)-7,12- secoishwaran-12-01, isolated from this plant, possessed significant antifertility activity in mice (103-105).

Recently, Wang and Zheng reported that aristolochic acid, isolated from A. mollissima, when given orally to mice at a dose of 3-4 mg/kg showed significant antiimplantation and early pregnancy-interrupting effects; however, these effects were not observed in rats. This acid showed neither estrogenic nor antiestrogenic actions. Treatment with exogenous progesterone failed to prevent its pregnancy- interrupting action.


In addition, intraamniotic injection of aristolochic acid I in mid-term pregnant dogs and rats led to termination of pregnancy (106). Later, Che et al. reported that four Aristolochia alkaloids, aristolochic acid I and its methyl ester, aristolic acid, and (12S)-7,12-secoish-waran-12-01 were ineffective in antifertility tests, when administered to mice, hamsters, or rats (107).

D. MISCELLANEOUS

Aristolochic acid inactivated snake venoms including hose of Naja atra and Bungarus multicinctus but did not inactivate Trimeresurus muorosquamatus, Agkistroden acutus, or T. gramineus venoms (108). Moupinamide, a new alkaloid isolated from A. moupinensis, was found in vitro to inhibit rat platelet aggregation and MDA formation in platelets (109). Jaxena reported that aristolochic acid I was an insect chemosterilant (62).

E. CLINICAL USE

Wu et al. reported the use of aristolochic acid I, containing a small amount of aristolochic acids I1 and IIIa, for treatment of 44 cases of tumors and 15 cases of leukemia. The cases received aristolochic acid at 0.9 mg per day PO for 4-6 months while maintaining routine chemotherapy and radiotherapy. The clinical results showed that the numbers of rosette-forming cells (RFC) of patients treated with aristolochic acid significantly increased compared with the control group (p < .01). WBC counts elevated significantly (p= .02). DNCB induced delayed hypersensitivity. Responses were positive in 78.6% of patients who were negative before aristolochic acid administration. It was concluded that aristolochic acid possessed stimulatory activity of both T lymphocytes and macrophages. Aristolochic acid produced regession of cancer in about 50% of cases (110). Wu and co-workers did not find any detectable renal toxicity during the period of treatment (1 10).

Aristolochic acid was tested for therapy of tuberculosis, chronic bronchitis, bronchial asthma, pneumocardial diseases, etc. Clinical results showed curative effects, and the index of immune function of cases increased significantly compared to the control group (111). In Germany, an aristolochic acid preparation called Tardolyt that had been used as an antiinflammatory was canceled due to its potential carcinogenicity (12).

F. TOXICITY

Aristolochic acid has been tested in the clinical treatment of cancer; however, it was found to produce toxicity in kidney and liver (98). Peter reported that a single injection of aristolochic acid at 30 mg/kg in rats induced kidney failure

TABLE 11 Physical Data on Previously Reported Aristolochia Alkaloids

Molecular Molecular Compound formula weight mp CC) [alD (") Plant source

Aristolochic acid I C17H1107N 341.053554 275-278 (DMF- - A. acuminata (99), A. argentina (116,117), A. (1) (aristolochic EtOH); badamae (52), A. baetica (118), A. bum- acid A) 280 (EtOH) busifolia (119), A. bracteata (29,47,76,

77,120), A. championii (113,115,121), A. (MeOH- chilensis (122), A. clematitis (26.28,52,61, CHC13) 73,114,123-125,127,129), A. cucurbitoides

(130), A. debilis (29,76,77,120), A. elegans (52,55), A. esperanzae (116), A. fangchi (22,24,131,139), A. jimbriata (52), A. grifithii (133), A. heterophylla (134,154), A. indica (9,32,34,37,44,135,136), A. kaempferi (120). A. kwangsiensis (81,128, 132,137,138), A. longa (33,44,67,124), longgangensis (140), A. manshuriensis (30), A. maurorum (100,141), A. muxima (124), A. mollissima (57,126,142,143), A . moupinensis (144), A. multiflora (115), A. ornithocephala (52), A. pallida ( I d ) , A. reticulata (44,133, A. rotunda (52,61,123), A. serpentaria (34,44,124), A. sipho (52,53,124,126), A. tagala (147), A. triangularis (148), A. tuberosa (85), A. westandii (149)

283-285

Aristolochic acid C16H907N 237.037904 278 - A. argentina (65,122), A. chilensis (122) Ia (50)

(continued)

TABLE 11 (Continued)

Molecular Molecular Compound formula weight mp C'C) [ W I D (") Plant source

Aristolochic acid C16H906N 311.042987 267-271 II (2) (aristolochic acid B)

Aristolochic acid I1 methyl ester

Aristolochic acid IIIa (4) (aristolochic acid C) ul 00

Aristolochic acid 111 (3)

Aristolochic acid IVa (6) (aristolochic acid D)

C17H1106N 325.058639 277

C16H907N 327.037904 280

C17H1107N 341.053554 270-272 (meth-

C17HllOXN 357.048469 254-259 yl ester)

Aristolochic acid I X H 1 3 0 X N 371.064119 328-340 (meth- IV (5 ) yl ester)

Aristolochic acid C19H150xN 385.079770 240-241 IV methyl ester

methyl ester Aristolochic acid I CxXHl307N 355.069204 285-286

A. argentina (65,122), A. clematitis (73,125, 126,128), A. debilis (24,77,141), A. esperanzae (116), A. fangchi (24), A. longa (33,67), A. manshuriensis (70), A. moupinensis (144), A. rotunda (123), A. sipho (146)

A. argentina (65), A. indica (32), A. pallida

A. bambusifolia (119), A. clematitis ( 7 9 , A. debilis (24,26-28,61), A. fangchi (24), A. longgangensis (140), A. rotunda (1231, A. tagala (147,151), A. tuberosa (M), A. watsonii (152)

esperanzae (116), A. longa (33)

clematitis (153), A. esperanzae (116), A. heterophylla (134), A. indica (32,37), A. manshuriensis (30), A. mollissimu (57,142), A. rnoupinensis (1441, A. multiflora (99)

esperanzae (116), A. longa (33), A. mol- Iisima (57,126)

(144), A. championii (115)

(16)

A. argenrina (116), A. clematitis (26), A.

A. acuminata (99), A. argentina (I16), A.

A. argentina (116), A. clematitis (26), A.

A. kwangsiensis (81,139, A. moupinensis

A. argentina (65), A. indica (127)

7-Hydroxy-aristo-

7-Methoxyaristo-

Debilic acid (9) 2-(Phenan-

lochic acid I (7)

lochic acid I (8)

thr0[3,4-d]- 1,3- dioxole-6- nitro-5-carboxamido)propionic acid methyl ester (12)

Argentinine (32)

v, a Aristoloside (10)

Aristolamide (11) N-@-Hydrox-

yphenethy1)-p- cuomaramide

N-@-Hydrox- yphenethy1)-fer- ulamide (moupinamide)

(aristolactam 11) Cepharanone A

(14)

(17) Aristolactam Ia

357.048469

37 1.0641 19

355.069204 396.095753

295.157229

5 19.10 1294

271.084459 283.120844

313.131409

263.058244

279.053 159

282

284

>300 -133 (CHC13)

176-177 (oxalate)

235-236 (picrate)

193- 196

293-294 235-239

84-86

297-298

>350

- A. debilis (28), tagala (147)

- A. debilis (28)

- A. debilis (76,155), A. manshuriensis (70) A. longa (33)

- A. argentina (44,116)

-69.5 A. manshuriensis (30) (MeOH) - A. indica (32) - A. moupinensis (144)

- A. moupinensis (144)

- A. argentina (43)

- A. argentina (43)

-

(continued)

TABLE I1 (Continued)

Molecular Molecular Compound formula weight mp ("C) [alD (") Plant source

Aristolactam 111

Aristolactam IIIa

Aristolactam AIIIa

Aristolactam IV

Aristolactam AIa

Aristolactam A11

(15)

(18)

(27)

(16)

(26)

(24)

Aristolactam BII

Aristolactam I (22)

(13)

Aristolactam AIII

Aristolactam BIII

Aristolactam BI (taliscanine) (21)

Aristored

(25)

(23)

C19H1 7°6N

293.068809

279.053 159

281.068809

323.079374

281.068809

265.073894

279.089544

293.068809

295.084459

309.100034

309.100034

355.105589

297-304

>350

>350

345

>350

27 1

264-265

3 15-3 17

275

225

272-277

286.5

- A. argentina (43)

- A. argentina (43)

- A. argentina (43)

-

- A. argentina (43)

A. argentina (43), A. indica (37)

- A. argentina (43), A. indica (64), A. longgangensis (140), A. mollissima ( 5 3 , A. tagala (151)

A. argentina (42)

A. argentina (43,116), A. debilis (24), A. fangchi (24), A. indica (37), A. rotunda (123)

A. argentina (42,43), A. mollissirnu (57)

A. argentina (42.43)

A. argentina (43) , A. taliscana (38)

A. bracteata (156), A. reticulata (44,135), A serpentaria (44)

Aristolactam C N-p-D-glucoside (20)

Aristolactam N-p- D-glucoside (19)

Tuberolactam (18) 4,5-Dioxodehy-

dro-asimilobine (49)

Tuberosinone (33)

Tuberosinone N-P-D-glucoside

Magnoflorine (28) (34)

Asimilobine (29) Cyclanoline (30) Hydrastine (31) (-)-(R,R)-7’-0-

Methylcus- pidaline (35)

1-Curine

44 1.105984

455.121634

279.053 159 293.068809

307.048074

469.100899

342.170534

267.125927 34 1.162709 283.136889 624.3 19938

594.257338

286 >320

331-33

298-300 3 10-3 12

340

235-237

248-249

-97.1 (penta- acetate),

(CHC13)

(NzO) - 14

-

-

-

-

+ 200 (MeOH)

- -

2 15-220 -

149 (picrate) - - 105

(CHC13)

22 1 -337 (EtOH)

A. argentina (43), A. bambusifolia (119), A indica (80), A . tuberosa (89)

A. indica (32,37, 80), A. longgangensis (140)

A. tuberosa (89) A. indica (64)

A. longgangensis (140), A. tagala (151), A tuberosa (85,89)

A. tuberosa (85,89)

A. argentina (42), A. baetica (118), A . bracteata (158), A. clematitis (159), A , debilis (160,157), A. elegans (120), A . fangchi (24), A . heterophylla (134), A. indica (79), A. kaempferi (24,120), A. macedonica (145), A . moupinensis (144)

A . kaempferi (150) A. debilis (157) A. serpentaria (44) A . elegans (50)

A . indica (48)


with a decrease in the glomerular filtration rate (GFR) and increased urea and creatinine concentrations in plasma; it caused impairment of urinary concentrat- ing ability as well (112). It was also probable causative agent in Balkan endemic nephropathy (114).

VII. Summary of Physical Properties

Table I1 summarizes physical data for Aristolochia alkaloids

REFERENCES

1. Foon-Chew How, “A Dictionary of the Families and Genera of Chinese Seed Plants” 2nd ed. p. 43. Science Press, Beijing, China, 1985.

2. “Pharmacopeia of the Peoples Republic of China,” Vol 1, pp. 36, 38. Peoples Press, Beijing, China, 1985.

3. Shi-Zhen Li, “Ban Tso Gan Mo” (1595); 1977 ed., Peoples Health Press, Beijing, China, 1977.

4. K. Kimura and T. Kimura, “Medicinal Plants of Japan in Colour,” p. 63. Koikushe Publishing Co., 1981.

5. M. Pailer, Fortschr. Chern. Org. Naturst. 18, 66 (1960). 6. D. B. Mix, H. Guinaudeau, and M. Shamma, J . Nut. Prod. 45, 657 (1982). 7. L. S. Ding and F. C. Lou, Zhung Tsao Yuo 14, 40 (1983). 8. P. Homsberger, Schweiz. Apoth. Ztg. 109, 380 (1971). 9. S. M. Kupchan and R. W. Doskotsch, J . Med. Pharm. Chem. 5, 657 (1962).

10. Br. Pat. 895,037; CA 57, 2350f. 11. L. N. Filitis and P. S. Massagetov, Vopr. Onkof. 7, 97 (1961). 12. Anonymous, Pharm. Ztg. 126, 1373 (1981). 13. V. P. Arya, Drugs Future 4, 475 (1979). 14. Anonymous, Drugs Future 8, 640 (1983). 15. Z. L. Chen, B. S. Huang, D. Y. Zhu, M. L. Yin, Z. C. Chui, W. Z. Bao, C. Guei, and J . F.

16. B. Podolesov and Z. Zdrarkovski, Actu Pharm. Jugosl. 31, 249 (1981); CA 96, 82732j. 17. L. Gracza and P. Ruff, Dtsch. Apoth. Ztg. 121, 2817 (1981). 18. G. Kamphuis, P. Patt, and W. Winkler, Osterr. Apoth. Ztg. 24, 535 (1970); G. Kamphuis, P.

19. Ger. Pat. 1,768,090; CA 75, 80260~; Ger. Pat. 1,186,980; CA 63, 161388. 20. Ger. Pat. 2,646,545; CA 89, 117789t. 21. Rum. Pat. 55,389; CA 81, 111458~. 22. Jpn. Pat. 7,127,834; CA 75, 343989~. 23. H. Rosenmund and T. Reichstein, Pharm. Actu Helv. 28, 243 (1943). 24. M. Tomita and S. Sasagawa, J . Pharm. SOC. Jpn. 79,974 (1959); M. Tomita and S. Sasagawa,

25. M. Pailer, L. Belohlav, and E. Simonitsch, Monatsch. Chem. 87, 249 (1956). 26. M. Pailer, P. Bergthaller, and G. Schaden, Monatsch. Chem. 96, 863 (1965). 27. S. Sasagawa, J . Pharm. SOC. Jpn. 82, 921 (1962). 28. Z. L. Chen, B. S. Huang, D. Y. Zhu, and M. L. Yin, Acta Chem. Sinica 39, 237 (1981). 29. Y. T. Ku and K. F. Tseng, Kexue Tongbao, 568 (1957); Y. T. Ku and K. F. Tseng, Kexue

30. T. Nakanishi, K. Iwasaki, M. Nasu, I. Miura, and K. Yoneda, Phytochemistry 21, 1759

Zhou, Zhung Tsao Yao 9, 8 (1978).

Patt, and W. Winkler, Osterr. Apoth. Ztg. 24, (1970).

J . Pharm. SOC. Jpn. 79, 1470 (1959).

Tongbuo, 761 (1957).

(1982).


31. Jpn. Pat. 83,152,897; CA 100, 91346q. 32. S. C. Pakrashi, P. Ghosh-Dastidar, S. Basu, and B. Achari, Phytochemistry 16, 1103 (1977). 33. J. De Pascual Teresa, J. G. Urones, and A. Fernandaz, Phytochemistry 22, 2745 (1983). 34. R. W. Doskotch and P. W. Vanevenhoren, Lloydia 30, 141 (1967). 35. P. R. Krishnaswamy, B. L. Manjunath, and S. V. Rao, J. Indian Chem. SOC. 12,476 (1935). 36. B. L. Manjunath and M. S. S. Rao, J. Indian Chem. SOC. 15, 646 (1938). 37. S. M. Kupchan and J. J. Merianos, J. Org. Chem. 33, 3735 (1968). 38. L. A. Maldonado, J. Herran, and J. Rome, Ciencia 24, 237 (1966); CA 65, 15438e. 39. M. Akasu, H. Itokawa, and M. Fujita, Tetrahedron Lett., 3609 (1974). 40. S. F. Duke and E. Gellert, Phytochemistry 17, 599 (1979). 41. C. R. Chen, J. L. Beal, R. W. Doskotch, L. A. Mitscher, and G. H. Svoboda, Lloydia 37,493

42. R. Crohare, H. A. Priestap, M. Farina, M. Cedola, and E. A. Ruveda, Phytochemistry 13,

43. H. A. Priestap, Phytochemistry 24, 849 (1985). 44. R. T. Coutts, J. B. Stenlake, and W. D. Williams, J. Pharm. Pharmcol. 11, 607 (1959). 45. H. A. Priestap, E. A. Ruveda, S. M. Albonico, and V. Deulofeu, An. Assoc. Quim. Argent.

46. D. Y. Zhu, B. D. Wang, B. S. Huang, R. S. Xu, Y. P. Qiu, X. Z. Chen, Heterocycles 17,345

47. F. T. Hussein, Planta Med. 18, 30 (1969). 48. T. R. Govindachari and N. Viswanathan, Indian J. Chem. 5, 655 (1967). 49. K. P. Guha, B. MuWlerjee, and R. Mukherjee, J . Nat. Prod. 42, 1 (1979). 50. N. El-Sebakhy and P. G. Waterman, Phytochemistry 23, 2706 (1984). 51. I. D. Spenser and H. P. Tiwari, Chem. Commun. 55 (1966). 52. H. R. Schuette, U. Orban, and K. Mothes, Eur. J. Biochem. 1, 70 (1967). 53. F. Comer, H. P. Tiwari, and I. D. Spenser, Can. J. Chem. 47, 481 (1969). 54. V. Sharma, S. Jain, D. S. Bhakuni, and R. S. Kapil, J. Chem. SOC., Perkin Trans. I, 1153

55. F. T. Hussein and N. A. El-Sebakhy, Planta Med. 25, 310 (1974). 56. R. Hansel and A. Leuschke, Phytochemistry 15, 1323 (1976). 57. L. X. He, H. Z. Xue, Y. X. Xu, and J. Weng, Zhiwu Xuebao 26, 527 (1984). 58. R. Braz P, S. J. Gabriel, C. M. R. Gomes, 0. R. Gottlieb, M. Das, G. A. Bichara, and J. G.

59. L. Castedo, R. Suau, and A. Mourino, Tetrahedron Lett., 501 (1976). 60. A. Nahrstedt, Plantg Med. 44, 2 (1982). 61. J. von Euw, T. Reichstein, and M. Rothschild, Israel J. Chem. 6,659 (1968); CA 70,76099e. 62. M. Rothschild, J. van Euw, and T. Reichstein, Insect Biochem. 2, 334 (1972). 63. A. Urzua, G. Salgado, B. K. Cassels, and G. Eckhardt, Coll. Czech. Chem. Commun. 48,

64. B. Achari, S. Chakrabarty, S. Bandyopadhyay, and S. C. Pakrashi, Heterocycles 19, 1203

65. H. A. Priestap, Phytochemistry 21, 2755 (1982). 66. P. Patti, Arzneim. Forsch. 15, 90 (1965). 67. W. Schunack, E. Mutschler, and H. Rochelmayer, Pharmazie 20, 685 (1967). 68. X. Q. Zhang and L. X. Xu, Zhung Tsao Yao 13, 448 (1982). 69. G. Eckhardt, A. Urzua, and B. K. Cassels, J. Nut. Prod. 46, 92 (1983). 70. G. Rucker and B. S. Chung, Planta Med. 27, 68 (1975). 71. L. Hruban and F. Santary, Pharmazie 20, 357 (1965). 72. M. Pailer, L. Belohlav, and E. Simonitsch, Monatsch. Chem. 86, 676 (1955). 73. M. Pailer and A. Schleppnik, Monatsch. Chem. 88, 367 (1957).

(1974).

1957 (1974).

60, 309 (1972); CA 77, 164898q.

(1982).

(1982).

S. Maia, Phytochemistry 15, 1187 (1976).

1513 (1983).

(1982).


74. M. Pailer and A. Schleppnik, Monutsch. Chem. 89, 175 (1958). 75. M. Pailer and B. Bergthaller, Monutsch. Chem. 97, 484 (1966). 76. K. F. Tseng and Y. T. Ku, Actu Pharm. Sinicu 6,174 (1958); K. F. Tseng and Y. T. Ku, Actu

77. K. F. Tseng and Y. T. Ku, Acta Chem. Sinicu 23, 156 (1957). 78. K. Ito, H. Farukawa, and M. Haruna, J . Pharm. SOC. Jpn. 92, 92 (1972). 79. S. Mukhopadhyay, S. Funayama, G. A. Cordell, and H. S. H. Fong, J . Nut. Prod. 46, 507

80. B. Achari, S. Chakrabarty, and S. C. Pakrashi, Phytochemistry 20, 1444 (1981). 81. F. X. Zhou, P. Y. Liang, S. C. Chu, and C . Wen, Chin. Pharm. Bull. 16, 56 (1981). 82. P. Gorecki and H. Otta, Phurmazie 30, 337 (1975). 83. J. Kunitomo, Y. Murakami, and M. Akasu, J . Phurm. SOC. Jpn. 100, 33 (1980). 84. J. Kunitomo, Y. Murakami, M. Oshikata, T. Shingu, M. Akasu, S. T. Lu, and I. S. Chen,

85. D. Y. Zhu, B. D. Wang, B. S. Huang, R. S. Xu, Y. P. Qiu, X. Z. Chen, and D. J. Quan, Actu

86. S. M. Kupchan and H. C. Wormser, J . Org. Chem. 30, 3792 (1965). 87. S. M. Kupchan and H. C. Wormser, J . Org. Chem. 30, 3933 (1965). 88. S. M. Kupchan and H.C. Wormser, J . Org. Chem. 30, 3935 (1965). 89. D. Y. Zhu, F. X. Jiang, R. S. Xu, Y . P. Qiu, and X. Z. Chen, Zhung Tsuo Yuo 12,529 (1981). 90. H. C. Wormser, Diss. Abttr. 26, 2640 (1966). 91. I. I. Kunitomo, Y. Murakami, and M. A. Akasu, J . Pharm. SOC. Jpn. 100, 337 (1980). 92. H. G. Kiryakov, E. Iskrenova, B. Kuzmanov, and L. Evstatieve, Pluntu Med. 43, 51 (1981). 93. V. B. Chervenkova, N. M. Mollov, and S. Paszye, Phytochemistry 20, 2285 (1981). 94. 3. M. Saa, M. J. Mitchell, and M. P. Cava, Tetrahedron Lett., 601 (1976). 95. T. Kametani, S. Shibuya, H. Sugi, 0. Kusama, and K. Fukumoto, J . Chem. SOC. (C), 2446

96. L. Castedo, R. J. Estevez, J. M. Saa, and R. Suan, J . Heterocycl. Chem. 19, 1319 (1983). 97. N. Kamatsh, H. Nawata, K. Tadashi, J. Shoji, and A. Tada, Showu Igukkui Zusshi 33, 776

98. L. Jackson, Cancer Chemother. Rep. 42, 35 (1964). 99. C. Moretti, M. Rideau, J. C. Chenieux, and C. Viel, Pluntu Med. 35, 360 (1979).

100. J. R. Mose, Arzneim. Forsch. 16, 118 (1966). 101. A. Key , A. A. Askari, and K. A. Sharefi, Znt. J . Crude Drug Res. 21, 141 (1983). 102. J. R. Mose and J. Porta, Arzneim. Forsch. 24, 52 (1974). 103. A. Pakrashi and B. Chakrabarty, Experientia 34, 1377 (1978). 104. A. Pakrashi and C. Shaha, Experientiu 34, 1192 (1978). 105. A. Pakrashi and C. Shaha, Experientiu 33, 1498 (1977). 106. H. W. Wang and J. H. Zheng, Actu Phurm. Sinicu 19, 405 (1984). 107. C. T. Che, M. S. Ahmed, S. S. Kang, D. P. Waller, A. S . Bingel, A. Martin, P.

Razamahendron, N. Bunyapraphatsara, D. C. Lankin, G. A. Cordell, D. D. Soejarto, R. D. B. Wizesekera, and H. S. H. Fong, J . Nut. Prod. 47, 331 (1984).

108. L. H. Tsai, L. L. Yang, and C. Chang, Taiwan KO Hsesek 34, 40 (1980); CA 93, 162353q. 109. L. Z. Xu and N. J. Sun, Actu Phurm. Sinicu 19, 48 (1984). 110. N. X. Wu, H. D. Hua, Y. L. Han, 2. H. Gao, and B. Y . Wu, Shanghai Yi Xue 2, 620

111. F. X. Zhou, Chin. Pharm. Bull. 16, 163 (1981). 112. G. Peters and P. R. Hedwall, Arch. Int. Pharmcodyn. 145, 334 (1966). 113. F. X. Zhou, J. Wen, P. Y. Liang, and Y. Ma, Chin. Phurm. Bull. 17, 243 (1982). 114. K. V. Rao, V. Tanrikut, and K. Killion, J . Phurm. Sci. 64, 345 (1975). 115. F. X. Zhou, J. Wen, Y. P. Liang, and Y. Ma, Zhung Tsuo Yuo 13, 3 (1982).

Phurm. Sinica 6 , 316 (1958).

(1983).

Phytochemistry 19, 2735 (1980).

Chem. Sinica 41, 74 (1983).

(1971).

(1973); CA 82, 68199~.

(1979).


116. H. A. Pnestap, E. A. Ruveda, 0. A. Mascaretti, and V. Deulofeu, An. Asoc. Quim. Argent.

117. E. A. Reveda, H. A Priestap, and V. Deulofeu, Anal. Assoc. Quim. Argenr. 54,237 (1966). 118. L. M. Cameras, Anal. Inst. Bot. A . J . Cavanilles 30, 253 (1973); CA 80, 24780g. 119. Y. P. Qiu, X. Z. Cheu, D. Y. Zhu, F. X. Jiang, and R. S. Xu, Guihaia 2, 209 (1982). 120. M. Tomita and S. Kura, J . Pharm. SOC. Jpn. 77, 812 (1957). 121. F. X. Zhou, J. Wen, and P. Y. Liang, Zhung Tsao Yao 13, 147 (1982). 122. A. Urzua, G. Salgado, B. K. Cassels, and G. Eckhardt, Planta Med. 45, 51 (1982). 123. S. Carboni, 0. Livi, D. Segnini, and L. Mazzanti, Gazz. Chim. Ztal. 96, 641 (1966). 124. H. Ganshirt, Pharmuzie 3, 584 (1953). 125. I. Halm, Herba Hung. 19, 179 (1980). 126. M. S. He, H. Fang, and A. Liu, Zhung Tsao Yao 13, 534 (1982). 127. B. Podolesov and M. Micevska, God. Prir. Mat. Fak. Univ. Skopje. Mat. Fiz. Hem. 20, 205

128. S. Y. Li and C. Yao, Zhung Tsao Yao 12, 25 (1981). 129. L. T. Chou and C. M. Chen, Chin. Phurm. Bull. 16, 51 (1981). 130. Y. P. Qiu, X. Z. Chen, and D. Y. Zhu, Guihaia 1, 46 (1981). 131. L. T. Cheu and C. M. Chen, Chin. Phurm. Bull. 16, 117 (1981). 132. S. Y. Li and Q. Yao, Chin. Pharm. Bull. 16, 16 (1981). 133. A. Tada, K. Sase, I. Ohmura, J. Shoji, and 0. Tanaka, Shoyakugaku Zasshi 23, 99 (1969). 134. B. Z. Tian, W. L. Zhou, T. Q. Tan, and L. Q. Lu, Zhung Tsao Yao 13, 106 (1982). 135. R. T. Coutts, J. B. Stenlake, and W. D. Williams, J . Chem. SOC., 4120 (1957). 136. A. V. Subbaratnam and W. B. Cook, J . Med. Phurm. Chem. 5 , 1376 (1962). 137. F. X. Zhou, P. Y. Liang, S. C. Chu, and C. Wen, Chin. Pharm. Bull. 16, 248 (1981). 138. S. Y. Li and Q. Yao, Zhung Tsao Yao 12, 73 (1981). 139. F. X. Zhou, P. Y. Liang, C. J. Qu, and J. Wen, Acta Pharm. Sinica 16, 638 (1981). 140. Y. P. Qiu, X. Z. Chen, and D. Y. Zhu, Guihaia 2, 47 (1982). 141. A. Kery, A. A. Askari, and K. A. Sharefi, Fitoterapia, 201 (1981). 142. L. S. Ding, M. S. Ho, and F. C. Lou, Zhung Tsao Yao 11, 487 (1980). 143. L. H. Ho, W. W. Hua, and H. C . Hsueh, Chin. Phurm. Bull. 15, 44 (1980). 144. L. Z. Xu and N. J. Sun, Acta Pharm. Sinica 19, 48 (1984). 145. B. Podolesov and Z. Zdrarkovski, Acta Pharm. Jugosl. 30, 161 (1980). CA 94, 12804~. 146. W. Cisowski, H. Rzadkowska-Bodalska, and J . Lutomski, Rocz. Chem. 51,2125 (1977); CA

147. L. S. Ding, Q. Zeng, and F. C. Lou, Zhung Tsao Yao 12, 436 (1981). 148. M. L. Ambros and N. S. De Siqueira, Rev. Brasil Farm. 52, 61 (1971); CA 76, 70075~. 149. R. R. L. Chen, Taiwan Yao Hsueh Tsa Chih. 26, 31 (1974); CA 84, 95559k. 150. K. Ito, H. Furakaw, H. Tanaka, and S. Koto, J . Pharm. SOC. Jpn. 90, 1169 (1970). 151. Y. P. Qiu, K. Y. Ge, X. L. Chen, D. Y. Zhu, F. X. Jiang, and R. S. Xu, Guihaia 2, 142

152. B. P. Sexena, 0. Koul, K. Tikku, C. K. Atal, 0. P. Sun, and K. A. Suri, Indian J . Exp. B i d .

153. E. A. Ruveda, S. M. Albonico, H. A. Priestap, V. Deulofeu, M. Pailer, E. Gossinger, and P.

154. M. S. He, Y. L. Li, and Q. C. Liu, Zhung Tsao Yao 14, 158 (1983). 155. K. F. Tseng and Y. T. Ku, Acta Pharm. Sinica 6, 33 (1958). 156. K. V. Jagannadha Rao, L. R. Row, and Y. S. Murty, J . Sci. Ind. Res. 18B, 245 (1959). 157. M. Tomita and K. Fukagawa, J . Phurm. SOC. Jpn. 82, 1673 (1962). 158. M. S. Sastry, Indian J . Phurm. 27, 264 (1965). 159. M. Pailer and G. Pruckmayer, Monatsch. Chem. 90, 145 (1959). 160. R. Nishida, Agr. Biol. Chem. 37, 314 (1973).

59, 245 (1971).

(1972); CA 78, 133332s.

88, 86014j.

(1982).

17, 354 (1979); CA 91, 15146e.

Bergthaller, Monatsch. Chem. 99, 2349 (1968).


- CHAPTER 3 -

CHROMONE ALKALOIDS

PETER J. HOUGHTON

Chelsea Department of Pharmacy Kings College London (KQC)

London SW3 6LX, England

I. Introduction 11. Botanical Distribution

A. Flavonoid Alkaloids B. Noreugenin-Related Alkaloids

111. The Flavonoidal Alkaloids A. Isolation B . Structural Elucidation C. Spectral Characteristics D. Synthesis and Derivatives E. Pharmacology

IV. Noreugenin-Related Alkaloids A. Isolation B. Structural Elucidation C. Spectral Characteristics D. Synthesis and Derivatives E. Pharmacology References

I. Introduction

The term “chromone alkaloid” is used to describe a structure consisting of a pyridine, piperidine, or pyrrolidine ring linked to the A ring of chromone (1). In

1 Chromone nucleus

all the compounds so far isolated the chromone nucleus exists either as rings A and C of a flavonoid (2) or as noreugenin (3). It is reasonable to classify these


All rights of reproduction in any fom reserved.

68

3'

PETER J . HOUGHTON

2 Flavonoid nucleus 3 Noreugenin

two types together since the ring A in both types is generally considered to have a common biogenetic origin, being formed from acetate units (I , 2 ) .

The structures used for the alkaloids in this chapter are numbered conven- tionally for the flavonoid or noreugenin moiety. The carbon atoms of the nitrogen-containing ring are numbered separately l ' , 2', etc. These alkaloids are of interest due to their amphoteric nature, being both bases and phenols, and also because of the reputed biological activity of some of the plants which contain them.

11. Botanical Distribution

A. FLAVONOID ALKALOIDS

The first flavonoidal alkaloids to be isolated were ficine (4) and isoficine (5 ) in 1965 from Ficus pantoniana King. (Moraceae) (3 ) . These alkaloids have not

4 Ficine 5 Isoficine

been reported from any other source, nor have any similar alkaloids been reported from the Moraceae. In 1980 phyllospadine (6), another pyrrolidine flavonoid, was isolated from the leaves of a monocotyledon, Phyllospadix iwaten- sis Makino (Zosteraceae) (4 ) , an aquatic species growing in waters off Japan. The next reported isolation of a flavonoidal alkaloid was that of vochysine (7)

3. CHROMONE ALKALOIDS 69

b H 6 Phyllospadine 7 Vochysine

from the fruits of Vochysiu guiunensis (Aubl.) Poir (Vochysiaceae) from French Guyane (5).

Most recently a series of piperidinyl-flavonoid alkaloids have been isolated from two Buchenuviu spp. (Combretaceae) (6). The leaves of B . mucrophyllu Eichl. yielded buchenavianine (8) and N-demethylbuchenavianine (9). The fruits

8 (R = CH3) Buchenavianine 9 (R = H) N-Demethylbuchenavianine

of the same species were also found to contain 8 as well as four other alkaloids, namely 0-demethylbuchenavianine (lo), 0,N-bisdemethylbuchenavianine (ll),

10 (R = CH3) 0-Demethylbuchenavianine 11 (R = H) 0,N-Bisdemethylbuchenavianine

N-demethylcapitavine (12), and 5,7-dihydroxy-6-(N-methy1-2”-piperidinyl)flavanone (13). The seeds of B . cupitutu Eichl. were found to contain three other such alkaloids. These were named capitavine (14), 5,7,4’-trihydroxy-6-(N-meth-

70 PETER J . HOUGHTON

12 (R = H) N-Demethylcapitavine 14 (R = CH3) Capitavine

13 (R = H) 5,7-Dihydroxy-6-(N-methyl-2”-piperidinyl)flavanone 16 (R = OH) 5,7,4’-Trihydroxy-6-(N-methyl-2”-piperidinyl)flav~one

15 5,7,4’-Trihydroxy-6-(~-methyl-2”-piperidinyl)flavone

yl-2”-piperidinyl)flavone (15) and 5,7,4‘-trihydroxy-6-(N-methyl-2”-piperidin- y1)flavanone (16).

The flavonoidal alkaloids have thus been found widely scattered throughout the higher plants. In view of the ubiquitous occurrence of flavonoids and the simplicity of the nitrogenous component in the compounds so far isolated, it is quite possible that they may occur in more species. The occurrence of the flavonoid alkaloids in Buchenavia but not TerminaEia has been used to confirm the taxonomic distinction between these genera (6).

B . NOREUGENIN-RELATED ALKALOIDS

To date the noreugenin-related alkaloids have been isolated from only two families, Meliaceae and Rubiaceae. Rohitukine (17) was the first of this type of


OH 0

17 Rohitukine

alkaloid to be isolated. It was extracted from the leaves and stem of Amoora rohituku (Meliaceae) Wight and Am. in 1979 (7). An alkaloid with identical characteristics has been found in another meliaceous species, Dysoxylum binec- tariferum Hook. (8). Two other alkaloids were isolated from A. rohituku (7) , but the elucidation of their structures has not been reported.

Rohitukine (17) has also been isolated from Schumunniophyzon mugnificum Harms. (Rubiaceae) (13). This genus occupies a section of the Rubiaceae which has been somewhat neglected phytochemically . Recent work on Schuman- niophyton has resulted in the extraction of several noreugenin alkaloids. The first of these were reported in 1978 from the root bark of S. problematicum (A. Chev.) Aubrev. from the Ivory Coast (9). Schumanniophytine (M), a nicotinic

0

18 Schumanniophytine

acid-noreugenin congener, and two unnamed noreugenin-piperidine-2-one derivatives (19 and 20) were the compounds found.

19 (R = H), 20 (R = CH3) Unnamed compounds isolated by Schlittler and Spitaler

72 PETER J. HOUGHTON

Subsequent phytochemical interest has focussed on S. magnificum Harms. The stem juice of this species is used in Nigeria for the treatment of snakebite (11). However, most of the work performed has dealt with the rootbark since this contains the highest proportion of alkaloids. The noreugenin-piperidine compounds schumannificine and N-methylschumannificine, first isolated by Okogun et al. (10) and subsequently by Houghton and Yang ( ] I ) , were given structures 21 and 22, respectively. The latter workers also isolated four other alkaloids.

R’ N WCH3 21 (R = H) Schurnannificine (original structure)

22 (R = CH3) N-Methylschumannificine (original structure)

Two of these, anhydroschumannificine and N-methylanhydroschumannificine, were analogs of 21 and 22 and assigned structures 23 and 24. Recently the

0 OH 0

23 (R = H) Anhydroschumannificine (original structure) 24 (R = CH3) N-Methylanhydroschurnannificine (original structure)

structures of these four alkaloids have been revised to give schumannificine (25), N-methylschumannificine (26), anhydroschumannificine (27), and N-methylanhydroschumannificine (28) (12).

25 (R = H) Schumannificine (revised structure)

26 (R = CH3) N-Methylschurnannificine (revised structure)

3. CHROMONE ALKALOIDS 1 3

27 (R = H) Anhydroschumannificine (revised structure) 28 (R = CH3) N-Methylanhydroschumannificine (revised structure)

The other two alkaloids isolated by Houghton and Yang were very similar to schumanniophytine (18). They were originally thought to be two new compounds and were assigned structures 29 and 30 (11). Recent work has shown that

29 Isoschumanniophytine

0

30 Schumanniophytine isomer

in fact one of them is identical to 18, and the other has the structure 29 and was named isoschumanniophytine (12). Later work by Houghton and Yang (13) on the water-soluble fraction of the root bark has resulted in the isolation of the N- methyl derivatives of 18 and 29, the quaternary alkaloids 31 and 32. Two other alkaloids isolated were named schumaginine and N-methylschumagnine and given structures 33 and 34, respectively (13). The betaine, trigonelline (35), was also isolated from the aqueous portion of the root extract and found to occur in large amounts in the stem and leaves. Although not a chromone alkaloid it is not

14 PETER 3 . HOUGHTON

31 N-Methylschumanniophytine

32 N-Methylisoschumanniophytine

R I lN\

33 (R = H) Schumaginine

34 (R = CH3) N-Methylschumagnine

35 Trigonelline

difficult to envisage its relationship to 31 and 32. Another quaternary alkaloid, schumanniofoside (36), which is also a glycoside, has recently been isolated from S. magnificum (14). No data or chemical confirmation of the structure assigned have yet been published.

Although Schumanniophyton is the only genus of the Rubiaceae in which this type of alkaloid has been found it should be noted that related genera have shown


HO

OH HO

36 Schumanniofoside

the presence of alkaloids in screening procedures (Z5,Ze. All such genera await the isolation and structural elucidation of the alkaloids present, however, and it might well be that new compounds will be found. The same consideration applies to the Meliaceae.

111. The Flavonoidal Alkaloids

A. ISOLATION

Details of the extraction methods for ficine (4) and isoficine (5) were not given. Phyllospadine (6) was isolated from the flavonoid-containing n-butanol- soluble extract from dried plant material (4). The alkaloids from Vochysia and Buchenavia were isolated by conventional procedures, utilizing acid-base extraction and subsequent column or thin-layer chromatography using silica gel or alumina (5,6).

B . STRUCTURAL ELUCIDATION 1. Ficine (4) and Isoficine (5) (3)

The flavonoidal moiety of ficine was deduced from its UV spectrum, which was very similar to chrysin (37), and the bathochromic shift indicated a saturated alkyl substituent on ring A. Treatment with Gibb’s reagent to detect the presence of a proton para to a phenolic OH ( 1 7 ) gave a positive result for 5 but not 4. Although no molecular ion could be seen in the mass spectrum, the peaks obtained were equivalent to the sum of the individual spectra of chrysin (37) and


37 Chrysin

N-methylpyrrole. It was assumed that pyrolysis occurred at the inlet temperature and that ficine and isoficine consisted of chrysin substituted with N-methylpyrrole at positions 8 and 6, respectively. The presence of chrysin as part of the molecule was confirmed by its formation from 4 by alkaline hydrolysis.

The IH-NMR spectra confirmed these structures; they showed characteristic signals for the flavone part of the molecule such as an aromatic H singlet at 6 6.25 in 4 and 6 6.33 in 5. This indicated that the aromatic ring A was pentasubstituted. The more downfield shift of this signal in 5 is consistent with the structures assigned, as it is established that 5,7-dialkyloxyflavones give a signal for H-8 more downfield than that given by H-6. The 'H-NMR spectrum also showed that the N-methylpyrrole was linked to the flavonoid through C-2". The 2"-H gave a 1H triplet at 6 4.15 coupled with a 2H multiplet at 6 2.08 given by the 3"-CH,.

2. Phyllospadine (6) (4)

Phyllospadine was characterized as its triacetate. Its alkaloidal nature was detected by a positive Dragendorff's reaction and its flavonoidal nature by its UV spectrum and the co-occurrence of the parent flavonoid hispidulin (38). The 'H- NMR spectrum showed signals identical to those of 38 apart from the lack of the signal at 6 7.22 attributed to 8-H. The attachment of the nitrogenous ring was therefore reckoned to be at this position. The characterization of the ring as N-

38 Hispidulin

methylpyrrole was made from the mlz peak of 84 in the mass spectrum and the similarity of the signals for this ring to those given by ficine (4) and isoficine (5) (3).


3. Vochysine (7) (5)

The phenolic nature of vochysine was deduced from the bathochromic shift in the presence of alkali observed in the UV spectrum. The UV spectrum showing peaks at 215 and 275 nm together with peaks at mlz 272, 153, and 120 in the mass spectrum indicated the presence of a 4’-OH flavan. The peak at mlz 69 was indicative of pyrrolidine substituent.

The ‘H-NMR spectrum features confirmed the proposed C ring structure as it showed a 4H aromatic AB system. An isolated aromatic proton signal at S 5.93 indicated a pentasubstituted A ring. The 3H singlet at S 3.65 showed that one of these was a methoxy substituent. The other two were thought to consist of OH and the pyrrolidine ring. The actual positions of substitution were determined by comparison with various derivatives and analogs.

Ethanolic degradation produced a compound whose lH-NMR spectrum showed no signals corresponding to the pyrrole ring but an extra aromatic H signal meta coupled to the existing aromatic H. Dimethyl sulfate methylation of this product resulted in the formation of a substance identical to 5,7,4’-tri- methoxyflavan. Thus the substitution of the pyrrole ring at C-8 was confirmed. The question as to whether the methoxy group in the original compound was at C-5 or C-7 was resolved by the formation of 7,4’-dihydroxy-5-methoxyflavan and the 7-methoxy isomer from naringenin (39). The vochysine degradation product was identical to the 7-methoxy isomer.

39 Naringenin

The attachment of the pyrrole ring at C-8 was confirmed by noting that the shift of the aromatic H in the ‘H-NMR spectrum moved from 6 5.93 to 6.38 in the acetylated product. This showed that the free proton is ortho to the phenolic OH at C-5 and that the pyrrole must therefore be at C-8. Further proof of the structure of vochysine was obtained when it was synthesized from 5,4’-dihydroxy-7-methoxyflavan and an alcoholic solution of pyrroline.

4. Buchenuviu Alkaloids (6)

The flavonoidal moiety in Buchenavia alkaloids was deduced from their UV spectra. The more detailed structure determination for individual alkaloids is outlined below.


a. Buchenavianine (8). The mass spectrum of 8 gave a molecular ion at mlz 365 and a large peak at mlz 98 corresponding to N-methylpiperidine. The 'H-NMR spectrum showed a 5H aromatic multiplet due to the unsubstituted B ring and two other isolated aromatic protons at 6 6.70 and 6.40. 3H singlets at 6 4.00 and 2.33 were assigned to aromatic OMe and NMe, respectively. Consid- eration of the 13C-NMR spectrum established that buchenavianine was either 5- or 7-methoxychrysin substituted with N-methylpiperidine at either 6 or 8. A negative Gibb's test indicated that the piperidine ring was probably substituted at C-8. NOE difference spectra with irradiation at the aromatic methoxy frequency showed that the 6-H signal at 6 6.40 was enhanced, but no such event occurred in any of the signals of the piperidine moiety. THe OMe group was therefore deduced as being at C-5. The 13C-NMR spectrum showed that C-4 gave a signal at 178.3. If C-5 were OH substituted the C-4 signal would be seen at 184 due to the influence of hydrogen bonding. Thus the OH must be at C-7.

The spectra of N-demethylbuchenavianine (9) showed many features similar to those of 8. However, the molecular ion was less by 14, and there was an absence of the NMe peak from the 'H-NMR spectrum.

c. O-Demethylbuchenavianine (10). The spectral data of O-demethylbuchenavianine (10) also agreed very closely with that given by 8. Dif- ferences were seen in that the molecular ion was less by 14 mass units and no OMe peak was observed in the 'H-NMR spectrum.

d. Capitavine (14). Capitavine (14) gave the same molecular ion peak as 10 and was similar in many ways in the features observed in the various spectra. The flavonoidal carbon atoms gave 13C-NMR signals identical to those given by apigenin (40). In distinction to 8, 9, and 10, however, it gave a positive Gibb's reaction, indicating that the piperidine ring was attached at C-6 rather than C-8.

The UV spectrum of 11 indicated the presence of a flavone nucleus, and other spectral characteristics were similar to those of 10 and 14. However, the molecular ion was only mlz 337, 28 less than 8. The 'H-NMR spectrum showed no signals corresponding to N- methyl or methoxy groups. Compound 11 gave a negative Gibb's reaction and so was reckoned to be substituted at C-8 with the N-methylpiperidine ring.

b. N-Demethylbuchenavianine (9).

e. 0,N-Bisdemethylbuchenavianine (11).

40 Apigenin


f. N-Demethylcapitavine (12). N-Demethylcapitavine (12) had the same molecular weight as 11 and gave spectra very similar in all respects. Since it gave a positive Gibb's test it was reckoned to be the C-6 substituted isomer of 11.

g. 5,7-Dihydroxy-6-(N-methyl-2"-piperidinyl)flavanone (13). The molecular ion given by 13 was mlz 353, 2 more than given by buchenavianine (8). The mass spectrum showed the presence of N-methylpiperidine as a large peak at mlz 98. Some features of the 'H-NMR spectrum were similar but an important difference was the absence of the C-3 H signal at 6 6.70 seen for 8. However, the two coupled signals at 6 5.38 and 2.90 were typical of the 2-CH-3-CH2 system seen in flavanones. The 13C-NMR spectrum confirmed this assignment, showing signals for the two relevant C atoms at 6 79.5 and 43.0, respectively. Since the Gibb's reaction and other spectral features were very similar to capitavine, 13 was proposed as the structure.

h. 5,7,4'-Trihydroxy-6-(~-methyl-2"-piperidinyl)flavone (15). TLC behavior showed that compound 15 was more polar than most of the other Buchenavia alkaloids. The molecular ion was 16 greater than buchenavianine (8) and capitavine (14). The 'H-NMR spectrum showed many similarities to those of 8 and 14, but a major difference was the 4H AB aromatic system at 6 7.78 and 6.95 instead of a 5H multiplet. This was taken to indicate that ring B was substituted at 4'. The substituent was identified as OH by comparison of the 13C- NMR spectrum of 15 with that of apigenin (40). A positive Gibb's reaction showed that 15 was the 4'-OH derivative of capitavine (14).

i. 5,7,4'-Trihydroxy-6-(N-methyl-2''-piperidinyI)flavanone (16). The molecular ion for 16 of 369 was 2 mass units higher than that for 15. Both the 'H- and I3C-NMR spectra showed signals similar to those given by 13, indicating a flavanone nucleus. The 4'-OH substituent on the B ring was shown by a pair of doublets similar to those seen for 15. Compound 16 was therefore considered to be the 4'-OH derivative of 13.

C. SPECTRAL CHARACTERISTICS

1. Ultraviolet Spectra

The UV spectra of all flavonoidal alkaloids is related entirely to the flavonoid part of the molecule. Table I lists the data reported for each alkaloid. Flavones exhibit maxima in the region of 270-325 nm whereas the flavanones show maxima at about 250-320 nm. The flavan vochysine shows an absorbtion only at 275 nm since there is no conjugation system in ring C.


TABLE I Ultraviolet Spectra of Flavonoid Alkaloids

Compound Solvent Maxima, nm (log E) Ref.

Ficine (4)

Isoficine (5)

Phyllospadine (6) (acetate)

Vochysine (7)

Buchenavianine (8)

N-Demethylbuchena- vianine (9)

0-Demethylbuchena- vianine (10)

Capitavine (14)

0,N-Bisdemethyl- buchenavianine (11)

N-Demethylcapitavine (12)

5,7-Dihydroxy-6-(N- methyl-2-"piperi- diny1)flavanone (13)

6-(N-methyl-2"- piperidiny1)flavone

5,7,4'-Trihydroxy-

(15) 5,7,4'-Trihydroxy-

6-(N-methyl-2"- piperi-din y I) flavanone (16)

Ethanol NaOH aq. Ethanol NaOH aq. Methanol

Ethanol Ethanol + NaOH Ethanol Ethanol + NaOH Ethanol + HCI Ethanol Ethanol + NaOH Ethanol + HC1 Ethanol Ethanol + NaOH Ethanol + HCI Ethanol Ethanol + NaOH Ethanol + HCl Ethanol Ethanol + NaOH Ethanol + HC1 Ethanol Ethanol + NaOH Ethanol + HCI Ethanol Ethanol + NaOH Ethanol + HCl Ethanol Ethanol + NaOH Ethanol + HC1

Ethanol Ethanol + NaOH Ethanol + HC1

275 (4.5), 329 (4.0) 282, 349 275 (4.5) 262, 280 264, 302

215 (4.15), 275 (3.34) 228 (4.46), 245 (4.42), 288 (3.57) 216, 263, 326 217, 241, 250, 339 216, 263, 311 217, 240, 272, 344 220, 236sh, 280, 346 217, 263. 302 215, 275, 347 217, 265, 284, 347 215, 270, 338 218, 277, 341 218, 246, 275, 374 215, 269, 316 216, 242sh, 266sh, 279, 324 244sh, 267sh, 283, 390 216, 246sh, 270, 313 214, 241, 276, 352 216, 236sh, 264, 272sh, 240 212, 249, 267, 302 217, 251sh, 323 217, 296, 337 217, 227, 289, 330 220, 278, 311, 346 220, 279, 333, 400 216, 270, 345

220, 326 220, 249, 332 225, 228, 326

3 17 17 17 4

5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

6 6 6 6 6 6

6 6 6

2. Infrared Spectra

Table I1 lists the IR characteristics of the alkaloids. The IR spectra are of little use in structural identification apart from noting the absence of a carbonyl peak in the flavans and the bands for phenolic and aromatic bonds in the 3200 and 1590 cm- regions, respectively.


TABLE I1 Infrared Spectra of Flavonoid Alkaloids

Compound Medium Important peaks (cm-1) Ref.

Vochysine (7) KBr 3300, 1595, 755 5 Buchenavianine (8) Chloroform 3440, 1700, 1600 6 N-Demethylbuchenavianine (9) KBr 3400, 1655, 1595 6 0-Demethylbuchenavianine KBr 3440, 1660, 1612, 1595 6

Capitavine (14) Chloroform 1630, 1600, 1590 6 0,N-Bisdemethylbuchena- KBr 3420, 1675, 1620, 1605, 1590 6

N-Demethylcapitvaine (12) Chloroform 3400, 1650, 1630, 1590 6 5,7-Dihydroxy-6-(N-methyl-2”- Chloroform 1700, 1640 6

5,7,4’-Trihydroxy-6-(N-meth- KBr 3400, 1635, 1570 6

5,7,4‘-Trihydroxy-6-(N-meth- KBr 1630 6

(10)

vianine (11)

piperidiny1)flavanone (13)

yl-2”-piperidinyl)flavone (15)

y l-T’-piperidin y 1) flavanone (16)

3. Mass Spectra

In the mass spectra of some of the first compounds to be isolated, i.e., ficine (4), isoficine (3, and vochysine (7), the molecular ion peak was not seen, but significant peaks corresponding to the flavonoid and nitrogenous ring parts of the molecule were seen, The mlz value for these enabled both the substitution on the flavonoid and the size of the N-containing ring to be deduced. Thus a pyrrolidine ring gives an ion mlz 69, e.g., vochysine (7), an N-methylpyrrolidine mlz 84, e.g., fincine (4), and an N-methylpiperidine mlz 98, e.g., buchenavianine (8). Later work on ficine by Leete (17), however, showed that it was possible to obtain a molecular ion if the inlet temperature was reduced to 200°C from the 290°C initially used.

The molecular ions of some of the alkaloids isolated more recently have been obtained and have been useful indicators of the substituents present on a common nucleus, particularly for the Buchenuviu alkaloids (6). All spectra so far reported have been obtained using electron impact fragmentation. Table I11 lists the fragmentation patterns reported. Thus far no studies have been made on the break- down mechanisms, but the cleavage of the flavonoid and nitrogenous rings is obviously an important process.

4. ‘H-NMR Spectra

As is the case with many natural products isolated in the last 25 years, ‘H- NMR spectroscopy has played a major role in the structural elucidation of the


TAELE 111 Mass Spectra of Flavonoidal Alkaloids

Compound Major peaks m/z (relative intensity) Ref.

Ficine (4)

Isoficine (5)

Phyllospadine (6), triacetate Vochysine (7) Buchenavianine (8)

N-Demethylbuchenavianine (9)

0-Demethylbuchenavianine (10)

Capitavine (14)

0,N-Bisdemethylcapitavine (11)

N-Demethylcapitavine (12)

5,7-Dihydroxy-6-(N-methyl-2"- piperidiny1)flavanone (13)

5,7,4'-Trihydroxy-6-(N-methyl-2"- piperidiny1)flavone (15)

5,7,4'-Trihydroxy-6-(N-methyl-2"- piperidiny1)flavanone (16)

338 (29), 337 (100, M + ) , 336 (29), 322 (lo),

337 (51, M+), 322 (loo), 280 (31), 294 (12),

509.1695 (M') 272 (91), 153 (loo), 120 (46), 69 (42) 365 (loo), 350 (14), 281 (27), 267 (35), 98

351 (86), 322 (loo), 294 (21), 91 (36), 83

351 (loo), 336 ( l l ) , 322 (l l) , 308 (24), 294

351 (46), 336 (loo), 268 (27), 98 (20), 91

337 (87), 308 (loo), 295 (28), 281 (48), 267

337 (90), 320 (35), 309 (48), 308 (loo), 281

353 (loo), 311 (18), 296 (19), 98 (82)

294 (48), 280 (39), 84 (92)

254 (17), 84 (11)

(68)

(50), 57 (93)

(29), 280 (45), 98 (84)

( 100)

(22), 98 (19)

(58), 254 (97), 98 (20)

367 (48), 352 (loo), 283 (30), 98 (16)

369 (loo), 354 (78), 234 (36), 98 (78)

17

17

4 5 6

6

6

6

6

6

6

6

6

flavonoid alkaloids. The presence or absence of signals and couplings for the aromatic protons yield information on the substitution pattern of the aromatic parts of the molecules. The characteristic peaks for 0- and N-methylation are also important. Table IV records the 'H-NMR data reported for the alkaloids, and significant features are described above (Section IILB).

5. 13C-NMR Spectra

13C-NMR spectral data have been recorded for vochysine (7) (5) and the Buchenavia alkaloids (8-16) (6) (Table V). In both cases comparison of the spectra with those of the parent flavonoid enabled the identity of this part of the molecule to be established. The chemical shifts of the A ring carbon atoms in some of the Buchenavia alkaloids have also been used to determine the point of substitution of the piperidine ring as described above, e.g., for buchenavianine (8).


TABLE IV 1H-NMR Spectra of Flavonoidal Alkaloids

Compound Signals observed (6, ppm, from TMS) in CDC13 Ref.

Ficine (4) (CDCL,)

Isoficine (5) (CDC13)

Phyllospadine (6), triacetate (CDCL3)

Vochysine (7) (CDC13)

Buchenavianine (8) (CDCI,)

N-Demethylbuchenavianine (9)

O-Demethylbuchenaviaine (10)

Capitavine (14)

0,N-Bisdemethylbuchenavianine

N-Demethylcapitavine (12) (11) (CF3COOD)

5,7-Dihydroxy-6-(N-methyl-2"- piperidiny1)flavanone (13)

5,7,4'-Trihydroxy-6-(N-methyl-2"-

5,7,4'-Trihydroxy-6-(N-methyl-2"- piperidinyl)flavone( 15)

piperidiny1)flavanone (16)

12.6 1H bs (5-OH), 12.0 1H bs (7-OH), 8.0- 7.3 5H m (ring B Hs), 6.60 1H s (3-H), 6.25 1H s (6-H), 4.15-1.99 6H m (N-ring Hs), 2.43 3H s (N-CH3)

13.0 1H bs (5-OH), 11.0 1H bs (7-OH), 8.0- 7.3 5H m (ring B Hs), 6.55 1H s (3-H), 6.33 1H s (8-H), 4.06-1.80 6H m (N-ring Hs), 2.38 3H s (N-CH3)

7.78 2H d (2',6'-H), 7.19 W d (3',5'-H), 6.53 1H s (3-H), 6.08 1H t (2'-H), 3.82 3H s (6- OCH3), 2.45 3H s (5-OAc), 2.33 3H s (7-

CH3), 2.74-2.17 6H m (N-ring CH2) OAC), 2.30 3H s (4'-OAc), 2.42 3H s (N-

7.24 2H d (2',6'-H), 6.76 2H d (3',5'-H), 5.93 1H s (6-H), 4.82 1H dd (2-H), 4.58 1H dd (2"-H), 3.65 3H s (OCH,), 3.20-1.75 1OH m

8.0-7.4 5H m (ring B Hs), 6.7 1Hs (3-H), 6.4 1H s (6-H), 4.0 3H s (OCH,), 2.33 3H s (N- ' 33 )

7.24 5H m (ring B Hs), 6.12 1H s (3-H), 5.93

7.65 5H m (ring B Hs), 6.56 1H s (3-H), 6.23

8.0-7.3 5H m (ring B Hs), 6.47 1H s (3-H),

8.2-7.5 5H m (ring B Hs), 7.38 1H s, 7.06 1H s

7.8-7.3 5H m (ring B Hs), 6.33 1H s (3-H), 6.1 1H s (8-H)

7.33 5H m (ring b Hs), 5.95 1H s (8-H), 5.38 1H dd (2-H), 2.90 2H m (2-H), 2.21 3H s (N-CH3)

1H s (6-H), 3.76 3H s (OCH3)

1H s (6-H), 2.28 3H s (N-CH3)

6.24 1H s (8-H), 2.26 3H s (N-CH3)

7.78 2H d (2',6'-H), 6.5 1H s (3-H), 6.42 1H s (8-H), 2.32 3H s (N-CH3)

7.30 2H d (2',6'-H), 6.95 2H d (3',5'-H), 6.00 1H s (8-H), 5.32 1H dd (2-H), 3.0-2.75 2H m (3-CH2), 2.50 3H s (N-CH,)

3

3

4

5

6

6

6

6

6

6

6

6

6

D. SYNTHESIS AND DERIVATIVES

1. Biosynthesis

No- studies have been carried out on the biosynthesis of the flavonoidal alkaloids. It is assumed, however, that the flavonoid moiety is formed by the usual


TABLE V '3C-NMR Spectra of Flavonoidal Alkaloids"

Compound

Carbon No. 7 8 9 10 14 12 13 15 16

2 3 4 4a 5 6 7 8 8a 1' 2' 3' 4' 5' 6' 2" 3" 4" 5" 6" O-CH3 N-CH3

76.8 29.2 19.3

105.4 154.7 89.6

156.9 102.5 155.6 132.2 127.5 115.1 157.7 115.1 127.5 55.9 33.1 25.1 44.7

55.3 -

-

160.1 108.5 178.3 106.4 156.0 97.2

163.2 107.5 160.0 131.8 125.8 129.1 131.3 129.1 125.8 62.4 31.5 24.0 25.4 56.1 56.0 43.9

160.6 107.5 178.9 104.1 156.4 100.9 171.4 103.6 160.6 131.4 125.7 129.4 131.8 129.4 125.7 54.8 28.1 22.9 23.7 45.4 56.1 -

164.9 105.8 182.6 104.6 154.1 100.5 163.4 105.4 161.1 31.7

126.1 129.3 131.9 129.3 126.1 62.1 31.7 24.0 25.5 56.0

44.0

-

166.2 105.4 182.5 103.9 158.0 110.0 163.8 95.1

157.4 131.6 126.3 129.1 131.7 129.1 126.3 61.2 30.8 23.7 25.4 55.7

45.6 -

165.4 105.8 183.2 104.7 158.3 106.7 162.4 94.9

159.7 129.8 126.8 129.6 132.7 129.6 126.8 53.2 27.9 22.6 23.5 46.5

43.6 -

79.5 43.0

194.7 101.0 159.3 105.2 164.0 98.8

172.3 139.5 129.0 129.2 126.2 129.2 129.0 62.7 31.1 23.6 25.1 55.6

43.0 -

169.9 103.2 182.8 103.0 158.6 109.0 165.0 96.9

161.6 123.0 128.7 116.5 161.6 116.5 128.7 62.6 30.6 23.7 25.3 56.0

43.3 -

79.4 42.4

195.9 101.2 158.1 103.4 163.7 97.4

163.7 130.0 128.2 116.0 161.3 116.0 128.2 62.6 30.0 23.4 24.7 56.6 - -

~ ~ ~

a Spectra were run in CDC13, except for that of 7 which was run in DMSO.

pathways. The N-containing ring may be formed from ornithine or lysine for 5- and 6-membered rings, respectively, in a way similar to other alkaloids. It is proposed that the A ring of the flavonoid undergoes electrophilic substitution by the N-containing ring (5,6,19).

2. Synthesis

a. Ficine (4) and Isoficine (5). The first synthesis of (+)-fiche was reported as a nine-step process by Anjaneyulu and Govindachari (19). The details are shown in Scheme 1. The pyrrolidine-ring A part of the molecule was formed by conjunction and subsequent cyclization of GABA and trimethylbenzene. The introduction of the C ring carbonyl bridge by the Friedel-Crafts reaction was followed by condensation with benzaldehyde to yield ring B.

A later one-step synthesis was designed as a biomimetic process (18). The N - methyl pyrrolidine ring in alkaloids such as nicotine is derived from ornithine via

3. CHROMONE ALKALOIDS

n 85

SCHEME 1 . Synthesis of ficine (4) (18).


a N-methyl-2'-pyrrolinium salt, and the biomimetic synthesis of several such alkaloids has been accomplished using such a compound. The same approach was used whereby the pyrrolinium salt 41 was reacted with chrysin (37) (the flavonoid part of ficine) to give a mixture of ficine and isoficine (3.6 and 4.3%, respectiueiy). The 5- and 1 -OH groups acfhate the 6 and 8 pskions 101 ekc- trophilic attack by the pyrrolinium salt.

C N + - C H , x -

41 Pyrrolinium salt used in synthesis of ficine

b. Vochysine (7). Vochysine has been synthesized by a process similar to that used for the biomimetic synthesis of ficine referred to above. The parent flavonoid, 7-methoxy-5,4'-dihydroxyflavan, was reacted with an ethanolic solution of 1-pyrroline to give a 34% yield of vochysine (5).

3. Derivatives

The triacetates of phyllospadine (6) and vochysine (7) have been prepared by conventional procedures ( 4 3 . Although not reported, there seems no reason why the other alkaloids should not form similar derivatives.

Cleavage of ficine (4) to yield the parent flavonoid has been achieved, using pyrolysis or mild alkali in methanol (3) . Vochysine (7) has been cleaved in the presence of alcohol to give the parent flavan (7). The nitrogenous part of the molecule cannot be detected after cleavage as it breaks down under alkaline conditions.

Interconversion of ficine (4) and isoficine (5) has been carried out by refluxing in 70% HC1 (3) . The mechanism involved was thought to be due to a Wessely- Moser rearrangement.

N-Methylation of vochysine (7) took place when it was treated with sodium cyanoborohydride in 30% HCHO and acetic acid (5). Additional methylation of OH groups was accomplished by refluxing with methyl iodide in acetone containing potassium carbonate (5).

E. PHARMACOLOGY

No work has been reported on the pharmacology of any of the alkaloids isolated. There is also very little known about the traditional medicinal uses of the plants from which they have been obtained.

3. CHROMONE ALKALOIDS 8.1

IV. Noreugenin-Related Alkaloids

A. ISOLATION

All reports of isolation of the less polar alkaloids show that a similar pattern has been followed. It consists of an initial alcoholic extraction followed by fractionation on a silica gel column. The alkaloids first isolated from Schuman- niophyton problematicum were extracted from the root bark with methanol containing 2% acetic acid (9). Rohitukine (17) was obtained from the leaves and stem of Amoora rohituku following conventional acid-base workup for alkaloids (7). The same technique was used for its isolation from Dysoxylum hinec- tariferum (8). The first alkaloids reported from S. magnifcum were isolated from fractions following column separation of an ethanolic extract (ZO, IZ). The more polar alkaloids rohitukine (17) and the N-methyl derivatives of schumanniophytine (31) and isoschumanniophytine (32) have been separated from the water-soluble fraction of the crude ethanolic extract using droplet counter-current chromatography (13).

The fact that these alkaloids have both phenolic and alkaloidal properties causes some problems in extraction from aqueous media by conventional means, particularly for the secondary amines. Thus schumagnine (33) and N-methylschumagnine (34) were present in the aqueous fraction of the alcoholic extract of S. magnificum but on acidification were taken into chloroform (13).

B . STRUCTURAL ELUCIDATION

1. Introduction

The co-occurrence of the chromone noreugenin (3) with all the alkaloids so far isolated enabled the recognition of this structure as part of the alkaloid molecule (9). Degradations, interconversions, and spectral studies have been used to determine the structure of the alkaloids.

2. Schumanniophytine (18)

Schumanniophytine was characterized by Schlittler and Spitaler (9). Mass spectral studies gave a molecular ion of 295 which by accurate mass measurement gave the formula C,,H,NO,. The formation of a monoacetate indicated that at least one OH was present. The noreugenin part of the molecule gave characteristic features in the UV, IR, and 'H-NMR spectra. Signals at S 8.48, 8.97, and 9.58 in the 'H-NMR spectrum indicated a 3,4-disubstituted pyridine portion. Degradation of 18 with concentrated nitric acid yielded cinchomeric


acid and with strong alkali yielded 4,6-dihydroxybenzopyrano-5,4-pyridine-9- one (42). These products showed that the pyridine ring was attached to the noreugenin via a lactone bridge to the 7 position and directly to the 8 position of noreugenin. The signal at 6 13.47 in the ‘H-NMR spectrum confirmed that the 5- OH was free.

OH

42 Schumanniophytine hydrolysis product

3. Isoschumanniophytine (29)

Isoschumanniophytine was isolated from Schumanniophyton magnificum and originally given structure 30 (11). Another isomeric alkaloid isolated at the same time was first given structure 29 but was subsequently shown to be schumanniophytine (18) (12).

Isoschumanniophytine had the same molecular weight as 18 and showed many of the same spectral characteristics. Differences included a golden-yellow rather than a lemon-yellow fluorescence wherrviewed on silica gel under UV light and different values for the pyridine ring protons in the ‘H-NMR spectrum. Instead of three separate signals, two obviously from ortho coupled protons, 29 showed a 2H broad singlet at 6 8.93. When the diacetate was prepared this resolved into two doublets easily assignable to ortho protons. It was assumed that in 29 the 5’ and 6’ protons had the same chemical shift. The 5’-H would normally be more upfield but is presumably deshielded by the presence nearby of an acetylable OH group. In both structures 29 and 30 this could be the case.

Structure 30 was originally chosen for isoschumanniophytine (ZI), but further work has showed that 29 is more likely to be correct (12). Compound 29 gives a positive Gibb’s test, indicating that the 8-H is free. NOE experiments showed that there was no enhancement of the aromatic H signal at 6 6.94 when irradiated at the frequency of the 5-OH seen at 6 15.6. Therefore it is unlikely that the aromatic H is ortho to this phenolic group and so must be at C-8. The very low shift of the 5-OH signal in 29 was explained by the proximity of the pyridine ring. If 30 were the structure it is unlikely that the 7-OH would have such a lowfield signal since it is not hydrogen bonded to the 3a carbonyl as is the 5-OH.


4. N-Methylschumanniophytine (31)

A very polar compound with a yellow color was isolated from the aqueous fraction of the root bark extract of Schumanniophyton magnificum (13). Its spectral features were very similar to those of schumanniophytine (18). The UV spectrum showed a peak at 355 nm, and the 'H-NMR spectrum was almost identical apart from a 3H singlet at 6 4.3. This signal is the same as seen for the quaternary methyl in trigonelline (35). Since the molecular ion at mlz 310 was 15 higher than that given for 18, it was decided that the compound in question was the N-methyl derivative. This view was confirmed by the formation of 31 from 18 by methyl iodide methylation.

5. N-Methylisoschumanniophytine (32)

Small amounts of another yellow compound co-occurring with 31 were isolated. By comparing spectra with 29 and by methyl iodide methylation of 29, this compound, N-methylisoschumanniophytine, was given structure 32.

6. Piperidine-2-one-Noreugenin Compounds (19 and 20)

Schilttler and Spitaller isolated two alkaloids from Schumanniophyton problematicum which they did not name (9). These compounds were very similar to one another, having a molecular weight difference of mlz 14. Spectral data showed that noreugenin was present having two free OH groups. The major difference between the two compounds as far as the 'H-NMR spectrum was concerned was that the higher molecular weight compound showed a 3H singlet at 6 2.84 attributable to an N-methyl whereas the other compound showed a N-H signal at 6 7.53. The two compounds were thus reckoned to be N-CH, and N-H homologs. IR and double resonance NMR evidence was used to show the presence of the piperidine-2-one ring attached at C-6. More recent work on related compounds, however, has raised the question as to whether the point of attachment is actually at C-8 (12).

7. Rohitukine (17)

Rohitukine was the first noreugenin alkaloid to be isolated (7). The molecular formula was established as C,,H,, NO, by high-resolution mass spectroscopic measurement and elemental analysis. The IR spectrum showed that a ketone and an OH were present and also showed a pyrone structure. No N-H bands were seen so the nitrogen was presumed to be tertiary. 'H- and 13C-NMR studies confirmed the presence of the N-methyl group and also suggested a resorcinol or


phlorglucinol portion in the molecule. The spectra also showed that a carbinol proton was present at 6 4.44 and also some methylene groups. The final structure was determined by X-ray crystallography.

8. Schumannificine (25)

Schumannificine was first isolated by Okogun et al. from Schumanniophyton magnificum (10). They assigned it structure 21. The molecular ion at mlz 317 gave a formula C,,H,,NO,. Alkaline hydrolysis yielded noreugenin, showing it to be part of the molecule. The other hydrolysis product could not be isolated. When the 'H-NMR spectra of schumannificine and noreugenin (3) were compared, it was seen that schumannificine exhibited only one aromatic proton signal, indicating that substitution occurred at either C-6 or C-8. Okogun et al. proposed C-6 as the point of attachment because no alkylation took place when schumannificine was refluxed with methyl iodide and siver iodide in chloroform. They reasoned that C-alkylation should have taken place if C-6 was free. They also considered that C-8 was free because of the shift of the aromatic proton at 6 6.67 was very similar to that given for the 8-H in noreugenin (10).

Acetylation and methylation reactions showed that two OH groups were present, only one of them being aromatic. It was thought that there must be another linkage through the 7-OH of noreugenin since the signal for this was missing in the lH-NMR spectrum of schumannificine. A 1H doublet at 6 5.70 suffered a downfield shift on acetylation and was therefore reckoned to be a carbinol proton flanked by a tertiary carbon on one side and a nitrogen atom on the other.

Taking these factors into consideration 21 was proposed as the most likely structure. Recent NOE studies on the N-methyl analog of schumannificine (26) have proposed that schumannificine should in fact have structure 25 (12) although this was rejected by the original authors. When Houghton and Yang isolated Schumannificine they showed that it consisted of a 5 : 1 mixture of the 8- OH a and 8-OH p isomers by consideration of the duplicate peaks in the 'H- NMR spectrum (11). The diacetates of the two isomers could be separated.

9. N-Methylschumannificine (26)

The spectral features and chemical derivatives of N-methylschumannificine, first isolated by Okogun et al. ( lo) , were very similar to those of schumannificine (25). The molecular weight was 14 mass units greater, and a 3H singlet seen at 6 2.95 in the 'H-NMR spectrum was reckoned to be due to an N-methyl group. Structure 22 was assigned on the same basis as 21 was given for schumannificine. More recently, however, it has been shown that N-methylschumannificine does not give a positive Gibb's test as would be expected from the free H-8 in 22 (12). In addition NOE experiments showed an enhancement in the 'H-

3. CHROMONE ALKALOIDS Y 1

NMR signal for the aromatic proton at 6 6.35 when irradiated at 6 12.6, the frequency of the 5-OH. Such enhancement could only occur if the proton were ortho to 5-OH. This evidence was considered proof that 26 is the right structure.

When N-methylschumannificine was isolated by Houghton and Yang (11) they found NMR evidence for a mixture of two compounds which were presumed to be isomers about C2’. When acetylation was performed two compounds were obtained and separated from each other. The configuration at C-2’ was established for each by consideration of their ‘H-NMR spectra, particularly the shifts of the N-CH3 signals. The major isomer present was shown to have the 2’-H p configuration (11).

10. Anhydroschumannificine (27)

Houghton and Yang isolated an alkaloid from Schumanniophyton magnificum root bark with a molecular weight of 229 (11). The mass and ‘H-NMR spectra showed the presence of the noreugenin moiety. The molecular weight was 18 mass units less than schumannificine (25), and since it formed only an aromatic monoacetate it seemed that the OH group had been lost. A 1H doublet at 6 7.78 in the ‘H-NMR spectrum coupled with the N-H signal was assigned to 2’-H where C-2’<-3’ was a double bond, i.e., a dehydration product of schumannificine. This proposed structure was confirmed by the formation of 27 from schumannificine by heating with anhydrous copper(I1) sulfate. Anhydroschu- mannificine was originally given structure 23 by analogy with the structure first proposed for schumannificine, but the NOE work referred to above suggests that 27 is the more likely structure (12).

1 1. N-Methylanhydroschumannificine (28)

Another compound isolated by Houghton and Yang (11) had a molecular weight 14 mass units greater than 27. The ‘H-NMR sectrum showed the presence of an N-methyl group at 6 3.14, but other spectral features were very similar to those of 27. It was considered to be the N-methyl analog of 27, and this was confirmed by its preparation by heating N-methylschumannificine (26) with anhydrous copper(I1) sulfate. Originally given structure 24, N-methylanhydroschumannificine is now considered to be 28 on the basis of NOE experiments mentioned above (12).

12. N-Methylschumagnine (34)

Houghton and Yang isolated two alkaloids from the chloroform extract of the acidified aqueous fraction of the crude alcoholic extract of the root bark of Schumanniophyton magnificum (13). The less polar alkaloid gave a molecular


weight of 287, and spectral data implied the presence of noreugenin and N- methylpiperidine moieties in the molecule. No acetate could be easily formed, and it was concluded that the 5-OH was the only free OH group; it is difficult to acetylate due to hydrogen bonding with the carbonyl group. The molecular weight indicated the loss of 18 mass units from rohitukine or its isomer, possibly a loss of H,O arising from an internal condensation between the 7-OH and a piperidine ring OH at C-2’ or C-3’ to form an ether bridge. The C-2’ position was favored since the 1H signal seen at 6 5.06 in the ‘H-NMR spectrum was more downfield than that observed for the C-3’ carbinol proton in rohitukine (17). The downfield shift could be ascribed to the effect of the adjacent nitrogen atom.

Confirmation of structure 34 was obtained by examination of the two-dimensional COSY spectrum which showed no coupling between the 2’-H and 4’-H signals at 6 5.06 and 3.46 but coupling of both of them with the 3’-methylene signal at 6 2.21. NOE experiments showed enhancement of the 6-H signal at 6 6.28 when irradiated at the frequency of the 5-OH group. This confirms that the piperidine ring is attached at C-8.

13. Schumagnine (33)

The other compound isolated from the chloroform extract of the acidified aqueous fraction was assigned structure 33 by direct analogy with 34 (13). Its spectral characteristics were very similar apart from the molecular ion being less by 14 and the absence of an N-methyl signal in the ’H-NMR spectrum.

C. SPECTRAL CHARACTERISTICS

1. Ultraviolet Spectra

The noreugenin chromophore makes an important contribution to the UV spectrum of these compounds, giving peaks at 225, 257, 295 and 318 nm. In some of the compounds the conjugation is extended so that appreciable absorbtion occurs in the visible range, giving a yellow color to the compounds. This is particularly seen in the N-methyl quaternary compounds 31 and 32. The chromophore is also extended in schumannificine and its analogs (25-28). Details of the UV spectra for each compound are given in Table VI.

2. Infrared Spectra

Table VII lists the important IR peaks given for the alkaloids isolated. The noreugenin moiety contributes peaks at 1550, 1660, and about 3300 cm-I for the C=C, C=O, and OH groups, respectively. In the pyridine-noreugenin congeners an additional band due to the lactone C=O is seen at about 1750


TABLE VI Ultraviolet Spectra of Noreugenin Alkaloids”

Compound Maxima (log E) Ref.

Schumanniophytine (18)

Isoschumanniophytine (29)

N-Methylschumanniophytine (31)

N-Methylisoschumanniophytine (32)

Compound 19

Compound 20

Schumannificine (25)

N-Methylschunrnannificine (26)

Anhydroschumannificine (27) N-Methylanhydroschumannificine (28)

Schumagnine (33)

N-Methylschumagnine (34)

225 (4.4), 237 (4.41), 251 (4.46), 256 (4.43, 292 (4.07), 318 (4.11)

226 (4.11), 245 (3.96), 260 (3.96), 272 (3.56), 314 (2.98)

204 (4.69), 225 (4.4), 236 (4.39), 282sh (4.07), 355 (4.12)

204 (4.69), 225 (4.4), 236 (4.39), 282sh (4.07), 355 (4.12)

205 (4.33, 225 (4.18), 251 (4.25), 257 (4.27), 295 (3.78), 318 (3.68)

205 (4.33, 225 (4.16), 251 (4.22), 257 (4.23), 295 (3.77), 318 (3.66)

220 (4.13), 225 (4.13), 253 (3.86), 260 (3.88), 280 (3.88), 290 (3.85), 290 (3.85), 310 (3.99, 320 (3.96), 333 (3.97)

220 (4.12), 225 (4.12), 253 (3.89), 260 (3.90), 277 (3.89), 290 (3.90), 310 (3.99, 320 (3.96)

224 (4.08), 253 (4.32), 310 (2.40) 224 (4.20), 246 (4.10), 256 (4.10), 310

(2.30) 205 (3.49, 228sh (4.16), 251sh (4.24),

259 (4.26), 295 (3.76), 316 (3.64) 206 (3.43, 228sh (4.16), 251sh (4.24),

258 (4.27), 296 (3.77), 314 (3.67)

9

i1

13

13

9

9

10

10

11 11

13

13

~ ~

Spectra were run in methanol.

cm- (9,lZ). Additional amide bands for compounds 19 and 20 (9) and C=C bands for 27 and 28 (11) were also noted.

3. Mass Spectra

All the compounds thus far isolated have given a significant molecular ion. This has been used to distinguish between N-H and N-CH, homologs. The N- CH, derivatives usually give a strong M+ - 15 peak. In most compounds cleavage occurs to give a strong peak at m/z 192 corresponding to noreugenin, but sometimes a peak at mlz 205 is more abundant. No further details of fragmentation processes have been published. Important peaks in the mass spectra of the various alkaloids are listed in Table VIII.

TABLE VII Infrared Spectra of Noreugenin Alkaloids

Compound Medium Important peaks (cm - 1) Ref.

Schumanniophytine (18)

Isoschumanniophytine (29) N-Methylschumanniophytine (31)

Compound 19

Compound 20

Schumannificine (25) N-Methylschumannificine (26) Anhydroschumannificine (27) N-Methylanhydroschumannificine (28) Rohitukine (17) Schumagnine (33)


KBr

Nujol Nujol

KBr

KBr

Nujol KBr Nujol Nujol KBr Nujol

Nujol

3200-2400, 3070, 1750, 1660, 1620, 1580

1750, 1660, 1620, 1590 3200, 1750, 1660, 1620,

3370, 3300-2400, 1670, 1585

1625, 1600

1620, 1600 3400-2400, 2950, 1670,

1650, 1620, 1165, 1090 3300, 1670, 1630, 1575 1670, 1640, 1620 1660, 1620, 1592 3400, 1660, 1612, 1560 3400, 1665, 1624, 1590,

3400, 1668, 1620, 1590, 1268

1312

9

11 13

9

9

10 10 11 11 7

13

13

TABLE VIII Mass Spectra of Noreugenin Alkaloids

Compound Major peaks (relative intensity) Ref.

Schumanniophytine (18) Isoschumanniophytine (29) N-Methylschumanniophytine (31)

N-Methylisoschumanniophytine (32)

Compound 19

Compound 20


N-Methylschumannificine (26)

Anhydroschumannificine (27) N-Methylanhydroschumannificine (28) Rohitukine (17) Schumagnine (33)


295 (100, M + ) , 267, 255 (18), 227 295 (100 M+), 267 (12), 255 (15) 310 (5, M+) , 295 (20), 243 (76), 228

310 (3, M + ) , 295 (23), 243 (73), 228

289 (88, M+) , 272 (79), 245 (64), 231

303 (57, M+), 272 (13), 245 (19), 218

317 (21, M + ) , 299 (15), 287 (17), 192

331 (46, M+), 313 (24), 205 (43), 192

299 (14, M+), 192 (100) 313 (25, M + ) , 298 (20), 192 (100) 305 (M+) 273 (100, M + ) , 244 (30), 229 (29),

287 (100, M+), 244 (lo), 229 (14),

(56), 200 (32), 196 (20)

(51), 200 (29), 196 (17)

(40), 205 (loo), 192 (41)

(24), 205 (loo), 192 (43)

(100)

( 100)

205 (29), 202 (18)

205 (7)

9 11 13

13

9

9

10

10

11 11 7

13

13


TABLE IX INMR Spectra of Noreugenin Chromone Alkaloids

Compound Solvent Signals (6, ppm, from TMS) Ref.

Schumanniophytine (18) CDC13

Isoschumanniophytine (29) CDC13

N-Methylschumanniophytine (31) CD30D

N-Methylisoschumanniophytine (32) DzO

Compound 19

Compound 20


N-Methylschumannificine (26) (2’-H a)

d-6 DMSO

d-6 DMSO

d-5 Pyridine CDCl3

CDC13

13.47 1H bs (5-OH), 9.58 1H s (2‘-H), 8.97 1H d (6’-H), 8.48 1H d (5’-H), 6.82 1H s (6-H), 6.34 1H s (3-H), 2.66 3H s (2-CH3)

15.6 1H s (5-OH), 9.52 1H s (2’-H), 8.93 2H s (5’,6’-H), 6.94 1H s (6-H), 6.24 1H s (3-H), 2.50 3H s (2-CH3)

8.99 1H s (2’-H), 8.69 1H d (5‘-H), 8.10 1H d (6’-H), 6.32 1H s (6-H), 6.10 1H s (3-H), 4.39 3H s (N-CH3), 2.26 3H s (2-CH3)

8.81 1H s (3’-H), 8.59 1H d (5‘-H), 8.02 1H d (6’-H), 6.23 1H s (6-H), 6.03 1H s (3-H), 4.35 3H s (N-CH3), 2.22 3H s (2-CH3)

12.9 1H bs (5-OH), 10.88 1H bs (7-0H), 7.53 1H bs (N-H). 6.30 1H s (6-H), 6.16 1H s (3-H), 2.38 3H s (2-CH3), 3.8-1.6 7H m

12.9 1H bs (5-OH), 10.89 1H bs (7-OH). 6.26 1H s (6-H), 6.14 1H s (3-H), 2.84 3H s (N-CH,), 2.36 3H s (2-CH3), 3.8-1.6 7H m

6.62 1H s (6-H), 6.20 1H s (3- H)

12.6 1H bs (5-OH), 7.17 IH bs (N-H), 6.34 1H s (6-H), 6.11

H), 2.40 3H s (2-CH3) 1H s (3-H), 5.76 1H d (2’-

12.6 1H bs (SOH), 6.87 1H bs (2‘-OH), 6.35 1H s (6-H), 6.09 1H s (3-H), 5.60 1H d (2’-H), 3.7 1H m (4’-H), 3.3-3.1 3H m (5’-CH2,3’-

1H m (6’-H), 2.39 3H s (2- CH3), 2.20 1H m (6‘-H)

H), 3.05 3H s (N-CH3), 2.65

2.97 3H s (N-CH3)

9

11

13

13

9

9

10

11

10,11

11

(continued)


TABLE IX (Continued)

Compound Solvent Signals (6, ppm, from TMS) Ref.

Rohitukine (17)

Schumagnine (33)


Anhydroschumannificine (27) CDC13 12.7 1H s (SOH), 7.77 1H dd (2'-H), 7.2 1H bs (NH), 6.27 1H s (6-H), 6.20 1H s (3-H), 4.00 1H dd (4'-H), 2.45 3H s (2-CH3), 3.6-1.5 4H m (5',6'-CH2)

N-Methylanhydroschumannificine (28) CDCI3 12.73 1H s (5-OH), 7.72 1H s (2'-H), 6.46 1H s (6-H), 6.12 1H s (3-H), 3.85 1H dd (4'- H), 3.6-3.0 4H m (5',6'-

2.41 3 s (2-CH3)

H), 4.44 1H d (3'-H), 3.63

rn (2',5,6'-H), 2.27 3H s (2-

1.57 1H m (6'-H)

CHZ), 3.14 3H s (N-CH3),

d-5 6.79 1H s (6-H), 6.17 1H s (3- Pyridine

1H dt (4'-H), 3.16-2.36 5H

CH3), 2.21 3H s (N-CH3),

CDC13 12.57 1H bs (5-OH), 6.27 1H s (6-H), 6.03 1H (3-H), 5.27 1H s (2'-H), 3.53 1H rn (4'- H), 2.82 2H m (3'-H,N-H), 2.35 3H s (2-CH3), 2.3-1.8 5H m (3',5',6'-H)

CDCI, 12.56 1H bs (5-OH), 6.28 1H s (6-H), 6.03 1H s (3-H), 5.06 1H s (2'-H), 3.46 1H m (4'- H), 2.8-1.7 6H m (3',5',6'-

3H s (2-CH3) H), 2.52 3H s (N-CH3), 2.36

11

11

7

13

13

4. 'H-NMR Spectra

'H-NMR has been used extensively in the elucidation of the structural details of this group of compounds, and the significant characteristics of each of the compounds is mentioned above (Section IV,B). Full details of the NMR spectra are given in Table IX. The noreugenin moiety is distinguished by the 2-CH3 signal seen at about 6 2.4 as a singlet and the 3-H, also seen as a singlet at about 6 6.1. The 5-OH is observed between 6 12.0 and 13.00 but as low as 6 15.60 in isoschumanniophytine (29) where it is deshieded by the pyridine ring protons. Since the noreugenin may be substituted at positions 6 , 7 , and 8 the corresponding proton signals are not always seen. The 6-H and 8-H signals usually occur in the range 6 6.3-6.8 while the 7-OH is usually noted at 6 10-11 ppm.


The pyridine-noreugenin compounds 18, 29, 13, and 32 show characteristic downfield aromatic protons between 6 8.0 and 9.5, and the quaternary nitrogen alkaloids 31 and 32 exhibit a distinct N-methyl singlet at 6 4.3. The chemical shift of the N-methyl group in the other alkaloids which contain it is influenced by the substituents on the adjacent carbon atoms. Thus in rohitukine (17), where the adjacent groups are both methylene, the signal is seen at 6 2.21 whereas in N - methylschumannificine (26) (where a CHOH is adjacent) it is seen at 6 2.95 and in N-methylanhydroschumannificine (28) (where HC=CR, is adjacent) it is seen as far downfield as 6 3.14.

The presence of a piperidine ring is shown by signals below 6 4.0. The 4'-H at the carbon attached to the noreugenin system gives a signal at about 6 3.6. Signals appear more downfield where an oxygenated substituent is attached.

Some of the more polar molecules have presented solubility difficulties in solvents normally used to show OH signals. In these cases, e.g., schumannificine (25) acetates have been prepared to clarify the NMR spectrum (ZI).

5. 13C-NMR Spectra

has been published (7). No assignments were made. Rohitukine (17) is the only compound in this group for which 13C-NMR data

D. SYNTHESIS AND DERIVATIVES

1. Biosynthesis and Synthesis

No work has been reported on either the biogenesis or synthesis of this group of compounds. The occurrence of free noreugenin (3) in the plants from which they have been obtained indicates that this compound formed prior to some form of conjugation with the nitrogen-containing portion. The presence of trigonelline (35) in Schumanniophyton rnagnificum (13) could point to its being a precursor for the pyridine-related alkaloids. Synthesis of the compounds in question has been achieved only by the conversion of related structures as described below.

2. Interconversioas

a. Methylation. The quaternary amines 31 and 32 were prepared from the parent alkaloids 18 and 29 by the conventional method of reluxing with methyl iodide (13).

The "anhydro" derivatives 23 and 24 of schumannificine (25) and N-methylschumannificine (26) were obtained by heating with anhydrous copper(I1) sulfate at 155°C for 3 hr (11).

b. Dehydration.


c. Isomerization of Schumanniophytine. Houghton and Yang isolated two alkaloids from Schumanniophyton magnijicum which were isomeric with schumanniophytine (18) (11). These two alkaloids were assigned structures 29 and 30 partly on the basis that they could be interconverted by heating in aqueous alkali for 3 hr and then extracted after reacidification. It was proposed that scission and recombination of the lactone ring took place. However, these structures have now been proved to be wrong ( 1 2 ) , and the two compounds have been shown to be 18 and 29. Repetition of the interconversion experiment did show that some interconversion took place, but a more complicated process must be responsible since scission of a carbon-carbon bond would then be involved.

3. Derivatives

a. Acetylation. Acetates of many of these alkaloids have been prepared using conventional procedures either in the cold or by refluxing over a water bath for several hours (10,11,13). The 5-OH is very difficult to acetylate since it is hydrogen bonded to the 3a-carbonyl group. The acetates of schumannificine (25) and N-methylschumannificine (26) were prepared in order to separate the 2’-H ci and p isomers (11).

b. Methylation. Methylation of the OH groups of 25 and 26 has been carried out by refluxing with methyl iodide and silver oxide in chloroform for 6 hr (10). C-Alkylation on the aromatic ring was also attempted by this process but could not be achieved (10).

c. Alkaline Hydrolysis. Alkaline hydrolysis of several alkaloids has been shown to yield noreugenin (3). The nitrogenous portions of the molecules are unstable in the alkaline medium used and cannot be isolated.

Schumanniophytine (18) was hydrolyzed with strong alkali to yield 42 rather than 3 (9). Schumannificine yielded 3 after refluxing with 5% aqueous KOH for 8 hr (10).

Okogun et al. made the amide 43 of schumannificine (21) by leaving the parent compound for 24 hr with acetic acid and acetic anhydride containing the catalyst p-toluenesulfonic acid (10). Various salts of rohitukine (17) have been prepared (8). In each case the free base in methanol was added to the free acid. In this way the nicotinate, maleate, methanesulfo- nate, hydrochloride, and thiocyanate were prepared as crystalline compounds.

d. Miscellaneous.

43 Schumannificine amide


E. PHARMACOLOGY

Rohitukine (17) is the only one of these alkaloids for which pharmacological activity has been reported (8). It has been shown to have good antiinflammatory, analgesic, and immunomodulatory effects in both in vitro and in vivo tests.

Schumanniophyton rnagnificurn has been the source of most of the alkaloids so far isolated. It has several interesting uses in traditional medicine. In Cameroun the bark is used for dysentery as an enema (10). The phenolic compounds present may exert an astringent effect to account for this. In Nigeria the stem juice is used as a treatment for snakebite and the roots are used to treat madness.

An anti-snake venom principle has recently been reported as a glycosidal quaternary chromone alkaloid named schumanniofoside 36 (14). Extracts of the stem bark were tested against the venom of the black cobra, Naja melanoleuca, in mice. The methanolic extract showed the greatest activity. This was frac- tionated and monitored to yield 36 as the active component.

The best protection was given when schumanniofoside was administered 1 min after the venom as a dose of 80 mg/kg. Protection decreased if the time interval between giving the toxin and alkaloid was increased and when this was 1 hr no protection was afforded. Little prophylactic effect was observed if schumanniofoside was injected before the venom except in the case of only 1 min. Schumanniofoside (36) was found to have a positive oxidant activity and this was proposed as the basis of its action in oxidizing the disulphide bonds of peptides in the venom.

In vitro studies elsewhere have shown the presence of a substance in the bark which antagonizes the cardiotoxin present in cobra venom (20). This fraction did not contain alkaloids, however.

REFERENCES

1. H. Grisebach, 2. Nuturforsch. 14b, 485 (1959). 2. G. P. Ellis, in “Chromenes, Chromanones and Chromones” (G. P. Ellis, ed.), p. 455. Wiley

3. S. R. Johns and J . H. Russell, Tetrahedron Lett. 24, 1987 (1965). 4. M. Tagaki, S. Funahashi, K. Ohta, and T. Nakabayashi, Agric. Biol. Chem. 44, 3019 (1980). 5. G . Boudouin, F. Tillequin, M. Koch, M. Vuilhorgne, J.-Y. Lallemand, and H. Jacquemin, J .

6. A. Ahond, A. Fournet, C. Moretti, E. Philogene, C. Poupat, 0. Thoison, and P. Potier, Bull.

7. A. D. Harmon, U. Weiss, and J. V. Silverman, Tetrahedron Lett., 721 (1979). 8 . S. Vasudev, V. Shah, A. N. Dohadwalla, S. S. Mandrekar, and N. J . de Souza, Ger. Pat.

3,329,186 A1 (1985); Chem. Abstr. 103, 109923 (1985). 9. E. Schlittler and U. Spitaler, Tetrahedron Lett., 2911 (1978).

(Interscience), New York, 1977.

Nut. Prod. 46, 681 (1983).

SOC. Chim. Fr. 2, 41 (1984).

10. J. I. Okogun, J. 0. Adeboye, and D. A. Okorie, Pluntu Med. 49, 95 (1983). 1 1 . P. J. Houghton and H. Yang, Plunru Med. 23 (1985). 12. P. J. Houghton, Pluntu Med. 264 (1987).


13. P. J. Houghton and H. Yang, Plunta Med. 262 (1987). 14. D. N. Akunyili and P. I. Akubue, J . Ethnopharrnacol. 18, 167 (1986). 15. A . Bouquet, “Plantes Midicinales du Congo-Brazzaville,” p. 40. O.R.S.T.O.M., Paris,

16. A. Bouquet and M. Debray, “Plantes Midicinales de la CBte d’Ivoire,” p. 151.

17. F. E. King, T. J. King, and L. C. Manning, J. Chem. Soc., 563 (1957). 18. E. Leete, J. Nut. Prod. 45, 605 (1982). 19. B. Anjaneyulu and T. R. Govindachari, Tetrahedron Lett. 33, 2847. (1969). 20. A. L. Harvey, personal communication.

1969.

O.R.S.T.O.M., Paris, 1974.

- CHAPTER 4 -

DIBENZOPYRROCOLINE ALKALOIDS

I. W. ELLIOTT

Department of Chemistry Fisk University

Nashville, Tennessee 37203

I. Introduction A. Dibenzopyrrocoline Alkaloids B. Properties of Dibenzopyrrocolines C. Nomenclature

11. History 111. Cryptaustoline and Cryptowoline

A. Natural Occurrence B. Structure Proof C. Synthesis

IV. Synthesis and Reactions of Dibenzopyrrocolines A. Oxidative Coupling of Phenolic Derivatives B. Synthesis of Dibenzopynocolines through Benzyne Intermediates C. Other Methods of Synthesis

V. Pharmacology References

I. Introduction

A, DIBENZOPYRROCOLINE ALKALOIDS

Only two naturally occurring dibenzopyrrocolines are known: (S)-( -)-cryptaustoline (1) and (S)-(-)-cryptowoline (2), both isolated as iodides (1 ,2 ) . The alkaloids and related synthetic compounds played a significant role in the development of theories on biogenesis of isoquinoline alkaloids, particularly regarding the importance of oxidative coupling of phenols in formation of isoquinoline natural products. Chronologically, like pavines, isopavines, and 3-aryliso- quinolines, dibenzopyrrocolines were synthesized before the natural alkaloids were discovered. Discussions of dibenzopkocolines have appeared in standard works on isoquinoline alkaloids (3).

B . PROPERTIES OF DIBENZOPYRROCOLINES

Physical constants and references to sources for spectral data for the alkaloids and key synthetic relatives are given in Table I.

101 THE ALKALOIDS, VOL. 31 Copyright 6 1987 by Academic Press, he.

All rights of reproduction in any form reserved

TABLE I Properties of Dibenzopyrrocolines

Compound mp ("C) (solvent) [a13 (conc., solvent) Additional data

(S)-( -)-Cryptaustoline iodide (t)-Cryptaustoline iodide

(S)-(-)-Cryptowoline iodide (2)-Cryptowoline iodide

(S)-( -)-0-Methylcryptaustoline

(*)-0-Methylcryptaustoline iQdide iodide

(S)-(-)-0-Methylcryptowoline iodide

214 (MeOH) ( 2 ) 260 (EtOH) (4 )

245-246 (MeOH) (2 ) 150-151 (MeOH) (7) 245-246 (EtOH-Ca,) (4,9) 153-155 (HzO) (2)

243-245 (EtOH) (4,8)

-151" (0.4%, EtOH) (2) - lH NMR: 4

MS: 5,6 -186" (0.4%, EtOH) (2 )

- lH NMR: 4 MS: 5,6

-175" (0.4%, EtOH) ( 2 )

- 'H NMR: 4 MS: 6

- 179" (0.4%, EtOH) ( 2 )

4. DIBENZOPYRROCOLINE ALKALOIDS 103

HO HO

1 2

3

C. NOMENCLATURE

Robinson and Sugasawa (8) selected dibenzo[b,g]pyrrocoline for the parent ring system, and this name was adopted for the alkaloid family. The numbering is shown on structure 3 although Robinson used a different pattern. The system- atic name for the ring system is indolo[2,l-a]isoquinoline, but dibenzo[b,g]indolizine also appears in the literature.

11. History

Biogenetic theory, discussed in Robinson’s Weizmann Lectures (ZO), established a cosmology of organic natural products and provided useful guides for structural determination and synthesis, including biosynthesis. Gadamer first suggested that a limited series of isoquinoline alkaloids were biogenetically related (II), and a later hypothesis that morphine or aporphine alkaloids could be obtained by oxidative coupling of laudanosoline was unsuccessfully tested by Robinson and Sugasawa (8) and Schopf and Thierfelder (12). Phenol oxidation, a key reaction in anticipated structural changes, resulted in formation of a dibenzopyrrocoline by C-N coupling. The importance of phenol oxidation in biosynthesis and synthesis of isoquinoline alkaloids was reviewed by Battersby (13), Franck et al. (14), and Kametani and Fukumoto (15).

Initially Robinson and Sugasawa (8) proposed that laudanosoline (5), prepared from laudanosine (4) by 0-demethylation with aluminium chloride in refluxing xylene, could be oxidized to an aporphine or morphine prototype. To demon- strate that no rearrangement had occurred, 4 was regenerated from 5 by 0- methylation. Oxidation of 5 was accomplished with chloranil in buffered alcohol solution, and 6 was isolated in 60% yield as the chloride (Scheme 1). Di- benzopyrrocoline 6 was also obtained in 30-50% yield when aqueous solutions

104 I . W. ELLIOTT

CH,O ~ 1% 1% CH, 0 - ---t "CH, -

/ \

\ / ' OH OCH, OCH, OH

4 5 6

SCHEME 1 . Synthesis of dibenzopyrrocoline by Robinson. Reagents: (a) A1Cl3, xylem; (b) (CH&S04, KOH; (c) chloranil, EtOH, KOAc.

of 5HC1 were exposed to air for 2 months. Independently Schopf and Thier- felder (12) prepared 6 (X- = Br-) from 5 with tetrabromo-o-quinone in acetic acid and demonstrated that oxidation of 5 to 6 succeeded with potassium ferricyanide at physiological pH or with oxygen in the presence of platinum catalyst.

Elucidations of the structure of 6, named dehydrolaudanosoline by Robinson and Schopf, were model studies of classic degradations combined with logical interpretation of results. Formation of the dehydrolaudanosoline ring, a quarternary ammonium salt, was by aryl-amine oxidative coupling in analogy to Raper's enzymatic oxidation of tyrosine (7) (Scheme 2) to 5,6-dihydroxy-2,3-dihydroindole (9), possibly via dopaquinone (8) as an intermediate (16), and o-quinone 10 was proposed as a precursor of 6. Acetic anhydride afforded with 6 the N- demethylated products 11 and 12. The dehydro compound 12 could not be catalytically hydrogenated to 11, but platinum readily dehydrogenated 11 and

11 12

13 R = A c 14 R = C H ,

12. Schopf, acetylating 6 under milder conditions, isolated the quarternary iodide 13. Tetramethoxydehydrolaudanosoline iodide (14), now named O-methylcryp-

taustoline iodide, was used in Hofmann and Emde degradations (Scheme 3). The


10

SCHEME 2. Raper's oxidative coupling reaction.

methine produced either by Hofmann elimination and reduction or by Emde degradation was assigned structure 15. The alternative formulation 16 was rejected since 15 showed indole color reactions and could not be ring closed to 14, a reaction expected to occur with acid, by analogy with compounds obtained by degradation of berbines. Hydrogenation of 15 afforded dihydroindole 17. Emde

CH3O 14 *

CH, 0

\ l5

17

6CH3

18 R=N(CH3) , 19 R = H

SCHEME 3. Emde degradation of 0-methylcryptaustoline iodide by Robinson.

106 I. W. ELLIOTI

CH; 0

'4 - CH, 0

20

CHoYYCHo

22 &

+ CHO

bCH,

23 bCH,

21

SCHEME 4. Schopf's degradation of dibenzopyrrocoline 14.

degradation of 17-methosulfate gave the aromatic amine 18. Further degradation of the methosulfate of 18 afforded trimethylamine and the diphenylethane 19, identical with an authenic sample obtained by degradation of laudanosine.

Schopf and Thierfelder, treating dehydrolaudanosine (6, X- = Br- ) with cold sodium bicarbonate solution, obtained a crystalline material possessing an N-methyl group and classified as a betaine. Schopf showed that compounds 6 and 14 were unaffected by reducing agents such as catalytic hydrogenation, and structures with a double bond in the laudanosoline skeleton could therefore be excluded. Two Hofmann eliminations of 14 afforded a mixture of cis- and trans-dienes 20 which on ozonolysis gave aldehydes 21 and 23 and rn-opianic acid (22) (Scheme 4). Compound 23 was identical with the product obtained by methylation of 6-aminoveratraldehyde, and this established toe correctness of the structure for 0-methylcryptaustoline (14) proposed by Robinson and Sugasawa.

111. Cryptaustoline and Cryptowoline

A. NATURAL OCCURRENCE

(-)-Cryptaustoline (1) and (-)-cryptowoline (2) were obtained as iodides from the Australian plant Crypfocarya bowiei (Hook) Druce, and their structures


were elucidated by chemical degradation. The plant, also known as Cryptocuryu australis (Benth), was investigated because of reports that it contained physiologically active alkaloids. In 1887, Bancroft, in a series of brief communica- tions, surveyed Australian plants for physiologically active agents and isolated a colorless crystalline alkaloid from the bark of a small tree, C . australis (17) . Bancroft described the toxic properties of the alkaloid but reported no physical or chemical properties of the material. From later knowledge of C . bowiei and the chemical work of Schopf, it may be inferred that Bancroft’s alkaloid was the betaine of cryptaustoline.

Ewing et al. (2) noted that C . bowiei, a small shrub in New South Wales and southern Queensland and a tree growing to about 10 m (30 feet) in northern Queensland, afforded alkaloids which were different but structurally closely related. Methods of isolation were essentially the same, and the alkaloids were obtained as sparingly soluble iodide salts after addition of potassium iodide. (-)- Cryptaustoline iodide (C20H24N0,1) was obtained from extracts of the bark of larger northern trees, and (-)-cryptowoline iodide (C,9H20N0,1) was found to be present in the smaller southern shrubs.

B. STRUCTURE PROOF

Major efforts to determine the structures of the optically active alkaloids were made with cryptaustoline iodide, and preliminary examination showed that the molecular formula could be expressed as C,,H,,(OH)(OCH,),(NCH,) + I-. Products obtained after Hofmann degradation and ozonolysis were identical with compounds obtained earlier by Robinson and Schopf from racemic 14, and the structure as one of the optical isomers of 0-methylcryptaustoline iodide was established.

The position of the phenolic group relative to the three methoxy substituents in 1 remained to be determined. To settle this question cryptaustoline iodide was converted to its 0-ethyl ether (24) by ethylation with ethyl iodide (Scheme 5 ) . Hofmann degradation, partial hydrogenation, and ozonolysis afforded aldehyde 23 and 3-ethoxy-4-methoxy-6-ethylbenzaldehyde (26). With the stilbene intermediate formulated as 25, cryptaustoline iodide, without defining its configuration, was assigned structure 1.

The structure of cryptowoline iodide (2) was determined by a similar set of reactions. Both 0-methyl and 0-ethyl ethers were subjected to exhaustive methylation, elimination, reduction, and ozonolysis. The key compounds obtained from the ethyl ether were 26 and 6-aminopiperonal. The amine fragment showed the methylenedioxy group to be at the 9,lO position in cryptowoline, and the fact that the same aldehyde 26 was obtained from 0-ethylcryptowoline iodide fixed the position of the free OH as in cryptaustoline to C-2.

108 I. W. ELLIOlT

C H 3 0 cH30r EtO CH II

EtO

24 6CH3

25

cH30xr W H 3 12

_j

CH, 0 p + OCH, EtO cno

23 26

SCHEME 5 . Hofmann degradation of 0-ethylcryptaustoline iodide (24).

C. SYNTHESIS

Following the structure proof of the alkaloids by degradation, Hughes et al. (18) synthesized (-)-0-methylcryptaustoline iodide (14) by methods elaborated by Schopf and Robinson. (+)-Laudanosine was resolved by quinic acid (19), and (S)-( -)-laudanosine was 0-demethylated by Schopf's procedure, oxidized by chloranil, and remethylated to afford chiral 14 as the iodide in 40% yield. Their product had the same specific rotation and melting point as O-methylcryptaustoline iodide obtained from the natural alkaloid 1. Methine derivatives obtained from synthetic and natural compounds had identical optical properties.

Synthesis of (-)-0-methylcryptaustoline iodide (14) from (S)-( -)-laudanosoline by chemical and later by enzymatic means (vide infru) established the (S) configuration at C-12a in cryptaustoline (1). The stereochemistry of the N- methyl group in 1 has not been determined.

IV. Synthesis and Reactions of Dibenzopyrrocolines

A. OXIDATIVE COUPLING OF PHENOLIC DERIVATIVES

Extension of oxidative coupling of laudanosoline by Harley-Mason (20), who investigated the oxidation of tetrahydropapaveroline (27) with potassium ferricyanide, afforded 2,3,9,10-tetrahydroxy-5,6-dihydrodibenzopyrrocoline (28) in

4. DIBENZOPYRROCOLINE ALKALOIDS

HoqH HO

OH 27

28

29 R = H 30 R = A c

31 R = H 32 R = A c

109

2

33

64% yield, which was converted to the known tetraacetate 12. Subsequent air oxidation of the tetrahydroxy compound 28 afforded a product assigned structure 29 and acetylation gave a derivative believed to have structure 30. The tetraacetate 12 in contrast to the tetraphenol did not undergo air oxidation.

Oxidation products from tetrahydropapaveroline with potassium ferricyanide were reinvestigated by Mak and Brossi (21), who confirmed structure 28 for the initial product. Air oxidation of 29 gave after acetylation a product with the same physical properties reported by Harley-Mason, but its mass spectrum showed a parent ion at mle 900 and molecular composition C,8H,oN,0,6, suggesting it to be a dehydro dimer of 12. The lH-NMR spectrum of the dimer showed that the double bonds at the 5,6 positions were intact. The point of dimerization was determined by comparing the multiplicities of carbons in the 13C-NMR spectra of the dimer and dibenzopyrrocoline models. For monomeric compounds the peak ascribed to C-12 in compound 11 was a triplet and a doublet in 12, but a singlet in the dimer. Thus, the products from oxidation of 28 had structures 31 and 32 rather than 29 and 30, respectively.

The aromatic dibenzopyrrocoline dimer 33 was obtained by Hess et al. (22) by electrochemical oxidation of papaverine at a platinum anode in methanolic so-

110 I. W. ELLIOTT

dium methoxide. A parent ion at mle 672 in the mass spectrum of the product and relatively simple 'H- and l 3 C-NMR spectra indicated coupling at C-12, and formation from papaverine was assumed to occur by oxidative coupling of the tetramethoxy ether of 29. Dreiding models and chemical shifts for methoxy groups in the 13C-NMR spectrum indicated nonplanarity with restricted rotation of the tetracyclic moieties, in agreement with the conclusions made by Brossi and Mak (21) for 32.

Lead tetraacetate in acetic acid oxidizes phenolic 1 -benzylisoquinolines to p - quinol acetates which usually rearrange to aporphines in trifluoroacetic acid (23). However, Blasko et al. (24) recently reported that lead tetraacetate oxidized (2)-N-norlaudanosine (34) to dibenzopyrrocoline 35 in 16% yield.

Oxidative coupling of (+)-laudanosoline (27) and its quarternary salts with ferrichloride, studied by Franck et al. (25,26), showed the direction of coupling to be dependent on nitrogen substitution and concentration of oxidizing agent. Exclusive formation of aporphines from 27 in concentrated but not in dilute ferrichloride solution was explained with formation of iron complex 36, resisting further oxidation to o-quinones required for C-N coupling. In dilute ferrichloride solution dibenzopyrrocoline was obtained from 27 in 70% yield.

dn 34

/ 'L.

c1 c''Fr" 0 WNH 36

Oxidative coupling of (S)-( -)-laudanosoline (5) with horseradish peroxidase in the presence of hydrogen peroxide, studied by Brossi et al. ( 2 3 , afforded dibenzopyrrocoline (-)-6 in 81% yield, and conversion to (S)-( -)-0-methylcryptaustoline (14) by methylation provided additional proof for the absolute configuration of this and related alkaloids. Enzyme specificity in the C-N coupling reaction was demonstrated with similar oxidation of (R)-( -)- laudanosoline methiodide, which afforded an aporphine converted by O-methylation to (R)-( -)-glaucine.


CH,O

38

PhCHO

39

SCHEME 6. Synthesis of (2)-cryptowoline iodide (2) by Bennington and Morin.

B . SYNTHESIS OF DIBENZOPYRROCOLINES THROUGH

BENZYNE INTERMEDIATES

Dibenzopyrrocolines have been prepared by intramolecular addition of benzyne intermediates and by nucleophilic substitutions, as shown in Scheme 6 with the synthesis of (+)-cryptowoline (2) and the related dehydro base 39 by Ben- nington and Morin (7). (+)-6’-Bromotetrahydroisoquinoline 37, prepared by standard procedures, when heated with copper powder in dimethylfonnamide afforded dibenzopyrrocoline 38 in low yield, and 39 was formed when 37 was allowed to react with potassium amide in liquid ammonia. Compound 39 was converted to (+ )-cryptowoline iodide (2) by hydrogenolysis of O-benzyl ether 39 and quartemization with methyl iodide.

In an effort to synthesize the chiral alkaloid, optically active 37 was prepared by chemical resolution, but both enantimoers were partially racemized when reacted with potassium amide in ammonia. Efforts to resolve (+)-39 failed to give the desired enantiomer.

The benzyne route to dibenzopyrrocoline alkaloids with the l-benzyltetrahy- droisoquinolines (40) listed in Table I1 was investigated by Karnetani et at. (28), Kessar et al. (29), and Gibson and Ahmed (31). Secondary amines protected as 7-O-benzyl ethers, affording unstable tetrahydro intermediates with benzyl ether functions difficult to deprotect, were less favored than the corresponding N- methyl-substituted analogs, affording the desired quartemary alkaloids directly.

When potassium amide, with added potassium metal in liquid ammonia, was substituted in the benzyne reaction, further cleavage of C-N bonds of the intermediate dibenzopyrrocolines was often observed. The indoline 41 (32) and

112 I. W. ELLIOTT

TABLE I1 1-(Halobenzy1)isoquinolines Used to Synthesize Dibenzopyrrocolines

~ ~~

Compound RI R2 R3 R4 X Y Ref.

40a 40b 40C

4od 40e 4of

40h 40i 40j 40k 401 40m 40n

4og

PhCH2 PhCHz PhCH2

H H

PhCH2 PhCH2

H H

CH3 PhCH2

H H

CH3

R4

40

OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3

M H 2 - 0 M H 2 - 4

M H 2 - 0 M H 2 - 4

OCH3 OCH3 OCH2Ph H

Br OCH3 OCH3 H OCH3 OCH3

Br H c1 H H Br Br H H Br Br H H Br Br H H Br Br H H Br

OCH3 H H Br Br H

4 4 4

9.27 5,9,29,30

4 ,7 4

9,27,29,30 9,29,30

4 4 4

28,29 31

CH, 0 CH, 0

41 R' R2

42a CH, CH,

42b -CH,-

3 43


benzoazonines 42a and 42b (33) were products of such side reactions. The formation of dibenzopyrrocoline 3 in Kessar’s reaction of a 1 ,2-dihydroisoquinoline is believed to be the product of a further oxidation. Stevens rearrangement of intermediate dibenzopyrrocolinium ion affording C- 12a-methylated tetrahydrodibenzopyrrocoline 43 and analogs was observed by Kano et al. (34,353 when appropriate isoquinolines were treated with dimsyl sodium in DMSO. The intermediacy of dibenzopyrrocolines in the dimsyl sodium reaction was demonstrated by Kano et al. (36), affording C-13-substituted di- benzoazonines as major reaction products with alkaloids 1 and 2.

C. OTHER METHODS OF SYNTHESIS

The parent dibenzopyrrocoline 3 was prepared by von Braun and Nelles (37) from 1 -benzylisoquinoline when heated with copper powder at elevated temperatures. The product obtained was a yellow, weakly basic solid, melting at 238°C and reduced to a tetrahydro derivative by tin and hydrochloric acid. However, no structure was assigned to this product.

Ninomiya et al. (38) synthesized dibenzopyrrocolines by enamine photocyclization. In model studies designed to determine the feasibility of the photochemical reaction, an ether solution of the enamine 44a was irradiated at room temperature, and tetrahydrodibenzopyrrocoline 45a and a dehydro derivative (46) were obtained in 10 and 20% yield, respectively. The more abundant compound 46 was reduced to 45a by tin and hydrochloric acid.

R’ R2 R 3

44a en, n H R’ RZ R3 R4

45a CH, n n n 45b ;-pr ocn, OCH, n 4 5 ~ ;-PI n om, OCH,

44b PI ow, ocn3

46

114 I . W. ELLIOTT

CH, CH30% 0 - CH30T CH, 0

\

/ / OCH, OCH,

OCH, OCH,

47 R = H 48 R = N O ,

49 R = N O , 50 R = N H ,

51

SCHEME 7. Synthesis of (+-)-O-methylcryptaustoline iodide (14) by Elliott.

Following the successful demonstration of an enamine photocyclization, Ninomiya synthesized (?)-cryptaustoline iodide from 44b. Irradiation of isopropyl ether 44b gave a mixture of dibenzopyrrocolines 45b and 45c in 12 and 11% yield, respectively. The isopropyl ether group in 4% was selectively hydrolyzed by hydrobromic acid, and the resulting phenolic compound was converted to cryptaustoline iodide with methyl iodide. An attempt to photocyclize an 0- benzyl ether analog of 44b was less satisfactory.

(&)-O-Methylcryptaustoline iodide (14) was synthesized from phenylacetic acid 47 by Elliott (39) as shown in Scheme 7. Nitration of 47 to the 6-nitro compound 48 and reduction with sodium borohydride afforded lactone 49. Re- duction of the aromatic nitro group with iron powder in acetic acid gave ami- nolactone 50, which was converted to tetracyclic lactam 51 with trifluoroacetic acid in dichloromethane. Reduction of the lactam by a borane-THF complex followed by treatment with methyl iodide afforded (-+)-O-methylcryptaustoline iodide (14).

V. Pharmacology

Since the report by Bancroft (17) of an alkaloid from Crytocara bowiei, possibly cryptaustoline, which affected respiration of warm blooded animals and caused paralysis in frogs, no serious pharmacological studies with either cryptaustoline or crytowoline have been reported.


Note Added in Proof

A novel approach to the synthesis of dibenzopyrrocoline alkaloids recently reported by Takano’s group afforded ( 2 )-cryptaustoline (1) from a known 4,5-dimethoxybenzylsilane by a multistep procedure (40). ’H-NMR analysis of (-)-cryptaustoline (1) and (-)-cryptowoline (2) measured as iodides using decoupling and NOE allowed to assign to both alkaloids the 7R, 13s configuration with rings B/C cis-connected (41).

REFERENCES

1. J. Ewing, G. K. Hughes, E. Ritchie, and W. C. Taylor, Nature (London) 169, 618 (1952). 2. J. Ewing, G. K. Hughes, E. Ritchie, and W. C. Taylor, Aust. J . Chem., 6, 78 (1953). 3. G. A. Cordell, “Introduction to Alkaloids: A Biogenetic Approach.” Wiley (Interscience), New

York, 1981; M. Shamma, “The Isoquinoline Alkaloids.” Academic Press, New York, 1972. M. Shamma and J. L. Moniot, “Isoquinoline Alkaloid Research 1972-1977.” Plenum, New York, 1978.

4. T. Kametani and K. Ogasawara, J . Chem. SOC. C, 2208 (1967). 5. T. Kametani, K. Fukumoto, and T. Nakano, J . Heterocycl. Chem. 9, 1363 (1972). 6. T. Kametani and K. Ogasawara, Chem. Pharm. Bull. 16, 1468 (1968). 7. F. Bennington and R. D. Morin, J . Org. Chem. 32, 1050 (1967). 8. R. Robinson and S . Sugasawa, J . Chem. Soc., 789 (1932). 9. S. V. Kessar, R. Randhawa, and S. S . Gandhi, Tetrahedron Lett., 2923 (1973). 10. R. Robinson, “The Structural Relations of Natural Products.” Oxford Univ. Press, London,

11. J. Gadamer, Arch. Pharm. 249, 224 (1911). 12. C. Schopf and K. Thierfelder, Liebigs Ann. Chem. 498, 22 (1932). 13. A. R. Battersby, Quart. Rev. 15, 259 (1961). 14. B. Franck, G. Blaschke, and G. Schlingloff, Angew. Chem., Int. Ed. Engl. 3, 192 (1964). 15. T. Kametani and K. Fukumoto, Synthesis, 657 (1972). 16. H. S. Raper, Biochem. J . 21, 89 (1927). 17. T. L. Bancroft, Proc. Roy. SOC. Q . 4, 12 (1887). 18. G. K. Hughes, E. Ritchie, and W. C. Taylor, Aust. J . Chem. 6, 315 (1953). 19. A. Pictet and B. Athanasescu, Chem. Ber. 33, 2346 (1900). 20. J. Harley-Mason, J . Chem. Soc., 1465 (1953). 21. C.-P. Mak and A. Brossi, Heterocycles 12, 1413 (1979). 22. U. Hess, K. Hiller, and R. Schroeder, J . Prakt. Chem. 319, 568 (1977). 23. H. Hara, 0. Hoshino, and B. Umezawa, Chem. Phurm. Bull. 24, 1921 (1976). 24. G. Blaskb, G. Dornyei, M. Barczai-Beke, P. Pechy, and C . Szantay, Heterocycles 20, 273

25. B. Franck, G. Blaschke, and G. Schlingloff, Tetrahedron Lett., 439 (1962). 26. B. Franck and L. Tietz, Angew. Chem., Int. Ed. Engl. 6, 799 (1979). 27. A. Brossi, A. Ramel, J. O’Brien, and S. Teitel, Chem. Pharm. Bull. 21, 1839 (1973). 28. T. Kametani, A. Ujiie, K. Takahashi, T. Nakano, T. Suzuki, and K. Fukumoto, Chem. Pharm.

29. S. V. Kessar, S. Batra, U. K. Nadir, and S . S . Gandhi, Indian J . Chem. 13, 1109 (1975). 30. T. Kametani, S. Shibuya, and S. Kano, J . Chem. SOC., Perkin Trans. 1 , 1212 (1973). 31. I. Ahmad and M. S. Gibson, Can. J . Chem. 53, 3660 (1975). 32. S. V. Kessar, R. Randhawa, U. K. Nadir, and S . S. Gandhi, Indian J . Chem., 1113 (1975). 33. S. V. Kessar, P. Singh, and S. S. Gandhi, Indian J . Chem. 13, 1116 (1975).

1955.

(1983).

Bull. 21, 766 (1973).

116 I. W. ELLIOTT

34. S. Kano, T. Yokomatsu, N. Matumoto, S. Tokita, and Shibuya, Chem. Pharm. Bull. 22, 1607

35. S. Kano, E. Komiyama, T. Ogawa, Y. Takahagi, T. Yokomatsu, and S. Shibuya, Chem.

36. S. Kano, E. Komiyama, E. Nawa, and S. Shibuya, Chem. Pharm. Bull. 24, 310, (1976). 37. J. V. Braun and J. Nelles, Chem. Ber. 70, 1767 (1937). 38. I. Ninomiya, J. Yasui, and T. Higuchi, Heterocycles 6, 1855 (1977). 39. I. W. Elliott, J . Org. Chem. 42, 5398 (1982). 40. S. Takano, S. Satoh, and K. Ogasawara, Heterocycles 26, 1483 (1987). 41. S. Takano, S. Satoh, Y. Oshima, and K. Ogasawara, Heterocycles 26, 1487 (1987).

( 1974).

Pharm. Bull. 23, 2058 (1975).

CHAPTER 5 - -

LUPINE ALKALOIDS

KH. A. ASLANUV, Yu. K. KUSHMURADOV

Chemical Faculty State University Tashkent, USSR

AND

A. S. SADYKOV

Institute of Bioorganic Chemistry Uzbek Academy of Sciences

Tashkent, USSR

I. Introduction 11. 13C-NMR Spectroscopy of Quinolizidine Alkaloids

111. X-Ray Structural Investigation of Quinolizidine Alkaloids IV. Bicyclic Quinolizidine Alkaloids

A. (-)-Lupinhe and (+)-Epilupinine B. Esters of Lupinine and Epilupinine C. (-)-Lamprolobine and (-)-Epilamprolobine D. (+)-Mamanine and (-)-Pohakuline E. Cadiamine, 4-Oxyphenylacetylcadiamine, and 2-Pyrroloylcadiamine F. Sophorine G. Myrtine and 4-Epimyrtine H. Petrosine, Petrosine-A, and Petrosine-B I. (+)-Leontiformine

V. Tricyclic Quinolizidine Alkaloids A. (+)-Kuraramine and Isokuraramine-Possible Precursors of (-)-N-Methylcytisine B. (-)-N-Formylcytisine, (-)-N-Acetylcytisine, (-)-N-Ethylcytisine, and

(-)-N-(3-Oxobutyl)cytisine C. Virgidivarine and Virgiboidine D. Alkaloid LC-2 E. (-)-11-Allylcytisine and (-)-Tinctorine F. (-)-Argentine G. (+)-Dimethamine H. Tsukushinamines A, B, and C

A. (-)-7-Hydroxy-P-isosparteine B. 10,17-Dioxo-P-isoparteine C. Epiaphylline D. (-)-4a-Hydroxysparteine E. (+)-Thermopsamine

VI. Tetracyclic Quinolizidine Alkaloids of the Sparteine Group


All rights of reproduction in any form reserved.

118 KH. A. ASLANOV, YU. K. KUSHMURADOV, AND A. S. SADYKOV

F. (-)-Lindenianine G. 5,6-Dehydrotupanine and 5,6-Dehydro-a-isolupanine H. (+)-Nuttallhe I. (+)-Chamaetine J. 10,13-Dioxylupanine

K. Calpurmenine L. Esters of Hydroxylupanines

M. (+)-Argentmine N. (+)-Ditermamine

A. (-)-Leontidine B. Camoensine, Camoensidine, and Hydroxy Derivatives C. Desoxocamoensidine (1 1-Epileontidine)

A. (-)-Aloperine, (+)-N-Methylaloperine, and N-Allylaloperine B. Nitraramine and N-Hydroxynitraramine

IX. Tetracyclic Alkaloids of the Matrine Group A. (-)-Sophoridine and (+)-Sophoridine B. (+)-Isornatrine C. (+)-Albertidine D. (-)-Darvasine and (+)-Darvasamine E. (-)-Leontalbine F. (-)-Leontalbinine G. (+)-Lemannine H. 13,14-Dehydrosophoridine I. ( - )-Neosophoramine J. (-)-7,8-Dehydrosophoramine

K. (-)-Albertine L. (+)-Albertamine, (-)-Leontalbamine, and (+)-Leontismidine

M. (+)-9a-Hydroxymatrine N. (-)-3a-Hydroxysophoridine 0. (+)-Darvasoline and (+)-Leontismine P. (+)-5a,9a-Dihydroxymatrine Q. (+)-Sophorbenzamine R. (-)-Goebeline References

VII. Tetracyclic Alkaloids of the Leontidine Group (Quinolizidine-Indolizidine Alkaloids)

VIII. Tetracyclic Alkaloids of the Aloperine Group

I. Introduction

Quinolizidine alkaloids (lupine alkaloids) occur in the family Leguminosae, especially the subfamily Papilionaceae. They are also found in some species of other families such as Chenopodiaceae, Berberidaceae, Papaveraceae, Nymphaeaceae, Ranunculaceae, Scrophulariaceae, Solanaceae, Compositae, Rubiaceae, Monimiaceae, Ericaceae, and Adociidae.

The quinolizidine structure is sometimes found in molecules of complex alkaloids belonging to the indole, isoquinoline, or other families of alkaloids that

TABLE I Isolation and Properties of the Quinolizidine Alkaloids

Molecular Alkaloid Source formula mp (“C) [a]: UV IR MS ‘H NMR *3C NMR X-Ray

(-)-Lupinine (2)

(-)-(trans-4’-Hydroxy-3’- methox ycinnamoyl) lupinine (36)

(-)-(tran~-4’-Hydroxycin- namoy1)lupinine (37)

(-)-(trans-4‘-Rhan- nosyloxycin- namy1)lupinine (40)

nosyloxy-3‘-methoxycin- namyl) lupinine (41)

Glucopyranosyloxy-3’- methoxycinnamy 1) lupinine (39)

( - ) - ( t r a n s 4 ’ - P - ~ - Glucopyranosyloxycin- namoyl) lupinine (38)

(-)-(trans-4’-Rham-

( - ) - ( t rans -4 ’+~

(+)-Epilupinine (33)

Lupinus formosus CI,$I19N0 (242), L. hispanicus (82)

Lupinus luteus L. (94) C2&7N04

Lupinus luteus L. C19H26N03

Lupinus luteus L. (97) -

(95 I 96)




Lupinus hispanicus Cl,$I19N0 (82), L. hirsutus (83,247), Sophora secundiflora (Oa.) (85)

70-71 -21” (a)

130 -11.9”

Oil -

Amorph. -105” (e)

Amorph. -78”

Amorph. -18.9” (a)

Amorph. -58.9” (a)

77-78 t37” (a)

242

94

95

97

-

-

-

-

83, - 21,34 138, 242

95 95 -

97 97 -

- 98 98

99 99 -

100 100 -

34 83, - 138

(continued)

TABLE I (Continued)

Alkaloid

~

Molecular Source formula mp ("C) [a]b UV IR MS 1H NMR I3C NMR X-Ray

( + )-Epilupinine N-oxide Lupinus hirsutus C10HIgN02 212-213 (83,247)

(+)-Epilupinyl acetate (42) Lupinus cosentinii C12H21N02 -

Guss (87) (+)-Epilupinyl acetate N- Lupinus cosentinii C12H21N03 192

oxide (47) Guss. (87) (+)-Epilupinyl trans-feru- Lupinus cosentinii C20H27N04 1 19

late (43) Guss. (87) Epilupinyl trans-p-couma- Lupinus cosentinii C19H25N03 165

rate (44) Guss. (87) Epilupinyl cis-p-coumarate Lupinus cosentinii CI9H25N03 144

(45) Guss. (87) (+)-Lamprolobine(48) Lamprolobium C15H24N202 Oil

fruticosum Benth. ( I OI), Lupinus holosericeus (102), Sophora chrysophylla Seem. (103, Thermopsis villosa (= T. caroliniana) (244)

(-)-Epilamprolobine (54) Sophora tomentosa C15HuN202 101.5 (21) , S. chrysophylla Seem. (107)

(+)-Epilamprolobine N-ox- Sophora tomentosa C15H24N203 Amorph. ide (21), S. chrysophylla

Seem. (107)

Seem. (61,107), S. fZavescens Ait. (22)

(+)-Mamanine (16) Sophora chrysophylla C15H22N202 171-172

+34.8' (a) -

+33" -

+ 14" -

+35" 87

87

87

-

-

+29" (a) -

-13.8" (a) -

+14.9" (a) -

+31.7" (a) 61

-

87

87

87

87

87

I01

21

21

61

87

87

87

87

87

101, 102

21

21

61

-

87

87

87

87

87

21

21

61

21 -

21 -

61 61

(-)-Pohakuline (17) Sophora chrysophylla Seem. (61,107)

Sophora chrysophylla Seem. (107)

Cadia purpurea Picc., Ait. (108,109), C . ellisiana (109)

Cadia purpurea Picc., Ait. (108), C . ellisiana (109)

Cadia purpurea Picc., Ait. (108), C. ellisiana (109)

Sophora alopecuroides L. (26,191)

Vaccinium myrtillus

Vaccinium myrtillus

Petrosia seriata (112) Petrosia seriata (113) Petrosia seriata (113) Leontice leontopetalum

L. (114-116) Sophora flavescens

Ait. (22,120) Sophora flavescens

Ait. (22) Ormosia indurata

(243)

(110)

(111)

+17.2" (a) - 61 61 61

-9" (a) 107 - 107 107

- - 108 108 108

(-)-Mamanine N-oxide

Cadiamine (56) (55)

2-Pyrroloylcadiamine (58) - _ 108 108 108 108 -

_ _ 108 108 108 4-Oxypheny lacety lcad- iamine (57)

(-)-Sophorine (59)

c (+)-Myrtine (60) c!

4-Epimyrtine (64)

-18.9" (a) -

+11.3" (d) -

26.191 26,191 26,191 26 -

110 110 110

C1a17N0 - 111 I l l 111

Petrosine (65) (-)-Petrosine-A (66) (-)-Petrosine-B (67) (+)-Leontiformine (68)

I12 112 112 113 113 113 113 113 113 115 - 115

- -

-5" (c) - -12" (c) -

+51.9" (a) -

(+)-Kuraramine (75) C1zH18Nz0 Amorph. +8.4" (a) 120 120 22,120 22,120 22,120 -

- 22 22 22 - Isokuraramine (76)

N-Methyltetrahydrocytisine

(continued)

TABLE I (Continued)

Alkaloid Molecular

Source formula rnp ("C) [a]; UV IR MS 'H NMR I3C NMR X-Ray ~~

(-)-Dehydroisoalbine (20) Lupinus albus L. CI4Hl8NZO Oil

(-)- 1 I-Allylcytisine (83) Sophora secundijlora C14H18N20 Oil (64,651

(0fl.I ( 1 2 9 , Clathrotropis brachypelata (Tul.) (153)

(-)-Tinctorine (alteramine) Genista tinctoria L. C15HZON20 112-1 13 (92) (130,131), Thermop-

sis alternijlora Rgl. et Schmalh. (132,

N h) 133), Eaptisia australis (L.) R.Br.

e

(246) Isotinctorine Eaptisia australis (L.) Cl5Hz0N2O -

R.Br. (246) (-)-N-Formylcytisine (81) Sophora franchetiana C12H14NzOz 172

Dunn. (119), S. mollis ( I21) , Thermop- sis chinensis (123), Echinosophora koreensis Nakai (I26), Euchresta horsfeldii (235)

sis Nakai (124) (-)-N-Ethylcytisine (82) Echinosophora koreen- CI3Hl8N20 112

(-)-N-(3-Oxobutyl)cytisine Echinosophora koreen- C15H2,-&02 1 18 (83) sis Nakai (125,126)

-103" (e) -

_ _

-49" (a) 131- I33

- -

-232.6" (a) 123

-216.7" (a) 124

-21 1.6" (a) 125

-

129

131- I33

-

I23

-

125

129, 129 - -

153

133 131-133 - -

- - 124 124

125 125 - -

(-)-N-Acetylcytisine (78)

Virgidivarine (22)

Virgiboidine (84)

Alkaloid LC-2 (87)

(-)-Argentine (99)

(+)-Dimethamine (101)

(-)-Tsukushinamine A

(-)-Tsukushinamine B

Tsukushinamine C (105)

(21)

(104)

(-)-7-Hydroxy-P-isosparteine (106)

Sophora tomentosa C13H16N202 210-213 (122), Thermopsis alterniflora Rgl. et Schmalh. (132)

(67,128)

(Berg.) ( 1 2 3 , V. divaricata (128)

Guss. (87)

teum 0. Ktze. (134,139), Sophora grifithii Stocks (135), Thermopsis lanceolata R.Br. (136), T. alterniflora Rgl. et Schmalh. ( I 3 7,138)

Rgl. et Schmalh.

Virgilia divaricata CI5H2&"02 -

Virgilia oroboides C15H24N20 -

Lupinus cosentinii CI5H22N20 60

Ammodendron argen- CZ3H26N403 255-256

Thermopsis alternij7ora CZ4H32N402 2 16-2 17

(140) Sophora franchetiana C15HZON20 Oil

Sophora franchetiana C15H2d2O Oil

Sophora franchetiana C15H2&0 -

Dunn. (66,119)

Dunn. (119)

Dunn. (119)

h r s h . (142) 104.5 Lupinus sericeus C15HxN20 103.5-

-208" (a)

-520"

-318" (a)

+143" (a)

-72.3" (a)

- 144.4" (a)

-8" (a)

- 122 122

- 128 128

127 127 -

134, 134, 139 139 I39

140 140 140

- 118, 118, 119 119 - 119 -

i28

127

87

139

140

128 67

118,119

119

119

-

118,119 66,119

119 -

119 -

- -

(continued)

TABLE I (Continued)

Molecular Alkaloid Source formula mp ("C) [a]: UV IR MS lH NMR l3C NMR X-Ray

10,17-Dioxo- P-isosparteine

Epiaphylline (110) (109)

( -)-4a-Hydroxysparteine

(+)-Thermopsamine (115) F (111)

(-)-Lindenianine (117)

5,6-Dehydrolupanine (120)

Lupinus sericeus Pursh. (143)

Lupinus hartwegii Roots. (146,149, Teline monspessulanus (L.) (= Cytisus monspessulanus L.) (245)

Acosmium panamense Benth. (148)

Therrnopsis lanceolata R.Br. (137)

Lupinus lindenianus (149), L. ver- bascijormis Sand- with. (150)

Thermopsis rhombifolia (Nutt.) Richards. (152), Baptisia australis (L.) R.Br. (246), Echynosopho- ra koreensis ( 1 2 ~ 9 , Sophora mollis (12I), s. chrysophylla Seem. (103, Clathrotropis

- - - ClSH26N20 Oil -31" (a) - - I48

137 137 C1sH26N20 154-155 +26.4" (a) - - - -

CIsH24N202 212-213 - 1 1 " (d) - 149 149 149 - -

C15H22N20 Oil - 126, - 126, 126,152 - - I52 152,

153, 246

brachypetala (Tul.) Kleinh. (153), Lupinus polyphyllus (154)

5,6-Dehydro-a-isolupanine Lupinus bicolor ssp. C15H22N20 Oil - -

(122) 1 1,12-Dehydrosparteine

12,13-Dehydrosparteine 13-Acetoxyanagyrine

(+)-NuHalline (113)

L

N VI

(+)-Chamaetine (127)

10,13-Dihydroxylupanine (128)

Calpurmenine (12f3,13a- dihy ydroxylupanine) (129)

microphyllus (151)

Muell) Benth. (192), Sarothamnus scoparius (147)

Templetonia egena (F. C15H24N2 - - -

Cytisus scoparius (240) CI5H24N2 - - - Baptisia nuttalliana C17H22N203 - - -

Small. (244), B. australis (147,246)

(155), L. hartwegii Roots. (146,241)

valdszkyanus (Deg.) Kuzm. (156), C. albus Rothm., C. janae (Vel) Rothm., C. supinus (L.), C. calcareus, and C . polytrichus Rothm.

Lupinus nuttallii L. C15H24N202 108-109 +25.3" (a) 155

Chamaecytisus fri- C15H24N202 207-209 +59.2" (a) -

(157) Calpurnia aurea sp. C15H24N203 - - -

sylvatica (158), Ca- dia purpurea Picc., Ait. (108)

sylvatica (158)

Calpurnia aurea sp. C15H24N203 - - -

155 146, 155 - 155

- 156 156 -

158 158 - -

158 158 - -

(continued)

TABLE I (Continued)

Molecular Alkaloid Source formula mp (“C) [a]: UV IR MS ‘H NMR I3C NMR X-Ray

1 ~ -O- (~ ’ -F ‘ JT~OIOY~C~~- bonyl) calpurmenine (133)

13-Ethoxylupanine (130)

13-Benzoyloxymultiflorine

(+)-Cineverine [(3’,4’-di- methoxybenzoyl)-13- oxylupanine] (136)

(+)-Cinevanine [(4’-hy- F h) droxy-3’-methox- Q\ ybenzoy1)- 13-

oxylupanine] (134) Isocinevanine (135)

(+)-Cinegalline [3’,5‘-dihydroxy-3’ ,4’-dimethox- ybenzoyl)-13-oxylupanine (137)

(+)-Cinegalleine [(5’-hydroxy-3 ‘ ,4’-dimethox- ybenzoy1)- 13-oxylupanine] (138)

Formylcinegalleine (formyl-5’-oxy-3‘,4’-di- methoxybenzoy1)- 13- oxylupanine (139)

Calpurnia aurea sp. syivatica (158)

Cadia purpurea Picc., Ait. (159,160)

Lupinus cosentini Guss. (87)

Genista cinerea DC. (164,168), Sarothamnus patens (L.) Webb. (170, 171)

Genista cinerea DC. (168)

Sarot!mmnus patens (L.) Webb. (170,

Genista cinerea DC. 176)

( I 65,168)

Genista cinerea DC. (166,168)

Genista cinerea DC. (168)

- - - 159, - C17H28N202 - 160

CzzH26N203 - - 87 87 87 87

C24H32N205 155-157 +66.6” (a) 168, 168, 168, 168,175 170, 170, 175 175 175

C23H3d205 207-208 +69” (e) 168, 168, 168, - 175 175 175

C23H30N205 210-211 - 170, 170, 176 - 176 176

C23H3$J206 223-225 +46.7” (a) 168, 168, 168, 168,175 175 175 175

C24H32N206 182-183 +48” (e) 166, 166, 168, 168,175 168, 168, 175 175 175

C25H32NZ07 188-189 - 168, - 168, I

169, 169, 175 175

(+)-Sarodesmine [(3' ,4' ,5'-trimethox- ybenzoyl)-13-oxylupanine] (140)

(+)-Catalauverine [(3',4'- dimethoxybenzoy1)- 13- oxylupanine] (141)

Catalaudesmine [(3' ,4' 3 - trimethoxybenzoy1)- 13- dioxylupanine] (142)

(-)-Argentamine (143)

Sarothamnus cata- launicus Webb. (167), S . patens (L.) Webb. (170,171)

Sarothamnus cata- launicus Webb. (I 71 ,I 74)

Sarothamnus cata- launicus Webb.

Ammodendron argenteum O.Ktze. (134), - Thermopsis alter- nifora Rgl. (140)

Thermopsis lanceolata R.Br. (180)

Leontice alberti Rgl. (181), L. Smirnovii Traut. (182), Ca- moensia maxima Welw. ex. Benth. (183)

Camoensia maxima Welw. ex Benth. (183), C . brevicalyx Benth. (186)

Camoensia maxima Welw. ex Benth. (183), C . brevicalyx Benth. (186)

Camoensia brevicalyx Benth. (186)


(171)

+73.6" (e) 167, 170, 171, 175

175 171,

167, 170, 171, 175

175 171,

167, 170, 175

+328" (e)

+320" (e)

-142.3" (a)

171, 175

171, 175

171 171

134, 179

134, 179

179

(+)-Ditermamine (147)

5 (-)-Leontidine (152)

C30H4fi2°2 235

C14H18N20 118-119

+121.8" (a)

-190" (e)

180 180 180 180

181 181, 183

181 181, 183

(-)-Carnoensine (157) CI4H18N20 Amorph. - 186" (d) 183, 186

183, 186

183 183.186 186

(-)-Camoensidine (159) C14H22NzO Amorph. -67" (a) 183, 186

183 186 186 -

(-)- 12a-Hydroxycamoen-

(-)-12-Hydroxycamoen- sine (161)

sidine (162)

C14H18N2OZ Amorph.

C14H22N202 2oo

-115" (e)

-50" (e)

186

-

186

186

-

186

(continued)

TABLE I (Continued)

Alkaloid Source Molecular formula

12-Hydroxy-16-methoxy- 1 1,12,13,14- tetradehydrocamoensine (163)

1 1-Epileontidine (164)

(-)-Aloperine (165)

(+ )-N-Methylaloperine L2 (169)

N-Allylaloperine (170)

Nitraramine (171)

N-H ydroxynitraramine

(-)-Sophoridine (8) (176)


Maackia amurensis Rupr. and Maxim. (187)

Sophora alopecuroides L. (188,189), Lep- torhabdos parvij7ora Benth. (192)

Sophora alopecuroides L . (1 88,190,191, 193)

Sophora alopecuroides L . . (189)

Nitraria Schoberi L . (194)

Nitraria Schoberi L . (193

Sophora alopecuroides L. ( I 89.1 90,191, 250), S . flavescens Ait. (22), Lep- torhabdos parviflora Benth. (192), Eu- chresta japonica Benth. (40), Retama

1 6N203

c 1 6 H Z 6 N Z

mp ("C) [a]; UV IR MS IH NMR 13C NMR X-Ray

Amorph. - 186 186 186 186 - -

73 -64.5" (a) - 189 189 189 I89 -

85-86 r 0" - 194 194 194 - -

220-221 +.oo - 195 195 195 - -

109 -61.6" (a) - 40 40, 80,205, 40 71,72 230, 206 23 I

(+)-Sophoridine (8)

(+)-Isomatrine (29)

(+)-Allomatrine (5)

(+)-Albertidine (182)

(+)-Damasamhe (184)

(-)-Damashe (183)

+ (-)-Leontalbine (185) N W

(-)-Leontalbinine (7,l l- dehydromatrine) (188)

(-)-Isoleontalbine

(+)-5,17-Dehydromatrine

(+)-Lemannine (192) N-oxide

Lemannine N-oxide (28)

monosperma Lam. (248), R. monosperma ssp. rho- derhiziodes (249)

( I 96,197)

Ait. (79,208,225)

Ait. (22,225)

Leontice albertii Rgl. C15H24N20 108-109 +59.3" (a) - 197

Sophoraflavescens C1JH24N20 132-134 +44" (d) - 79

Sophora flavescens Cl5HZ4N20 105-106 +46" (a) - 80

Leontice albertii Rgl. C15H24NZ0 71 +33.8" (a) - i96 (196)

Leontice darwasica CI5Hz4NZO 102 f72" (a) - 212 Rgl. (211,212)

(210,211)

(213,214)

Leontice darwasica C15H22N20 145 -183" (a) 210 210

Leontice albertii Rgl. C15H22N20 Oil -167" (a) 214 214

Leontice albertii Rgl. Cl5Hz2NZ0 107-108 -135" (a) 22,216 22,216 (216), Sophorafla- vescens Ait. (22)

Traut. (229)

Benth. (40,251)

Leontice Smirnovii C15H22N20 Oil -149" (a) - -

Euchresta japonica Cl5Hz2N2OZ - +209.3" (a) 251 251

Ammothamnus ClsH22N20 93-94 +37.03" 217 217 Lehmanni Bgl. (a) (21 7 ) , Sophora flavescens Ait. (22)

Lehmanni Bgl. (78) - - - Ammothamnus Ci5H2zN202 136

197 205

79 79

231 80

196 -

212 212

210 210

209, 214 214, 216

22 22

- -

251 251

217 217

- -

(continued)

TABLE I (Continued)

Molecular Alkaloid Source formula mp ("C) [a]: UV IR MS lH NMR 13C NMR X-Ray

(+)-13,14-Dehydro- sophoridine (30)

(-)- 13,lCDehydro- sophoridine (30)

(+)-13,14-Dehydro- sophoridine N-oxide (193)

(+ )-Sophoridine N-oxide (9)

(-)-Sophoridine N-oxide (10)

(-)-3a-Hydroxyso- phoridine (218)

(-)-Neosophoramine (194)

c W

(-)-7,8-Dehydroso- phoramine (197)

(-)-Albertine (13-hydroxy-7,1 l-dehydromatrine) (198)

(+)-Albertamine (203)

(-)-Leontalbamine (204)

(+)-Leontismine (220)

Sophora alopecuroides

Sophora flavescens

Sophora alopecuroides

L. (218)

Ait. (80)

L. (221)

Sophora alopecuroides L. (191,207)

Euchresta japonica Benth. (49)

Sophora alopecuroides L. (230)

Sophora alopecuroides L . ( I 91,207,222, 223)

Sophora flavescens Ait. (225)

Leontice albertii Rgl. (21 6,226,227)

Leontice albertii Rgl.

Leontice albertii Rgl.

Leontice Smirnovii

(228)

(229)

C15H24N202 163-165

C15H24N202 Oil

C15H24N202 162- 164

C15H2fl2O 124-125

C15HlgN20 146-148

1 5H22N202 161

C15H24N202 190-192

C15H24N202 195

C15H24N202 168-169

+77.9" (a) 218

-77" (a) 80

+27.5" (a) 221

f15.4" (a) -

-5.6" (a) -

-50.6" (a) -

-29.4" (a) -

- 110" (a) 225

-101" (a) 226

Traut. (234)

+ 11.2" (a) 228

-90" (a) -

+70.0" (a) -

218

80

22 1

191

40

230

222

225

226

228

-

234

218 218 -

80 80 -

221 221 -

191 38,39 38,39

40 - 40

230 230 -

222, 222 - 224

- 225 225

226 227 -

(+)-Darvasoline (219)

(+)-9a-Hydroxymatrine

(+)-Sophoranol N-oxide (217)

(+)-Sophocarpine N-oxide (Sophocarpidine)

F

(-)-9a-Hydroxy~opho~~- pine

pine N-oxide

ymatrine (222)

sophoramine

(223)

( - ) - ~ ~ - H ~ & o x ~ s o ~ ~ o c x -

(+)-5a,9a-Dihydrox-

( - ) - ~ ~ - H Y & O X ~ -

( + )-Sophorbenzamine

(-)-Goebeline (227)

Leontice darvasica C15H24N202

Sophora macrocarpa Cl~H24N202

Sophora flavescens ClsH24N203

Rgl. (233)

Sm. (24)

Ait. (22,225,235), Euchresta japonica Benth. (40)

C. A. Mey. (252), S. tomentosa (21), Ammothamnus Lehmanii Bge. (217), S. flavescens Ait. (22), S. alopecuroides L. (223)

Ait. (22)

Ait. (22)

(235)

Ait. (22)

C. A. Mey. (23)

C. A. Mey. (236)

Sophora pachycarpa C15H22NZ02

Sophora flavescens C1JH22N202

Sophora flavescens C15H22N203

Euchresta horsfeldii Cp&&03

Sophora flavescens C15HZON202

Sophora pachycarpa C22H26N20

Sophora pachycarpa C3&6N202

115- 116

158-159

259-261

204

-

-

192-193

230

118-119

23 1

+28" (a)

+25.4" (e)

f38.1" (a)

+32.4" (a)

-

-

+40.6" (a)

-129" (a)

+90" (d)

- 12.9" (e)

233

24

40

223, 252

-

-

235

-

23

236

233

24

40

223

-

-

235

-

23

238

- -

24 24

40 -

223 -

- -

- -

235 235

- -

23

237, 238 20

-

a Solvents for [a],, measurements: (a) EtOH, (b) HzO, (c) CH2C12, (d) CHCl,, (e) MeOH


do not belong to the quinolizidine series. The main quinolizidine alkaloids are divided into the following groups: bicyclic alkaloids, tricyclic alkaloids, tetracyclic alkaloids of the sparteine series, tetracyclic alkaloids of the leontidine group, tetracyclic alkaloids of the matrine series, and alkaloids of the aloperine group. The last group is considered to be special. This chapter deals with alkaloids isolated and studied during 1967-1985 (see Table I). For earlier publica- tions on quinolizidine alkaloids, see Bohlmann and Schumann (I), Dopke (2), Saxton (3) , Grundon (4), and Sadykov et al. (4a).

11. 13C-NMR Spectroscopy of Quinolizidine Alkaloids

Many investigators have studied conformations and configurations of quinolizidine alkaloids by IH NMR (1,5,6). In spite of obvious success achieved with the use of this method, it proved unsatisfactory for determining the molecular structure of these rather complicated systems. 13C-NMR spectroscopy is different from 'H NMR because it allows the use of all spectral signals. The chemical shifts change at narrow line widths and are highly sensitive. The possibility of using spin-spin coupling and relaxation time T , are additional techniques making I3C-NMR spectroscopy particularly attractive for the elucidation of molecular structure (7-9). The application of pulse NMR spectroscopy by Fourier transformation at various pulse sequences as well as two-dimensional NMR spectroscopy (10) contribute even more to the solution of problems.

I3C-NMR spectroscopy of quinolizidine alkaloids is based on spectral parameters of quinolizidine (1) and its derivatives, as well as various alkaloids containing a quinolizidine nucleus (11-19). The values to be used in calculating chemical shifts of 13C nuclei in quinolizidine alkaloids were found by treating 140 chemical shift values by the method of least squares (11,12). The set of parameters thus obtained allows a precise determination of chemical shifts, taking into account molecular conformations (20). Bohlmann et al. analyzed 13C-NMR spectra of 47 quinolizidine and piperidine alkaloids as well as some of their deuterated derivatives (15). They showed that depending on structure the chemical shift distribution followed the general law of an additive scheme elaborated earlier. To determine the conformation of an unknown lupinine alkaloid the chemical shift values of the following alkaloids should be considered: lupinine (2), cytisine (3), matrine (4), allomatrine (9, sparteine (6), and a-isosparteine (7); the data should be used as a basis for a comparison with the spectrum of the substance under investigation (15). Subsequently, the additive scheme is used. Such an approach to the solution of structural problems proved to be quite useful (21 -26).

A comparative analysis of the effect of cis- and trans-quinolizidine fragments and nondivided electron pairs on 13C-NMR spectral parameters of quinolizidine

5 . LUPINE ALKALOIDS

30.5

55.9

4%-

25.6 bt.7

2

133

57.2 -21.2

4

36.7

and other alkaloids has been reported (22). Protonation of the quinolizidine nitrogen atom and its influence on 13C spectra were discussed (27-29). An analysis of 13C spectra of substituted quinolizidine iodomethylates showed the contribution of N-methyl groups to be similar to that of a C-methyl group, though a bit smaller in value (30-32). If there is no change in ring coupling, chemical

134 KH. A. ASLANOV, YU. K . KUSHMURADOV. AND A. S . SADYKOV

shifts of a, p, and y carbon atoms in quinolizidine N-oxides are altered by +10.53, -6.02, and $0.99 ppm, respectively (33). It should be noted that in certain reactions, including protonation, iodomethylation, and N-oxidation , of compounds having cis-coupled quinolizidine fragments (34) with boat conformations, inversion at the nitrogen atom is possible during isomerization. It has been demonstrated in the case of the simplest alkaloid, lupinine, that protonated lupinine exists in solution in two interchangeable conformations (35). Further investigation using I3C-NMR. spectroscopy showed the quinolizidine alkaloids sophoridine, sparteine, lupanine, and 13-hydroxylupanine to be present in concentrated HC1 solution in two conformations (II,12,36,37). These alkaloids give two isomeric N-oxides. For example, in the case of sophoridine (8) the conformation of the natural N-oxide (9) coincides with the conformation of the base itself, as determined by 13C NMR, while its synthetic isomer (10) is the result of C-N- 1 bond inversion (38-40). Similar processes of quinolizidine alkaloid isomerization should be taken into consideration when making comparative analysis of 13C-NMR spectra.

28.5

8

63.5 55.8 0*7;+y 47.0 30.7

59.4 39.7

45.8 N O

9 10

111. X-Ray Structural Investigation of Quinolizidine Alkaloids

The X-ray data available suggest that some alkaloids have a different conformation in solution than in crystal form (41). The presence of a nitrogen atom, capable of inversion, ensures certain conformational mobility of quinolizidine molecules, and the reaction conditions should be considered in establishing their

5 . LUPINE ALKALOIDS 135

conformations. In analysis of spatial structures, quinolizidine bases should be measured as solid entities.

Among quinolizidine alkaloids, sparteine and its stereoisomers have been studied in detail by X-ray analysis (42-50). It was demonstrated that proper conformation was not reorganized in monohydrates (42), diperchlorates (43), or methyliodides of a-isosparteine (11) (53). Unlike in the case of a-isosparteine, in spareteine diperchlorate rings C/D appear to have a boat-chair conformation (44-46). On the basis of spectroscopy data a cis conformation for sparteine methyliodide (12) was proposed (51,52). However, radiographic examination (53) of this compound showed it to have the trans conformation (13).

H,C-N

Y7 11 12

13

In P-isosparteine (14) all rings have a chairlike shape (54). Protonation of the N-16 atom makes the distance between N-1 and N-16 equal to 2.61 A, owing to the presence of an intramolecular hydrogen bond. Molecules of sparteine stereoisomers in crystals are sterically conjugated, and in all cases the angles between atoms C-6--C-7-€-17 and C-lo--C-9--C-l1 were increased to 116- 120" (42-50). The B and C rings are flattened at their N termini as a result of noncovalent interaction of atoms with those situated next to them. The conformation of such strained molecules is stabilized by intramolecular hydrogen bonds

The crystal structures of lupanine (15) and its derivatives were investigated as free bases (54-56) as well as protonated forms (57-60). In all structures examined ring A was a half-chair. The conformation of ring C is a boat, and rings B and D have chair conformations. In other cases rings B, C, and D had chair conformations (54-57,59). Lupanine derivatives mamanine (16) and pohakuline (17), possible metabolites in the biosynthesis of sparteine, were studied by

(46).


14 b

15

O C

O N

0 0

17

radiographic methods (61). The hydroxymethyl substituent and the flat 01-

pyridone rings were shown to occupy equatorial positions relative to the trans-quinolizidine nucleus.

The structure of anhydro-N-hydroxymethyldesoxyangustifoline (18) was in-

18 vestigated as the perchlorate (62). A methylene bridge leads to the appearance of four rings by binding the nitrogen atoms in a chair conformation. To study the biosynthetic origin of the tetracyclic alkaloid angustifoline 13-epihydroxy- 15-(5’-0xymethyl-Zfury- 1)lupanineeHBr (19) was examined. Preservation of the geometry during cyclization with aldehydes of fragments of angustifoline makes three of the six-membered rings chair-linked (60). The absolute configuration of 19 was determined as (6R,7S, 1 lS, 13S, 15R, 16R) (63).

X-Ray analysis of the cytisine alkaloid dehydroalbine did not c o n f m the structural formula determined earlier, and the compound was renamed de-


O C

0 0

O N

hydroisoalbine (20) (64,65). Japanese investigators isolated a new alkaloid tsukushinamine A from Sophoru franchetianu and established structure 21 with

21 absolute configuration (6R,7R,9S, 14R) (66). The configuration at centers C-7 and C-9 of this alkaloid is identical to that in (-)-cytisine, (-)-baptifoline, and


(-)-rhombifoline found in the same plant, which led to the conclusion that tsukushinamine-A appears to be a metabolite of anagyrine, rhombifoline, or baptifoline.

The structure of virgidivarine (22) is well established (67). This alkaloid has been demonstrated to be a sparteine derivative in which rings B and D are broken.

p$gjp 3' 4 5 2

3

22

Molecular and crystal structures of the majority of matrine steroisomers have been discussed by Sadykov et al. (68-78). Three-dimensional structures of the following compounds were elucidated: (+ )-matrine (4) (68), (+)-matrine N-oxide

4


27

29 30

(23) (69), (+)-allomatrine (5) (70), allomatrine N-oxide (24) (70), (-)-sophoridine (8) (71,72), sophoridineN-oxides (9 and 10) (73), (+)-isosophoridine (25) (74,75), (-)-tetrahydroneosophoramine (26) (76), cis-matrine (27) (77), and lehmannine N-oxide (28) (78). The structure of two other matrine alkaloids (+)- isomatrine (29) (79) and (-)-13,14-dehydrosophoridine (30) (80) was also reported. In all compounds examined ring A has a chair conformation, and ring D is a half-chair or a “sofa” as a result of conjugation of N-16 with the carbonyl bond through an electron pair. Only in (+)-isomatrine and (-)-sophoridine is the conformation of rings B and C a boat; in all other cases it is a chair. The following alkaloid structures are shown with the hydrogen atom directed to the investigator and marked by a dot to show the absolute configurations:


4 5 8 29

(+) -Matrine ( + )-Allomatrine (-)-Sophoridine (+)-Isomatrine (5S,6S,7R, 11R) (5S,6R,7R, 11R) (5S,6R,7S, 11s) (5S,6R,7S, 11R)

The absolute configurations of (+)-matrine, (+)-allomatrine, (+)-isomatrine, and other alkaloids of this series having the ( S ) configuration at C-5 has been established (81).

g& N N N N

25 26 31 32

(+)-Isosophoridine Tetrahydroneosophor- (5S,6R,7R, 11s) (5S,6S,7S, 11R) (5S,6S,7S, 11s) amine (5S,6R,7S, 11R)

IV. Bicyclic Quinolizidine Alkaloids

A. (-)-LUPININE AND ( +)-EPILUPININE

Lupinine (2) is easily epimerized to epilupinine (33), a compound occurring in nature and also formed by synthesis (82-87). The synthesis of optically active natural lupinine and epilupinine was accomplished in 1967 (88). Optically active

CH,OH CH,OH 1

2 33


(+)-1 -methylenequinolizidine (35), obtained by Wittig reaction from (+)-hexa- hydroquinolizidone-I (34), on hydroboration gave a mixture of optically active lupinine and epilupinine as shown. Several syntheses of lupinine and epilupinine were performed (89-93).

CH, CH,OH CH,OH dCH=F%pJJ-rn 2 3 + a 34 35 2 33

B. ESTERS OF LUPININE AND EPILUPININE

Alkaloids 36-41 were isolated from Lupinus luteus L. seedlings. They are considered to be lupinine esters with 4-hydroxycinnamic acids (94-100). The structures of these new alkaloids were elucidated on the basis of 'H NMR, MS, and chemical and enzymatic transformations. All these alkaloids were obtained from lupinine and hydroxycinnamic acid by two enzymatic systems (96-97): ligase catalyzed formation of the CoA-thioester, and transferase catalyzed lupinine ester formation from the CoA-thioester.

Alkaloids 42-47 were isolated from the leaves and seeds of Lupinus cosentinii Guss. They are considered to be epilupinine esters with various organic acids. The structure of the new alkaloids was established by IR, 'H NMR, MS, and investigation of hydrolysis products.

142 KH. A. ASLANOV, YU. K. KUSHMURADOV, AND A. S . SADYKOV

CH,OR FHZOCOCHS

0

47

c. ( -)-LAMPROLOBINE AND ( -)-EPILAMPROLOBINE

Lamprolobine was first isolated from Larnprolobiurn fruticosum Benth. (101) and then from Lupinus holosericens Nutt. (102). The products of the acidic hydrolysis of lamprolobine (48) appear to be (+ )-1-aminomethylquinolizidine (49) and glutaric acid. Lamprolobine was reduced with lithium aluminum

51 52 48 50

49 hydride (LAH) to piperidinoepilupinane (50) (103). The structure of lamprolobine (48) was confirmed by synthesis (21,104-106). In one synthesis bromoepilupinane was used (105): condensation of bromoepilupinane with potassium glutarimide (52) in dimethylformamide afforded lamprolobine (48). In

5. LUPINE ALKALOIDS 143

2 53 52 0"

54

another synthesis starting with (- j-lupinine (2) the alkaloid (-)-epilamprolobine (54) was obtained as shown. (-)-Epilamprolobine (54) and its N-oxide were isolated from Sophoru tomentosu, and their structures were elucidated by Ja- panese scientists (21).

D. ( +)-MAMANINE AND ( -)-POHAKULINE

Mamanine and pohakuline were isolated from Sophoru chrysophylla (61). Pohakuline (17) is considered to be the tetrahydro derivative of mamanine (16).

CH,OH CH,OH I

The structure of these alkaloids was established on the basis of UV, IR, NMR, and MS, and proved by X-ray analysis. Further detailed studies (107) carried out on Sophoru chrysophyllu resulted in the isolation of one more new alkaloid that appears to be mamanine N-oxide (55). (+)-Mamanine (16) was obtained by photoreduction and is easily oxidized to 55 by m-chlorobenzoic acid.

CH20H CHZOH I

55 56

E. CADIAMINE, 4-OXYPHENYLACETYLCADIAMINE, AND

2-PYRROLOYLCADIAMINE

Cadiamine, 4-oxyphenylacetylcadiamine, and 2-pyrroloylcadiamine were isolated from Cudiu purpureu Picc., Ait. along with other quinolizidine alkaloids


(108-109). Acid hydrolysis of 4-oxyphenylacetylcadiamine (57) and 2-pyrroloylcadiamine (58) gave cadiamine (56). Comparative study of the IR, NMR, and mass spectra of 56-58 with sparteine showed similarity. Ring B is opened between N-1 and C-10 (109) as evidenced by the absorption band at 1640-1650 cm- (-CO-, -NH-CO-) in the IR spectra of 56-58, as well as by the presence of a proton signal at 6 3.55 (-CH20-) and the loss of a C,H,NO fragment in the mass spectrum; this was confirmed by the 13C-NMR spectra.

F. SOPHORINE

Sophorine was isolated from Sophoru ulopecuroides (26). The nature of MS decay showed that sophorine is a quinolizidine alkaloid of the lupinine type. The IR spectrum suggests the presence of a trans-quinolizidine moiety (2675-2945 cm-I) and an -NH-CO- group (1605 and 1683 cm-'). On the basis of chemical shift analysis and signal multiplicity of 'H- and 13C-NMR spectra as well as biosynthetic considerations, structure 59 was proposed for sophorine.

59

G . MYRTINE AND 4-EPIMYRTINE

Myrtine and 4-epimyrtine were obtained from Vuccinum myrtillus (110). The structure of myrtine (60) and the absolute configuration at C-4 (R) and C-10 (R) were established on the basis of IR and 'H-NMR spectra. Synthesis was accomplished from (I?)-( -)-pelletierine (61) and acetaldehyde (Scheme 1) (111). Racemic myrtine (60) and 4-epimyrtine (64) were also obtained by the method of Scheme 1.


GTO- qo-m I

R 61 62 / 63

60 R = H, g = C H , HV0 64 R = CH,,R'= H

R SCHEME 1

H. FETROSINE, PETROSINE-A, AND PETROSINE-B

The bisquinolizidine alkaloid petrosine, C,,H,,N,O,, was isolated from Pe- trosia seriata (112). IR absorption bands occur at 1712 (-CO-), 2770, and 2810 em-' (trans-quinolizidine); protons of a secondary methyl group are at 6 0.94 (J = 6.4 Hz) in the 'H-NMR spectrum. Examination of l3C-NMR and 'H- NMR spectra as well as X-ray structural analysis revealed the presence of two quinolizidine fragments in the petrosine molecule (65). They are joined by pen-

CH3

65

tamethylene chain connecting C-9 with C-1' and C-1 with C-9', forming a 16- member macrocyclic system. Two other stereoisomers, petrosine-A (66) and petrosine-B (67), were isolated from Petrosia seriata ( I 13). Their structures were determined on the basis of data of NOE and two-dimensional 'H-NMR experiments.

1. ( +)-LEONTIFORMINE

Leontiformine (68) was isolated from the aboveground portion of Leontice Zeon- topetalum L. (114-116). There is a band at 1660 cm- in its IR spectrum that is


66

67

68 R = CHO 69 R = CH, 70 R = H-

typical for an amid carbonyl group. Reduction of leontiformine (68) by LAH resulted in 69, which had no carbonyl group in the IR spectrum and an N-methyl signal in the ’H-NMR spectrum originating from the reduction of the formyl group to a methyl group. Hydrolysis of 68 by concentrated HC1 led to the formation of 70, which appears to be the (+) enantiomer of “base V” obtained by Bohlmann from sparteine (6) (Z17), as shown in Scheme 2. IR spectra and melting points were identical, but the specific rotations value of 70 and “base V” were opposite.

V. Tricyclic Quinolizidine Alkaloids

A. (+ )-KURARAMINE AND ISOKURARAMINE-POSSIBLE PRECURSORS OF ( -)-N-METHYLCYTISINE

The minor components (+)-kuraramine and isokuraramine were isolated from Sophora franchetiana (118,Z19), S . tomentosa (21), S . JZavesens (22,120), S . mollis (121) along with the well-known alkaloid (-+)-ammodendrine (74).


H H f H H

"&Se 5 " 70 73 SCHEME 2

Kuraramine (75) and isokuraramine (76) were suggested to be possible precursors of N-methylcytisine (77) type alkaloids (Scheme 3).

Analysis of the IR (1645,1610, and 1550 cm- l) and UV spectra (226 nm, log E = 3.59, and 304 nm, log E = 3.64) of kuraramine (75) point to the presence of a 2-


pyridone ring in the molecule. On the other hand, the 'H-NMR spectrum of this alkaloid speaks for the presence of a 2-pyridone (79) substituted at C-6 and N- methyl-3-hydroxymethylpiperidine (80) substitued at C-5. On the basis of these data structure 75 is ascribed to kuraramine. MS fragmentation patterns of kuraramine and of isokuraramine (76) totally coincide. 13C-NMR signals of these two alkaloids are also similar, but the signals at C-7 and C-9 in isokuraramine are shifted by 6 4.6 and 3.5, respectively.

H

79

%

OCH2OH 1

CH3

80

There are signals in the 'H-NMR spectrum of isokuraramine at 6 12.64, 7.36, 6.41, and 6.02, originating from the presence of a substituent at C-6 in the 2- pyridone molecule. Magnetic nonequivalence of the hydroxymethylene protons suggest that this group is axially oriented and that the hydroxy group forms an intramolecular hydrogen bond with the N-methyl group. Thus, kuraramine and isokuraramine are diasteromers with the hydroxyl group equatorial in kuraramine and axial in isokuraramine.

B. ( -)-N-FORMYLCYTISINE, ( -)-N-ACETYLCYTISINE, (-)-~-ETHYLcYTISINE, AND (-)-N-(3-OXOBUTYL)CYTISINE

N-Formylcytisine (81) and N-acetylcytisine (78) were isolated from the plants of Suphoru (21,118,119,121,122) and Thermupsis (123), and N-ethylcytisine (82) and N-(3-oxobutyl)cytisine (83) from plants of Echinusuphuru kureensis

78 R = COCH,

82 R = CH,CH3 -("lR 81 R = CHO

F > 2 83 R = CH,CH2COCH3

0

Nukui (124-126). UV and IR spectra of 78 and 81-83 are characteristic of lupinine alkaloids of the cytisine series containing an a-pyridine ring. MS fragmentation patterns are similar to those of cytisine alkaloids. The structures of these alkaloids were confirmed by synthesis from cytisine by reaction with HCOOH (81), (CH,CO),O (78), C,H,Br (82), or CH,=CH--COCH, (83).


C. VIRGIDIVARINE AND VIRGIBOIDINE

Virgidivarine (C,,H,,N,O,) and virgiboidine (C,,H,,N,O) were isolated from Virgilia divaricata and V. oroboides (67,127,128). Virgidivarine easily splits off a water molecule in methanol solution at room temperature to afford virgiboidine. Virgidivarine's mass spectrum showed a molecular ion M+ (266) and an ion at mlz 248 obtained by loss of water. Further fragmentation was similar to that of virgiboidine. There are absorption bands of a trans- quinolizidine system (2750-2930 cm-'), a lactam group 1635 cm-'), and an ally1 group (3070, 910 cm- l) in the IR spectrum of virgiboidine. On the basis of the above data, combined with results of 'H- and 13C-NMR spectroscopy, virgiboidine (84) is considered to be tricyclic with a butenyl group attached to N-16, while virgidivarine (22) is a ring B-open analog.

22 84

D. ALKALOID LC-2

The new alkaloid LC-2 was isolated from Lupinus cosentinii (87). It is considered to be a multiflorine derivative, probably an intermediate product in the biosynthesis of the latter alkaloid and occurring in plants together. There are absorption bands at 1580-1625 (-N-CH=CH-€O-), 920, and 990 cm- (-CH=CH,) in the IR spectrum of this alkaloid. In the 'H-NMR spectrum there are proton signals presented as doublets at 6 4.92 and 6.86, as in multiflorine (85). Alkaloid LC-2 is converted to desoxyhexahydrorhombifoline (86) by reduction with zinc in 2 1V HC1 (Scheme 4). Alkaloid LC-2 appears to be a tricyclic quinolizidine alkaloid, and its structure is given by formula 87.

E. (-)-1 ~-ALLYLCYTISINE AND ( -)-TINCTORINE

1 l-Allylcytisine (89) was isolated from the seeds of Sophoru secundiflora (129). There are characteristic IR bands at 2800-2700 (trans-quinolizidine), 1645 (a-pyridone), and 914cm-' (--CH=CH,). The 'H-NMR spectrum is analogous to that of cytisine but a signal at 6 5.75 (m, 1H) suggests the presence of vinylic protons. MS shows the presence of M+ at 230. Further MS fragmentation is similar to that of cytisine. Catalytic hydrogenation of 89 over PtO, afforded hexahydrodeoxoangustofoline (90), a reduction product obtained from angustofoline (91) (Scheme 5).


87 /LC-2/ t

86

4

85 ' 88

SCHEME 4

89 90 n

91

SCHEME 5

(-)-Tinctorhe is considered to be an N-methyl derivative of allylcytisine but with a different configuration at C-1 1 . (-)-Tinctorhe was isolated from Genistu tinctoria (130,131). There are absorption bands in its IR spectrum at 1660, 1580, and 1550 cm- characteristic for a-pyridone ring. The absorption bands at 915, 985, and 3085 cm- bespeak the presence of vinyl group in the alkaloid molecule. There are two characteristic absorption maxima at 235 and 311 nm in the UV spectrum of tinctorine (92). The presence of the a-pyridone ring is supported by a positive reaction with ferrous chloride. Reduction with LAH gave hexahydrodesoxytinctorine (93) with bands at 2800-2700 cm-I in its IR spectrum. There are signals of three olefinic protons in the 'H-NMR spectrum of tinctorine, suggesting the presence of a vinyl group (6 5.5,5.0) as well as aN-methyl group (6 2.16). The signals at 6 6.3, 7.16, and 5.85 correspond to a, p, and y protons of the a-pyridone ring. Catalytic reduction of tinctorine (92) over PtO, in acetic acid afforded the hexahydro derivative (94) and gave hexahydrodesoxytinctorine (95) in 2 N HCl (Scheme 6). The main fragments in the mass spectrum of tinctorine (92) were M+ and ions at m/z 203, 160, 146, 108, 98, and 58. The fragment mlz 203 originates by splitting of an ally1 radical. The structure proposed for tinctorine (92) is confirmed by the fact that the fragment miz 58 observed was also seen in the fragmentation of N-methylcytisine (77).

The configuration of tinctorine was established (131) on the following basis


0 92

SCHEME 6

(Scheme 7): (-)-Hexahydrotinctorine (94) obtained by hydrogenation over PtO, in acetic acid was identical with N-methyldihydroangustifoline (98) obtained from angustifoline (91) by methylation and hydrogenation (except that it has opposite optical rotation). The reduction product (+)-hexahydrodesoxytinctorine

\

0 91 SCHEME 7


(95) is the antipode of ( -)-N-methyldihydrodesoxyangustifoline (97). The absolute configuration suggested for 95 is (6S,7R,9R, 11R).

The alkaloid isolated from Thermopsis alterniflora Bge. described as “alteramine” (132,133), is, in our opinion, identical with tinctorine.

F. (-)-ARGENTINE

Argentine was first isolated from Ammodendron argenteum 0.Ktze. (134). It has also been obtained from Sophora griffithi Stocks (133, Thermopsis lanceolata R. Br. (136), and Thermopsis alpina Ldb. (137). There are two bands in its UV spectrum (A,,, = 232 and 308 nm, log E = 4.19 and 4.16) that are typical for an a-pyridone ring. IR spectral data showed the presence of a lactam group by bands at 1645 and 1665 cm- l . Four moles of hydrogen were absorbed by catalytic hydrogenation of argentine (99), and octahydroargentine (100) was formed (Scheme 8). There were no bands at 1500-1600 cm-’ in the IR spectrum corresponding to conjugated double bonds. The lactam absorption was shifted to 1615-1645 cm-l.

0 0

SCHEME 8

Mass spectral investigation of argentine showed a mass spectrum which looked like that of cytisine up to rnlz 190 (138). In addition, there was a molecular ion M+ at 406 and peaks at mlz 217 (M+ - 189) and 189 (M+ - 217). Octadehydroargentine showed an M+ (414) and the ions at mlz 221 (M+ - 193) and 193 (M+ - 221), respectively. The fact that ion peaks appear at mlz 406, 217, and 189 is evidence of the presence of two a-pyridone nuclei in the argentine molecule, and since argentine contains two a-pyridone rings and since its ‘H-NMR spectrum is similar to that of cytisine the presence of two cytisine moieties in argentine was suggested.

The low basicity of argentine and the possibility that a change of proton signals in its spectrum could be due to the presence of a group connecting two cytisine fragments by nondivided electron nitrogen pairs suggested structure 99 for argentine. This was confirmed by the following reaction: Hydrolysis with 30% NaOH at 140- 150°C afforded cytisine (3) quantitatively. Argentine (99) was synthesized according to Scheme 9 (139).


G. ( +)-DIMETHAMINE

Dimethamine was isolated from Therrnopsis alternijloru (140). There are two ion peaks at m / z 146 and 160 in the mass spectrum of dimethamine suggesting the presence of a 1,3-disubstituted tetrahydroquinolizone system. This fragemen- tation is similar to that observed with N-methylcytisine (77). Hydrogenation of dimethamine (101) in acetic acid over PtO, (Scheme 10) led to tetrahydrodimethamine (102) with a UV absorption maximum at 270 nm, IR absorption bands at 1630 and 1680 cm-l. (amide carbonyl and double bond, respectively), and ‘H-NMR signals of two N-methyl groups present as singlets at 6 1.97 and 2.13. Catalytic hydrogenation of 101 in alcoholic 2 N HC1 afforded hexahydrodimethamine (103), and the absorption band typical for the double bond had disappeared from the IR spectrum. Pyrolysis of 101 under reduced pressure resulted in the formation of (-)-N-methylcytisine (77). On the basis of these data it was assumed that dimethamine is a bimolecular alkaloid consisting

. CH3

SCHEME 10


of N-methylcytisine and dihydro-N-methylcytisine residues, connecting the pyridone rings. The presence of two olefinic protons in dimethamine at 6 5.77 and 6.18 as doublets with J , = J2 = 10 Hz, a splitting of the y-proton signal at J = 3 Hz, and the absence of olefinic protons in 102 suggested 33’-(3’,5‘- dihydro)-di-N-methylcystisine (101) as structure of dimethamine.

H. TSUKUSHINAMINES A, B, AND C

Tsukushinamines A, B, and C, isolated from Sophora franchetiana (66,118,119), are considered to be isomeric compounds. Tsukushinamines A (21) and B (104) are epimers at C-14, and tsukushinamine C (105) differs from them in the position of the double bond and affords 21 on heating to 200°C in a

15 i6 17

CH,-CH=CH, CH,-CH=CH, CH,-CH=CH

0 0 0 21 104 105

sealed tube in a nitrogen atmosphere. The structure and absolute configuration of these alkaloids were established on the basis of their spectral data and confirmed by X-ray analysis (66,119). The configuration of the tsukushinamine alkaloids at C-7 and C-9 is the same as that of cytisine (3) and rhombifoline (88) (7R,9S). This is supported by the formation of a mixture of 21 and 104 by intramolecular photocyclization of rhombifoline (88) (Scheme 11) (141).

SCHEME I 1


VI. Tetracyclic Quinolizidine Alkaloids of the Sparteine Group

A. (-)-y-HYDROXY- P-ISOSPARTEINE

7-Hydroxy-P-isosparteine (106) was isolated from Lupinus sericeus (142). The reduction of the iodo derivative of the alkaloid with LAH resulted in the formation of P-isosparteine (14) (Scheme 12). The hydroxyl groups were supposed to be at C-7 because of their low reactivity. This was confirmed by the formation of the monolactam 7-hydroxy-10-0x0-P-isosparteine (107) via oxidation of 106 with potassium ferricyanide.

OH OH

14 106 0 107

SCHEME 12

B . ~0,~7-DIOXO-~-ISOSPARTEINE 10,17-Dioxo-P-isoparteine was isolated from Lupinus sericeus (143). The

mass spectrum, with M + at m/z 262 and signals at m/z 234 (M + - 28) and 206 (M+ - 56), is characteristic for 10- and 17-oxosparteines and successive splitting of two carbonyl groups. Oxidation of p-isosparteine (14) by potassium fenicyanide resulted in 10-oxosparteine (108) as well as 10,17-dioxo-~-isosparteine (109) (Scheme 13). This confirmed the alkaloid structure. Although 109 was found as a natural compound it had already been synthesized by Bohlmann et al. (144). The problems of configuration and conformation of sparteine (6), a- isosparteine (7), and P-isosparteine (14) were discussed (145).

0

14

SCHEME 13

0 109


C. EPIAPHYLLINE

Epiaphylline was isolated from Lupinus hurmegii (146-147). The mass spectrum of this alkaloid is characterized by peaks at miz 248 (70), 247 (46), 220 (45), 137 (47), 136 (loo), 97 (53), and 96 (45%) that are tyical for sparteine alkaloids. The peak at miz 220 originates from the splitting of a carbonyl group. Epiaphylline (IlO), in contrast to aphylline (108), did not react under mild catalytic hydrogenation conditions, but under harsher conditions epiaphylline (110) converted to P-isosparteine (14) (Scheme 14). This established the presence of a carbonyl group at C-10.

0 110

14

0 108

SCHEME 14

D. (-)-4ol-HYDROXYSPARTEINE

4a-Hydroxysparteine was obtained from Acasmium punumense (148). The mass spectrum of this alkaloid, with M + at m/z 250 and signals at m/z 233,221, 209, 153, 136, 122, 114, 110,98,97, 96, 84,54, and41, is typical forhydroxy derivatives of sparteine alkaloids with a hydroxyl group in ring A. The reduction product of the known alkaloid multiflorine (85) obtained with sodium borohydride in methanol was identical with 4-hydroxysparteine (111) (Scheme 15). On the other hand, 4-hydroxysparteine (112) obtained from nuttalline (113) by reduction with sodium borohydride in methanol was not identical with 111, suggesting that 111 and 112 are epimers with the hydroxyl group in 111 in equatorial and in an axial position in 112.

E. ( +)-THERMOPSAMINE

Thermopsamine was isolated from Thermopsis lunceolutu R. Br. (137). There are two absorption bands of an axial hydroxyl group at 3370 and 1023 cm- and bands representative of truns-quinolizidine at 2680-2800 cm- in the IR spectrum. Heating of thermopsamine with hydrogen iodide over red phosphorus


85 111

112

SCHEME 15

resulted in formation of a desoxy base identical with the alkaloid pachycarpine (6) (Scheme 16). Thermopsamine is thus hydroxypachycarpine. Ketone 14 was obtained from thermopsamine by Oppenauer oxidation, confirming the presence of a secondary hydroxyl group. Formation of thermopsamine from 13-hydroxylupanine (116) by reduction with LAH positioned the hydroxyl group to (2-13. On this basis the formula of 13a-oxypachycarpine (115) was proposed for thermopsamine.

115 114 SCHEME 16

F. ( -)-LINDENIANINE

Lindenianine was isolated from Lupinus lindenianus and L. verbasciformis (149,150). There are two IR absorption bands at 3330 (hydroxyl) and 1620


Il5 \ 6

0 119

SCHEME 17

cm-l (lactam carbonyl) in the IR spectrum. Lindenianine’s mass spectrum showed peaks for M + at mlz 264 and peaks at mlz 247 (M+ - 171), 236 (M+ - 28), 207 (M+ - 57), 152, 138, 137, 136, 134,97,96, and 84, suggesting the alkaloid to be a member of the sparteine series.

Lindenianine (117) absorbed 2 mol of hydrogen over PtO, in 2 N HC1 and afforded 13P-hydroxysparteine (115) (Scheme 17). The latter gave sparteine (6) after dehydration with P,O, and hydrogenation. Lindenianine (117) and virgiline (119) were easily oxidized to ketolactam 118 by Oppenauer oxidation. Virgiline (119) was characterized by absorption bands at 1715 (six-membered ring carbonyl) and 1624 cm- (>N-CO-) in the IR spectrum. Treatment of 118 with NaBH, in methanol gave 117, establishing the hydroxyl group in lindenianine to be in the thermodynamically stable equatorial orientation, further evidenced by a wide multiplet (-40 Hz) at 6 3.70. Wolff-Kischner reduction of 118 gave aphylline (108). This established the lactam carbonyl at C-10, and lindeniane (117) and virgiline (118) appeared to be epimers at C-13. Conversion of virgiline (118) to lindeniane (117) was reported (150).


G. 5,6-DEHYDROLUPANINE AND

5,6-DEHYDRO-a-ISOLLJPANINE

The bases 5,6-dehydrolupanine and 5,6-dehydro-a-isolupanine were isolated from species of Lupinus and Thermopsis, Echinosophoru koreensis, and Clathrotropis brachypetala (126,151-154). Their mass spectra are identical and show the presence of a double bond at C-5=C-6. Catalytic hydrogenation of 5,6-dehydrolupanine gave lupanine. 5,6-Dehydrolupanine (120) is supposed (152) to be an intermediate product in the biosynthesis of anagyrine (121) from lupanine (15) (Scheme IS), while 5,6-dehydro-c~-isolupanine (122) is an intermediate product in the biosynthesis of thermopsine (124) from a-isolupanine (123) (Scheme 19).

0

15

0

123

0 0 120 121

SCHEME 18

0 0 122

SCHEME 19

124

H. ( +)-NUTTALLINE

Nuttalline was isolated from Lupinus nuttallii L. (155). The tetracyclic structure of nuttalline was established by dehydration of deoxonuttalline (112), obtained from nuttalline (113) by reduction with sodium borohydride, and by catalytic reduction to sparteine (6) (Scheme 20). Oppenauer oxidation of nuttalline gives 2,4-dioxosparteine (125). The UV spectrum of this 1,3-diketone

epimers, and nuttalline has the structure of 4P-hydroxy-2-oxosparteine (113). was pH dependent. Thus, deoxonuttalline and 4a-hydroxysparteinc appear to he

I. (+)-CHAMAETINE

Chamaetine was isolated from a species of Chamuecytisus (156,157). Cham- aetine (127) was reduced by LAH to hydroxysparteine (lll), and further reduction with red phosphorus in the presence of iodine gave sparteine (6) (Scheme

160 KH. A. ASLANOV, YU. K. KUSHMURADOV, Ah'DA. S . SADYKOV

0 113

126

SCHEME 20

21). Heating chamaetine in the presence of P,O, gave anhydrochamaetine (126), which afforded lupanine (15) on hydrogenation over 5% PdIC. The 'H-NMR spectrum of chamaetine showed a secondary hydroxyl group between two CH, groups. The mass spectrum had the ion peak M + at mlz 264 and peaks at mlz 235 and 165. The fragment rn lz 235 is the result of C,H, (M+ - 29) splitting, showing that ring D was not substituted. The fragment at miz 165 contains two oxygen atoms and points to the presence of a hydroxyl and carbonyl group in ring A. That position C-4 bears the hydroxyl group is shown by the three CH, multiplets observed. On the basis of the NMR analysis, the hydroxyl group in chamaetine (127) is equatorial and axial in nuttallin (113).

J. 10,13-DIOXYLUPANINE

10,13-Dioxylupanine was isolated from Cadia purpurea (109). Its structure (128) was proved by IR and mass spectroscopy.


\ 111 126

/

6 15

SCHEME 21

K. CALPURMENINE

Calpurmenine was isolated from Culpurniu uureu (158). The mass spectrum showed peaks typical for a lupanine skeleton, containing two hydroxyl groups, but the alkaloid differed from 10,13-dioxylupanine (128). The peaks at miz 168, 150, 132, and 112 showed the second hydroxyl group to be in ring C or D. X- Ray analysis established the position and configuration of the two hydroxyl groups in calpurmerine, having the structure of a 12p, 13a-dihydroxylupine (129).

0 OH

128 Q 129

L. ESTERS OF HYDROXYLUPANINES

Several alkaloids (130-142) were isolated from plants of the genera Cudiu, Culpurniu, Surothumnus, and Genistu. They are believed to be ethers and esters of hydroxylupanine derivatives (159-1 78). Alkaloid esters on hydrolysis gave the respective organic acids and hydroxylupanines. The structures of these alkaloids have been established mainly by spectral methods.


130 1 3 - E t h o ~ y b p a n i n e : R '=H; R'=H; R3=H; R'=-OC,H,

131 C a d i a i n e : R' =H; R1 =H; R' =H; R4 =-OCOCH,-

132 10-oxy-13-0- h -pyrr olylcarb onyl/-lupan i n e : R'=H; R*=OH; R3=H; R ' = - O C O G / \

X N ; 133 13-0-/2-pyrrolylcarbonyL/ c a l p u r m e n i n e :

R '=H; R'=H; R'=OH; R ~ = O C O H O C H ~

134 C i n e v a n i n e :

135 Isocinevanine: R'=H; Rz=H; R3=H; R'=OCO+,

R' =H; R2=H; R3=H; R4=OC0 ---(=&OH

OH

OCH3 136 C i n e v e r i n e : R '=Hi RL=H; RJ=H; X 4 = O C O G 4 C H ,

- on 137 C i n e g a l l m e :

138 C i n e g a l ' l e i n e :

R ~ = H , R'=H; R3=Hi R 4 = O C O - @ X H ,

R'=H; R2=H; R'=H; R 4 = O C O e F C H , OCH, OH

OH

OCHB 141 C a f a l a u v e r i n e : R' =OH; RL=H R3=H; R4=OCO+OCH

M. ( +)-ARGENTAMINE

Argentamine was isolated from Ammodendron argenteum 0.Ktze. (134). Its UV spectrum has two maxima at 232 and 308 nm (log E = 4.31 and 4.41), typical for an a-pyridone chromophore. There were bands in the IR spectrum at 3260 (wide) and 1045 cm- l , belonging to the hydroxyl and carbonyl group, respectively. The argentamine mass spectrum (mlz 260 M + , 243, 215, 160, 152, 146, 114, 96, and 88) is typical of quinolizidine alkaloids. On catalytic


145 7

SCHEME 22

hydrogenation over nickel, argentamine (143) absorbed 2 mol of hydrogen and was converted to tetrahydroargentamine (144) (Scheme 22) (179). Reduction of 143 in 2 N HCl over PtO, gave desoxohexahydroargentamine (145). Hydration of the latter followed by hydrogenation gave a-isosparteine (7). The 1R spectrum of 143 differed from that of baptifoline (146) and showed trans-quinolizidine bands. On the other hand, 144 appeared to be identical to 13-hydroxy-a-isosparteine, suggesting a trans-coupling of rings C/D in argentamine and the position of the hydroxyl group at C-13. Argentamine and baptifoline are epimers at C- 13.

N . ( + )-DITERMAMINE

Ditermamine was isolated from the aboveground portions of Thermopsis lun- ceoluta R. Br. (180). The IR spectrum showed two absorption bands in the region 2600-2800 cm- l , suggesting the presence of a trans-quinolizidine system. Bands at 1670, 1645, and 1610 cm-’ originate from lactam carboxyls and conjugated double bonds. The “fingerprint” region is similar to that seen in thermopsine. The UV spectrum showed an absorption maximum at 280 nm (log E = 3.6). There were ion peaks at m/z 146 and 160 in the mass spectrum of ditermamine, suggesting the presence of a 1,3-substituted tetrahydro- quinolizinone. Ozonization of ditermamine and thermopsine (124) gave the identical product (148) (Scheme 23). Thus, ditermamine has the thermopsine structure 124 with a substitpent at ring A.

Hydrogenation of ditermamine in acetic acid over Pt gave tetrahydroditerm- amine (149). There were absorption bands in the IR spectrum of 149 at 1630 cm- ’ (>N-CO-) and at 1680 cm-l (double bond). There were no signals for olefinic protons in the ‘H-NMR spectrum. Catalytic hydrogenation of diter-

164 KH. A. ASLANOV, YU. K . KUSHMURADOV, AND A. S. SADYKOV

149 t / /

150 1 f

0

147 \ 151

148 124

SCHEME 23

mamine over PtO, in alcoholic HC1 led to 150, showing no double bond absorption in the IR spectra. Reduction of 150 with LAH gave 151, lacking amide carbonyl bands in the IR spectrum. There are signals of two olefinic protons in the 'H-NMR spectrum of ditermamine present as doublets at 6 5.75 and 6.12 with J = 10 Hz. This points to f3 and y position of the olefinic protons in the pyridone ring and structure 147 for ditermamine.

VII. Tetracyclic Alkaloids of the Leontidine Group (Quinolizidine-Indolizidine Alkaloids)

A. (-)-LEONTIDINE

Leontidine was obtained from Leontice and Camoensia (181 -183). The pres- cence of a-pyridine ring was evidenced by UV and 'H-NMR spectroscopy. The IR spectrum showed a transquinolizidine system (2800-2700 cm- ').

The mass spectrum of leontidine is characterized by intensive ion peaks at mlz 160 and 146 typical €or quinolizidine alkaloids. Ion peaks at mlz 96 and 84 speak for the pesence of a five-membered heterocyclic ring.

Leontidine (152) when hydrogenated over PtO, in acetic acid gave tetrahydroleontidine (153), which formed leontidane (154) on reduction with LAH (Scheme 24). Oxidation of leontidine with potassium permanganate gave


oxoleontidine (155), lacking trans-quinolizidine bands in the IR spectrum, and dehydrogenation over palladized asbestos gave tetradehydroleontidine (156). The proposed structure for leontidine (152) was confirmed by partial synthesis from 1 1-allylcytisine (89) by treatment with hydrogen iodide (Scheme 25) (181). The absolute configuration of leontidine (7R,9R, 1 IS) was established by comparing CD spectra of different optically active alkaloids containing an a-pyridine ring (184).

0

0

153 \ \

0

/

152 \ 0

I .

154 156

SCHEME 24

SCHEME 25

B. CAMOENSINE, CAMOENSIDINE, AND

HYDROXY DERIVATIVES

Camoensine and camoensidine were isolated from Camoensia maxima Welw . ex Benth. (183). Camoenzine is considered to be an isomer of leontidine. The mass spectra of these alkaloids were identical. Dehydrogenation of carnoensine (157) with mercury acetate formed the immonium base (158), which was converted to leontidine (152) by sodium borohydride (Scheme 26). Camoensine


/fN

* 158 152 * 157

SCHEME 26

159 160 153

(157) has the absolute configuration (7R,9R, 11R). Camoensidine (159) proved identical with tetrahydrocarnoensine obtained from the immonium base (160) by reduction with sodium borohydride (Scheme 27). The results of photochemical oxidation of camoensidine (159) and tetrahydroleontidine (152) were described (185). 12-Hydroxy derivatives of camoensine and camoensidine (161 and 162) as well as 12-hydroxy- 16-methoxy- 1 1,12,13,14-tetrahydrocamoensine (163) were isolated from Camoensia brevicalyx Benth. (186). The structures and position of hydroxyl and methoxyl groups in these alkaloids were determined on the basis of IR, NMR, and mass spectra.

SCHEME 27

OCH,

T N , p P N yz7+ Fd2H A N '-, N\/ OH "OH

0 0 0 161 162 163

C . DESOXOCAMOENSIDINE ( 1 1 -EPILEONTIDINE)

Desoxocamoensidine was isolated from Maackia arnurensis Rupr. and Max- im. (187). The structure of the alkaloid (164) was established by its identity with the product obtained from camoensidine (159) with LAH (Scheme 28).

- 159 164

SCHEME 28


VIII. Tetracyclic Alkaloids of Aloperine Group

A. ( -)-ALOPERINE, ( +)-N-METHYLALOPERINE, AND

Aloperine, N-methylaloperine, and N-allylaloperine were isolated from Soph- ora alopecuroides L. (188-191). Later aloperine was also isolated from Lep- torhabdos pawzjlora Benth. (192). On reductive methylation, aloperine gave N-methylaloperine (167) (190-Z93), and interaction with ally1 bromide gave N- allylaloperine (170) (Scheme 29) (189). Hence, one of the two nitrogen atoms in aloperine was considered to be secondary.

High-resolution MS showed aloperine to be different from all known types of quinolizidine alkaloids by fragmentation. It was demonstrated that cleavage of one heterocycle takes place first, accompanied by elimination of nitrogen fragments CH,N, C,H,N, and C3H,N. The splitting of a CH3N fragment confirmed the presence of a secondary nitrogen atom. Mass spectra of N-methyl- and N- allylaloperine revealed a different fragmentation pattern to that observed for aloperine. Aloperine (165) contains one double bond, which is hydrogenated in the presence of PtO, with the formation of dihydroaloperine (166).

N- ALLYLALOPERINE

OH

\ 168

/

167 169 R = CH, 170 R = CHZCH =CH,

SCHEME 29


The nature of the double bond was deduced by NMR spectra of 165 (6 5.27, J = 6.5 Hz). Mild dehydrogenation with sulfur gave the tetradehydro derivative 167, while oxidation with potassium permanganate gave dioxylactam 168. Three signals of a, p, and y protons of a pyridine ring were observed in the NMR spectrum of 167. Thus, aromatiziation was accompanied by migration of the double bond. The presence of a quinolizidine nucleus and support for, the extra double bond were confirmed by the mass spectrum of 168. The spectrum showed fragments (m/z 136, 137, and 150) typical for a quinolizidine nucleus and the hydroxyl-containing fragments (mlz 134, 148, and 195), explaining the oxygenated part. The presence of weak Bohlmann absorption bands in the IR spectrum of aloperine and their absence in N-methyl, N-acetyl, and N-benzyl derivatives proved rings AIB to be cis-fused.

B . NITRARAMINE AND N-HYDROXYNITRARAMINE

Nitraramine and N-hydroxynitraramine were isolated from Nitruria schoberi (194,195). There are active hydrogen absorption bands in the IR spectrum of nitraramine at 3280 and 3530 cm-l and a low intensity band at 1660 cm-I (double bond). Acetylation of nitraramine (171) gave N-acetyl and N , 0-diacetyl derivatives. Hydrogenation over Adams’ catalyst in acetic acid gave dihydronitraramine (172) and dihydrodesoxynitraramine (173) (Scheme 30). The presence of peaks typical for quinolizidine alkaloids in the mass spectra of 171-

OH OH 0

172 171 174

173

CH, 175

SCHEME 30

176


173 and the presence of >NH groups in their IR spectra as free bases allowed classification of nitraramine into the aloperine group of alkaloids.

Formation of 173 from 171 on hydrogenation pointed to the presence of an allylic alcohol group in 171. This was confirmed by oxidation of 171 to ketone 174. There were strong bands at 1650 and 1580 cm-' in the IR spectrum of 174 typical for a -CO-C=C-N- system. The absence of olefinic protons in the NMR spectrum of 171 suggested the double bond to be at C - 1 1 4 - 1 6 , while a hydroxyl group is positioned at C-15 or C-17.

Dehydrogenation of 171 by Pd/C resulted in dehydro base 175. The 'H-NMR spectrum of 175 showed the a-proton signals of the pyridine rings as two multiplets at 6 8.49 and a muitiplet centered at 6 7.04 (5H, Ar-H). The methylene group showed two one-proton triplets at 6 4.48 and 4.13 (J = 4 Hz) arising from interaction with the axial proton at C-8. The quartet (2H) at 6 2.98 was attributed to the protons at C-8, while the multiplet at 6 2.13 is supposed to belong to the proton at C-7. On the basis of structure 175 the hydroxyl group at nitraramine was placed at C-17. Oxidation of 171 with 5% hydrogen peroxide gave N- hydroxynitraramine (176), identical to that isolated from natural sources. Com- pound 176 was reduced by sodium borohydride in methanol and with LAH in ether to 171.

IX. Tetracyclic Alkaloids of the Matrine Group

A. ( -)-SOPHORIDINE AND ( +)-SOPHORIDINE

(-)-Sophoridine was isolated from Sophora alopecuroides L. (190,191), Lep- torhabdos parvgora Benth. (192), S . jlavenscens Ait. (22), and Euchresta japonica Benth. (40). (+)-Sophoridine was also isolated from Leontice albertii Rgl. (196,197). The structure of the carbon-nitrogen skeleton was established with the formation of octodehydromatrine (177) on dehydrogenation over palladized

177

asbestos (198). Bohlmann bands in the region 2800-2700 cm- and the relative dehydrogenation rates of matrine (4), allomatrine (5) , and sophoridine allowed


4 5 25 178

determination of the rings in sophoridine as A/B-, A/C-, B/C-trans, and C/D-cis (199,200). Sophoridine was shown to isomerize by hydrogenation over PtO,/H, (196,201,203) to isosophoridine (25) with rings A/B- and A/C-cis, B/C- and C/D-trans. Reduction of sophoridine iodomethylate gave sophoridane iodomethylate (178), characterized by the absence of an absorption at 2800- 2700 cm-l (199, 202, 203). The spatial structure of 179 was suggested for sophoridine (204).

7

0

179 181 8

N

180 6

10

8


Sophoridine (8) was converted by oxidation with mercury acetate to 5-hydroxy-6,7-dehydromatrine (180) with C/D-trans-fused rings as in matrine and allomatrine. Therefore spatial structure 181 for sophoridine was proposed (196,203,205). The controversial views regarding the configurations of sophoridine may be explained by different conformations of the molecule in solution (different from 179 or 181). The structure of sophoridine is conformationally labile since the nitrogen atoms are capable of inversion. To establish the conformation of sophoridine in solution it was necessary to use methods that did not affect conformational equilibria. 'H-NMR and INDOR methods led to proposed structure 8 for sophoridine, with rings A/B-, A/C-, C/D-trans, and B/C-cis. Rings A and D have chair, and rings B and C, boat conformations (206). This is supported by spectral analysis, including 13C-NMR analysis (11,12,36,37), and has been confirmed by X-ray analysis (71,72).

Conformation 8 agrees with the chemical transformations of sophoridine obtained earlier (203). Matrine isomers are known to react faster by dehydrogenation over palladized asbestos or with mercuric acetate if they contain cis hydrogens. Sophoridine has been shown to dehydrogenate faster than allomatrine (9, but slower than matrine (4) (196). Since there are three cis hydrogens (H-5, H-6, H-7) in matrine and none in allomatrine, the sophoridine molecule is supposed to contain two cis hydrogens; a cis orientation of H-6 and H-7 in 8 meets this requirement.

On dehydrogenation with mercuric acetate, matrine, allomatrine, and sophoridine afforded the same dehydro product, 5-hydroxy-6,7-dehydromatrine (180) (196,203). The attachment of a hydroxyl group to C-5 and the double bond in the 6,7 position eliminate differences in the molecular conformations of 4, 5, and 8. The absence of trans bands in the spectrum of 178 may be explained by isomerization taking place during reduction.

Examination of Sophoru ulopecuroides L. sprouts led to the isolation of sophoridine N-oxide as the main alkaloid (191,207). Later the N-oxide also was isolated from Euchrestu juponicu Benth. (40). Oxidation of sophoridine by m- chloroperbenzoic acid resulted in two N-oxides in a ratio of 1 : 5. The minor N- oxide was identical to the natural one, and its conformation corresponds to that of sophoridine (8). The other N-oxide (10) as suggested by IH- and I3C-NMR spectra, appears to be the N-oxide of one of the labile conformations (38,39).

B. ( +)-ISOMATRINE

Isomatrine was isolated from Sophoru fluvescens Ait. (79,208). There are absorption bands of a lactam group at 1620 cm- and a truns-quinolizidine at 2740, 2760, and 2780 cm-l in the IR spectrum. Heating of isomatrine (29) in aqueous solution with PtO,/H, results in epimerization, and a mixture of matrine


2-2 +g N H

29 4 5 SCHEME 31

(4) and allomatrine (5) is formed (Scheme 31). The configuration of 29 was determined by NMR and X-ray analysis (79). Rings A, B, C, and D in isomatrine have, respectively, chair, boat, boat, and chair conformations, and its absolute configuration is (5R,6R,7S, 11R).

C. ( +)-ALBERTIDINE

Albertidine, isolated from Leontice Albertii Rgl. (Z96,197), is a crystalline, optically active tribase. There are IR absorption bands for a trans-quinolizidine system at 2750 and 2793 cm-’ and a six-membered lactam carbonyl at 1640 cm- The absorption in the “fingerprint” region is similar to that of matrine. The mass spectrum of albertidine is characterized by ion peaks at mlz 247 (M - l), 219, 205, 192, 177, 150, 137, 98, and 96 which are typical for matrine alkaloids (209). On the basis of spectroscopic data and taking into account the trans-quinolizidine band in the IR spectrum, the probable structure 182, with rings AIB-trans, was proposed.

182

D. ( -)-DARVASINE AND ( +)-DARVASAMINE

Darvasine, isolated from Leontice darvasica Rgl. (2Z0,21 l ) , is a monoacidic tribase. There are absorption bands in its IR spectrum that are typical for a double bond (1670 cm-l) and a lactam (1645 cm-*). There is one UV maximum at 244

nm (log E = 4.3), typical for a --C=CH-N--C=O group. The mass spectrum differs from that of leontalbine in the intensity of some peaks. This suggests that darvasine and leontalbine might be diastereomers. Dehydrogenation of dar-

I


4- I_t

N

183 177

N

184 SCHEME 32

vasine over palladized asbestos gave octadehydromatrine (177) (Scheme 32). The 'H-NMR spectrum of this alkaloid showed a single olefinic proton in the a position to nitrogen at 6 6.81, which corresponds to the proton of the double bond at C-5-C-17. There were no Bohlmann bands in the IR spectrum of darvasine. The alkaloid appears, therefore, to be a representative of the matrine group of alkaloids and most probably has the structure of 5,17-dehydroiso- matrine (183). (+ j-Darvasamine (184), isolated from Leontice Albertii Rgl. (211,212), turned out to be dihydrodarvasine.

E. ( -)-LEONTALBINE

Leontalbine, isolated from Leontice Albertii Rgl. (213), is considered to be monoacidic unsaturated tribase (214). The IR spectrum is characterized by absorption bands typical for a trans-quinolizidine system (2800-2700 cm- l ) , a double bond (1670 cm- l ) , and a lactam (1640 cm- l) . Reduction of leontalbine (185) with LAH gave deoxoleontalbine (186) with the double bond preserved (Scheme 33). Hydrogenation of deoxoleontalbine gave a diacidic tribase that appeared to be the antipode of (+)-deoxomatrine (187). Leontalbine perchlorate could not be reduced with sodium borohydride, while deoxoleontalbine perchlorate afforded deoxodihydroleontalbine. The double bond in leontalbine is, therefore, situated in ring C between the a and @ carbons of the nitrogen atoms, as shown in 185. The olefinic proton is shown as a singlet at 6 6.9 in the 'H-NMR spectrum of the base and is a-positioned with respect to the amide nitrogen. This alkaloid is known to have a (-) rotation and appears to be the antipode of (+ j-5,17-dehydromatrine (215).

185 186 SCHEME 33

187


F. ( -)-LEONTALBININE

Leontalbinine was isolated from Leontice Albertii Rgl. (216). It is considered to be monoacidic tribase. It shows IR absorption bands typical for a trans-quinolizidine (2800-2700 cm- l ) , a double bond (1670 cm- l ) , and a lactam carbonyl at (1645 cm- '). Reduction with LAH gave deoxoleontalbinine, which absorbed 1 mol of hydrogen on catalytic hydrogenation to give deoxodihydroleontalbinine. Hydrogenation of leontalbinine in acetic acid in the presence of platinum catalyst led to dihydroleontalbinine, identical by IR with allomatrine but different from allomatridine.

Structure 187 was proposed for deoxodihydroleontalbinine. Leontalbinine perchlorate could not be reduced, while deoxoleontalbinine perchlorate was reduced by sodium borohydride. This suggested an a,P position of the double bond with respect to the amine nitrogen, which was confirmed by oxidation to glutaric acid, probably via the intermediate product 189 (Scheme 34). Since structure 188 proposed for leontalbinine is correct, structure 187 given to deoxodihydroleontalbinine is incorrect and has to be changed to 190.

g- N J H O O C / j

H

___c a- H -.- COOH 3 COOH

188 189 2 H H N $ 8 N N

187 190

SCHEME 34

191

There are typical Bohlmann bands at 2800-2700 cm- in the IR spectrum, suggesting trans-fused AIB rings. This is confirmed with the formation of allomatrine by the catalytic hydrogenation of leontalbinine. Deoxodihydroleon- talbinine (190) differs from allomatridine, suggesting a matrine-allomatrine type isomerization of leontalbinine during hydrogenation in the presence of platinum catalyst. Deoxodihydroleontalbinine (190) was obtained from 191 by catalytic hydrogenation, and 191 was prepared from leontalbinine (188) by reduction with


LAH. In the hydrogenation of 191, hydrogen approaches from the most favor- able site giving the cis product 190.

G . (+)-LEMANNINE

Lemannine was isolated from Ammothamnus Lehmanni Bgl. (217). The IR spectrum shows bands at 2680, 2750, 2770, and 2810 cm-' typical for a trans- quinolizidine and a band at 1650 cm- ' corresponding to a six-membered lactam. The mass spectrum shows ion peaks at rn lz 245 (M+ - l), 232,217, 203, 190, 188, 177, 159, 136, 122, 110, 98, 97, 96, 83, and 55, typical for the matrine series of alkaloids with a double bond in ring D. The double bond in ring D is not coupled with a lactam carbonyl since there was no chromophore --C=CH-C=O absorption in the UV spectrum of lemannine. The 'H-NMR spectrum shows signals of two olefinic protons at 6 5.6-5.9. Double resonance experiments showed the olefinic protons to be connected with H-1 1 spin-spin interaction. The double bond in lemannine (192) is therefore situated at C-124-13 in ring D. Hydrogenation over Raney nickel gave matrine.

192

H. 13,14-DEHYDROSOPHORIDINE

(+)- 13,14-Dehydrosophoridine was isolated from Sophora alopecuroides L. (218), and (-)-13,14,-dehydrosophoridine was obtained from S. flavescens Ait. (80). There is an absorption maximum at 253 nm in the UV spectrum which is typical for an a,@-unsaturated ketone. The IR spectrum showed absorption bands at 2700-2800 cm-' of a trons-quinolizidine, at 1650 cm-' of an amide carbonyl, and at 1597 cm- ' of an a,@-unsaturated lactam. There are several signals in the 'H-NMR spectrum of the free base: Two signals of olefinic protons present as a doublet of triplets at 6 5.73-6.25 and 3.74-3.26 (H-17e and H-11). The signals for H-2e, H-lOe, and H-17a occur at 6 2.86-2.30. Nonoverlapping multiplet signals occur at 6 2.24-0.82. The mass spectrum is characterized by the molecular ion peak at mlz 246 (83%) and by ion peaks at mlz 245 (loo), 231 (8.1), 217 (9.1), 203 (13.4), 192 (3), 188 (4.3, 177 (82), 160 (12), 150 (91), 138 (53), 122 (20), 98 (18), and 96 (78%). This MS decay pattern is typical for quinolizidine alkaloids of the matrine group. The ions with mlz 217 and 203


2-g-2 N N 3 N

0 193 30 8

SCHEME 35

speak for the presence of a double bond in ring D. (219,220). 13,14-De- hydrosophoridine (30) is converted to sophoridine (8) on catalytic hydrogenation in the presence of Raney nickel or PtO, in acetic acid (Scheme 35). The N-oxide of 13,14-dehydrosophoridine (193) was obtained from Sophoru alopecuroides L. (221).

I. ( -)-NEOSOPHORAMINE

Neosophoramine was isolated from Sophoru alopecuroides L. (191,207,222,223). There are no trans-quinolizidine bands in the IR spectrum, but there is a lactam carbonyl absorption band at 1650 cm- l. The MS spectrum is characterized by peaks of the molecular ions M + (244) and M + - 1 (243) and by ion peaks at m / z 215, 149, 136, and others, typical for matrine alkaloids containing an a-pyridine ring. A comparative study of UV, IR, 'H-NMR, and mass spectroscopic data of neosophoramine (194), sophoramine (199, and isosophoramine (196) showed that these alkaloids differ mainly in the configuration $ g g N N

194 195 196

of the A/B part of the molecule. The configurations of the three steroisomeric alkaloids was confirmed by an analysis of mass spectra of daughter ions (DADJ) (224).

J. (-)-7,8-DEHYDROSOPHORAMINE

7,8-Dehydrosophoramine was isolated from Sophora flavescens Ait. (225). The IR spectrum of the base is characterized by the presence of an a-pyridone


197 195 SCHEME 36

ring (1650, 1570, 1535 cm- I ) . 7,8-Dehydrosophoramine (197), on catalytic hydrogenation over Pd/C benzene, gave sophoramine (195) (Scheme 36). The NMR spectrum of 197 showed signals of four olefinic protons (6 6.0,6.07,6.57, 6.85). The signal at 6 6.0 (multiplet) overlapped with the multiplet of H-12 and was attributed to the proton of the double bond conjugated with a-pyridone ring.

K. ( -)-ALBERTINE

Albertine, isolated from Leontice Albertii Rgl. (216,226,227), is an optically active monoacidic tribase. There are the absorption bands at 1655 (lactam carbonyl), 1675 (double bond), 2795-2760 (truns-quinolizidine), and 3300 cm- ] (hydroxyl group) in the IR spectrum. The UV spectrum shows an absorption maximum at 224 nm (log E = 4.2) for a -C=C-N-C=O group. Albertine (198), on catalytic hydrogenation over PtO, in acetic acid, gave dihydroalbertine (199) (Scheme 37). Reduction of 199 with LAH gave deoxo base 200. The spectrum of this last compound lacked the double bond protons, while the band of the hydroxyl group was shifted to 3150 cm-'. Dihydroalbertine (199), on heating with P,O,, gave an anhydro base found to be identical to sophocarpine (201) by UV and MS analysis (227). Desoxohydroalbertine (200) on dehydration afforded 202, which gave matridine (157) on catalytic hydrogenation with PtO,. The position of the hydroxyl group in albertine was proved by dehydration with phosphorus anhydride, giving 195.

L. ( +)-ALBERTAMINE, ( -)-LEONTALBAMINE, AND

(+ )-LEONTISMIDINE

(+)-Albertamine, (-)-leontalbamine, and (+)-leontismidine were isolated from Leontice ulbertii and L. Smirnovii (228,229). They have the same composition, CI5H,,N,O,. The IR spectra of these alkaloids are characterized by the absorption bands giving evidence for the presence of hydroxyl and amide carbonyl groups. There is also absorption (except in the albertamine spectrum) in the region of 2700-2800 cm- attributed to trans-quinolizidine systems. The UV spectra show absorption maxima at 220 nm.

Reduction of albertamine (203), leontalbamine (204), and leontismidine (205)


202 187 200

\goH N $OH N

198 J 199 /

20 1 195 SCHEME 37

with LAH gave the deoxo bases 206, 207, and 208, respectively (Scheme 38). Their mass spectra resembled those of saturated matridines. The ion peaks in the spectra of these deoxo bases coming from the lactam portion were shifted by 16 mass units. Heating deoxobases 206, 207, and 208 with P,O, gave anhydro bases 209, 210, and 211, which afford desoxodarvasamine (212), allomatridine (213), and sophoridane (214), respectively, on catalytic hydrogenation. De- hydration of 203,204, and 205 gave anhydro products 215,216, and 30 with UV spectra typical for ol,P-unsaturated lactams. On the basis of a comparative study of IR and MS spectra of these bases and 5-hydroxymatrine, it was suggested that the hydroxyl groups be located at C-13.

M. (+)-9Ci-HYDROXYMATRINE

9a-Hydroxymatrine was isolated from Sophora macrocarpa (24). It shows IR absorption bands typical for a hydroxyl group, lactam carbonyl, and


6 N

215

203

t no"

N 206

1 Pl

209 I

1 p" N . 3

8 H N

216

O f i O H (g N

204

& 207

I &$ N

210

I &$ N

30

205

&OH 208 N

1 8 21 1

1 n

M

212 213 SCHEME 38

214


217

trans-quinolizidine. MS fragments were typical for a matridine skeleton: M +

(100%) with a peak at (M - 1) + , average intensity signals at m/z 96, and a weak signal at mlz 98. Comparison of the I3C-NMR spectrum of matrine with that of the new alkaloid showed close similarity; the slight difference observed might best be explained by the presence of an equatorial hydroxyl group at C-9. NOE experiments also supported the structure of 9a-hydroxymatrine (217).

N. (-)-3a-HYDROXYSOPHORIDINE

3a-Hydroxysophoridine was isolated from Sophora alopecuroides L. (230). The mass spectrum is characterized by the peaks at m/z 264 M+ (78%), 263 (M - 1) (loo%), 205, 193, 166, M - 17, etc. The type of fragmentation allows classification of the base into the alkaloids of the matrine series with sophoridine configuration (231,232). 3a-Hydroxysophoridine (218) differs in molecular weight from that of sophoridine (8) by 16 mass units. This also speaks for the

21 8 8

presence of hydroxyl group. The IR spectrum (3620 cm-l- hydroxyl, 2810 cm- trans-quinolizidine, 1620 cm- lactam carbonyl) is very similar to that of sophoridine and differs from the latter only by the additional absorption band at 3620 cm-'.

The fact that 3a-hydroxysophoridine belongs to the sophoridine series is also suggested by the similar optical rotation dispersion curves of the two alkaloids, characterized by a smooth negative shape in the region of 600-300 nm. The position of the hydroxyl group and its configuration were determined by IH- NMR analysis of 3a-acetoxysophoridine. The signal of the proton at the carbon with the acetoxy group showed as a multiplet centered at 6 4.82. The value of J


= 25 Hz gave evidence that the proton was axial with two methylene groups in the a positions. Double resonance spectroscopy and chemical shifts proved the methylene group to be adjacent to the nitrogen atom and together with the MS spectra allowed assignment of the hydroxyl group in 3a-hydroxysphoridine to c-3.

0. ( +)-DARVASOLINE AND ( +)-LEONTISMINE

Darvasoline was isolated from Leontice Albertii Rgl. (233) and leontismine was obtained from L. Smirnovii Traut. (234). Both alkaloids have the same elemental composition (C,,H,,N,O,), and their spectral characteristics are very similar. The IR spectra showed bands of a hydroxyl group, lactam carbonyl, and trans-quinolizidine. Mass spectra also were identical, and were typical for matrine alkaloids with a hydroxyl group. Reduction of darvasoline (219) and leontismine (220) by LAH gave bases without any oxygen and apparently identical to matridine (187) to leontane (221), respectively (Scheme 39). Heating of darvasoline and leontismine with P,O, resulted in dehydration with simultaneous dehydrogenation and formation of sophoramine (195) and isosophoramine (196), respectively. This points to the presence of hydroxyl groups in both alkaloids considered to be steroisomers at C-11.

n & N H

187 219 195

c- 8- N H

221 220

SCHEME 39

196


P. (+)-5a,!h-DIHYDROXYMATRINE

5a,9a-Dihydroxymatrine was isolated from Euchresta horsfeldii (235). There are absorption bands of two hydroxyl groups (3400 and 3250 cm-I), a lactam carbonyl (1602 cm- I ) , and a trans-quinolizidine (2700-2800 cm- l) in IR spectrum of the base. The 'H-NMR spectrum is identical to that of sophoranole (5a-hydroxymatrine) and is characterized by the presence of one additional hydroxyl group at C-9. Structure 222 of this alkaloid is in agreement with these data.

222

Q. ( +)-SOPHORBENZAMINE

Sophorbenzamine, found in Goebelia pachycarpa C . A. Mey. (23), has a UV spectrum with maxima at 238 and 310 nm (log E = 4.10 and 4.16). The base is very similar to quinolizidine alkaloids with a a-pyridone ring in their structure. The IR spectrum of the base has typical absorption bands of carbon-carbon double bonds (1550, 1660 cm-'), an >N--CO group (1645 cm-l), a trans- quinolizidine system (2580, 2630, 2700 cm-l), and an a-pyridone ring (810 cm- l ) . Oxidation with chromic acid gave succinic and benzoic acids. Glycine, p-alanine, and a-aminobutyric acid also were obtained and identified by chromatography. This result is characteristic of quinolizidine alkaloids, and the appearance of benzoic acid speaks for the presence of an aromatic ring in the molecule.

The mass spectrum of sophorbenzamine is characterized by the presence of the most intensive molecular ion peak at mlz 334. It should be noted that the (M - 1)+ peak was much smaller than that of the M+ ion. The ion peak at m / z 91 is a benzyl radical. The emergence of ion peaks at rn lz 305 (214 + 91) and 291 (200 + 91) and the bias of an m/z 149 peak suggested the benzyl group to be in ring D. The general pattern of the mass spectrum was similar to that of quinolizidine alkaloids of the matrine group. There were 18 signals in the 13C-NMR spectrum of sophorbenzamine which were assigned by analogy with spectra of other matrine alkaloids (11). Of particular interest were 8 signals between 162 and 102 ppm suggesting the presence of an a-pyridone ring and a benzyl group. Com- parison of the 13C-NMR spectrum of sophorbenzamine with those of other


n

quinolizidine alkaloids containing an a-pyridone ring showed that the benzyl group is attached to C-14 as shown in 223.

R. ( -)-GOEBELINE

Goebeline, isolated from Goebelia pachycurpa C. A. Mey. (236), contains one double bond. On catalytic hydrogenation goebeline converts to dihydrogoebeline. There are absorption bands of a trans-quinolizidine and lactam group in the IR spectra of both goebeline and dehydrogebeline. Reduction with LAH or electrolytic reduction gave deoxotetrahydrogoebeline. Comparison of the IR spectrum of deoxotetrahydrogoebeline with that of matridine showed close similarity. Dehydrogenation of goebeline with palladized asbestos gave octadehydromatrine (177).

Oxidation of dihydrogoebeline with chromic acid gave glutaric acid, while oxidation of goebeline gave succinic acid. The double bond in goebeline was therefore positioned in ring D between C-11 and C-12, as shown in 224. The fact that dihydrogoebeline was easily hydrolyzed with sulfuric acid to give goebelinic acid whereas goebeline was not supports this assignment. Another team of investigators, however, suggested the double bond in goebeline to be between C-13 and C-14, as shown in 225, and they supported their assignment by the UV

177 20 1 224 225

spectrum and the results of reduction with LAH, affording a saturated deoxo base (216). To establish the position of the double bond in goebelin an 'H-NMR comparison of sophocarpine (201) and goebeline was carried out (237).

The molecular weight of goebeline of 492, corresponding to the molecular composition C30H,,N,0, (238), however, suggested goebeline might be a di-


226

227

mer. Since in matrine alkaloids hydrogen atoms a to lactam carbonyls are easily exchanged by deuterium and goebeline did not show any shift in its M-+ peak when heated in D,O in the presence of potassium carbonate, the authors suggested the dimeric structure 226 to represent goebeline, linking a matridine molecule with a sophocarpine molecule at carbon atoms C-14. The analysis of other dimeric alkaloidal structures was also derived by deuterium exchange, and one linking C-13 of matrine with C-14 of sophocarpine is shown in 227 (238). Synthesis of goebeline from sophocarpine (201) by thermolysis (239) does not answer the location of the interconnection of the two molecules. A Fourier spectral analysis of goebeline, matridine, matrine, and sophocarpine in the presence of europium shift-reagents proved structure 227 of a 13,14-13r,14r-di- dehydrodimatrine to be the correct structure of goebeline (20).

Acknowledgments

Our appreciation is expressed to F. Kamayev for assistance in writing Section 11, ‘‘I3C-NMR Spectroscopy of Quinolizidine Alkaloids,” and to B. Ibragimov for assistance in writing Section 111, “X-Ray Structural Investigation of Quinolizidine Alkaloids. ”

REFERENCES

1 . Bohlmann, F., and Schumann, D. (1967). In “The Alkaloids” (R. H. F. Manske, ed.), Vol. 9, pp. 175-222. Academic Press, New York.


2. Dopke, W. (1976). “Ergebnisse der Alkaloid-chemie (1960-1968),” Vol. 1, pp. 220-270.

3. Saxton, J. E. (1975). Alkuloids (London) 5, 93-102. 4. Grundon, M. F. (1976). Alkaloids (London) 6 , 90-102. Grundon, M. F. (1977). Alkaloids

(London) 7, 69-80. Grundon, M. F. (1978). AZkuloids (London) 8, 66-76. Grundon, M. F. (1979). Alkaloids (London) 9,69-77. Grundon, M. F. (1984). Alkaloids (London) 11,63-70.

4a. Sadykov A. S., Aslanov Kh. A., and Kushmuradov, Yu. K. (1975). “Alkaloids of Quinolizidine Series.” Science, Moscow.

5. Grabb, T. A. (1975). “Annual Reports on NMR Spectroscopy,” Vol. 6A, p. 249. Academic Press, New York.

6. Grabb, T. A. (1978). “Annual Reports on NMR Spectroscopy,” Vol. 8, p. 2. Academic Press, New York.

7. Levy, G. C., and Nelson, G. L. (1972). “Carbon-13 Nuclear Magnetic Resonance for Organic Chemistry,” Topics I and 11. Wiley, New York.

8. Wehrli, F. W., and Wirthlin, T. (1978). “Interpretation of Carbon-13 NMR Spectra,” L. Heyden.

9. Bates, R. B. (1981). “Carbon-13 NMR Spectral Problems.” The Human Press, Crescent Manor.

Akademic Verlag, Berlin.

10. Shoolery, J. N. (1984). J . Nut. Prod. 47, 226-259. 11. Leont’ev, V. B., Kamaev, F. G., Subbotin, O., Ustynyuk, Yu. A,, Nesmeyanov, A. N., and

12. Mukhamedkhanova, S. J., Leont’ev, V. B., Kamaev, F. G., Aslanov, Kh.A., and Sadykov,

13. Wenkert, E., Bindra, J. S. , Chang, Ch. J . , Cochran, D. W., and Schell, F. M. (1974). Acc.

14. Wenkert, E., Chauney, B., Dave, K. G. , Jeffcoat, A. R., Schell, F. M., and Schenk, H. P.

15. Bohlmann, F., and Zeisberg, R. (1975). Chem. Ber. 108, 1043-1051. 16. Wenkert, E., Chang, C. I., Chawla, H. P. S., Cochran, D. W., Hagaman, E. W., Ksing, J.

C., and Onto, K. (1976). J . Am. Chem. SOC. 98, 3645-3655. 17. Pai, B. R., Natarajan, K., Suguna, H., andNatarajan, S. (1977). Heterocycles6, 1377-1439. 18. T o m e , D., and van Binst, G. (1978). Heterocycles 9, 507-533. 19. Broadbent, T. A., and Paul, E. G. (1983). Heterocycles 20, 863-980. 20. Sadykov, A. S . (1983). Izvest. Akud. Nauk S.S.S.R., Ser. Khim., 2432-2456. 21. Murakoshi, J . , Kidogushi, E., Nakamura, M., Haginiwa, J:, Ohmija, S., Higashijama, K.,

22. Murakoshi, J., Kidogusbi, E., Haginiwa, J., Ohmija, S., Higashijama, K., and Otomasu, H.

23. Abdusalamov, B. A., Khoraschkova, 0. A., and Aslanov, Kh. A. (1976). Khim. Prir.

24. Negrete, R., Cassels, B. K., and Eckhardt, G. (1983). Phytochernistry 22, 2069-2072. 25. Skolik, J. J . , and Podhowinska, H. M. (1981). Acta Nut. Prod. Sofia 3/1, 362-366. 26. Kamaev, F. G., Kuchkarov S. , Kuschmuradov, Yu. K., and Aslanov, Kh.A. (1981). Khim.

27. Morishima, J., Yoshikawa, K., Okuda, K., Yonezawa, T., and Goto, K. (1979). J . Am.

28. Batchelor, J. G. (1975). J . Am. Chem. SOC. 97, 3410-3415. 29. Seidman, K., and Maciel, G. E. (1977). J . Am. Chem. SOC. 99, 3254-3263. 30. Sugiura, M., and Sasaki, Y. (1976). Chem. Pharm. Bull. 22, 2988-2992. 31. Arata, Y., Aoki, T., Hanaoka, M., and Kamei, M. (1975). Chem. Pharm. Bull. 23,333-337.

Sadykov, A. S. (1972). Abstr. 8th Int. Symp. Chem. Nut. Prod. New Delhi, p. 47.

A. S. (1973). Abstr. 11th Eur. Symp. Mol. Spectrosc., Tallin, p. 138.

Chem. Res. 7, 46.

(1973). J . Am. Chem. SOC. 95, 8427-8436.

and Otomasu, H. (1981). Phytochemistry 20, 1725-1730.

(1982). Phytochemistry 21, 2379-2384.

Soedin., 71-74.

Prir. Soedin., 604-608.

Chem. SOC. 95, 165-171.


32. Arata, y . , Hanaoka, M., and Kim, S. K. (1975). Chem. Phurm. Bull. 23, 1142-1 145. 33. Lalonde, R. T., Donvito, T. N., and Tsai, A. J. (1975). Can. J . Chem. 53, 1714-1725. 34. Podkowinska, H., and Skolik, J. (1984). Org. Mugn. Resotz. 22, 379-384. 35. Yunusov, T. K., Leont’ev, v. B., Kamaev, F. G., Aslanov, Kh. A., and Sadykov, A. s.

(1972). Khim. Prir Soedin., 477-483. 36. Leont’ev, v. B., Kamaev, F. G., Mukhamedkhanova, S. I., and Sadykov, A . s. (1979). in

“Modem Successes in High Resolution NMR Spectroscopy” P. 9. Uzb.S.S.R., Tashkent, 37. Mukhamedkhanova, s. I., Ananchenkov, v. I . , Leont’ev, V. B., and Sadykov, A. s. (1977).

Abstr. 7th Int. Conf. At. Spectrosc. Prague, p. 404. 38. Kamaev, F. G., Kuschmuradov, Yu. K., Aslanov, Kh. A., and Sadykov, A. S. (1978). Abstr.

11th Int. Symp. Chem. Nut. Prod., Golden Sands, Bulgaria 2, 269-270. 39. Kamaev, F. G., Leont’ev, V. B.. Kuschmuradov, Yu. K., and Aslanov Kh. A . (1979). In

“Modern Successes in High Resolution NMR Spectroscopy,” p. 92. Uzb.S.S.R., Tashkent. 40. Ohmija, S. , Otomasu, H., Haginiva, I., and Murakoshi, I. (1980). Chem. Pharm. Bull. 28,

546-55 1. 41. Yunusov, T. K., Matweeva, A. P., Leont’ev, V. B., Kamaev, F. G., Aslanov, Kh. A,, and

Sadykov, A. S. (1972). Khim. Prir. Soedin., 200-207. 42. Przybylaska, M., and Barnes, W. H. (1953). Actu Crytullogr. 6 , 377-384. 43. Przybylska, M. (1974). Acta Crystullogr., Sect. B 30, 2455-2459. 44. Borowjak, I. (1973). Roczniki Chem. 47, 1575-1576. 45. Borowjak, I., Bokij, N. G., and Struchkov, Yu. T. (1973). Zh. Strukt. Khim. 14, 387-388. 46. Pyzalska, D., Cawron, M., and Borowjak, I. (1979). Actu Crystullogr., Sect. B 35,256-258. 47. Srivastava, S . , and Przybylska, M. (1969). Acta Crystullogr., Sect. B 25, 1651-1659. 48. Pinkerton, J. M., and Steinrauf, L. K. (1967). J . Org. Chem. 32, 1828-1832. 49. Childers, L., Folting, K., Merritt, L., and Streib, W. (1975). Actu Crystullogr., Sect. B 31,

50. Katrusiak, A., Kaluski, Z., Pietrzak, P., and Skolik, I. (1983). J . Cryst. Spectrosc. Res. 13,

51. Mosquera, R., Castedo, L., and Ribas, I. (1974). Ann. Quim. 70, 609-614. 52. Langowska, K., Skolik, I., and Wiewiorowski, M. (1977). Bull. Pol. Acad. Sci. Ser. Chim.

53. Majechrzak-Kuezynska, U., Koziol, A. E., Langowska, K., and Wiewiorowski, M. (1984).

54. Doucerain, H., and Riche, A. C. (1976). Acta Crystullogr., Sect. B 32, 3213-3215. 55. Pyzalska, D., Gawran, M., and Borowjak, T. (1983). J . Cryst. Spectrosc. Res. 13, 31-41. 56. Gawron, M., Borowjak, T., Pyzalaska, D., and Wysocka, W. (1983). J . Cryst. Specrrosc.

57. Skrzypczak-Iankun, E., and Kaluski, 2. (1978). Acra Crystullogr., Sect. B 34, 2651-2653. 58. Kaluski, Z., Garbarczyk, I., Gusev, A. I., Struchkov, Yu. T., Skolik, I., and Wiewiorowski,

59. Kaluski, Z. , Gusev, A. I., Struchkov, Yu. T., Skolik, I., and Wiewiorowski, M. (1972). Bull.

60. Garbarczyk, I., Kaluski, Z., Bratek-Wiewiorowski, M. D., Skolik, I., and Wiewiorowski, M.

61. Kadaoka, M., Chang, M. Y., Fukami, H. , Scheuer, P. I., Clardy, I . , Solheim, B. A., and

62. Bimbaum, G. I., Cheung, K. K., Weiwiorowski, M., and Bratek-Wiewiorowski, M. D.

63. Cheklov, A. N., Struchkov, Yu. T., and Kitaigorodskii, A. I. (1974). Zh. Strukt. Khim. 15,

924-925.

15 1- 163.

25, 11-18.

Bull. Pol. Acad. Sci. Ser. Chim. 32, 233-253.

Res. 13, 165-172.

M. (1977). Bull. Acad. Pol. Sci. Ser. Chim. 25, 347-357.

Acud. Pol. Sci. Ser. Chim. 20, 1-14.

(1974). Bull. Acud. Pol. Sci. Ser. Chim. 22, 651-664.

Springer, I. P. (1976). Tetrahedron 32, 919-924.

(1967). J . Chem. Soc. B , 1368-1374.

877-885.


64. Cheklov, A. N., Kaluski, Z. , Struchkov, Yu. T., Wolinska-Motsyldljz, I . , and Kitaigorodskii,

65. Cheklov, A. N., Struchkov, Yu. T., and Kitaigorodskii, A. I. (1975). Kristallographiju 20,

66. Bordner, I., Ohmija, S. , Otomasu, H., Haginiwa, I., and Murakoshi, I. (1980). Chem. Phurm.

67. De Kok, A. I., Romers, C., and van Eijk, I. L. (1982). Acta Crystullogr., Sect. B 38, 466-

68. Ibragimov, B. T., Talipov, S. A., Tichchenko, G. N., Kuschmuradov, Yu. K., and Aripov, T.

69. Ibragimov, B. T., Talipov, S. A., Tichchenko, G. N., and Kuschmuradov, Yu. K. (1979).

70. Ibragimov, B. T., Tichchenko, G . N., Kuschmuradov, Yu. K., Aripov, T. F., and Sadykov,

71. Ibragimov, B. T., Talipov, S. A., Kuschmuradov, Yu. K., and Aripov, T. F. (1978). Khim.

72. Ibragimov, B. T., Tichchenko, G. N., Kuschmuradov, Yu. K., Aripov, T. F., and Sadykov,

73. Ibragimov, B. T., Tichchenko, G. N., Talipov, S. A,, Kuschmuradov, Yu. K., Aripov, T. F.,

74. Ibragimov, B. T., and Talipov, S. A., Tichchenko, G . N., Kuschmuradov, Yu. K., and

75. Ibragimov, V. T., Tichchenko, G. N., Talipov, S. A., Kuschmuradov, Yu. K., and Aripov, T.

76. Ibragimov, B. T., Talipov, S. A,, Tichchenko, G. N., Kuschmuradov, Yu. K., Aripov, T. F.,

77. Ibragimov, B. T., Talipov, S. A,, Kuschmuradov, Yu. K., and Aripov, T. F. (1981). Khim.

78. Ibragimov, B. T., Talipov, S. A., Kuschmuradov, Yu. K. , Aripov, T. F., and Kuchkarov, S.

79. Ueno, A., Morinaga, K., Fukusihima, S . , Jitaka, Y . , Koiso, Y., and Okuda, S. (1975). Chem.

80. Morinaga, K., Ueno, A., Fukushima, S . , Namikoshi, M., Jitaka, Y., and Okuda, S. (1978).

81. Ibragimov, B. T., Tichchenko, G . N., Kuschmuradov, Yu. K., Talipov, S. A,, and Aripov, T.

82. Ribas-Merques, I., and Requeiro-Gareia, M. (1971). An. Quim. Real. SOC. ESP. Fis. Qutm.

83. Batra, V., and Rajagopalan, T. R. (1976). Zndian J . Chem. 14B, 123-124. 84. Kinghom, A. D., Selim, M. A., and Smolenski, S. J . (1980). Phytochemistry 19,1705-1710. 85. Hatfield, G. M., Valdes, L. I., Keller, W. I., Memll, W. L., and Jones, V. N. (1977). J . Nut.

86. Baurgeois, I., Faugeras, G., Paris, R. R., and Dobremez, I. F. (1979). Plant Med. Phytother.

87. Beck, A. B., Goldspink, B. H., and Knox, I. R. (1979). J . Nut. Prod. 42, 385-398. 88. Takehisa, K . , and Shun-Ichi, V. (1967). Chem. Pharm. Bull. 15, 240-242. 89. Tamelen, E., and Foltz, R. (1969). J . Am. Chem. SOC. 91, 7372-7377. 90. Yasuhiro, Y., Kota, H., and Masanao, M. (1971). Agric. Biol. Chem. 35, 285-286. 91. Tufariello, I., and Tegeler, I. I. (1976). Tetrahedron Lett., 4037-4040. 92. Okita, M., Wakamatsu, T., and Ban, Y. (1983). Heterocycles 20, 401-404.

A. I. (1974). Zh. Strukt. Khim. 15, 950-952.

75 1-757.

Bull. 28, 1965-1968.

468.

F. (1978). Kristallographija 23, 1189-1 195.

Kristallographija 24, 45-51.

A. S. (1979). Khim. Prir. Soedin., 416-417.


A. S. (1979). Khim. Prir. Soedin., 355-362.

and Kuchkarov, S. (1981). Khim. Prir. Soedin., 588-596.

Aripov, T. F. (1979). Khim. Prir. Soedin., 588-590.

F. (1981). Khim. Prir. Soedin., 460-465.

and Kuchkarov, S. (1981). Khim. Prir. Soedin., 751-757.


(1981). Khim. Prir. Soedin., 757-763.

Pharm. Bull. 23, 2560-2566.

Chem. Phurm. Bull. 26, 2483-2488.

F. (1982). Khim. Prir. Soedin., 71-75.

61, 93-99.

Prod. 40, 374-383.

13, 87-91.


93. Bremmer, M. L., and Weinreb, S. M. (1983). Tetrahedron Lett., 261-264. 94. Podkowinska, H., and Wiewiorowski, M. (1965). Bull. Acad. Pol. Sci., Ser., Sci. Biol. 13,

95. Murakoshi, I., Sugimoto, K., Haginiwa, I., Ohmija, S. , and Otomasu, H. (1975). Phy-

96. Murakoshi, I., Ogawa, M., Toriizuka, K., Haginiwa, I., Ohmija, S., and Otomasu, H. (1977).

97. Murakoshi, I., Kakegawa, F., Toriizuka, K . , Haginiwa, I., Ohmija, S., and Otomasu, H.

98. Murakoshi, I., Toriizuka, K., Haginiwa, I., Ohmija, S., and Otomasu, H. (1978). Phy-

99. Murakoshi, I., Toriizuka, K., Haginiwa, I., Ohmija, S. , and Otomasu, H. (1979). Phy-

100. Murakoshi, I., Toriizuka, K., Haginiwa, I., Ohmija, S., and Otomasu, H. (1979). Chem.

101. Hart, N. K., Johns, S. R., and Lamberton, I. A. (1968). Aust. J. Chem. 21, 1619-1624. 102. Keller, W. I. (1980). Phytochemistry 19, 2233-2234. 103. Hart, N. K., Johns, S. R., and Lamberton, I. A. (1968). Chem. Commun., 302. 104. Gamada, G., Kota, H., and Massana, M. (1970). Agric. Biol. Chem. 34, 1536-1542. 105. Goldberg, S. I., and Lipkin, A. H. (1970). J. Org. Chem. 35, 242-244. 106. Wenkert, E., and Jeffcoat, A. R. (1970). J . Org. Chem. 35, 515-517. 107. Murakoshi, I., Ito, M., Haginiwa, I., Ohmija, S., Otomasu, H., and Hirano, R. T. (1984).

108. Van Eijk, I. L., Radema, M. H., and Versluis, C. (1976). Tetrahedron Lett., 2053-2054. 109. Van Eijk, I. L., and Radema, M. H. (1976). Pharm. Weekbl. 111, 1285-1289. 110. Slosse, P., and Hootele, C. (1978). Tetrahedron Lett., 397-398. 111. Slosse, P., and Hootele, C. (1979). Tetrahedron Lett., 4587-4588. 112. Braekman, I. C., Daloze, D., Macedo de Abreu, P., Piccinni-Leopardi, C., Germain, G., and

113. Braekman, I. C., Daloze, D., Defay, N., and Zimmermann, D. (1984). Bull. SOC. Chim. Belg.

114. Panov, P. P., Panova, L. N., and Mollov, N. M. (1972). C. R. Acad. Sci. Bulg. 25, 55-57. 115. Mollov, N. M., and Ivanov, I. C. (1970). Tetrahedron 26, 3805-3808. 116. Mollov, N. M., and Ivanov, I. C. (1970). Abstr. 7th Int. Symp. Chem. Nut. Prod., Riga, p.

117. Bohlmann, F. (1959). Chem. Ber. 92, 1798-1808. 118. Ohmija, S., Higashijama, K., Otomasu, H., Haginiwa, I., and Murakoshi, I. (1979). Chem.

119. Ohmija, S . , Higashijama, K., Otomasu, H., Haginiwa, I., and Murakoshi, I. (1981). Phy-

120. Murakoshi, I., Kidogushi, E., Haginiwa, I., Ohmija, S., Higashijama, K., and Otomasu, H.

121. Murakoshi, I., Kidoguchi, E., Ikram, M., Israr, M., Shafi, N., Haginiwa, I., Ohmija, S., and

122. Ohmija, S . , Otomasu, H., Murakoshi, I . , and Haginiwa, I. (1974). Phytochemistry 13, 1016. 123. Ohmija, S . , Otomasu, H., Murakoshi, I., and Haginiwa, I. (1974). Phytochemistry 13, 643-

124. Murakoshi, I., Watanabe, M., Haginiwa, I., Ohmija, S., and Otomasu, H. (1982). Phy-

125. Murakoshi, I., Fukuchi, K., Haginiwa, I., Ohmija, S . , and Otomasu, H. (1977). Phytochemis-

623-627.

tochemistry 14, 2714-2715.

Chem. Pharm. Bull. 25, 527-529.

(1977). Phytochemistry 16, 2046-2047.

tochemistry 17, 18 17- 18 18.


Pharm. Bull. 27, 144-146.

Phytochemistry 23, 887-891.

Van Meersche, M. (1982). Tetrahedron Lett., 4277-4280.

93, 941-944.

542.

Pharm. Bull. 27, 1055-1057.


(1981). Phytochemistry 20, 1407-1409.

Otomasu, H. (1982). Phytochemistry 21, 1313-1315.

644.


try 16, 1460-1461.


126. Murakoshi, I., Kidoguchi, E., Kubota, M., Haginiwa, I., Ohmija, S. , and Otomasu, H.

127. Van Eijk, I. L., and Radema, M. H. (1982). Planta Med. 44, 224-226. 128. Van Eijk, I. L., De Kok, A. I., Romers, C., and Seykens, D. (1982). Planta Med. 44, 221-

129. Keller, W. I., and Hatfield, M. (1979). Phytochemistry 18, 2068-2069. 130. Knofel, D. (1971). “Abhandlungen der Deutschen Akademie der Wissenschaften zu Berlin, 4

Intemationales Symposium, Biochemie und Physiologie der Alkaloide, Halle (Saale),” Vol. B, S. 477. Akademie Verlag, Berlin.

(1982). Phyrochemistry 21, 2385-2388.

223.

131. Knofel, D., and Schiitte, H. R. (1971). J . Prakt. Chem. 312, 887-895. 132. Shaimardanov, R. A., Iskandarov, S. , andYunusov, S. Yu. (1970). Khim. Prir. Soedin., 276-

133. Shaimardanov, R. A., Yunusov, S. Y., and Iskandarov, S. (1971). Khim. Prir. Soedin., 169-

134. Kusshmuradov, Yu. K., Pham Hoang Ngok, Sadykov, A. S . , and Aslanov, Kh. A. (1968).

135. Primukhamedov, I., Gupta, P. C., Aslanov., Kh. A,, and Sadykov, A. S. (1968). Nauk. Tr.

136. Orazgel’diev, K., Aslanov, Kh. A,, Sadykov, A. S. , and Abdullaeva, D. A. (1969). Nauk. Tr.

137. Vinogradova, V. I., Iskandarov, S., and Yunusov, S. Yu. (1971). Khim. Prir. Soedin., 463-

138. Neuner-Iehle, N., Nesvadba, W., and Spiteller, G. (1964). Monatsh. Chem. 95, 687-709. 139. Pham Hoang Ngok, Kuschmuradov, Yu. K., Aslanov, Kh. A., and Sadykov, A. S. (1968).

140. Iskandarov, S . , Vinogradova, V. I . , Shaimardanov, R. A,, and Yunusov, S . Yu. (1972).

141. Ohmija, S . , Otomasu, H., and Murakoshi, I. (1984). Chem. Pharm. Bull. 32, 815-817. 142. Carmack, M., Goldberg, S. I., and Martin, E. M. (1967). J . Org. Chem. 32, 3045-3049. 143. Chulle Kim, I., Balandrin, M. F., and Kinghorn, A. D. (1982). J . Agric. Food. Chern. 30,

144. Bohlmann, F., Weiser, W., Sander, H., Hanke, H. G., and Winterfeldt, E. (1957). Chem.

145. Skolik, I., Wiewiorowski, M., and Jedrzeiczak, K. (1969). Bull. Acad. Pol. Sci. Ser. Sci.

146. Anderson, J. N., and Martin, R. 0. (1976). J . Org. Chem. 41, 3441-3444. 147. Wink, M., and Hartmann, Th. (1982). Z . Naturjorsch., C. Biosci. 37, 369-375. 148. Balandrin, M. F., and Kinghorn, A. D. (1982). Heterocycles 19, 1931-1934. 149. Nakano, T., Spinelli, A. C., and Mendez, A. M. (1974). J . Org. Chem. 39, 3584-3587. 150. Nakano, T., Azcunes, B. C., and Spinelli, A. C. (1976). Planta Med. 29, 241-246. 151. Kinghorn, A. D., and Smolenski, S. I. (1980). Planta Med. 38, 280-282. 152. Cho, Y. D., andMartin, R. 0. (1971). Can. J . Chem. 49, 265-270. 153. Hatfield, G. M., Keller, W. I., and Rankin, I. M. (1980). J . Nat. Prod. 43, 164-167. 154. Wink, M., Witte, L., Schiebel, H. M., and Hartmann, T. (1980). Planta Med. 38,238-245. 155. Goldberg, S. I., and Balthrs, V. M. (1969). Chem. Commun., 660-661. 156. Daily, A, , Dutschewska, H., Mollov, N., Spassov, S . , and Schumann, D. (1978).

157. Daily, A., Dutschewska, H., and Mollov, N. (1977). Planta Med. 32, 380-383. 158. Radema, M. H., van Eijk, I. L., Vermin, W., De Kok, A. I., and Romers, C. (1979).

159. Van Eijk, I. L., and Radema, M. H. (1972). Pharm. Weekbl. 107, 13-20.

277.

174.

Nauk. Tr. Tashk. Gos. Univ. 341, 95-98.

Tashk. Gos. Univ. 341, 102-108.

Samark. Univ. 167, 154-158.

466.


Khim. Prir. Soedin., 218-222.

796-798.

Ber. 90, 653-661.

Chim. 17, 201-207.

Tetrahedron Lett., 1453-1454.

Phytochemisrry 18, 2063-2064.


160. Radema, M. H. (1975). Planta Med. 28, 143. 161. Faugeras, G., Paris, R. R., and Peltier, M. (1974). Ann. Phurm. Fr. 32, 323-329. 162. Van Eijk, I. L., and Radema, M. H. (1977). Planta Med. 32, 275-279. 163. Van Eijk, I. L., and Radema, M. H. (1975). Planta Med. 28, 139-142. 164. Faugeras, G., and Paris, R. R. (1966). C. R. Acad. Sci. D 263, 436-438. 165. Faugeras, G., and Pans, R. R. (1968). C. R. Acad. Sci. D 267, 538-540. 166. Faugeras, G., and Paris, R. R. (1970). C. R. Acad. Sci. D 270, 203-204. 167. Faugeras, G., and Paris, R. R. (1970). C. R. Acad. Sci. D 271, 611-612. 168. Faugeras, G . (1971). Ann. Pharm. Fr. 29, 241-258. 169. Faugeras, G., and Paris, R. R. (1970). C. R. Acad. Sci. D 271, 1219-1220. 170. Faugeras, G., Paris, R. R., and Valdes-Bermejo, E. (1972). Ann. Pharm. Fr. 30, 527-533. 171. Faugeras, G., and Paris, R. R. (1972). An. Quim. Real. SOC. ESP. Fis. Quim. 68, 811-819. 172. Faugeras, G., Paris, R. R., Debray, M., Baurgeois, I., and Delabos, C. (1975). Plant Med.

173. Gaugeras, G., and Paris, R. R. (1971). Boissiera 19, 201-218. 174. Faugeras, G., and Pans, M. (1968). Ann. Pharm. Fr. 26, 265-275. 175. Faugeras, G . , and Paris, R. R. (1971). Plant Med. Phytother. 5, 134-146. 176. Faugeras, G., Paris, R. R., and Valdes-Bermejo, E. (1971). C. R. Acad. Sci. C 273, 1372-

177. Wink, M., and Hartmann, Th. (1982). Planta 156, 560-565. 178. Wemin, W. I., De Kok, A. I., Romers, C., Radema, M. H., and van Eijk, I. L. (1979). Acta

179. Pham Hoang Ngok, Kuschmuradov, Yu. K., Aslanov, Kh. A,, Sadykov, A. S . , Zyjautdinova,

180. Winogradova, W. I., Iskandarov, S . , and Yunusov, S. Yu. (1972). Khim. Prir. Soedin., 87-

181. Iskandarov, S. , Shaimardanov, R. A., andyunusov, S. Yu. (1971). Khim. Prir. Soedin., 631-

182. Tkechchelaschvili, E. C., and Mudzhiri, K. S. (1975). Khim. Prir. Soedin., 807-808. 183. Santamaria, I . , and Khuong-Huu, F. (1975). Phytochemistry 14, 2501-2504. 184. Iskandarov, S . , Shaimardanov, R. A,, and Yunusov, S. Yu. (1971). Khim. Prir. Soedin., 636-

185. Santamaria, I., and Khuong-Huu, F. (1978). Tetrahedron, 34, 1523-1528. 186. Waterman, P. G., and Faulkner, D. F. (1982). Phytochemistry 21, 215-218. 187. Kinghom, A. D., Balandrin, M. F., and Lin, L. I. (1982). Phytochemistry 21, 2269-2275. 188. Ryzhkova, V. K., and Proskurina, N. F. (1965). Khim. Prir. Soedin., 194-198. 189. Tokachev, 0. N., Monakhova, T. E., Scheichenko, V. I . , Kabanov, V. S. , Fesenko, 0. G.,

190. Kuchkarov, S., Kuschmuradov, Yu. K., Begischeva, A. I . , and Aslanov, Kh. A. (1976).

191. Kuchkarov, S . , and Kuschmuradov, Yu. K. (1979). Khim. Prir. Soedin., 413-414. 192. Bocharnikova, A. V., and Massagetov, P. S. (1964). Zh. Obshch. Khim. 34, 1025-1028. 193. Kuchkarov, S . , Kushmuradov, Yu. K., Aslanov, Kh. A , , and Sadykov, A. S. (1978). 5th

194. Novgorodova, N. Yu., Maeckh, S. Kh., and Yunusov, S . Yu. (1975). Khim. Prir. Soedin.,

195. Novgorodova, N. Yu., Maeckh, S. Kh., and Yunusov, S . Yu. (1975). Khim. Prir. Soedin.,

196. Kamalitdinov, D., Iskandarov, S . , and Yunusov, S . Yu. (1969). Khim. Prir. Soedin., 409-

Phytother. 9, 37-43.

1373.

Crystallogr., Sect. B 35, 1839-1842.

Z. S . , Zayikyn, V. G., and Wulfson, N. S. (1970). Khim. Prir. Soedin., 11 1-1 14.

92.

636.

639.

and Proskumina, N. F. (1975). Khim. Prir. Soedin., 30-37.


Soviet-Indian Symp. Chem. Nut. Prod., Abst., Erevan, p. 44.

435-437.

529-530.

412.


197. Kamalitdinov, D., Iskandarov, S. , and Yunusov, S. Yu. (1967). Khim. Prir. Soedin., 352. 198. Rulko, F . , and Proskurnina, N. F. (1961). Zh. Obshch. Khim. 31, 308-313. 199. Sadykov, A. S., Aslanov, Kh. A,, and Begischeva, A. I. (1967). Dokl. Akad. Nauk Uzb.

S.S.R., 25-27. 200. Begischeva, A. I., Petrochenko, 2. U., Aslanov, Kh. A , , and Sadykov, A. S. (1969). Khim.

Pri. Soedin., 455. 201. Aslanov, Kh. A., Sadykov, A. S . , Leont’ev, V. B., and Begischeva, A. I . (1969). Khim. Prir.

Soedin., 93-96. 202. Begischeva, A. I . , Petrochenko, Z. U., Aslanov, Kh. A, , and Sadykov, A. S. (1971). Khim.

Prir. Soedin., 452-455. 203. Begischeva, A. I., Aslanov, Kh. A, , Petrochenko, 2. U., and Sadykov, A. S . (1971). Khim.

Prir. Soedin., 55-59. 204. Begischeva, A. I., Aslanov, Kh. A , , and Sadykov, A. S. (1968). Khim. Prir. Soedin., 371-

373. 205. Iskandarov, S., Kamalitdinov, D., Iagudaev, M. R., andYunusov, S. Yu. (1971). Khim. Prir.

Soedin., 174-179. 206. Kamaev, F. G., Leont’ev, V. B., Aslanov, Kh. A, , Ustynjuk, Yu. A., and Sadykov, A. S.

(1974). Khim. Prir. Soedin., 744-751. 207. Kuchkarov, S., Kuschmuradov, Yu. K. , and Aslanov, Kh. A. (1977). Khim. Prir. Soedin.,

288. 208. Kojima, R., Fukushima, S. , Ueno, A, , and Saiki, Y. (1970). Chem. Pharm. Bull. 18, 2555-

2563. 209. Iskandarov, S . , and Yunusov, S. Yu. (1968). Khim. Prir. Soedin., 106-109. 210. Iskandarov, S., and Yunusov, S. Yu. (1969). Khim. Prir. Soedin., 132-133. 211. Zunnunzhanov, A., Iskandarov, S. , and Yunusov, S. Yu. (1974). Khim. Prir. Soedin., 373-

377. 212. Zunnunzhanov, A , , Iskandarov, S . , and Yunusov, S. Yu. (1971). Khim. Prir. Soedin., 851-

852. 213. Iskandarov, S., Nuritdinov, R. N., and Yunusov, S. Yu. (1964). Dokl. Akad. Nauk. Uzb.

214. Iskandarov, S., Nuritdinov, R. N., and Yunusov, S. Yu. (1966). Khim. Prir. Soedin., 66-67. 215. Bohlmann, F., Rahtz, D., and Amdt, Ch. (1958). Chem. Ber. 91, 2189-2193. 216. Iskandarov, S., Nuritdinov, R. N., and Yunusov, S. Yu. (1967). Khim. Prir. Soedin., 26-31. 217. Kuschmuradov, Yu. K., Aslanov, Kh. A. , and Kuchkarov, S. (1975). Khim. Prir. Soedin.,

218. Kuschmuradov, Yu. K., Kuchkarov, S.,and Aslanov, Kh. A. (1978). Khim. Prir. Soedin.,

219. Timbekov, E. Ch., and Aslanov, Kh. A. (1972). Khim. Rastitelnych Veschestv., Tashk. 4, 54-

220. Vul’fson, N. S., and Zaikin, V. G. (1976). Uspekhy Khim. 45, 187#-It;94. 221. Kuchkarov, S., Kuschmuradov, Yu. K. , Aslanov, Kh. A, , and Sadykov, A.S. (1977). Khim.

Prir. Soedin., 541-544. 222. Monakhova, T. E., Tolkachev, 0. N . , Kabanov, V. S., Perel’son, M. E., and Proskurnina, N.

F. (1974). Khim. Prir. Soedin., 472-476. 223. Monakhova, T. E., Tolkachev, 0. N., Kabanov, V. S . , and Proskurnina, N. F. (1974). Khim.

Prir. Soedin., 259-260. 224. Kuschmuradov, Yu. K. , Eschbayev, Ph. Sch., Kasymov, A. K. , and Kuchkarov, S. (1979).

Khim. Prir. Soedin., 353-355. 225. Ueno, A., Morinaga, K., Fukushima, S. , and Okuda, S. (1978). Chem. Pharm. Bull. 26,

1832- 1836.

S.S.R., 32-33.

377-380.

23 1-233.

65.


226. Iskandarov, S . , and Yunusov, S. Yu. (1968). Khim. Prir. Soedin., 137-138. 227. Iskandarov, S. , Kamalitdinov, D., and Yunusov, S. Yu. (1972). Khim. Prir. Soedin., 628-

631. 228. Sadykov, B., Iskandarov, S . , and Yunusov, S. Yu. (1974). Khim. Prir. Soedin., 377-381. 229. Yunusov, S. Yu. (1981). Alkaloids (Uzb. S.S.R., Tashk. 146. 230. Monakhova, T. E., Proskurnina, N. F., Tolkachev, 0. N., Kabanov, V. S. , and Perel’son, M.

E. (1973). Khim. Prir. Soedin., 59-64. 231. Vul’fson, N. S . , Ziyavidinova, Z. S . , and Zaikin, V. G. (1974). Khim. Heterosikl. Soedin.,

25 1-260. 232. Iskandarov, S . , Raschkes, Ya. V., Karnalitdinov, D., and Yunusov, S. Yu. (1969). Khim.

Prir. Soedin., 331-332. 233. Zunnunzhanov, A,, Iskandarov, S.,and Yunusov, S . Yu. (1974). Khim. Prir. Soedin., 115-

116. 234. Tkeshelashvili, E. C. , Iskandarov, S. , Mudzhiri, K. S . , and Yunusov, S. Yu. (1973).

Soobshch. Akad. Nauk. Gruz. S.S.R. 69, 357-359. 235. Ohmija, S. , Higashijama, K., Otomasu, H., Murakoshi, S . , and Haginiwa, I . (1979). Phy-

tochemistry 18, 645-657. 236. Pakanaev, Y. I., and Sadykov, A. S. (1961). Zh. Obsch. Khim. 31, 2428-2432. 237. Aslanov, Kh. A,, Kuschmuradov, Yu. K., Zainutdinov, U. N., and Sadykov, A. S. (1969).

238. Iskandarov, S . , Sadykov, B . , Rashkes, Ya. V., and Yunusov, S . Yu. (1972). Khim. Prir.

239. Sadykov, B., Iskandarov, S. , and Yunusov, S . Yu. (1975). Khim. Prir. Soedin., 606-610. 240. Wink, M., Hartmann, Th., Witte, L., and Rheinheimer, I. (1982). Z . Naturforsch. C: Biosci.

241. Rastogi, R . , and Rajagopalan, T. R. (1984). J . Indian Chem. Soc. 61, 918-919. 242. Fitch, L., Dolinger, P. M., and Djerassi, C. (1974). J . Org. Chem. 39, 2947-2979. 243. McLean, S. Lau, P. K., Cheng, S. K., and Murray, D. G. (1971). Can. J . Chem. 49, 1976-

244. Balandrin, M. F., Robbins, E. F., and Kinghom, A. D. (1982). Biochem. Sysr. Ecol. 10,307-

245. Solatino, A,, and Gottlieb, 0. R. (1980). Biochem. Syst. Ecol. 8, 133-147. 246. Wink, M., Hartmann, T., Witte, L., and Schiebel, H. M. (1981). J . Nat. Prod. 44, 14-20. 247. Batra, V., and Rajogopalan, T.R. (1976). Indian J . Chem. 14B, 636-637. 248. Rodriquez, F., Gonzalez, A., and Mendez, A. (1966). An. Real. Soc. Espan. Fis. Quim. B 62,

249. Mendez, A., Gonzalez, A,, and Rodriquez, F. (1971). Rev. Fac. Farm. Univ. Los Andes 8,

250. Kuschmuradov, Yu. K., GTOSS, D., and Schutte, H. R. (1972). Phyfochemistry 11, 3441-

251. Ohmija, S. , Otomasu, H., Haginiwa, I., and Murakoshi, I. (1978). Phytochemistry 17,2021-

252. Zainutdinov, U. N . , Aslanov, Kh. A,, Kuschmuradov, Yu. K., and Sadykov, A. S . (1968).

Dokl. Akad. Nauk. Uzb. S.S.R., 24-25.

Soedin., 347-350.

37, 1081-1086.

1978.

311.

853-856.

77-87.

3445.

2022.

Nauk. Tr. Taschk. Gos. Univ., 341, 117-121.

- CHAPTER 6 -

ALKALOIDS FROM ANTS AND OTHER INSECTS

ATSUSHI NUMATA

Osaka University of Pharmaceutical Sciences Osaka 580, Japan

AND

TOSHIRO IBUKA

Faculty of Pharmaceutical Sciences Kyoto University

Kyoto 606, Japan

I . Introduction 11. Occurrence and Function

A. Hymenoptera B . Lepidoptera C. Coleoptera (Beetles) D. Diptera (Flies and Mosquitoes) E. Orthoptera F. Hemiptera G. Blattariae (Cockroaches) H. Neuroptera I. Trichoptera (Caddisflies) J. Phasmida (Walking Sticks)

K. Isoptera (Termites) and Other Insects L. Arthropods Excluding Insects

M. Tabulation of Alkaloid Occurrences

A. Piperidines B . Pyrrolidines C. Pyrrolizidines D. Indolizidines E. Quinolines F. Xanthommatin G . Papiliochromes H. Coccinellines I. Adalines J. Pyrazines

K. Acyclic Amines L. Pederin

M. Isoxazoles N. Quinazolinones

111. Structure and Synthesis

193 THE ALKALOIDS, VOL. 31 Copynght 0 1987 by Academ~c Press, Inc.

All rights of reproduction in any form resewed.

194 ATSUSHI NUMATA AND TOSHIRO IBUKA

0. Pteridines and Purines P. Aristolochic Acid

References

I. Introduction

Quite a number of messages between members of the same or different species in animals are exchanged through the chemicals they produce. These molecules acting as chemical messengers are called ecomones ( I ) or semiochemicals (2) and are divided on a functional basis into pheromones, allomones, and kai- romones. Insects deliver many kinds of ecomones, of which a greater part is volatile terpenes. However, quite a number of alkaloids have been found as chemical messengers in insects, and the study of alkaloids acting as attractants, defensive substances, trail pheromones, alarm pheromones, and aggregation pheromones has advanced particulariy in ants. This chapter surveys these alkaloids in insects including ants and arthropods such as millipedes, spiders, scorpions, and centipedes. Reviews on arthropod alkaloids by Tursch, Braek- man, and Daloze (3) and by Jones and Blum (4) are useful sources on earlier work. The term alkaloid is used here in a very broad sense. The present review will cover biogenic amines, pigments, purines, tryptophan metabolites, and acyclic amines, some representatives of which are used for defenses and commu- nications in arthropods.

11. Occurrence and Function

A. HYMENOFTERA

1 . Ants (Formicidae)

a. Myrmicinae. Unlike most insects, Hymenoptera (ants and wasps) can be sources of monocyclic and bicyclic alkaloids. The poison glands of myrimicine ants belonging to the subfamily Myrmicinae include many kinds of alkaloids such as piperidines, pyrrolidines, indolizidines, pyrrolizidines, indoles , pyridines, pyrazines, and histamine. The venoms of fire ants, Solenopsis (Solenop- sis) species, are characterized by a predominance of 2-alkyl-6-methylpiperidines (1 and 2) , although some Solenopsis species belonging to the subgenus Di- plorhoptrum also contain the alkaloid (Table I).

The fire ant causes damage to a variety of crops and attacks livestock and human beings. The fire ant venom, secreted at the sting to human beings, is a potent necrotoxin, producing edema, pustule, and necrosis (3, and in addition possesses pronounced hemolytic (6), phytotoxic (3, insecticidal (8), antibac-

6. ALKALOIDS FROM ANTS AND OTHER INSECTS 195

terial (8), and antifungal (9) activities. It has been demonstrated that the predominant piperidine alkaloids of the fire ant venom are responsible for most of the activity. Thus, localized skin lesions are shown to be produced by four piperidines , cis-6-methyl-2-n-undecylpiperidine (lc) , transd-methyl-2- n-tridecylpiperidine (lf), cis-6-methyl-2-n-pentadecylpiperidine (lg), and cis-6-methyl-2-n-pentadecenylpiperidine (2c) (10). truns-6-Methyl-2-n-undecylpiperidine (Id), trans-6-methyl-2-n-tridecylpiperidine (If), and trans-6- methyl-2-n-pentadecylpiperidine (lh), named solenopsin A, B , and C, respectively, inhibit a number of the gram-positive bacteria to some degree, and solenopsin A (Id) and B (If) slightly inhibit some species of gram-negative bacteria (11). Five of the 2-alkyl-6-methylpiperidines produce an inhibition of growth of 13 fungi (9).

In addition to the above-mentioned properties, the piperidine alkaloids exhibit a wide range of physiological activities. Thus, neuromuscular transmission is shown to be blocked by l c and Id (12). Mitochondria1 respiration is decreased and oxidative phosphorylation uncoupled at low concentrations of l g (13), which, in addition to cis-6-methyl-2-(cis-6'-n-pentadecenyl)piperidine (2c), inhibits the reactions of the Na + ,K + -ATPase (14).

Venoms from the fire ants Solenopsis invicta and S. geminata are free of detectable histamine but possess histamine-release activity. This activity can account for the edema, itch, redness, warmth, and possibly the pain and burning sensations resulting from fire ant stings. And it can be attributed to the piperidines which constitute the major component of the venom. It has actually been proved that 6-methyl-2-n-undecylpiperidines (lc and Id), components of S. geminata, possess the histamine-release activity (15). Due to some of the above- mentioned various activities the piperidine alkaloids play roles as defensive compounds. In addition to 2-alkyl-6-methylpiperidines, their N-methyl derivatives (3) are found in S. pergandei, S. carolinensis, and S. conjurata, and 1- piperideine derivatives (6 and 7) in S. sp. A (Puerto Rico) and S. xyloni (Table I).

Thief ants, many species of Solenopsis (Diplorhoptrurn), steal brood from the nests of other species of ants (16,17). While invading the brood chambers and preying on the brood, the thief ants secrete a highly effective and long-lasting repellent secretion from the poison glands (18,19). The principal components of the poison gland secretion are 2,5-dialkylpyrrolidines (lo), which S. punc- taticeps, a species more closely related to thief ants than fire ants, also include along with 2,5-dialkyl-l-pyrrolines (12) in the poison gland (Table 11). Thus, S. (Diplorhoptrurn) fugax secretes trans-5-butyl-2-heptylpyrrolidine (1Oc) in order to effectively repel several species of host ants, and hence it is the key element in the raiding strategy of this thief ant (16,18,19).

Workers of pharaoh's ant, Monomorium pharaonis, utilize their poison gland secretion as an effective repellent in the same way as that of thief ants, Solenop- sis (Diplorhoptrum) species, in order to steal brood from the nests of other


species of ants. In addition to this repellent or defense function, the venom plays a role as trail pheromone for the workers and queens of M . phuruonis (16). The poison gland secretion contains four 2,5-dialkylpyrrolidines (10a, 10f, log, and 10h, named monomorine 11, 111, IV, and V, respectively) as well as two indolizidines (16a and 18, named monomorine I and VI) (Table 11). The major components, (52,9E)-3-butyl-5-methylindolizidine (16a) and trans-2-(5-hexenyl)-5-pentylpyrrolidine (100 (monomorine I and III), have both attractant and trail-following activities. A mixture containing monomorine I (10 pg) and 111 (100 ng) is significantly more attractive than either of the single compounds. The mixture also acts as a repellent toward other insects and elicits alarm behavior. Monomorine 111, which is much more abundant in queens than workers, acts as an aggregation pheromone (16,19-23a, b) . A terpene, faranal, from Dufour’s gland of the pharaoh’s ant, produces a much greater trail-following activity than that of monomorine (24) . The venom of other Monomorium species appears to be utilized as repellents for other ant species and has been shown to contain 2,5- dialkylpyrrolidines (lo), their N-methyl derivatives (ll), and 2J-diakyl- 1 -pyrrolines (12) (Table 11) (16,25).

Solenopsis (Diplorhoptrum) conjurutu and some other thief ants contain indolizidines and/or piperidines (Tables I and 11). (52,8E)-3-Heptyl-5-methylpyrrolizidine (48) has also been shown to be contained in the thief ant Solenopsis xenovenenum (Table IV). The poison glands of Aphaenogaster fulva and A. tennesseensis contain the tobacco alkaloid anabaseine (S), which functions as an attractant in A. fulvu (Table I) (26).

Leaf-cutting ants of the genera Attu and Acromyrmex use trail-marking pheromone while foraging. The pheromone of the Texas leaf-cutting ant, Attu texunu (Buckly), which is produced in the true poison gland (27,28), has been identified as methyl 4-methylpyrrole-2-carboxylate (14) (Table 11). This compound shows trail-following activity to most other attine species (29), and it has also been isolated from the worker abdomens of Attu cephalotes, A. sexdens rubropilosu, and Acromyrmex octospinosus (Table 11). The bioassay of a number of synthetic analogs of 14 suggests that greatest activity is obtained with compounds having a free NH, an adjacent ester function, and a substituent at ring position 4 (30,31).

In addition to the pyrrole (14), A. sexdens rubropilosu contains 3-ethyl-2,5- dimethylpyrazine (20b) (Table 111) as the major component of the trail pheromone. Attu sexdens sexdens also responds strongly to the pyrazine (20b) (32). Although Acromyrmex octospinosus also contains the pyrazine (20b) and its isomer, 3-ethyl-2,6-dimethylpyrazine (21b) (Table 111), these compounds do not produce trail-following responses. 3-Ethyl-2,5-dimethylpyrazine (20b) has been identified as a single component of the trail pheromone of eight species of Myrmicu (Table 111). The same compound (20b) as well as 2,5-dimethylpyrazine (20a) have also been identified as the trail pheromone of Tetrumorium cuespitum


(Table 111). A 70 : 30 mixture of 20a and 20b provides the highest activity in artificial trail-following tests (33).

The plant growth regulator, P-indolylacetic acid (IAA) (139), has been isolated and identified together with phenylacetic acid (PAA) from the metathoracic glands of myrmicine ants such as Atta sexdens, Myrmica laevinodis, and Acro- myrmex sp. (Table VIII). Analysis of the fungal garden cultivated by the leaf- cutting ants, A . sexdens, shows that these acids contribute to the ant-fungus symbiosis by promoting growth of the fungus (34).

b. Ponerinae, Formicinae, Dolichoderinae, and Myrmeciinae. A number of alkylpyrazines are isolated from the mandibular glands of the ponerine, formicine, dolichoderine and myrmeciine ants belonging to the subfamilies Ponerinae, Formicinae, Dolichoderinae, and Myrmeciinae, in addition to the myrmicine ant (Table 111). Pyrazines such as 3-isopentyl-2,5-dimethylpyrazine (20h) and 2,5-dimethyl-3-(2-methylbutyl)pyrazine (209, which are contained in the mandibular glands of the ponerine ants Odontomachus species, Hypoponera opacior, and Ponera pennsylvanica, the formicine ant Calomyrmex sp., and the myrmicine ant Wasmannia auropunctata (Table III), have been shown to act as alarm pheromones and/or defensive substances for the respective species (35- 40). In 0. troglodytes there is a caste-specific difference in the behavioral response to the pyrazines of the mandibular glands. The males retreat from the pyrazines whereas the workers are not only attracted to but attack the pheromone source (36).

The presence of a series of alkylamines and amides (114-120, 125-129) in the gasterothorax characterizes the two ponerine ants, Mesoponera species (Table VIII), which contain 3-isopentyl-2,5-dimethylpyrazine (20h) as the major exocrine compound in their heads (Table 111). The major amine is N-isoamyl-N- nonylamine (114). These compounds are perhaps utilized as defensive compounds against selected predators (41).

Actinidine (9a) has been identified as an anal gland product of three species of dolichoderine ants in the genera Conomyrma and Iridomyrmex (Table I). The venoms of ants of the Myrmecia species are rich in histamine (136) (Table VIII), which can act as a defensive substance, together with hemolytic, smooth-muscle-stimulating, and histamine-releasing components.

Pteridines are widespread in the animal kingdom, and particularly among insects (Table VI) (42). The red ants in the genera Formica, Lasius, and Rap- tiformica contain pteridines such as isoxanthopterin (67) and biopterin (70) (Table VI). One of the catecholamines, noradrenaline (133), is also detected from Formica rufa (Table VIII).

Skatole (140) has been extracted from the heads of workers of army ants, Neivamyrmex nigrescens (Dorylinae) (Table VIII). This compound, probably produced by the mandibular glands, repels several insectivorous

c. Dorylinae.


snakes and inhibits the growth of the bacterium Escherickia coli and the fungus Aspergillus parasiticus; it therefore may contribute to the survival of this ant (43).

Agitated soldiers of the myrmicine ant Pkeidole fallax also produce skatole (140). In addition, males of the formicine ants Lasius neoniger, L . aliensus, and Acanthomyops claviger produce mixtures of skatole (140) and terpenes which originated in the heads (Table VIII). These mixtures are discharged during mating flights and probably are used as mating pheromones (44).

2. Wasps and Bees

Many wasps belonging to the families Eumenidae, Sphecidae, Nyssonidae, Tiphiidae, and Larridae contain various alkylpyrazines (Table 111). The alkylpyrazines of the cephalic secretion of four species of eumenid wasps in the genera Ancistrocerus, Stenodynerus, Pseudodynerus, and Eumenes may have a role in the wasp’s presocial behavior, e.g., aggregating at nocturnal roosting sites (45).

The venoms of many kinds of bees, wasps, and hornets (the genera Vespa, Polistes, Vespula, Ropalidia, etc.) contain biogenic amines such as histamine (136), serotonin (141), and catecholamines in addition to polyamines such as putrescine (lll), spermidine (110), and spermine (112) (Table VIII). The biogenic amines in the venoms act as the main pain-producing principles (46). The contents of these amines in the venom may affect the severity of pain production, edematous reaction of the skin, or increase in skin permeability by stings of these insects. Consequently these amines act as toxins for their defense, together with acetylcholine, enzymes, and peptides (47).

Purines such as xanthine (91), hypoxanthine (92), guanine (93), and uric acid (95) are found in excreta of many insects (Table VI) (48). Uric acid (95) is known to be the main end product of nitrogen metabolism in almost all insects. Various purines are found in the wasp (Vespa) and the sawfly (Gilpinia) in common with other insects (Table VI). In addition, various pteridines occur in Vespa and in the honeybee (Table VI). The latter also contains xanthurenic acid (52) or kynurenic acid (53), xanthurenic acid 4,8-diglucoside (56), and a yellow pigment, xanthommatin (58), as tryptophan metabolites (Table V).

B . LEPIDOPTERA

1. Butterflies

a. Pieridae. It was during initial studies on the naturally occurring pteridines that xanthopterin (65) and leucopterin (68) were isolated as wing pigments from the English brimstone butterfly (Gonepteryx rkamni) and the European cabbage butterfly (Pieris brassicae), respectively (49). Thereafter many kinds of


pteridines have been isolated from many species of butterflies, moths, and other insects, along with purines (Table VI). The accumulation of pteridines in butterflies as wing pigments is, however, seen only in the Pieridae. Originally, pteridines must have been either synthesized as wing pigments or deposited in the cuticular scales as a form of excretion. In the Pieridae as represented by P . brassicae, the “extra” pteridines are stored as excretory products of the general nitrogen metabolism, with a secondary function of pigmentation (50). The mar- velous coloration of some pierids may be a warning signal to would-be trans- gressors (51).

The cabbage worm butterfly Pieris rapae crucivoru and the sulfur-colored Catopsilia crocale are both found to afford the anticancer component isoxanthopterin (67) (51). In addition, isoxanthopterin (67) from the skin of the European minnow, Phoxinus phoxinus, elicits the fright reaction and hence acts as the alarm substance (52).

Butterflies and moths, in common with other insects, contain purines as an end product of nitrogen metabolism (Table VI). In Pieris rapae crucivoru, uric acid (95) is present in the male wings at three times the level in the female wings, and it occurs chiefly in the white parts. It is therefore believed to contribute partly to the sex differences of the wings under UV light, which are related to sexual behavior of this species. The male begins its mating behavior after recognizing the UV reflection of female wings (53).

Isoguanine (94), which is found in Prioneris wings along with hypoxanthine (92), xanthine (91), and uric acid (95), shows antineoplastic activities (Table VI) (51). Isolation of urocanic acid (137) from this wing material represents the first detection of this histidine derivative in an arthropod (Table VIII). A nonpteridine pigment, xanthommatin (58) (cf. Section II,B,l ,b), is found in the larval body of Pieris brassicae (Table V) .

b. Nymphalidae. Males of the danaid butterflies belonging to the subfamily Danainae possess a pair of abdominal brushlike scent organs called “hairpencils.” During courtship flight, males protrude and expand their hairpencils which are brushed against the head and antennae of the female to subdue and seduce her (54-56). Therefore, hairpencils secrete aphrodisiac pheromones which stimulate females for mating ( 5 7 3 ) . Four dihydropyrrolizines (25-28) and one pyrrolizidine ester (29) have been found in hairpencils of many danaid butterflies (Table IV).

Danaidone (25), which was first isolated from Lycorea ceres ceres (55) and Danuus gilippus berenice (59) by J. Meinwald et a l . , has been shown to act as an aphrodisiac pheromone necessary for successful courtship in D . gilippus berenice (57) and in D . chrysippus (56), since danaidone-lacking males have reduced courtship success (57,60). It seems likely that a similar role will be found for the closely related aldehydes, hydroxydanaidal(26) and danaidal(27).

In addition to the hairpencils, male Danaus butterflies possess pockets on the


hind wings which house a glandular organ. Independent of courtship behavior, a hairpencil is sometimes inserted into the wing pocket which itself contains danaidone (25). This contact behavior is shown by experiments on Danaus chrysippus to be prerequisite for the synthesis of danaidone (25) (56).

Male danaid butterflies are strongly attracted to, and sometimes feed on, dead and withering plants, e.g., the genera Tournefortia, Heliotropium, and Cyano- glossum (family Boraginaceae), Senecio and Eupatorium (family Compositae), and Crotalaria (family Leguminosae) (61,62). These plants are not normally larval food plants, and all contain pyrrolizidine alkaloids (PAS) (61). Many danaid butterflies are shown to store ingested plant PAS in their bodies (Table IV) (63-65). Danaidone (25) is not found in wing pockets and hairpencils unless male butterflies such as Danaus chrysippus are allowed to suck on a withered Heliotropium plant or feed on a mixture of PAS or the Heliotropium alkaloid, lycopsamine (29), found in hairpencils (66,67). Also, danaidone (25) does not appear on the hairpencil unless contacts between hairpencils and wing pockets are established or unless 25 is present in the wing pocket (56,67). Therefore, danaidone (25) occurs on the hairpencils only after the males have ingested plant PAS as precursors and then dipped the hairpencils into the wing pockets (56). In addition to the use as precursors for male pheromones, the toxic PAS stored in the bodies act as defensive substances against predators (65,68).

Three 3-alkyl-2-methoxypyrazines (24b, 24c, and 24d) are detected as odor components in the monarch butterfly, Danaus plexippus (Table 111). The wide variability in pyrazine content observed with this insect is correlated with similar variability in the larval food plants, Asclepias sp. It seems possible that the pyrazines may be one of the factors implicated in the food choice mechanism (69).

Pigment groups other than pteridines including ommochromes and papiliochromes occur as wing pigments in butterflies. Ommochromes are divided into three subgroups, ommatin, ommidin, and ommin. Rhodommatin and ommatin D are present in the Nymphalidae, especially in the red and orange scales of the genera Vanessa, Aglais, Znachus, and Arginnis, and xanthommatin (58) occurs in wings of the genus Heliconius (Heliconidae) (Table V) (70). Vanessa urticae contain xanthommatin (58) in adult secretions and two biogenic amines, noradrenaline (133) and dopamine (134), in the larvae (Tables V and VIII).

c. Papilionidae. Papiliochromes including papiliochrome I1 (142), papiliochrome M, and papiliochrome R are found as wing pigments in Papilio butterflies. Papiliochrome TI (142; see Section III,G) is a major pigment of the pale yellow scales in the species Papilio demoleus, P. protenor, P. helenus, P. castor, P. polytes, P. xuthus, and P. dardanus (71). 3-Ribosyluric acid (98) is widely distributed in wings of lepidopterous insects such as Papilio xuthus (Table VI), suggesting a physiological role in wing formation (72).

The swallowtail butterfly Pachlioptera aristolochiae, feeding on the leaves of

6. ALKALOIDS FROM ANTS AND OTHER INSECTS 20 1

Aristolochia species (Aristolochiaceae), stores the constituents of the host plant (Aristolochia clematis), aristolochic acid I (143; see Section IILP), in body tissues as do the danaid butterflies (73). The aposematic butterfly Zerynthia polyxena, feeding on the same plant, stores aristolochic acid Ia (144) and aristolochic acid C (145; see Section 111,P); the former is found in A . debilis and A. watsonii, while the latter has not yet been detected in the host plant. These alkaloids play roles as the defensive substances (74).

2 . Moths

Males of the arctiid moths (family Arctiidae) also have a pair of brushlike glandular structures, the coremata, which they evert from the abdomen during close-range precopulatory interaction with the female. The coremata of male arctiid moths of the genera Creatonotos and Utetheisa produce mainly hydroxydanaidal (26) (Table IV), which is shown to have a pheromonal role (75). This pheromone is derived from defensive PAS that the moths sequester from their larval food plants (Crotalaria sp.) (75,76). The PAS control the mor- phogenesis of the coremata (76). The cinnabar moths of the genus Callimorpha store plant PAS in their body tissues (Table IV) as do the danaid butterflies.

Males of the chrysomelid beetle, Gabonia gabriela (Coleoptera: Alticinae), and adults of both sexes of the elegant grasshopper, Zonocerus elegans (Orthop- tera: Pyrgomorphidae), are known to be attracted to and feed on withered plants of the genus Heliotropium containing PAS. It is assumed that these insects parallel the utilization of PAS by Lepidoptera (77.78). 3-Alkyl-2-methoxypyrazines are found in moths of the genera Zygaena

(Zygaenidae) and Amata (Amatidae) as odor components (Table 111). It seems that the striking pyrazine odors in these moths are a defense mechanism, alerting predators which hunt by smell to the dangerous qualities of the potential prey, in much the same way as the color red or black and yellow stripes alert predators which hunt by sight (69).

Larvae of the brown-tail moth Euproctis chrysorrhoea (Lymantriidae) contain histamine (136) along with a protein and enzyme. These constituents are presumably responsible for the toxic reaction in skin penetrated by the hairs (79). The presence of histamine (136) has been demonstrated in venomous hairs or spines of other caterpillars (Table VIII).

The silkworm, Bombyx mori (Bombycidae), contains in various body parts simple alkylamines, tryptophan metabolites, and pteridines (Tables V, VI, and VIII). One of the pteridines, violapterin (78), is synthesized from isoxanthopterin (67) by isoxanthopterin deaminase, occurring in the larvae and adults, and is stored in situ in the larval and adult integument (80). In addition, sepiapterin deaminase in the integument of the lemon mutant silkworm cqtalyzes the de- amination of sepiapterin (81) to 7,8-dihydro-6-lactyllumazine (79) (81).

Xanthommatin (58) and dihydroxanthommatin (59) are found as yellow and


red pigments in the larval integument of the Mediterranean flour moth, Ephestza kiihniella, and pteridines such as xanthopterin (65), ekapterin (74), and pterorhodin (86) occur in their heads (Tables V and VI). Various purines, especially uric acid (95), are found in many kinds of moths in common with other insects (Table VI). In the larvae of the rice stem borer, Chilo suppressalis, 3-ribosyluric acid (98) is detected in the fat body and integument but not in the blood, suggesting that it may play a role in the transfer of uric acid from fat bodies to Malpighian tubes and hindgut (82).

C. COLEOPTERA (BEETLES)

1. Coccinellidae

Ladybugs, in common with other insects, have the peculiar habit of emitting small droplets of blood from one or more points on their body surface when they are molested. This autohemorrhage, called “reflex bleeding,” constitutes an efficient protection against predators (83,84). The chemical deterrent present in the hemolymph droplets of the common European ladybug, Coccinella septem- punctatu, was shown initially to be the novel alkaloids, precoccinelline (100) and its N-oxide, coccinelline (99) (85). From a variety of Coccinellidae and one species of Cantharidae have been found thereafter these and six other related alkaloids, convergine (101), hippodamine (102), myrrhine (103), propyleine (104), hippocasine (105), and hippocasine oxide (106) (Table VII). These ladybug alkaloids constitute an effective defense against ants, Myrmica rubra, and quails, Coturnix coturnix, but all the beetles containing alkaloids do not possess the same degree of protection (86).

The bicyclic homotropane adaline (107) has been isolated from the defensive secretion of European ladybugs belonging to the genus Adalia (Table VII). It has been demonstrated to have repellent properties to various insects (87). A lower homolog (108) of adaline (107), previously isolated from the Australian plant Euphorbia atoto (88) and lately named euphococcinine (89), is found in the defensive secretion of the Australian mealbug ladybird, Cryptolaemus montrouzieri, along with 1 -(6-methyl-2-piperidyl)propan-2-one (4) (Tables I and VII) (87). Euphococcinine (108) is also present in the blood of the Mexican bean beetle, Epiluchna varivestis (Table VII) . When attacked by predators, these beetles ‘‘reflex bleed,” emmiting droplets of blood from the tibiofemoral joints of the legs. The alkaloid in the released blood has been proven deterrent to spiders and ants (89).

The ladybug, Hippodamia convergens, contains a novel aliphatic diamine, harmonine (121), identified as (a- lt17-diaminooctadec-9-ene, beside hippodamine (102), convergine (101), and n-octylamine (113). Harmonine (121) is also present in Hurmonia leis conformis and other ladybugs (Table VIII).


2. Staphylinidae

It has been known for long that a component in the hemolymph of many species of staphylinid beetles (the genus Paederus) acts on the skin and eyes of human beings and other warm-blooded animals to cause dermotoxic symp- toms-blister dermatitis, erythematic-vesicular dermatitis, and endemic ophthalmitis, etc.-called ‘‘pederosis” (90). The vesicant component has been isolated by M. Pavan and co-workers in a pure crystalline state from Paederus fuscipes and named pederin (147; see Section II1,L) (91). This compound is also found in P . melanurus, P . litoralis, P . rubrothoracicus, P . rufocyaneus, and P . columbinus (92). Furthermore, two other related components, pseudopederin (148) and pederone (149) have been isolated from P . fuscipes (91a,93). The latter is also found in P . columbinus (92).

It is doubtful whether the insect uses pederin for defensive purposes, because it acts on the skin of animals only when it is crushed and not through mere contact with the insect, even if prolonged. It also has neither insecticidal nor repellent properties (92). However, it causes epidermic necrotization as acute pederosis and desquamation as chronic pederosis on human skin. On the other hand, it stimulates bedsore cicatrization in lower doses and leads to complete healing. Application to mouse skin produces dermatitis with necrosis or huge edema, and the damaged tissue is reconstituted with a permanent loss of hair.

Beside this dermatoxic activity pederin (147) has various biological activities (92). When administered in appropriate doses to partially hepatectomized rats, this compound stimulates development of hepatic tissues. The inhibitory effect at the cellular level has been found in chicken heart fibroblast cultures, and mice embryo, dog kidney, HeLa, and KB cell lines. In plants, root growth of Lupinus albus is inhibited and mitosis in Allium cepa blocked at the metaphasic stage. Also, pederin (147) inhibits protein synthesis and growth of yeast cells. In addition, the treatment of rat ascites sarcoma with purified extracts of P . fuscipes produces almost complete regression.

Pseudopederin (148) and pederone (149) display the phytoinhibition, the dermotoxic, and toxic endoperitoneal action in mice, as well as the inhibitory activities on various animal and human cell strains. However, their effects are much less than those of pederin (147). Pederone (149) causes less endoperitoneal toxicity in viva than the other two substances.

Stenusin (5) is emitted from pygidial defense glands of an aquatic staphylinid, Stenus comma (Table I). When the beetle sometimes falls into the river during hunting for springtail or other actions, the alkaloid (5) can propel it toward the river bank owing to its extremely high spreading ability, in the same way ad a toy boat is propelled by camphor, and save it from drowning (94-96). This alkaloid may also have a protective function for this beetle, because it is weakly toxic to mice. Acridine (9a) is found in the defensive secretions of the rove beetles in the genera Cafius, Gabrius, Hesperus, and Philonthus (Table I).


3. Lycidae

The aposematic beetle, Metriorrhynchus rhipidius, contains three pyrazines as warning odor components and two amides as bitter principles (Tables 111, V, and VIII) (97). Of the three components with the beetlelike odor, the most characteristic is 2-methoxy-3-isopropylpyrazine (24b). The other two components are 2-methoxy-3-methylpyrazine (24a) and 2-methoxy-3-sec-butylpyrazine (24d). It would seem likely that these compounds will occur in the defensive systems of the aposematic beetles. The two amide components, detectable in the hemolymph exuded by adult beetles, are 3-phenylpropanamide (130) and 1 -methyl-2- quinolone (57), the latter being the major component. It seems likely that these bitter principles contribute to distastefulness to potential predators.

4. Chrysomelidae

The defensive secretion of adult chrysomelid beetles (leaf beetles) belonging to the subfamily Chrysomelinae is characterized by the presence of two isoxazolin-5-one glycosides (150 and 151; vid. 1II.M) (98). These compounds, first found in Crysomela tremulae (tribe Phaedonini), have been detected in the Phaedonini, C . populi, Gastrophysa viridula, Prasocuris phelladrii, Hydrotassa marginella, and Phaedon brassicae, and the Phratorini, Phratora laticollis, P . tibialis, and P . vitellinae.

5. Dytiscidae and Noteridae

The pygidial glands of many species of water beetles (Dytiscidae and Note- ridae) contain the plant growth regulator, 3-indoleacetic acid (139), along with benzoic acid, phenylacetic acid, and methyl p-hydroxybenzoate (Table VIII) . The water beetles use these chemicals mainly for preventing attachment of mi- croorganisms on their chitin surfaces. From time to time the beetles therefore leave the water and engage in a characteristic cleaning behavior, using their legs as brushes for coating their surfaces with pygidial gland secretions (99).

The prothoracic defensive secretion in one of water beetles, Ilybius fer- nestratus, contains as a main component methyl 8-hydroxyquinoline-2-carboxylate (51) (Table V), which is not toxic to amphibians and fishes but produces clonic spasms in small mammals like mice (96,100,101).

6. Other Beetles

Some pteridines are found in mealworm beetles, Tenebrio moritor (Ten- ebrionidae) , and some beetles in the family Catopidae; some purines, especially uric acid (99 , occur in several beetles (Table VI). In addition, T . moritor


contains three catecholamines, adrenaline (132), noradrenaline (133), and dopamine (134). Putrescine (111) is detected in the May beetle, Melolonthu vulgris (Table VIII).

D. DIFTERA (FLIES AND MOSQUITOES)

1. Trypetidae

A'-Pyrroline (12i) is emitted by sexually mature male Mediterranean fruit flies (Cerutitis cupitutu), together with 2-ethyl-3,5-dimethylpyrazine (21b) (Tables I1 and 111). This cyclic imine (12i) is the key component in the sexual attraction of virgin female flies to males (102). Xanthommatin (58) and two pteridines (81 and 84) are also found in this fruit fly (Tables V and VI).

The rectal gland secretions of the male melon fly, Ducus cucurbitue, contain three pyrazines and three amides. The major pyrazine component is tetramethylpyrazine (22a); methylpyrazine (23a) and 2,3,6-trimethylpyrazine (21a) are present as minor components (Table 111). The amide components are N- isoamylacetamide (122), N-2-methylbutylacetamide (123), and 2-methoxy-N- isoamylacetamide (124) (103). The former two amides are also present in the rectal gland secretion of the males of Ducus tryoni and D . neohumerulis (Table VIII) (104) . N-Isoamylacetamide (122) has been shown to elicit a zigzag flight response of virgin female D . cucurbitue toward the odor source (103). In D . oleue are found xanthommatin (58) and two pteridines (81 and 85) (Tables V and VI) .

2. Drosophilidae

The eyes of the fruit fly Drosophilu melunoguster contain tryptophan metabolites such as xanthurenic acid (52), kynurenic acid (53), xanthommatin (58), and dihydroxanthommatin (59) (Table V) in addition to some purines and serotonin (141) (Tables VI and VIII). Although various pteridines are found in dipterous insects, the genus Drosophilu is characterized by the occurrence of drosopterin (87a), isodrosopterin (87b), neodrosopterin (88), aurodrosopterin (89), and fraction e (90) (Table VI). Pteridines including isoxanthopterin (67) in the ejaculato- ry bulb of D . melunoguster are suggested to be involved in the reproductive physiology of this species, probably playing a role in sperm transfer (105).

3. Cailiphoridae

Xanthommatin (58) is detected in blowflies of the genera Culliphoru and Protophormiu beside xanthurenic acid (52) and kynurenic acid (53) in the latter


(Table V). Some pteridines are found in species of Calliphora, Chrysomya, and Lucilia in addition to uric acid (95) in the last species (Table VI).

4. Culicidae, Muscidae, and Others

Histamine (136) is detected in mosquitoes of the genera Aedes and Culex (Culicidae) beside uric acid (95) in the former (Tables VI and VIII). Cate- cholamines such as adrenaline (132), noradrenaline (133), and dopamine (134) are found in the larvae of the housefly, Musca domestica (Muscidae) (Table VIII). Some pteridines are found in species of the genera Cnephia (Simuliidae) and Piophila (Piophilidae) and in other Diptera. Species of the genus Glossina (Glossinidae) contain uric acid (95) (Table VI).

E. ORTHOPTERA

1. Acrididae (Locusts)

Three acyclic amines, dimethylamine (109), putrescine (lll), and spermidine (110), have been isolated from the accessary sexual glands of the mature male desert locust, Schistocerca gregaria (Table VIII). In addition, A'-pyrroline (12i) has been identified as a volatile emanating from the mature male locust colony (Table 11). It is an oxidation product of putrescine and probably could be responsible for the maturation-accelerating effect observed to be specific to the mature male insect ( I 06).

Some pteridines and uric acid (95) are detected in locusts of the genera Locust and Schistocerca (Table VI). Kynurine (54) is found in the genus Dociostaurus and xanthommatin (58) in the genus Locust, as tryptophan metabolites (Table V).

2. GryUidae (Crickets)

A yellow pigment, xanthommatin (58), is found in crickets of the genus Gryllus, and uric acid (95) occurs in the genus Acheta (Tables V and VI).

F. HEMIFTERA

Pteridines and purines are found in many species of Hemiptera, as shown in Table VI. A red pigment, erythropterin (73), detected in almost all species of Heteroptera, is very often considered to be responsible for the sometimes bright red color of these species, together with carotenoids (107). Histamine (136) is detected in bedbugs of the genus Cimex (Heteroptera, Cimicidae) (Table VIII).

6 . ALKALOIDS FROM ANTS AND OTHER INSECTS 207

G. BLATTARIAE (COCKROACHES)

Uric acid (95) is found in many kinds of cockroaches in addition to pteridines (Table VI). It is stored in the utriculi majores of the accessory sex glands of the German cockroach, Blattella germanica (Blattelidae). Most of the uric acid (95) is eliminated during copulation by being poured over the spermatophore. Mating appears to be an important means of excretion in this cockroach (108). In addition, 5-hydroxytryptamine (5HT) (141) and dopamine (134) are contained in the nerve cord of the American cockroach, Periplanetu americuna (Blattidae) (Table VIII).

H. NEUROPTERA

The secretion from the prothoracic glands of the lacewing Chrysopa oculatu (Chrysopidae) contains skatole (140) and tridecene (Table VIII) and offers some protection against invertebrate predators, such as ants. Uric acid (95) is stored as one of the excretory products of nitrogenous metabolism in fat bodies of the larvae of C . carnea (Table VI).

I. TRICHOFTERA (CADDISFLIES)

The exocrine glands of the caddisfly Pycnopsyche scabripennis (Lim- nephilidae) secrete a defensive exudate which contains indole (138) and skatole (140) along with p-cresol (Table VIII). This secretion effectively repels invertebrate predators such as ants.

J. PHASMIDA (WALKING STICKS)

The end products of tryptophan metabolism in the stick insect, Carausius morosus, are the ommochromes ommin and xanthommatin (58) in the epidermis, and kynurenic acid (53) in the feces. During larval development of this insect kynurenic acid (53) is the major end product of tryptophan metabolism (Table V) (109,110). Additionally, this insect contains five pteridines (Table VI), of which leucopterin (68), xanthopterin (65), and isoxanthopterin (67) are the origin of the yellow-white color of the insect (111).

K. ISOPTERA (TERMITES) AND OTHER INSECTS

Uric acid (95) is found in various species of wood-eating termites (Isoptera, Termitidae) along with kynurenic acid (53) (Tables V and VI). Three catecholamines, adrenaline (132), noradrenaline (133), and dopamine (134), are found in the whole body of earwigs of the genus Forficula (Dermaptera, For-


ficulidae) (Table VIII), and two pteridines, ichthyopterin (71) and sepiapterin (81), occur in Panorpa japonica (Mecoptera, Panorpidae) (Table VI).

L. ARTHROPODS EXCLUDING INSECTS

1. Myriapoda

The European small millipede, Glomeris marginata, has the characteristic habit of coiling into a tight sphere when disturbed, and in response to pinching, tapping, or prodding it discharges a defensive secretion, which oozes as single droplets from eight grandular pores spaced evenly in a row along the dorsal midline of the animal. The defensive secretion contains two crystalline alkaloids, glomerin (60) and homoglomerin (61) (Table V) (112).

Another millipede, Polyzonium rosalbum, contains two alkaloids, polyzonimine (19) and nitropolyzonamine (49), in its defensive secretion (Tables I1 and IV). Polyzonimine (19) is repellent to such natural enemies as ants and might effect the deterrence of various insects by acting as a topical irritant (113).

a. Diplopoda (Millipedes).

b. Chilopoda (Centipedes). The sting of the centipede, Scolopendra subspinipes, causes severe pain, swelling, edema, necrosis, and sometimes death. The venom contains histamine (136) and a histamine-releasing factor. Histamine (136) contributes to the pain production caused by centipede sting (114). The venom of another centipede (S. oraniensis institania) also contains histamine (136), while S. viridicornis contains 5HT (141) (Table VIII).

2. Arachnida

a. Acari (Ticks). Guanine (93) is regarded as the main end product of nitrogen metabolism in arachnids such as scorpions, spiders, and ticks in contrast to uric acid (95) in insect excreta (Table VI). A tick assembly pheromone present in the excretory waste pr6duct of the soft tick, Ornithodoros porcinus porcinus, has been identified as guanine (93). It is nonspecific and attracts different life stages of the same species as well as other species, namely, Argus persicus nymphs, Amblyomma cohaerens larvae, and Rhipicephalus appendiculatus adults. Among various purines tested in the assembly bioassay, xanthine (91), hypoxanthine (92), and uric acid (95) have been shown to be active for A. persicus (115).

The gluelike substance which is spread over the sticky spiral thread of the web of the garden spider, Aranea diadema, contains, in addition to two inorganic salts, pyrrolidone (13), which hinders drying out the thread (Table 11) (96,116). Histamine (136) and 5HT (141) beside polypeptides

b. Araneae (Spiders).


are present as smooth muscle active substances in the venoms of spiders in the generaLycosa and Phoneutria (118, 119). 5HT (141) is also found in the venoms of other five species (Table VIII). Since pain is absent for 15-20 min following the bite of black widow spiders (Latrodectus sp.), 5HT (141) may not serve a defensive role through induction of pain, but may facilitate the distribution and penetration of the toxic proteins (120). Spermine (112) is found in Atrax species (Table VIII) .

The defensive secretion of the harvestman, Sclerobunus robustus, contains N,N-dimethyl-P-phenylethylamine (131), a new natural product, as the major component, in addition to nicotine (SO) (Tables I and VIII) (117).

5HT (141) is present in the venoms of various scorpions (Leiurus quinquestriatus, etc.) (Table VIII). It can undoubtedly contribute greatly to the pain caused by a scorpion sting (121).

c. Opiliones (Harvestmen).

d. Scorpiones (Scorpions).

M. TABULATION OF ALKALOID OCCURRENCES

Tables I through VIII summarize the occurrences of alkaloids from ants and other insects. Each table presents chemical structures as well as specific sources of particular types of alkaloids; e.g., Table I covers piperidines and pyridines, Table 11, pyrrolidines, pyrroles, and indolizidines.

210 ATSUSHI NUMATA and TOSHIRO IBUKA

TABLE I Occurrence of Pipendines and Pyridines

Source Compound number" Ref.

Hymenoptera Fonnicidae (ants)

Mynnicinae Solenopsis invicta

S . invicta (alate queen) S . richteri (worker)

(worker)

S . richteri (alate

S . xyloni (worker) S. xyloni (alate queen) S . geminata (worker) S . geminata (alate

queen) S . geminata (soldier) S . aurea S. eduardi (worker) S . saevissimu S. littoralis S . pergandei S . carolinensis Solenopsis sp. A (Puer-

Solenopsis sp. B (Puer-

S. conjuruta (worker) Aphaenogaster fulva A. tennesseensis

Conomyrma sp. 1 (Wellborn, Texas)

Conomyrma sp. 2 (Athens, Georgia)

Iridomyrmex purpureus sensu stricta

queen)

to Rico)

to Rico)

Dolichoderinae

Coleoptera (beetles) Coccinellidae

Cryptolaemus montrouzieri

Staphylinidae Stenus comma Cafius xantholoma

lc, Id, le, If, lg, lh,

lc, Id lc, Id, le, If, 2a, 2b,

la, lb, lc, Id

2a, 2b, 2c, 2d

2c, 2d

lc, Id, le, 2a, 7 lc, Id lc, Id, le, 2a la, lc, Id

lc, Id, le, 2a lc, Id, le lc, Id id, le, If, 2a, 2b, 2d If Id, 3c lb, 3b 6

l b

la, lb, lc, 3a, 3b 8 8

9a

9a

9a

4

5 9a

122-127

125 123-125.127

125. I28

123- I25 125 123,125,128 I25

125 124.127 I24 124 16 16 16 16

16

I34 26 26

51 7

51 7

129

87

94-96 130

6 . ALKALOIDS FROM ANTS AND OTHER INSECTS 21 1

TABLE I (Continued)

Source Compound numbero Ref.

Gabrius piliger Hesperus semirufus Philonthus politus Ph. fimetarius Ph. splendens Ph. sanguinolentus Ph. varius Ph. rectangulus Ph. temporalis Ph. carbonarius Ph. fuscipennis Ph. marginatus Ph. laminatus Ph. cephalotes Ph. cruenatus Ph. nigrita

Arachnida Opiliones (Harvestman)

Sclerobunus robustus

9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a 9a

50

130 131 130,131 130 130 130 130 130 130 130 130 130 130 130 130 130

117

a Structures:

l a n=

l b n=

l c n=

I d n=

8 (cis) 1 e n= 1 2 (cis)

8 (trans) 1 f n= 1 2 ( t rans) solenopsin B

0 [cis) 1 g n= 14 (cis)

0 [trans) solenopsin A 1 h n= 1 4 (trans) solenopsin C

2 a n= 3 (cis)

2 b n= 3(trans) dehydrosolenopsin B

2 c n= 5 (cis)

2 d n= 5(trans) dehydrosolenopsin C

(continued)


TABLE I (Continued)

3 a n= 8 (cis)

3 b n= 8 (trans)

3 c n= 10 (trans)

f l yy N’ N’

8 9a 50


TABLE I1 Occurrence of Pyrrolidines, Pyrroles, and Indolizidines

Source Compound numbera Ref.

Hymenoptera Formicidae (ants)

Myrmicinae Solenopsis fugax S . punctuticeps

S . molestu S . texunas S . conjurutu (worker) Solenopsis sp. AA

Monomorium phuruonis (queen)

M . ebeninum M. lutinode

M . subopucum

Monomorium sp. near metoecus

M. viridum

1oc (trans) 10a (trans), 1Oc (trans), lod,

10b (trans) 10b (trans) 15a 17a

12a, 12b, 12c, 12d

10a, 10f (trans), log, lob,

10e, lOh, lOi, 12g, 12h 10a (trans), 1Oc (trans), l l a ,

10a (trans), 1Oc (trans), log,

10e, lOh, lOi, l lb , 12g,

lOe, lOh, lOi, l lb , llc,

10e lOi, l l c lOi, 10h

16a, ltib

12e, 12f

12f

12h

12g, 12h

10h, loi, l l b

M . jloricolu M. minimum Monomorium new sp.

near minimum Monomorium sp. near

emersoni M . cyuneum Attu texunu A . cephulotes A . sexdens rubropilosu Acromyrmex oc-

tospinosus

Trypetidae (flies) Diptera

Cerutitis cupitutu Orthoptera

Acrididae (locusts) Schistocercu greguriu 12i

Arachnida Aranae (spiders)

Aruneu d i a d e m 13

10h, l l b 14 14 14 14

12i

18 132,133

133 133 134 134

20-23u, b,

16,25 16

135-137

16

25

25,138

25 25 25

25

25 41 9,420,518 51 9 32 139

102

106

96,116

(continued)


TABLE I1 (Continued)

Source Compound numbera Ref

Mynapoda Diplopoda (millipedes)

P olvzonium rosnlhwm 19 113

a Structures:

R 1QR2

H

10 b ‘gH1 1 '5h13 10 c C7H15 C4H9

10d C7H15 ‘ZH5

10 e C9H19 '5h13 (CH2)4CH=CH2 M.111 10 f

l o g C7H15 (CH2)4CH=CH2 M . I V

1 0 h CgH19 (CH2)4CH=CH2 M . V

1 O i (CH2)7CH=CH2 (CH2)4CH=CH2

‘ g H l l

11 a C7H15 C4H9

l l b CgH19 ( CH2)4CH=CH2

CH3 11 c ( C H2 ) C H=CH2 ( C ) 4CH=CH2

12a C5Hll C2H5

1 2 b C2H5 ‘ g H l l

1 2 ~ C7H15 C2H5

12d C2H5 C7H15

12e C5Hll C4H9

1 2 f C7H15 C4H9

12 g ( c H ~ ) ~ C H = C H ~ (CH2)4CH=CH2

1 2 h ( c H ~ ) ~ C H = C H ~ (CH2)7CH=CH2

12 i H H



H

13

G? CH3 R

H3C 0 C 0 2 C H 3

H

14

** M = monomorine, configuration unknown Stereochemistry unknown.

1 5 a R = C2H5

16a R = C4H9 M - I

17a R = (CH,) ,CH,

18* R = ( C H ) CH=CH M.VI 2 4 2

19


TABLE 111 Occurrence of Pyrazines

~~



Ponerinae Anochetus sedilloti Brachyponera sen-

Hypoponera opacior Odontomachus hastatus 0. clarus 0. brunneus 0. troglodytes Odoniomachus sp . Ponera pennsylvunica Rhytidoponeru metallica Mesoponera castanea M . castaneicolor

Acromyrmex octospinosus

Aphaenogasier rudis Atta sexdens

rubropilosa Myrmica rubra M . ruginodis M. scabrinodis M. sabuleti M . ruglosu M . sulcinodis M . schencki M . lobicornis Tetramorium caespitum Wasmanniu auro-

naarensis

Myrmicinae

punctata Formicinae

Calomyrmex sp. Notoncus ectatom-

Polyrhachis sp. 2- moides

A.N.1.C Dolichoderinae

Iridomyrmex humilis

1. purpureus sensu stricta

20e, 20f, 20g, 21d, 21e, 21f 21d, 21g

20h 20h 20h, 21b 21b, 2112, 21d, 2lg 21b, 21d, 21g, 21i 21c, 21d, 21g, 2Ii 20h 20h, 201 20h 20h

20b,21b

23b 20b

20b 20b 20b 20b 20h 20b 20b 20h 20a, 20b 20h

20e, 20h, 20i 20h

20h

20c, 20h, 20j, 20k

20b, 20c, 20d

36.144 36,141

38,141,464 35,37,141,464 35,37,141,464 35,37,141,464 36,141,464 35,141 38,141,464 142,464 41 41

139

464 32,141

522,523 522,523 522,523 522,523 522,523 522,523 522,523 522,523 33 40

39,141 143

143

141,144,145,

129 464



Source Compound numberu Ref.

Myrmeciinae

Tiphiidae (wasps)

Eumenidae (wasps)

(MI

Myrmecia gulosa

Tiphia sp. (M&F)b

Ancistrocerus antilope

A. campestris (M&F) Eumenes fraternus

Euodynerus fuscus

Leptochilus acolhuus

( M W

( M W

(F) Monobia quadridens Pachodynerus erynnis

( M W Parancistrocerus

fulvipes (F) P. rufovestis (M) P. perennis (F) Parancistrocerus sp. A

Parancistrocerus sp. B

Stenodynerus floridanus S. fulvipes Pseudodynerus quad-

(M)

(F)

risectus (F) Sphecidae (wasps)

Eremnophila au- reonotata

Ammophila fernaldi ( M ) A. procera (M) A. nigricans (M&F) A. urnaria (M) A. urnaria (F)

Tachytes guatemalensis

Bicyrtes ventralis Argogorytes fargei

A. mystaceus (M&F) Nysson spinosus (M)

Larridae (wasps)

Nyssonidae (wasps)

( M W

20c

20h

22b

20h, 21d 20h, 21h

20h. 21d

20d, 20h

21g 20c, 21c

20c, 20h, 21d, 21h

20h, 21d 20h, 21d 20h, 21d

20h, 21d

2oc, 21c 20e, 21h, 22b 20h

20d, 20h

20h 20h 20h 21c 21d

20d, 20h

20d, 20h 20h

20h 20h

146

464

45,464

464 464

464

464

464 464

464

464 464 464

464

464 45,464 45

464

464 464,521 464,521 464,521 464,521

464

464 520

520 520

(continued)



Source Compound number” Ref

Philunthus triungulum

( M W Diptera

Trypetidae (flies) Dacus cucurbitue Ceratitis capitutu

Lepidoptera Nymphalidae (butterflies)

Danuus plexippus Amatidae (moths)

Amutu sp. Zygaenidae (moths)

Zyguenu lonicerue Coleoptera (beetles)

Lycidae Metriorrhynchus rhi-

pidius

20c, 20h 520

21a, 22a, 23a 2fb

24b, 24c, 2 4

24b, 24d

24c, 24d

24a, 24b, 2 4

147 102

69

69

69

97

a Stmctures:

R

20 a

20 b

20 c

20 d

2 0 e

20 f

2 0 g

20 h

20 i

2 0 j

20 k

20 1

2 1 a

H

Et

n-Pr

n-butyl

isobutyl

SeC-butyi

n-pentyl

isopentyl

2-methyibutyl

(Z) -styryl

(E) -styryl

citronellyl

Me



2 1 b

2 1 c

R 2 1 d

21 e

2 1 f

2 1 g

2 1 h

2 1 i

R1

Et

n-Pr

n-butyl

isobutyl

sec-butyl

n-pentyl

isopent yl

n-hexyl

R2

2 2 a Me Me

22 b H isobutyl

23 a H H

23 b n-Pr (E)-1-butenyl

24 a Me

2 4 b isopropyl

2 4 c isobutyl

2 4 d sec-butyl

* M&F, Males and females; M, males only; F, females only.

TABLE IV Occurrence of Fyrrolizidines

Source Sex" Locationb Compound numberc Ref.


Lycorea ceres ceres Danaus gilippus berenice D. gilippus strigosus D. hamatus hamatus D. hamatus moderatus D. hamatus D. affinis ajjinis D. affinis albistriga D. affinis

Danainae

D. pumilus hebridesius D. chrysippus petilea D. chrysippus dorippus D. chrysippus

D. limniace petiverana D. plexippus D. petiverana

D. formosa D. philene decipiens

D. juvenia sobrinoides

Euploea tulliolus tulliolus E. tulliolus E. sylvester sylvester E. sylvester E. nemertes polymela

E. nemertes E. treitschkei jessica E. treitschkei aenea

E. boisduvalii fraudulenta

E. lewinii lilybaea Amauris albimaculata

M M M M M M M M M M M M M M M F M M M F F M

M F M F

M M M M M

M F M M M F M M M M

H H H H H B H H B H H H H H, w B B H B B B B B

H B B B

H H H B E

H B H H B B B H H H

25 25 25 25, 26, 29 25, 26 29 25, 27 25, 27 29, 42 25, 27 26 25 25 25 29, 35, 36, 37, 42 29, 42 25 35, 36, 37 29, 35, 42 29, 42 35 29, 30, 32, 42, 43,

44 25, 27 42 29, 31, 32 29, 43, 44, 45, 46,

47 26, 29 26 26 29 29, 33, 43, 44, 45, 46, 47

26, 28 29, 31, 34 26 26 29, 43, 44 29, 43, 44 29, 32, 43, 44 28 26 25

55,148a 59 59 66,148b 61 63 148b 61 63 64 61 61 149 56,158,150 63,65 63 149 65 63 63 63 64

64 64 64 64

66,1486 61 148b 63 64

64 64 61 61 64 64 64 64 61 149

220

TABLE IV (Continued) ~~

Source Sexu Locationb Compound numberc Ref.

A . echeria

A. niavius A . ochlea

Arctiidae (moths) Utetheisa pulchelloides U. lorrix U. ornatrix Creatonotos gangis C . transiens

Nyctemendae (moths) Callimorpha jacobaeae C . jacobaeae

Farmicidae (ants) Mynnicinae

Hymenoptera

Solenopsis xenovenenum Myriapoda

Diplopoda (millipedes) Polyzonium rosalbum

M H M B M H M H M B F B

M C M C M C M C M C

P B

25 149 35 63 25 149 25 149,151 42 63 39. 42 63

26 423 26, 27 423 26 75 26 76 26 76

35, 36, 38, 40, 41 152 35, 36, 38 152

48 430

49 153

a M, Male; F, female. b H, Hairpencil; C, coremata; B, body tissue of imago; P, pupae; W, wing pocket. c Structures:

28 26 R=OH hydroxydanaidal

27 R=H danaidal 25 danaidone

1 2

1 2 30 R = COCH3, R = Me

1 2 3 1 R = H , R = H

1 2 32 R = H , R = Et

Me, ,R2 29 R = H , R =Me lycopsamine

yH ,OH

Me Me \ /

C Ha 0 C 0 y - C,H

Me Me Y H ,OH

OH Me HO

R? 33

(continued)

22 1


TABLE IV (Continued)

Me H OH

R2

F0 R = R = I

R1 I

N

35 senecionine

36 seneciphylline

Me H OH Me usaramine

R = R =

38 integerrimine

39

Me H OH O**.C-CH2-C-C-' \: .Me 4o jacobine

\

2 ' R = 1' R =

2 \ R -

1' R -

OH Me,OH Me. \ H-c-c:c..- Me

I \ 42 monocrotaline

2\ R = 1' R =



Me OH H, I I

2 1 ,C =C-CH -CH-C.-. M e

Me A0 co I

37 rosmarinine

M e & 48 C7H15n 49

TABLE V Occurrence of Quinolines, Xanthommatin, and Quinazolinones

Source Locationa Compound numberb Ref.

Hymenoptera Apidae (bees)

Apis mellifera


Vanessa uriticae Pieridae (butterflies)

Pieris brassicue Heliconidae (bumflies)

Heliconius sp. Bombycidae (moths)

Bombyx mori Phycitidae (moths)

Ephestia kiihniella Diptera

Drosophilidae Drosophila melanogaster

Trypetidae Ceratitis cupitata Dacus oleae

Calliphora erythrocephala Protophormia terrae-novae

Calliphoridae

Orthoptera Acrididae (locusts)

Locust migratoria cinerascens

Dociostaurus maroccanus

Gryllus bimaculatus Gryllidae

Coleoptera (beetles) Dytiscidae

Lycidae

Phasmida

Ilybius fenestratus

Metriorrhynchus rhipidius

Phasmidae Carausius morosus

Isoptera Temitidae (termites)

Reticulitermes flavipes R . virginicus

E H B, P

S

L

W

P

I

E B

E E

E B

E

B, E

Pr

H

F, H I

B B

58 52 or 53 56

58

58

58

52, 54, 55

58, 59

52, 53, 58, 59 59

58 58

58 52, 53, 58

58

54

58

51

51

53 58

53 53

I54 I54 I55

156

I57

70

159,160

I61

162-168 169

170 I73

171 172

174

I75

1 76

101

97

109, I I0 I09,110,177

178 178

(continued)

224

TABLE V (Continued)

Source Locationn Compound numberb Ref

Coptotermes formosanus B 53 178 Marginitermes hubbardi B 53 I78 Paraneotermes simplicicornis B 53 I78 Cryptotermes cavifrons B 53 I78

Mynapoda Diplopoda (millipedes)

Glomerida Glomeris marginata S 60, 61 96,112,179-181

a E, Eye; H, hemolymph; P, pupae; I, larval integument; B, whole body; F, feces; Pr, prothoracic

b Stuctures: gland; S , secretion; L, larvae; W, wings.

R1 R2 R3

@LRl R3

I

C H 3

COOH I CHNH2

I

5 1 COOMe H OH methyl 8-hydroxyquinoline-

2-carboxylate

52 COOH OH OH xanthurenic acid

53 COOH OH H kynurenic acid

54 H OH H kynurine

55 H OH OH 4,8-dihydroxyquinoline

56 xanthurenic acid 4,8-diglucoside

57 1 -methyl-2 -quinolone

COOH I FHNH2

58 xanthommatin 59 dihydroxanthommatin

I 3 60

CH3 glomerin

d 1 C H 2 c H C H 3 I

3 homoglomerin 61

225

TABLE VI Occurrence of Purines and Pteridineso

~~

Source Compound numberb Ref.

Hymenoptera Fonnicidae (ants)

Formica rufa F . polyctena F. pratensis F . nigriccans F . cordieri Lasius flavus Raptiformica sanguinea

Vespidae (wasps) Vespa orientalis

V. crabro V. germanica V. vulgaris V . lewisi

Apidae (bees) Apis mellifera

Diprionidae (sawflies) Gilpinia hercyniae

Formicinae

Lepidoptera Pieridae (butterflies)

Appias nero Pieris brassicae

P . rapae crucivora P . napi Catopsilia argante C . crocale C . rurina C. statira Colias croceus

C. eurytheme C . edusa C. helica Euchloe cardamines Gonepteryx rhamni Hebomoia glaucippe Prioneris chestylis

Papilionidae (butterflies) Papilio xuthus

P. protenor Nymphalidae (butterflies)

Vanessa atalanta

67, 70, 76 63, 67, 70, 72, 76 67 67, 70, 76 67, 70, 76 67 67

65, 67, 70, 78, 92, 95, 96

65, 68 65, 68 65, 68 67

62, 63, 67, 70, 72, 78

95

65, 67, 68, 73, 86, 94 65, 67, 68, 70, 73, 77,

81, 91, 92, 93, 94, 95, 96, 97

65, 67, 68, 73, 95 68,81,95 65, 68, 73, 86, 91, 94 63, 64, 67, 69, 73 91 91 62, 63, 65, 67, 68, 73,

65, 67, 68, 73, 81 65, 73 62, 65, 67, 68, 73, 81 65, 68, 73, 94 65, 68, 69, 73, 94 65, 68, 73 91, 92, 94, 95

95, 98 95, 98

80, 81, 86

95

182-1 84 182-185 I84 182, I83 183 I84 I84

186.187

I90 I90 I90 155

155,188

189

190,192 50,157,190,192-1 99

53,190,191,200 190, I93 190,201 -203 200 203 203 204-208

191,209 190 207 190 190 210 51

53.195 195

195

226

TABLE VI (Continued)


Pyralidae (moths) Ephestica kuehniella

Galleria mellonella Plodia interpunctella

Chilo suppressalis C. simplex

Bombycidae (moths) Bombyx mori

65, 67, 70, 73, 74, 75, 76, 86

91, 92, 95, 98 62, 65, 67, 70, 73,

74, 75, 81, 82 95, 98 95, 98

62, 67, 78, 79, 81, 91, 92, 93, 95, 96, 98

211-214

215-219 220-222

82 I95

80,223-236

Geometridae (moths) Ptychopoda sp .

Noctuidae (moths) Heliothis virescens H. zea Spodoptera litura Mmestra brassicae Conistra vaccinii Leucania separata Trigonophora meticulosa Achuea janata

Saturniidae (moths) Antheraea pernyi Philosamia ricini Attacus ricini

Celerio euphorbiae

Malacosoma americana

Hyphantria cunea

Sphingidae (moths)

Lasiocampidae (moths)

Arctiidae (moths)

Diptera Drosophilidae

Drosophila melanogaster

D. hydei

Dacus oleue Ceratitis cupitata

Calliphora erythrocephala Lucilia cuprina Chrysomya rubifacies

Trypetidae

Calliphoridae

86

91, 92, 95 91, 92, 95 95 95, 98 95 95 95 95

95, 98 95 95

95, 98

95

9 5 9 8

62, 65, 67, 70, 72, 73, 81, 82, 83, 87a, 87b, 88, 89, 90, 91, 92, 95

62, 65, 70, 81, 87a

81, 85 81, 84

67, 81, 82 62, 67, 81, 95 67

214

238 238 239 195,240 I95 241 I95 242

236,237 243 244

236

215

I95

42,50,105,165,166, 191.2&,245-256

24 7

173 I70

50 257,258 184

(continued)

221

TABLE Vl (Continued)

Source

~~

Compound numberb Ref.

Simuliidae

Culicidae

Glossinidae

Piophilidae

Cnephia tredecimata

Aedes aegypti

Glossina morsitans

Piophila casei

Acrididae (locusts) Orthoptera

Locust migratoriodes L. migratoria cinerascens Schistocerca gregaria

Acheta domesticus Gryllidae (crickets)

Hemiptera Heteroptera

F'yrrhocoridae Pyrrhocoris apterus Dysderus fasciatus

Rhodonius prolixus Reduviidae

Triatoma infestans

Oncopeltus fasciatus

Lygaeidae

Miridae

Homoptera

Geocoris punctipes

Lygus hesperus

Membracidae (treehoppers) Oxyrhachis taranda Oxyrhachis sp. Gargara contraria G. nigroapica

Cercopidae Philaenus spumarius

Ale yrodidae Aleyrodes proletella

Aphididae (aphids) Anurophis roseus Brevicoryne brassicae

Isoptera Termitidae (termites)

Reticulitermes flavipes

62, 70, 81, 82

95

95

62, 67, 70, 81, 82, 85

65 65, 67, 81, 95 65, 81, 95

95

67, 69, 73, 78, 95 65, 73

62, 63, 65, 66, 67,

62, 63, 65, 66, 67,

62, 65, 67, 69, 70,

69, 70, 73, 75, 95

69, 70, 73, 74, 75

73. 95

91, 92, 95

91, 92, 95

62, 65, 67, 70 65, 67, 70 65, 67 65

68

68

67, 68 65, 67, 68, 70

95

245

259-261

262

263

264 174,265-267 50,264,265,268

215

107.269,270 50

271 -274

2 72

50,215,275,276

238

238

277 2 77 2 77 277

2 78

278

2 79 2 79,280

178

TABLE Vl (Continued)


R. virginicus Coptotermes formosanus Marginitermes hubbardi Paraneotermes simplicicornis Cryptotermes cavifrons

Blattariae (cockroaches) Blattidae

Blattelidae Periplaneta americana

Blattella germanica Parcoblutta pennsylvania

Leucophuea maderae Blaberidae

Coleoptera (beetles) Tenebrionidae

Tenebrio moritor T. mauritanicus Tribolhm castaneum T. confusam

Dermestes maculatus

Caryedes brasiliensis

Anthonomus grandis Sitophilus oryzae S. granarius

Dermestidae

Bruchidae

Curculionidae

Catopidae Bathyscini

Anthrocharis querilhuci Speconomus sp. Boldoria sp.

Trechus sp. Aphuenops sp.

Trechini

Neuroptera Chrysopidae

Chrysopa carnea Phasmida

Phasmidae Curausius morosus

Mecoptera Panorpidae

Punorpa japonica

Scorpiones (scorpions) Adroctonus australis A. amereuxi

Arachnida

95 95 95 95 95

65, 67, 76, 95

95 95

95

67, 70, 95 95 95 95

91, 92, 95

95

95 91, 92, 95 91, 92, 95

65, 68 65, 68 65, 68

65, 68 65, 68

95

62, 65, 67, 68, 76

71, 81

93 93

i78 i78 178 178 178

215.281 -284

108 285

286

50,215,293,294 294 295 296

297

298

299 300 300

301 301 301

301 301

302

I11,I 77,281

303, 304

305 305

(continued)

229


Source Compound numberb Ref

Araneae (spiders)

Acari (ticks) Epeira diadema

Argas (Persicargas) arboreus A. (P . ) persicus Ornithodoros (0.) savionyi 0 . porcinus porcinus Hyalomma dromedarrii Haemaphysalis leporispalustris Rhipicephalus turanicus

93

93 93 93 93 93 93 93

306,307

308,309 308 308 115 308 308 308

~~~~~~~~~~~~~~~~ ~

Additional ocurrences as follows: Pteridines occur in other Lepidoptera (204,310,311), Diptera (312), and Hemiptera (107,313,314), and other insects (50,315). Unc acid is found in other Dros- ophila species (253,316), other cockroaches (285,287-292), and other insects (317-321). Guanine occurs in other scorpions (322-324), spiders (322,325,326), and ticks (308,327).

b Structures:

0

R1 R2

62 H H pterin

6 3 C 0 2 H H pterin-6-carboxylic acid

C O H pterin-7-carboxylic acid 64 H

65 O H H xanthopterin

66 OH

67 H OH isoxanthopterin

68 OH

2

C O H xanthopterin-7-carboxylic acid 2

O H leucopterin

chrysopterin 69 O H CH3

70 C H ( O H ) C H ( O H ) C H 3 H biopterin

7 1 C H ( O H ) C H ( O H ) C H 3 OH ichthyopterin

72 C H ( O H ) C H ( O H ) C H 2 0 H H neopterin

7 3 OH C H 2 C O C 0 2 H erythropterin

7 4 OH CH2 C H ( O H ) C O Z H ekapterin

75 O H CH=C ( N H ~ ) co2 H lepidopterin

R1 R 2 R3

76 NHZ OH H 2-amino-6-hydroxypteridine

C O H pteridine-7-carboxylic acid 77 H H 2

230


R1 R2

78 H 0 violapterin

79 C O C H ( 0 H ) CH3 H2 7,8-dihydro-6-lactyllumazine

R

80 OH

81 COCH(OH)CH3 sepiapterin

82 COCH2CH3 isosepiapterin (deoxysepiapterin)

83 COCH3 &acetyl-7,8-dihydropterin

84 H tetrahydropterin

85 C H ( O H ) C H ( O H ) C H 3 tetrahydrobiopterin

O H

86 pterorhodin

87a 87b droso- and isodrosopterin

88 neodrosopterin 89 aurodrosopterin 90 fraction e

R1 R2 R3

9 1 H OH OH xant hine

92 H H OH hypoxanthine

R 93 H NH2 OH guanine

94 H OH NH2 isoguanine

95 OH OH OH uric acid

96 H H N H 2 adenine

97 OH OH NH2 2,8-dihydroxyadenine

98 3-ribosyluric acid

23 1

TABLE VII Occurrence of Coccinellines and Adalines


Coteoptra (beetles) Cantharidae

Coccinellidae Coccinellinae

Sc ymnini

Hippodamiini

Chauliognathus pulchellus

Cryptolaemus montrouzieri

Anisostica 19-punctata Hippodamia convergens H . caseyi

Coccinellini Coccinella 5-punctata C . septempunctata C . 11-punctata C . 14-punctata C . cal$ornica C . transversoguttata Propylaea 14-punctata Myrrha Id-punctata Miraspis 16-punctata Cheilomenes propinqua Coleomegilla maculata Adalia bipunctata A. 10-punctata A. quadrimaculata A . pantherina Epilachna varivestis

100, 102, 104

108

102 101, 102 101, 102, 105, 106

99, 100 99, 100 99 99, 100 99 99, 100 104 103 100 99, 100 103 (or 100) 107 107 107 107 108

328

87

86,329,330 86,329-331 332

86,330 85,86,330,333 86,330 86,330 330 332 86,330,334 330 330 330 335,336 86,330,337,338 86,330,338 33 7 337 89

Structures:

H QH

H Q

M e 99

coccinelline

Me 104

propyleine

H QH

Me 100

H w 101

H vMe 102

H ?? Me

103 precoccinelline convergine hippodamine myrrhine

105 106 107 108

hippocasine hippocasine oxide adaline euphococcinine

232

TABLE VIII Occurrence of Acyclic Amines, Imidazoles, Catecholamines, and Indolesn

~

Source Locationb Compound numbere Ref.


Ponerinae Mesoponera castaneicolor

M. castanea

Myrmicinae Atta sexdens rubropilosa Myrmica taevinodis Acromyrmex sp. Pheidole fallax _I

Myrmecia gulosa M. pyriformis

Neivamyrmex nigrescens

Lasius neoniger L. aliensus Acanthomyops claviger Formica rufa

Vespidae (wasps) Vespa vulgaris V. crab0

Dorylinae

Formicinae

V . cincta V. orientalis

V. xanthoptera

V. maculifrons V. maculata V. germanica Polistes rothneyi

Polybia rejecta

Vespula lewisii

Ropalidia maculiventris

B

B

M M M Po V V

Hd

Hd Hd Hd B

V vs

V V

v s

V S t V v s

St, L P, B v s

v s

114, 115, 116, 117, 118, 119, 120, 125, 126, 127, 128, 129

114, 115, 116, 117, 118, 119, 120, 125, 126, 127, 128. 129

139 139 139 140 136 136

140

140 140 140 133

136, 141 110, 111, 112, 132,

133, 134, 135, 136, 141

136, 141 132, 133, 134, 136, 141 110, 111, 112, 135, 136, 141 133, 134, 141 141 132, 133, 134, 141 110, 111, 112, 134,

135, 136, 141 141 141 111, 112, 135, 136, 141 110, 111, 112, 133,

134, 135, 136

41

41

34,339,340 340 340 44 524 341,525

43

44 44 44 342

344 343,345-347

348 347,349-35 I

343,352

349,353 354 347,349 343,355

354 354 343

343

233

(continued)


TABLE VIII (Continued)

Source Locationb Compound numberc Ref.

Eumenes arcuatus

Rhynchium aruliferum

Abispa splendida

Paravespula germanica Dolichovespula saxonica Synoeca surinuma

Batzonellus annulatus Hemipapsis ichneumusnea

Pompilidae

Cnemora adusta

Xylocopa appendiculata Apis mellifera

Apidae (bee)

A. mellificu

Bumbus ignitus Amegilla macnamalae

Scoliidae

Sphecidae

Lepidoptera

Megascoliu jlavifrons

Sceliphron laetum

Saturniidae (moths) Dirphia sp.

Megalopygidae (moths) Megalopyge sp.

Limacodidae (moths) Monema jlavescens Latoia sinica L. lepida L. consocia

Lymantriidae (moths) Euproctis subjlava E. pseudoconspersa E. similis E. chrysorrhoea

Zygaenidae (moths) Batataea funeralis

vs

vs

VS

vs V St

VS

vs

vs

vs vs V B VS B vs vs

V

V

SP SP SP SP

Hr Hr Hr Hr

Hr

110, 111, 112, 134, 135, 136 110, 111, 112, 132,

133, 134, 135, 136

110, 111, 112, 134, 135, 136

132, 133, 134, 141 132, 133, 134, 141 141

111, 134, 135, 136 111, 112, 132, 133, 134, 135, 136 134, 135, 136

110, 111, 136 110, 111, 112, 136 133, 134, 136 133 141 132, 133, 134 110, 111, 112, 136 110, 111, 112, 134,

136

136

132, 133, 134, 136

136

136

136 136 136 136

136 136 136 136

136

343

343

343

347 353 354

343 343

343

343 343 349,356-365 342 366 367,368 343 343

369

343

3 70

370

371 371 3 71 371

3 71 3 71 3 71 79

79



Source Locationb Compound number= Ref.

Bombycidae (moths) Bombyx mori

Nymphalidae (butterflies) Vanessa urticae

Piendae (butterflies) Prioneris thestylis

Diptera Culicidae

Aedes uegypti Culex pipiens

Muscu domesticu

Drosophilu melunogaster

Dacus cucurbitae D . tryoni D. neohumerulis

Muscidae

Drosophilidae

Trypetidae

Orthoptera Acrididae (locusts)

Schistocercu greguriu Hemiptera

Cimicidae Cimex lectutarius

Coleoptera (beetles) Noteridae

Dytiscidae Noterus cluvicornis

Hyphydrus ovatus Coelumbus lernueus Gruptodytes pictus Hydroporus dorsulis Hygrotus inaequulis Potumonectes depressus Scurodytes halensis Stictonectes optutus Stictotursus

duodecimpustulutus Hydroglyphus pusillus

Metriorrhynchus rhipidius Lycidae

Coccinellidae Hippodamiini

Hippodumiu convergens Semiudaliu 1 I -notutu Adoniu vuriegata

109, 110, 111

133, 134

137

136 136

132, 133, 134

141

122, 123, 124 122, 123 122, 123

109, 110, 111

136

139

139 139 139 139 139 139 139 139 139

139

130

113, 121 121 121

106,372-374

367

51

370 3 70

367

375,376

147 147 147

106

370

99

99 99 99 99 99 99 99 99 99

99

97

3 78 3 78 3 78

~~

(continued)


Source Locationb Compound numberc Ref.

Coccinellini Harmoniu 4-punctatu H . leis conformis

Tenebrio moritor

Melontha vulgris

Tenebrionidae

Scarabaeidae

Dermaptera Forficulidae

ForJicula sp. Blattariae (cochroaches)

Blattidae

Neuroptera Periplaneta americana

Chry sopidae Chrysopa oculatu

Trichoptera Limnephilidae

Pycnopsyche scabripennis Arachnida

Scorpiones (scorpions) Leiurus quinquestriatus Parabuthus hunteri Buthotus minax Vejovis sp.

Opiliones (Harv6stman) Sclerobunus robustus

Araneae (spiders) Phoneutria fera Lycosa erythrognata Latrodectus mactans

tredecimg uttantus Acanthoscurria atrox A. sternalis Pterinopelma vellutinum Atrax robustus Phoneutria fera

Myriapoda Chilopoda (centipedes)

Scolopendra subspinipes S. viridicornis S . oraniensis institania

B B

B

B

B

N

Pr

E

V V V T

V V

V V V V \I

V V V

121 121

132, 133, 134

111

132, 133, 134

134, 141

140

138, 140

141 141 141 141

131

136, 141 136, 141 141

141 141 141 112 141

136 141 136

378 3 78

367,368

377

367

379

380

381

370,382,383 121 121 384

117

118,119 11 8.1 19,354 120

354 354 354 385 3 54

114 354 370

~~ ~ ~~ ~~~ ~~ ~

Additional occurrences as follows: Biogenic mines are found in other Vespidae and Apidae (343,347,349,353,354,356,386). Indoleacetic acid occurs in other Dytiscidae (99).

B, Whole body of adults; V, venom; Vs, venom sacs; St, sting apparatus; M, metathoracic gland; Po, poison gland; Hd, heads; Hr, hairs; Py, pygidial gland; L, larvae; P, pupae; Sp, spines; W, wings; S, secretion; N, nerve cord; E, exocrine gland; T, telson; Pr, prothoracic gland.

Structures:

283 7 6. ALKALOIDS FROM ANTS AND OTHER INSECTS

TABLE VIII (Conrinued) ~

109 (CH3)2NH dimethylamine 110 HZN(CH2)4NH(CH2)3NH2 spermidine

111 NH,(CH2),NH2 putrescine 112 H2N(CH2)3NH(CH2)4NH(CH2)3NH2 spermine

113 n -C8H17NH2 122 iso-C5H11NHCOCH3

114 iso-C5H11NHCgHlg 123 C2H5CH( CH3)CH2NHCOCH3

115 iso-C5H11NH 2-CgHl7 124 iso-C5Hl1NHCOCH2OCH3

116 iso-C5HI1N(CH3)CgHlg 125 iso-C5H11N(COCH3)CgHlg

117 iso-C5H11 N(CHO)CgHlg 126 CgHlgNHCOCM3

118 C7H15NHCgH19 127 iso-C4HgCONHCgHlg

119 (iso-C5H11)ZNCgH17 128 (iso-C5H11)2NCgHlg

120 iso-C5HllN(CgHlg)2 129 iso-C5H11N( C7H15 CgH19

121 H2NCH(CH3)(CH2)6CH=CH(CH2)8NH2 harmonine

130 PhCH2CH2CONH2 131 PhCH2CH2N(CH3)2

132 adrenaline 133 noradrenaline

134 dopamine 135 tyramine

CH=CHC02H

136 histamine L - 137 urocanic acid

H H

H H H H 138 139 140 141

indole 3-indolacetic acid s kat ole serotonin ( 5 H T )

23 8 ATSUSHI NUMATA AND TOSHIRO IBUKA

111. Structure and Synthesis

A. PIPERIDINES

1. 2-Alkyl-6-methylpiperidine

The structure of 2-alkyl-6-methylpiperidine (1 and 2) from fire ant venom (Table I) has been assumed by mass spectroscopy and chemical reaction, and confirmed by direct comparison with synthetic compounds having known structure and stereochemistry (16,122,126). The mass spectra show a base peak at mlz 98 (152) resulting from a-cleavage of the alkyl group as well as M - 15, M - 1 and M ions, the last being often absent (16,122,126). Their secondary amine character is suggested by a positive spot test. Carbon-skeleton chromatography (387) gives only n-alkanes with the same carbon number as the parent compound, proving that the side chains are not branched. This and the IR spectrum between 2920 and 2980 cm- suggest 2,6-dialkylpiperidine rather than 2,s- dialky lp yrrolidine .

1 or 2 152 m / z 98

Mass spectra of the cis and trans isomers of the two substituents are virtually indistinguishable, but the IR spectra allow easy differentiation in the region near 1320 cm- l . The relative stereochemistry of the natural alkaloids can be determined by comparison of gas chromatographic behavior with synthetic material of known stereochemistry, since the two isomers have different retention times.

The position and geometry of the side chain double bonds can be determined by ozonolysis and a potassium permanganate-sodium periodate oxidation, as well as by the IR spectrum. Results have shown that the side chain double bonds are always Z (16,122,126).

A number of syntheses have been reported for 2-alkyl-6-methylpiperidine (1 and 2). The first used synthetic route is the sodium-alcohol reduction of the corresponding pyridine derivatives, which are prepared by the alkylation of the lithium salt of 2,6-dimethylpyridine (153) with the appropriate bromoalkane (122,126). This reaction gives a mixture of the cis and trans isomers (85/15), from which (t)-solenopsins A (Id), B (If), and C (lh) can be separated. The catalytic hydrogenation of the corresponding pyridine (154a) with 5% rhodium on charcoal gives the cis isomer (lc) (Scheme 1). (+)-Dehydrosolenopsin B (2b) and C (2d) are synthesized along with their isomers by the sodium-alcohol reduction of the corresponding pyridine derivatives in the same manner (Scheme 2) (126).


153 154a (n= 10)

b ( n = 12)

c (n= 1 4 )

- l c i i i 154a

SCHEME 1 . Reaction conditions: i, CH3(CH2)n-1Br (n = 10, 12, 14); ii, Na-EtOH; iii,

5% Rh-C.

I i 2a (n= 3) 3 part 2b ( n = 3) 1 part

2d (n= 5 ) 1 part ?I!

H3C (CH2)nC=C-(CH2)7CH3 2c (n= 5 ) 3 part

155a (n= 3 )

b (n= 5 )

SCHEME 2. Reaction conditions: i , CH3(CH&CH=CH(CH2),_ 10Ts or CH3(CH2),CH= CH(CH3,- ,Br; ii, Na-EtOH.

Improved synthesis by this method has been achieved in order to obtain solenopsin A (Id) more stereoselectively (388). A cis and trans mixture of pyridine derivative 158, obtained from 156 by the Wittig reaction, was reduced by Raney nickel catalyst in the presence of PtO, to yield the cis-piperidine (lc). The N-nitroso derivative 159, obtained from l c by treatment with isoamyl nitrite, was treated with potassium tert-butoxide and then subjected to hydrogenolysis over Raney nickel to give a mixture of (2)-solenopsin A (Id, 1 part) and its isomer (lc, I part) (Scheme 3).

Some intramolecular aminations of olefins have been reported for solenopsin A (ld) and its isomer (lc) (389-392). The dimer (200) of methyl vinyl ketone was converted to the ketone (202) by a standard procedure. Borohydride reduction of 202, followed by acid-catalyzed cyclization, yielded an exof endo (60140)


l c 159

lc

SCHEME 3. Reaction conditions: i, PPh3-benzene; ii, NaH-CH2C1,; iii, decanal; iv, Raney Ni- Pt0.2; v, isoamyl nitrite; vi, KOBuf-DMSO; vii, Raney Ni.

mixture of bicyclic derivative 203. A novel ketal fragmentation reaction of 203 with acetyl iodide gave a mixture of olefin 204 in favor of the trans-alkene. Treatment of 204 with hydroxylamine gave the oxime (205) which was reduced with molybdenum trioxide and sodium borohydride to afford the amine (206) (81%) and (+)-solenopsin A (Id) (10%). The latter can be also obtained from the former by mercuration (Scheme 4) (389).

Another method by mercuration starts with keto alcohol 207 (390). The amino alcohol (208) obtained from 207 by reductive amination was protected by a standard procedure to afford the phthalimide (209). Successive treatment of 209

iv

JQy c 10H 21n v- i

M e M e

0 0

200 2 0 1 202

vi vii

M e Q C l O H 2 l n-Me&C10H2P

203 204

SCHEME 4. Reaction conditions: i, C6HI INH2; ii, EtMgBr; iii, "C9HI9Br; iv, NaBH4; v, p-TsOH; vi, AcI; vii, NH20H.HC1, NaOAc; viii, Moo3, NaBH4; ix, Hg(OAc)2, NaBH4.


with Collins' reagent and Wittig reagent afforded a mixture of (a- and (E)- olefins (210). Hydrolysis of 210 yielded the amine (206), which was successively treated with mercuric acetate and sodium borohydrate to give (*)- solenopsin A (Id, 4 parts) and its isomer, (+-)-isosolenopsin A (lc, 3 parts) (Scheme 5).

207

i

208

ii - M e O O H iii

iv -

O B 0 \ / 209 210

206 Id IC

is, x

M e HgOAc

CV 2Me CO ? M e

2 1 1 212 213-

SCHEME 5 . Reaction conditions: i, reductive amination; ii, protection of amino group; iii, Collins' reagent; iv, Ph3P=CHCIOH2,~; v, hydrolysis; vi, Hg(OAc)2; vii, NaBb; viii, 1-decen-3-one; ix, ethanedithiol; x, Raney Ni; xi, HC1-EtOH.

Cyclization by amidomercuration has been reported (391). Reaction of N- methoxycarbonyl-6-aminohept- l-ene (211) with mercuric acetate gave the organomercurial (212). Reductive coupling of 212 with l-decen-3-one in the usual way gave the cis and trans isomers (213). Successive treatment of 213 with ethanedithiol, Raney nickel, and ethanolic hydrogen chloride afforded (-+)-solenopsin A (Id, 2 parts) and its isomer (lc, 3 parts), which were separable by preparative gas chromatography (GC) (Scheme 5) (391).

On treatment with benzeneselenenyl chloride two olefinic urethanes (214 and 217) underwent cyclization to afford piperidine derivatives (215 and 218, respectively) having the cis stereochemistry . Their reduction with triphenyltin hydride gave the same product (216). Removal of the blocking group from the nitrogen gave (-+)-isosolenopsin A (lc) (Scheme 6) (392).

Application of the Mundy N-acyllactam rearrangement to 6-methyl-2- piperidone (219) led to a synthesis of (+)-solenopsin A (Id), but it is not a


i 0 ‘11 H23 O c 1 l H 2 3 COOEt - PhSe COOEt

1c

E; SePh

2 1 1 218

SCHEME 6. Reaction conditions: i, PhSeC1-silica; ii, Ph3SnH; iii, conc HCI-EtOH.

satisfactory route to the trans alkaloids. Pyrolysis of N-lauryld-methyl-2- piperidone (220) over calcium oxide gave imine 221 in about 5% yield. The imine (221) was reduced with sodium borohydride to afford a 4 : 1 mixture of cis and trans isomers (lc and Id) (Scheme 7) (393). More recently, a new olefinic cyclization promoted by the Beckmann rearrangement of an oxime sulfonate has been developed (222 + 223) (394). Thus, successive reaction of the oxime methane sulfonate (224) with diethylaluminum chloride and diisobutylaluminum hydride afforded the tetrahydropyridine (225) as a mixture of cis and trans isomers. Subsequent catalytic hydrogenation yielded (&)-solenopsin B (If, trans) and its isomer (le, cis) (Scheme 8) (394).

Another synthetic route via the Beckmann rearrangement, which is promoted by organoaluminum reagent along with alkylation, involves a new stereoselective reduction of the imino group. The starting oxime sulfonate (228) was synthesized from cyclopentanone (226) in three steps: Reaction of 226 with 1-undecene in the presence of silver oxide produced the a-undecylcyclopentanone (227) which on successive treatment with hydroxylamine and methanesulfonyl chloride-triethylamine gave the mesylate (228). Treatment of the oxime mesylate

219 220 221

l c Id

SCHEME 7. Reaction conditions: i , n-C, ,H23COCI-pyridine-benzene; ii, CaO, A; iii, NaBH,


N-OMS

222 223

...

Me 0 C u H n n

111

H

3 n - M e 0 c 1 3 H 2 7 n - H

224 225

Me c 13H 27

N-OMS l e / l f 46 /54

SCHEME 8. Reaction conditions: i, Et2A1CI; ii, DIBAH; iii, H2-Pd/C

(228) with trimethylaluminum resulted in the formation of I -piperideine (7) in 54% yield after workup by Nal-H,O. Reduction of 7 with a new reagent, LiAlH,-Me,Al, gave (+)-solenopsin A (Id, 95%) and its isomer (lc, 5%) (395). In a similar manner, (+)-solenopsin B (If, trans) was prepared with high selectivity (95% by GC assay) (Scheme 9) (395).

226 227 228

7 Id lc

SCHEME 9. Reaction conditions: i, l-undecene, Ag20; ii, 130"C, 5 hr; iii, NH20H; iv, MsCI- Et3N; v, Me,Al; vi, NaF-H20; vii, LiA1H,-Me3A1.

In addition, stereoselective synthesis of solenopsin A has been reported by four research groups. An approach utilizing the stereoselective reductive decyanation (396) starts with aminonitrile 229, prepared from 2-picoline. It was selectively hydrogenated in the presence of Pd-C, followed by alkylation with undecyl bromide, affording 231. Reductive decyanation of 231 with NaBH, in MeOH led to predominant (8 : 2) formation of the trans isomer (232) which was then debenzylated to (+)-solenopsin A (Id). The cis product (lc) was in turn prepared by treatment of 231 with sodium in liquid ammonia followed by debenzylation (Scheme 10).

In the synthesis through the highly regioselective a-alkylation of a pyridinium


n l v i J vi

n

SCHEME 10. Reaction conditions: i , H2-Pd/C; ii, LDA; iii, C11H~3~Br; iv, NaBH,; v, Na-NH3; vi, debenzylation.

salt (398, N-methoxycarbonyl-2-methylpyridinium chloride (235) was treated with Grignard reagent to give the a-alkylated 1,2-dihydropyridine (236). Con- trolled hydrogenation of 236 over 5% palladium carbon gave 1,2,3,4-tetrahydropyridine (237). Decarbomethoxylation of 237 afforded 1 -piperideine (7) which was reduced with lithium aluminum hydride in the presence of trimethylaluminum to yield (+-)-solenopsin A (Id, 9 parts) along with a small amount of its epimer (lc, 1 part) (Scheme 11) .

In the synthetic route starting with enamidine (238) (398), its metalation followed by alkylation in the presence of TMEDA or pentynyl cuprate gave the

iii M e 0- M e / Q - M e O C S C - C gH 19 n -

ii i

C O z M e c1- C O z M e

234 235 236

iv V

M e QCIl*23n- M e 0 C 11H 23n ---- M e 0 ’ * * C 1 1 H 2 3 n H 60 2 M e

237 7 Id

SCHEME 1 1 . Reaction conditions: i, ClCOOMe; ii, “C9Hl9--MgBr; iii, Hz-5% PdlC; iv, ISiMe,; v, LiAIH4-Me3AI.


238 239

SCHEME 12. Reaction conditions: i, 'BuLi; ii, CH3Br, TMEDA, or pentynyl cuprate; iii, NH2NH2-AcOH; iv, LAH.

I C 0 2 C H 2 P h

i - PhCH202C-N 'y&ScNL MeQ'..C11H2: H

SMe

M e

240 241 Id

. ii, three steps. 'SMe'

SCHEME 13. Reaction conditions: i, S = C

forhamidine (239). When 239 was subjected to hydrazinolysis, the cyclic imine (221) was obtained and reduced with lithium aluminum hydride, producing (*)- solenopsin A (la) and its isomer in a 9 : 1 ratio (Scheme 12). It should be noted that the cyclic imine (221) in this route has a reverse position of the alkyl group relative to the imine (7) of the synthetic route mentioned above.

Cycloaddition reaction of the 1 -acyl-l,2-dihydropyridine derivative 240 with methyl cyanodithioformate afforded adduct 241, which was converted by three steps to solenopsin A (Id) (Scheme 13) (399). This route constitutes a completely stereoselective synthesis of this alkaloid; however, details are not available.

The structures of the N-methyl-2,B-dialkylpiperidines (3b and 3c), found in S. pergandei and S. carolinensis (Table I), are indicated by a base peak (242) of rn lz 112 as well as the parent peaks in their mass spectra. Structures were confirmed by their identity with authentic samples which were prepared by reductive methylation of the corresponding N-H piperidine with formaldehyde and formic acid (16).

C H 3 242


2. 2-Methyl-6-(2-oxopropyl)piperidine

The structure of cis- 1-(6-methy1-2-piperidyl)propan-2-one (4), found in the ladybird C. montrouzieri (Table I), was assumed by the mass spectra and reduction, and confirmed by synthesis. A molecular ion at mlz 155, the intense fragment at M - 43 by loss of CH,CO, and the base peak at M - 57 by loss of CH,COCH, suggest an empirical formula and the nature of the side chain of the piperidine ring. A Wolff-Kishner reduction gave a product identical with di- hydropinidine having a cis configuration (87). This alkaloid was prepared by acetylation of the lithium salt of 2,6-lutidine (153) with acetyl chloride, followed by reduction with Adams’ catalyst (Scheme 14) (87).

153 2 4 3 4

SCHEME 14. Reaction conditions: i, CH,COCI; ii, H2. Adams’ catalyst

3. Stenusine

An N-ethylpiperidine, stenusine (5), isolated from a staphylinid beetle, Stenus comma (Table I), indicated the molecular ion at mlz 183.1993 in the mass spectra, corresponding to the elemental composition C,,H,,N. The NMR spectrum shows the presence of an N-ethyl group and two methyl groups attached to methylene and methine groups; it gives no evidence for a double bond, showing a ring structure. In addition, explanation of the fragment ion (244) at mlz 11 3 in the mass spectrum, occurring by direct loss of a pentene moiety from the molecular ion, leads to the structure 5. This postulated structure was confirmed by synthesis. Thus the monoester of 2-methylbutylmalonic acid (245) was converted to ethyl 2-(2-methylbutyl)acrylate (246) by a Mannich reaction. Addition of ethylamine and subsequent Michael addition of the resulting secondary amine with ethyl acrylate gave the teritary amine diester (247). Dieckmann cyclization, saponification, and decarboxylation led to piperidinone (248), of which Wolff- Kishner reduction provided 5 (Scheme 15) (94-96).

244 CH3


0 0

2 4 5 246

247 2 4 8 5

SCHEME 15. Reaction conditions: i, CH20, EtZNH; ii, EtNH2; iii, CH2=CHCOOEt; iv, Na; v , Wolff-Kishner reaction.

4. Piperideine

The structure of the 1-piperideine (7), found in S . xyloni (Table I), was assumed by characteristic fragmentation ions (249 and 250) at rnlz 97 and I10 (base peak) in the mass spectrum and was confirmed by comparison with a synthetic sample. The mlz 97 peak results from allylic cleavage with hydrogen transfer to nitrogen, while the 110 peak arises from the loss of the side chain after transfer of two hydrogens. In contrast, the isomeric 6-piperideine (221), the nonnatural product, exhibits a base peak (253) at mlz 11 1 arising from a McLaf- ferty rearrangement of the y hydrogen (123). Though the 1-piperideine (7) is prepared along with the isomeric 6-piperideine (221) by treatment of the corresponding piperidine (lc) with tert-butylhypochloride (Scheme 16) (123), it can

H3C O C H 2

7 249 m / z 97 250 m / z 1 1 0

C s H 1 7

2 5 1 C8H17 252 ‘gH17

2 5 3 m / z 111

‘gH17


l c 7 2 2 1

SCHEME 16. Reaction conditions: i, 'BuOCl.

be selectively prepared as the synthetic intermediate to solenopsin A as mentioned above (Schemes 9 and 11).

Another 1-piperideine (6), found in Solenopsis sp. A (Puerto Rico) (Table I), exhibits in the mass spectrum the molecular ion at mlz 151 and the base peak (254) at mlz 97, suggesting an a-substituted 1-piperideine system. A terminal double bond was explained by the fragmentation ion (255) at mlz 110 arising via simple allylic cleavage in the mass spectrum and the characteristic ABC pattern of a terminal olefin in the 'H-NMR spectrum. The presence of a 1-piperideine system was confirmed by sodium borohydride reduction of natural material giving 2-(4-penten- 1-y1)piperidine (16). Compound 6 was prepared by the Mun- dy rearrangement of N-(5-hexenoyl)-2-piperidone (257) which was prepared by acylation of piperidone (256) with 5-hexenoyl chloride (Scheme 17) (16). This method was far superior in ease of operation though it had been used to prepare a synthetic intermediate to 0-methylvalerolactim (400).

255 m / z 110

5. Anabaseine

The structure of anabaseine (8), isolated from ants of Aphaenogaster species (Table I), was established by gas chromatography-mass spectrometry, the 'H-

Qo i_ 0 0 I 2 C A ( C H 2 ) 3 C H = C H 2

H O=C( CH2)3CH=CH2

256 257 6

SCHEME 17. Reaction conditions: i, CH2=CH(CH2)-,COCI; ii, CaO, A


0 0

0 0 + Q k - O E i

COPh

258 259

I COPh

260

8 261

SCHEME 18. Reaction conditions: i, NaOEt; ii, conc HC1; iii, CaO, A.

NMR spectrum showing the presence of a 3-substituted pyridine with four none- quivalent methylene units in the substituent, and by its conversion to 2,3-bi- pyridyl with chloranil (26). Its synthesis was made by condensation of N-ben- zoylpiperidone (258) with ethyl nicotinate (259) followed by heating with concentrated hydrochloric acid, resulting in hydrolysis, decarboxylation, and ring closure (Scheme 18) (401). Application of the Mundy N-acyllactam rearrangement to N-nicotinoylpiperidone (261) has also led to a synthesis of anabaseine (8) (Scheme 18) (402).

6 . Actinidine

Actinidine (9a), found in an anal gland of dolichoderine ants and in the defensive secretions of rove beetles (Table I), was identified on the basis of gas chromatographic and mass spectral analysis and the UV spectrum. The mass

H 262

263 Yi

264 9a

SCHEME 19. Reaction conditions: i, PCI,, 100°C; ii, H2-Pd/C; iii, 2,4-DNPH; iv, HCI in AcOH; v, FeNH4(S04)*, A.


- ["r-] - Dc, 265 266 261

A ii T y 9 b

SCHEME 20. Reaction conditions: i, ({) , 110°C; ii, NHzOH, A

spectrum exhibits fragmentation peaks at mlz 132 (M+ - CH,, 100%) and 117 (M+ - C,H,, 42%) as well as the molecular ion at mlz 147, It is likely that the absolute configuration is the same as that of actinidine from plants.

Natural (-)-acthidine (9a) is prepared from nepetalinic acid imide (262) via dichloropyridine (263) (403) and from iridodial (264) via bis (2,4-dinitrophe- ny1)hydrazone (404) or treatment with ferric ammonium sulfate (Scheme 19) (405). (+)-Acthidine (9b), the enantiomer of natural alkaloid, is synthesized from acid chloride 265, derived from (+)-pulegone, via vinylketone 267 (Scheme 20) (406). Racemic actinidine (9) is prepared by intramolecular cycloaddition of an acetylene across a pyrimidine ring in 5-(hept-5-yn-2-~1)-4,6- dihydroxypyrimidine (268) followed by chlorination and hydrogenation (Scheme 21) (407).

Since the biosynthesis of iridoid monoterpenes in insects has been shown to

269

ii-+ iii 9

SCHEME 21. Reaction conditions: i, 200°C; ii, phosphoryl chloride, 195°C; iii, Hz-Pd/C.


follow the mevalonic acid route (408), it seems that the biosynthesis of 9a in insects also proceeds through this pathway, as in plants (4 ) .

B. PYRROLIDINES

1. 2,5-Dialkylpyrrolidines

Isolation and structural elucidation of pyrrolidine and pyrroline alkaloids found in ants (Table 11) have been achieved in most cases by the use of gas chromatography-mass spectrometry techniques, owing to the small amount of available samples, and the structures have been confirmed by synthesis (16,18,23a, b,25,132,409). Mass spectra of 2,5-dialkylpyrrolidines (10) exhibit two intense fragment ions (270 and 271) resulting from &-cleavage of the side chains as well as a weak molecular ion (16,18,23~,25,132,409). Their secondary mine character is confirmed by the early elution of their acetates on the gas chromatography relative to the corresponding free bases. Carbon-skeleton hydrolysis over 1% Pd on Gaschrom P gave n-alkanes and pyrroles bonded with side chains, proving that the side chains are not branched and not located on the same (Y

carbon atom of the pyrrolidine nucleus (16,132). The stereochemistry is established by direct comparison with synthetic isomers. The natural alkaloids of known stereochemistry are all of the trans configuration (16,18,25,133,138).

The technique of methoxymercuration-demercuration was utilized to determine the position of double bonds in the side chains. Since this method is not successful with the free alkaloids (272), the secondary amino groups must be protected as the N-heptafluorobutyramide. These amides are treated with mercuric acetate and methanol followed by reduction with sodium borohydride to yield the methoxylated compounds (273). The mass spectra of these compounds show a fragment ion (274) at mlz 59 indicating terminal double bonds in every case (Scheme 22) (16,25,410,411).

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction (132,412), the metal hydride reduction of pyrrolines (413,414), the a-alkylation of N-nitrosopyrrolidine (412,415), the catalytic hydrogenation of pyrroles (133), the reductive amination of 1,4-diketones (25,138), the direct alkylation of l-methoxycarbonyl-3-pyrroline (416), the versatile synthesis from the Lukes-Sorm dilac-


C H M e Me Me I

C H II

(CH2)m - +OMe

CHOMe (CH '' o(!::)m - i , ii (I,,),-- F H 2

i i i

COC3F7 H

272 273 274

Scheme 22. Reaction conditions: i, (C3F,CO)20; ii, H~(OAC)~-M~OH; iii, NaBH+

tam (418), and the chirospecific synthesis from glutamic acid (417). The Hofmann-Loffler reaction on the corresponding primary N-chloramines in concentrated sulfuric acid, using ferrous salts as initiators, gives 5-butyl-2-pentylpyrrolidine (monomorine 11) (10a) and 2-hexyl-5-pentylpyrrolidine (10d) (Scheme 23) (132,412).

c ~ H ~ ~ ~ - c H - R I i_ c ~ H ~ ~ ~ - c H - R I c ~ H ~ ~ nQR NHCl H NH2

275a R=C H 276a R=C H 10a R=C H d R=C6H13 ' n ' n d R=C6H13 ' n d R=C6H13

j R=C2H5 j R=C2H5 j R=C2H5

Scheme 23. Reaction conditions: i, 'BuOCI or NaOCI; ii, conc HZS04, (NH4)2Fe(SO,),, or UV.

Stepwise alkylation of I-nitrosopyrrolidine (277) via metalated nitrosoamine affords 5-ethyl-2-heptyl-I-nitrosopyrrolidine (279). Removal of the nitroso function gives an overall 33% yield of a 1 : 1 mixture of isomeric products (10d) (Scheme 24) (415). Following the same approach, 277 gives 5-butyl-2-pentylpyrrolidine (monomorine 11) (lOa), 2-hexyl-5-pentylpyrrolidine (lob), and 2-(5-hexenyl)-5-pentylpyrrolidine (monomorine 111) (100 (412).

Catalytic hydrogenation of the unstable pyrroles (281a-c), which are prepared by heating the 1 ,Cdiketones (280a-c) with an excess of ammonium carbonate at 120°C, gives 2,5-dialkylpyrrolidines (10a-c) (cis : trans = 85 : 15, -85% conversion) (Scheme 25) (133). Reductive amination of 1 ,Cdiketones (282b,f,h,i) with ammonium acetate and sodium cyanoborohydride produces 2,5-dialkylpyrrolidines (10b,f,h,i) identical to natural products in 50-90% yields. Each pyrrolidine is an approximately 1 : 1 mixture of cis and trans isomers (Scheme 26) (25,138).

G c 2 H 5 - R G c 2 H 5 - nC7H15

1) i , ii

2) i, iii

iv

H NO NO

10d 277 278 R = H

n 279 R=C7H15

SCHEME 24. Reaction conditions: i, LDA-THF; ii, EtI; iii, 1-iodoheptane; iv, HCI


A highly attractive synthetic method is as follows. Alkylation of the in situ generated anion of 283 occurs with high regioselectivity at the a-position to afford the monoalkylated derivative (284), and sequential alkylation of 284 generates truns-2,5-dialkylpyrroline (285) with high regio- and stereoselectivity . Catalytic hydrogenation of 285 followed by demethoxycarbonylation gives the trans isomer of 5-butyl-2-pentylpyrrolidine (10a) in 40% overall yield. This synthetic route proceeds with a high degree of selectivity in establishing the trans stereochemistry of the dialkyl groups (Scheme 27) (416).

280a - c 281a-c

H 10a-c (cis)

SCHEME 25. Reaction conditions: i , (NH4)2C03, 120°C; ii , HZ-RhlA1203.

The Lukes-Sorm dilactam (287) can smoothly afford various 5-oxoalkyl-2- pyrrolidones in high yield on treatment with Grignard reagents. This reaction has been applied to the synthesis of truns-5-butyl-2-heptylpyrrolidine (lOc), a repellent of ants. Reaction of 287 with methyl magnesium bromide afforded oxo- alkylpyrrolidone (288), the dithioketal (289) of which was converted by hydrogenolysis with Raney nickel to alkylpyrrolidone (290a). Treatment of 290a with phosphorus pentasulfide gave thiolactam 290b which was converted by treatment with methyl iodide to the thioether (291). The thiomethyl group of 291 was replaced with a butyl group by reaction with butyl magnesium bromide in methylene chloride to yield pyrroline (292). Reduction of 292 with sodium borohydride afforded a 1 : 1 mixture of truns- and cis-5-butyl-2-heptylpyrrolidine ( ~ O C ) , separable by chromatography. The desired trans isomer is identical to the repellent of ants by spectral properties (Scheme 28) (418).

Recently, both enantiomers each of cis- and truns-5-butyl-2-heptylpyrrolidine (1Oc) have been synthesized from glutamic acid by an excellent method with high diastereomeric and enantiomeric purity (417). The thiolactam (293) prepared from L-glutamic acid was reacted with benzyl 2-(trifluoromethylsul- fony1oxy)octanoate to yield the rather unstable salt (294), which without purification was treated with triphenylphosphine and N-methylpiperidine to afford


b

f

h

i

R1 R2

C5H11n 0 H 10 b , f , h , i

C6H13n

-( CH2)4CH=CH2

C9H19 -( CH2)4CH=CHz

282 b , f , h , i

C 5 H l l n c i s / t rans= 1 / 1

-(CH2)7CH=CH2 -(CH2I4CH=CH2

1 ) iv

I I nH9C4 R

0 - n H g C 4 . : Q R - 2 ) v

C 0 2 M e CO2Me

283 284 R = H 286 R = C 0 2 M e

285 R=C5HI1 lOa(trans) R = H n

SCHEME 27. Reaction conditions: i, LDA; ii, "BuBr; iii, C 5 H I I B r ; iv, H,-Pt0,-AcOH; v, Me3SiI.

$&J Los4-o+s+

W 0

287 288 289

2 9 0 a x= 0

2 9 0 b X= S

291 292

1Oc (trans) 1Oc (cis)

SCHEME 28. Reaction conditions: i , MeMgBr-CH2C12; ii, HSCH2CH2SH-BF,.Et20; iii, Raney Ni-H,; iv, P2S5-PhH; v, CH31; vi, n-BuMgBr-CH2C12; vii, NaBH4.


the vinylogous carbamate (295) as a 5 : 1 mixture of geometrical isomers. The carbamate (295) was transformed to cis-pyrrolidine (296) in a one-pot treatment with ammonium formate and 10% Pd-C in a mixture of MeOH and AcOH. Successive treatments of 296 with benzyl bromide-potassium carbonate and acetic acid gave the acid (298), which was treated with n-propyllithium to afford the ketone (299). Compound 299 was immediately reduced with NaBH, to the diastereomeric alcohols (300), which were converted to the secondary amines (301) by catalytic hydrogenolysis. Bisphenylsulfonylation of 301 followed by reduction with NaBH, in DMSO gave the sulfonamide (303). Finally, deprotection using 48% HBr or sodium in liquid ammonia gave (2S)-cis-S-butyl-2-heptylpyrrolidine (1Oc). (2R)-cis-lOc was prepared by a modification of this procedure.

Alternatively, treatment of the cis acid (298) with POC1, followed by po-

293 294 295

296 R = H

297 R = B n

298 R = O H

299 R = C n 3 1

3H7n ; 1 . . . Q . . C 7 H 1; 2 C4Hgn..

1 x1 R 0 i 2

303 R=SOZPh 300 R1=H, R 2 = B n

301 R1= R 2 = H (2S)-lOc (cis) R= H

302 R1=R2=SOZPh

Q'' C7H 1t 304 R = C N (2s)-lOc {trans) 305 R=COOH

H

HOOC - ' o ' . C 7 H l : xii R Q-C7nl: C4Hg

B n - Bn - xiii, xiv steps

298

SCHEME 29. Reaction conditions: i, nC6H,3CH(OTf)COOBn in CH3CH; i i , Ph3P and N-methylpiperidine; iii, HCOONH4, 10% Pd/C; iv, PhCH2Br-K&03; v, AcOH-H20-"PrOH; vi, "PrLi; vii, NaBH4; viii, H2-10% Pd/C; ix, phenylsulfonylimidazole and Me3+O-BF4-; x, NaBH4 in DMSO; xi, 48% HBr or Na-liq NH,; xii, POCL,; xiii, KCN; xiv, conc HCl.


tassium cyanide gave a mixture of cis- and trans-aminonitriles in favor of the trans isomer (304). This mixture was equilibrated in a silica gel slurry to produce a 1 : 9 cis : trans mixture. Hydrolysis with concentrated HCl followed by recrystallization of the resulting acid gave the pure trans acid (305), which was easily transformed to (2S)-truns-5-butyl-2-heptylpyrrolidine (10c) according to the procedure as described for cis-lOc from 298. (2R)-truns-lOc was prepared by the same method from D-glutamic acid (Scheme 29).

Structures of N-methylpyrrolidines (11) are suggested by the mass spectra which exhibit the a-cleavage and parent ions increased by 14 mass units relative to those of corresponding N-H pyrrolidines. These structures are confirmed by reductive N-methyiation of N-H pyrrolidines with formaldehyde in formic acid (I 6.25).

2. 2,5-Dialkylpyrrolines

Mass spectra of 2,Sdialkyl- 1-pyrrolines (12) exhibit relatively more intense molecular ions and two diagnostic fragment ions (306 and 307) resulting from a McLafferty rearrangement of the y hydrogen and from an allylic cleavage relative to the C=N bond as well as an ion (308) at mlz 82 arising from a-cleavage of an alkyl group from the odd electron ion (306) (16,25,132,409). Reduction of these pyrrolines with sodium borohydride gives nearly equal amounts of cis- and trans-pyrrolidines, proving unequivocally that the pyrrolines are substituted in the 2,5 rather than the 2,2 position (132).

307

1-Pyrroline (129, found in the desert locust and the Mediterranean fruit fly (Table 11), has been identified by formation of the l-dimethylaminonaphthalene-5-sulfonyl (dansyl) derivative (106) or the colored adduct with o-ami- nobenzaldehyde, in addition to gas chromatography-mass spectrometry (102). The 1-pyrrolines (12) have been prepared by treatment of their parent pyr-


lOj 12b

SCHEME 30. Reaction conditions: i, NaOCI; ii, NaOH

12a

rolidines with sodium hypochlorite followed by heating the resulting N-chlo- ropyrrolidines with aqueous alkali (16,133,138). Using this method, 5-ethyl-2-n- pentylpyrrolidine (l0j) gives a mixture of 2-ethyl-5-n-pentylpyrroline (12b) and its isomer (12a) (Scheme 30) (138). Reduction of the pyrroline mixture with sodium borohydride in methanol regenerates the pyrrolidines, in which the trans isomer predominates (133). 5-Ethyl-2-n-pentylpyrroline (12a) is also available as by-product in the Hofmann-Loffler reaction to prepare 5-ethyl-2-n-pentylpyrrolidine ( l O j ) (Scheme 23) (132). 1-Pyrroline (129 is prepared by heating a solution of (-t )-ornithine hydrochloride and ninhydrin or by the reaction of N- bromosuccinimide with (+)-ornithine hydrochloride (106).

3. Methyl 4-Methylpyrrole-2-carboxylate

The trail-following pheromone, methyl 4-methylpyrrole-2-caboxylate (14), of the genera Attu and Acromyrmex (Table 11) is characterized by spectral data (419,420) and by comparison with an authentic synthetic sample, which had been prepared by methylation of the acid (310) resulting from the action of strong alkali on 3-ethoxycarbonyl-4-methylpyrrole-2-carboxylic acid (309) (Scheme 31) (421). The following synthesis from pyrrole (311) gives a better overall yield (30): Pyrrole (311) is treated with trifluoroacetic anhydride-dimethylaniline fol- Lowed by hydrolysis to afford the acid (312). Diazomethane treatment and subsequent formylation with methoxydichloromethane and aluminum chloride give the aldehyde (313). Catalytic hydrogenolysis of 313 gave the pyrrole (14) in 83% yield (Scheme 32).

Me COOEt M e Me

0 COOH O C O O H ii O C O O M e

H H H

309 310 14

SCHEME 31. Reaction conditions: i, OH-; ii, CH2N2,


R1 M e

iii, iv O R z L QCOOMe H 0"" H H

14 1 2

1 2 311 312 R =H, R =COOH

313 R =CHO, R =COOMe

SCHEME 32. Reaction conditions: i, TFAA-PhNMe,; ii, OH-; iii, CH2N2; iv, C12CHOCH3- AIC13; V, H2-PdlC.

4. Polyzonimine

Polyzonimine (19), isolated from a millipede secretion by preparative gas- liquid chromatography (Table II), has been assigned the molecular formula

314 315 316

317 R = C H O

318 R'CH:O] 0

(?) -19

+j? N C OCH2Ph

322 320 R=COOEt 319

321 R = C H Z B r

323 324 (+)-19

SCHEME 33. Reaction conditions: i, LiBr-HMPA; ii, morpholine; iii, AcOCH2CH2NOz; iv, ethylene glycol-H+; v, Hz-Raney Ni; vi, H 3 0 + : vii, (EtO),P(0)CH2COOEt-NaH; viii, AIH,; ix, PBr3-pyridine; x, L-benzoyloxyprolinol-KzC03-DMSO; xi, PhS03CH2CN; xii, (a) KOBuf-THF- DMSO, (b) CuS04.5H20; xiii, CH3NOz-KOH-MeOH; xiv, MsCI-Et,N; xv, NaBH4-MeOH; xvi, 0,; xvii, Me$; xviii, ethylene glycol-triethyl orthoformate-H+; xix, H2-PtO,; xx, 10% HCI- THF.


C,,H,,N on the basis of high-resolution mass spectrometry. The structure has been deduced from its spectra and an X-ray crystallographic analysis of the perchlorate, and confirmed by synthesis (113).

The racemic polyzonimine (19) is prepared as shown in Scheme 33. The expoxide (314) is rearranged to the aldehyde (315) by refluxing with LiBr- HMPA in benzene. Morpholine enamine (316) derived from 315 is condensed with nitroethylene, generated in situ from 2-acetoxynitroethane, to afford the nitroaldehyde (317). Ethylene acetalization, reduction over Raney nickel, and subsequent deacetalization give (*)-polyzonimine (19) in 22% overall yield from the epoxide (314) (113).

Natural (+)-polyzonimine (19) has been synthesized by a reaction sequence using the asymmetric [2,3]sigmatropic rearrangement of the ammonium ylide to generate the chiral intermediate. The Homer-Emmons reaction of the ketone (319) gives the ester (320) accompanied by two isomers. Reduction of the ester (320) with aluminum hydride followed by bromination gives the bromide (321), which is aminated with L-benzoyloxyprolinol to afford an amine. This amine is converted to the quaternary salt (322) by treatment with cyanomethylbenzenesul- fonate. Treatment of 322 with potassium tert-butoxide followed by hydrolysis with CuSO,.SH,O affords the optically active olefin aldehyde (323), the optical purity of which is estimated to be 68% enantiomeric excess. Condensation of 323 with nitromethane followed by dehydration affords the nitroolefin (324) which is readily converted to ( + )-polyzonimine (19) by standard reaction sequences (Scheme 33) (422).

C. PYRROLIZIDINES

1. Danaidones

Four dihydropyrrolizines and many pyrrolizidine ester alkaloids have been found in danaid butterflies and arctiid moths (Table IV). The first isolation of danaidone (25), an important pheromone of hairpencils or coremata, has been carried out by chromatography of the hairpencil extract on a silicic acid column and vacuum sublimation of the resulting crystalline compound (14th). After this isolation, two other dihydropyrrolizines (26 and 27) were identified by thin-layer or gas-liquid chromatographic comparison with authentic compounds, in conjunction with specific color reactions with Ehrlich's reagent (61,64,14Bb,423). Nonvolatile alkaloid 28 can be seen in gas chromatograms only after tri- methylsilylation (64). Identifications of pyrrolizidine esters are made by using combined gas chromatography-mass spectrometry and by comparison and cochromatography with authentic samples (63,64).

The structure of danaidone (25), namely, 2,3-dihydro-7-methyl- 1H-pyr- rolizin-1-one, has been inferred from the IR (v 1681 cm-') and UV [A,,, 288


nm (log E 4.22)] spectra suggesting a conjugated carbonyl group, the mass spectrum (M + m/z 135, a base peak) indicating the molecular formula C,H,ON, and the 'H-NMR spectrum suggesting one methyl group (6 2.2 , s), a pair of methylene (6 2.84, 4.13, t, J = 6.5 Hz), and two coupled aromatic protons (6 6.09, 6.69, d, J = 2.5 Hz) (55,148~). Synthetic confirmation of structure 25 is obtained as follows. Cyanoethylation of 3-rnethylpyrrole (325) using Triton B as base gives N-cyanoethyl-3-methylpyrrole (326). Cyclization of 326 with hydrogen chloride followed by hydrolysis via the imine (327) gives danaidone (25), identical to the natural alkaloid (Scheme 34) (148~) . Danaidone (25) can also be easiIy obtained in high yields from ethyl 3-methyl- 1H-pyrrole-2-carboxylate (328) via Dieckmann reaction of the N-propanoate derivative (329) (Scheme 35) (424).

H 325 326 327 25

R H CHZOH

N

3 3 1 2 6 b 332 R= OH 2 6 a

333 R= H 27 R= H

SCHEME 34. Reaction conditions: i, CHFCHCN, Triton B; ii, dry HCI; iii, H2O-AcONa; iv, MnOz.

In contrast to the achiral pheromones (25 and 27), hydroxydanaidal (26) possesses an asymmetric carbon atom (C-7), but the absolute configuration has not yet been determined. The coremata of the male arctiid moth, Creatonotos gangis, have recently been shown to produce (R)-( -)-hydroxydanaidal (26a) both from heliotrine (330, 7 s ) and from monocrotaline (42, 7R) (Table IV), when the larvae are raised on a diet incorporating either 330 or 42. This fact indicates that the (7s) alkaloid is inverted at C-7 in its biosynthetic conversion to 26 and suggests the possibility that the natural hydroxydanaidal (26) has the (R) configuration (425). (R)-( - )-Hydroxydanaidal (26a) can be prepared by oxidation of retronecine (332) with manganese dioxide. In a similar manner, he- liotridine (331) affords @)-( +)-26b (75,423,426). Supinidine (333) is similarly oxidized by manganese dioxide to afford danaidal(27), identical with the natural product (Scheme 34) (423,427). Recent synthetic studies on the potential anti-


328 329

___) ii r ~ C 0 2 E j - & 25

SCHEME 35. Reaction conditions: i, Br(CH2)2C02Et; ii, Dieckmann condensation.

tumor agents derived from pyrrolizidine alkaloids and their derivatives have been reported (428).

Me, ,Me

CH20COC-C\H yH ,OMe

I OH Me

330 heliotrine

2. 3-Heptyl-5-methylpyrrolizidine

(5Z, 8Q-3-Hepty1-5-methylpyrrolizidine (48), from a cryptic thief ant S . xenovenenum (Table IV), shows in the mass spectrum a molecular ion at mlz 223 and two diagnostic fragment ion peaks (334 and 335), at mlz 208 (M+ - Me) and 124 (M+ - C,H,,), corresponding to the loss of the alkyl side chains from carbons adjacent to nitrogen. In addition to this fragmentation pattern, a molecular formula of C,,H,,N and an absence of double bonds suggest a 3 5 disubstituted pyrrolizidine ring system (430).

H H H

-c 7H 1 5 ’

Me

m / z 208 m l z 223 m / z 124

334 48 335

The overall carbon-nitrogen framework was confirmed by synthesis. Reduc- tive amination of the triketone (336) (429) with sodium cyanoborohydride and ammonium acetate formed a mixture of four isomeric pyrrolizidines. Pure sam-


ples of each isomer were obtained by preparative gas chromatography. The naturally occurring alkaloid (48) has a gas chromatographic retention time identical with that of the major synthetic 5Z,8E isomer (48) by direct comparison (Scheme 36) (430).

The selective synthesis of the enantiomer of 48 started with the ally1 alcohol (338). Oxidation of 338 by the Sharpless procedure (431) gave the chiral epoxide (339) which was reduced with bis(2-methoxyethoxy)aluminuminum hydride to yield the 1,3-diol (340). Monobenzoylation of 340 and subsequent treatment with phthalimide by employing the Mitsunobu condition (432) gave an imide. Suc- cessive treatment of the imide with potassium carbonate in methanol and hydrazine hydrate gave the amino alcohol (341). The amino alcohol (341) was converted to the imine (342) by treatment with aqueous perchloric acid. Reduc- tion of 342 with sodium cyanoborohydride gave a mixture of the pyrrolizidines (343a; R1 = H, R2 = OH, and 343b; R' = CN, R2 = OH). The cyano group in 343b could be reductively eliminated by sodium borohydride or by sodium in ammonia-ethanol to afford the pyrrolizidine (343a). Oxidation of 343a and Wittig reaction of the resulting aldehyde with pentylidenetriphenylphosphorane led to a mixture of (2)- and (E)-olefins. Catalytic hydrogenation afforded (-)-[(3~)-(3~,5~,8cu)]-3-heptyl-5-methylpy~olizidine (343c; R1 = H, R2 = C5Hlln) [(33)-48] (Scheme 36) (433).

0 Me C7H1jn

336 337

- . - 'f 'OH x, xi Me 5 v , Y t

N H 2

342 343 R 2 341

SCHEME 36. Reaction conditions: i , 'BuOOH-Ti(O'Pr)4, (+)-L-diethyltartarate; ii, (MeOCH2- CH20)2AIH; iii, PhCOC1-Et3N; iv, phthalimide, Ph3P; v, K2C0,-MeOH; vi, NH,NHz.H,O; vii, aq HC1O4; viii, NaBCNH3-THF-MeOH-20% AcOH; ix, DMSO oxidation; x, Me(CH2)2CHZ- CH=PPh3; xi, H2-Pt02.


19 344 49

SCHEME 37. Reaction conditions: i, I-(CH&NO*; ii, Py, reflux.

3. Nitropolyzonamine

Nitropolyzonamine (49) (Table IV) can be isolated as colorless crystals from the secretion of the millipede, P. rosalbum, by preparative gas chromatography or as its crystalline perchlorate from an ethereal solution of the crude defensive secretion. The structure and stereochemistry have been determined by an X-ray analysis of the base perchlorate (153). Racemic nitropolyzonamine (49) can be synthesized from polyzonimine (19). Treatment of polyzonimine (19) with 3- nitropropyl iodide gives a crystalline salt (344) which is readily cyclized to racemic nitropolyzonamine (49) in boiling pyridine (Scheme 37) (153).

D. INDOLIZIDINES

1. Monomorine I

The structure of monomorine I (16a), isolated from the extract of workers of the thief ant, Monomorium pharaonis, by gas-liquid chromatography (Table 11) , has been revealed to be 3-butyl-5-methyloctahydroindolizidine on the basis of mass and 'H-NMR spectra. The mass spectrum shows characteristic peaks at mlz 180 (345; M - CH,) and rnlz 138 (346; M - Bu, a base peak), indicating the presence of methyl and butyl group attached to the a carbons of an amine, in addition to a molecular ion at rnlz 195. The fact that the (M - I) peak is higher than the M peak indicates a cyclic amine. The 'H-NMR spectrum shows two methyl groups (triplet at 6 0.88, C€I,-CH,; doublet at 6 1.18, C€I,CH-N) and three methines adjacent to nitrogen (6 2.13, 2.27, and 2.52).

Structure 16a, assumed on the basis of these spectral data, was confirmed by

m / z 195 m / z 138 m / z 180

345 16a 346


comparison with a synthetic stereoisomeric mixture. The synthesis was carried out by condensing diethyl 3-oxoglutarate (347), acetaldehyde (348), and 4- aminooctanal diethylacetal (349). The resulting oxooctahydroindolizine (350) was subsequently saponified, decarboxylated, and reduced to yield a stereoisomeric mixture of 3-butyl-5-methylindolizidine (16) (Scheme 38) (21,23a).

COOEt C H ( 0 E t ) COOEt

CHO

COOEt Me

M e C4Hgn Me C4Hgn 347 348 349 350 ( i ) - 1 6

SCHEME 38

The stereochemistry was determined by evaluation of biological assays of four stereoisomers of monomorine I prepared by Sonnet and Oliver (434,435). The natural monomorine I was the all-cis isomer, namely, (SZ, 9Z)-3-n-butyl-S-methylindolizidine (16a), having both attractant and trail-initiating activity (22,236,427). Racemic synthesis of the four stereoisomers by Sonnet starts with 2,6-lutidine (351). Successive treatments of 351 with n-BuLi and hexene- 1 -oxide gave an alcohol (352). Cyclization of 352 with triphenylphosphine dibromide gave the quaternary base (353), which on reduction yielded the indolizidine (16a), racemic monomorine 1, as a sole product. Alternatively, catalytic hydrogenation of 352 yielded the amino alcohol (359, and successive treatments of 355 with triphenylphosphine dibromide and triethylamine gave an isomeric mixture of indolizidines (16a and 16b), which could be separated by spinning-band distillation. Similarly, trans-amino alcohol 354 can be transformed to a separable mixture of the indolizidines (16c and 16d) (Scheme 39) (434,435). Similar synthetic routes starting from 2-butylpyrrole (356), cis-amino alcohol 355, and trans-amino alcohol 354 have also been reported (Scheme 40) (434-436). The conformation of the four stereoisomers (16a-d) of monomorine I was investigated by ‘H- and 13C-NMR spectroscopy (436).

The stereoisomers 16c and 16d have also been prepared by a [3 + 31-type annelation between a,a ’-dimethoxylated amides and allyltrimethylsilane (363). Compound 366 was synthesized by ring formation with 363 and 365, prepared by methoxymethylation of 364, in the presence of TiC1,. Hydrogenation of 366 followed by butylation with n-BuLi and reduction with sodium borohydride gave a mixture of stereoisomers 16c and 16d (Scheme 41) (437).

A stereocontrolled synthesis of racemic monomorine I (16a) has been accomplished by Stevens and Lee (438). An ally1 alcohol obtained by reaction of acrolein with the Grignard reagent of the chloroacetal(367) was oxidized to yield the enone (368). The Michael addition of 1-nitropentane to 368 was catalyzed by tetramethylguanidine to yield the nitroalkane (369). Reductive cyclization of 369


oMe __c i , ii

Me

351 HO Me C 4 ~ g n

353 (+) -16a

Me..

HO Me C4Hgn

(+)-16a ( + ) - 1 6 b

HO

354 355

i i i L&J + @ Me C4Hgn Me C4Hgn

( f ) - 1 6 ~ (?)-16d

SCHEME 39. Reaction conditions: i, “BuEi; ii, hexene-I-oxide; iii, Ph3P.Br2-Et3N; iv, Hz-PtOz; v, Na-EtOH.

357 358

355 359

(f) -16b

Me C4Hgn

( t ) -16d

SCHEME 40. Reaction conditions: i, RMgX; ii, 5-methyl-2-oxotetrahydrofuran; iii, HZ-RO2; iv, PhsP.Br2-Et3N; v, Cr03; vi, HClOk; vii, LiAIH4.


C H 3 0 Q O L C H 3 0

A H

364 C H 3 0 C H 3

365

& + 4Hgn

... 111

O i v V

c1 d H 3 k 4 H g n ’CH3

366 (+)-16~ (+)-16d

SCHEME 41. Reaction conditions: i, NaH, CH3CH60CH3; ii,- Si(CH,), (363), TiC14; iii, Hz, Raney Ni, KOH; iv, “BuLi; v, NaBH4, AcOH.

gave the amine (370), which on sequential treatments with aqueous acid and sodium cyanoborohydride yielded (*)-monomorine I (16a) (Scheme 42).

Furthermore, two other stereoselective syntheses of (2)-monomorine I (16a) have been reported by the groups of Natsume and co-workers (439,441) and Kawanishi et aE. (440). Acetal372 prepared from the dihydropyridine derivative (371) was successively treated with p-toluenesulfonyl chloride-pyridine and DBU in toluene to afford acetal 373. Compound 373 was treated with aqueous hydrochloric acid to afford an aldehyde which on reaction with the anion of diphenyl(1 -phenylthiopentyl)phosphine oxide gave the thioether (374) as a mixture of the cis and trans isomers. Hydrolysis of 374 with aqueous hydrochloric acid in methanol gave a ketone and subsequent reductive cyclization gave (*)- monomorine I (16a) as a sole product (Scheme 43) (439). On the other hand, the pyridinium salt of a-picoline (375) was treated with Grignard reagent to give the a-alkyl- 1,2-dihydropyridine (376). Catalytic hydrogenation of 376 followed by

368 369 367

370 Me 6 4 H g n

(+)-16a

SCHEME 42. Reaction conditions: i, Mg-THF; ii, CH,=CHCHO; iii, MnOz; iv, 1-nitropentane; v, H2-Pd/C, NazS04; vi, H 3 0 + ; vii, NaBCNH3.


M e + C b z

Me

C b z

371 372

Me

M e C b z

374 (+)-16a 373

SCHEME 43. Reaction conditions: i, TsCl-Py; ii, DBU-toluene, 100°C; iii, aq HC1-DME; iv,

v, aq HCl-MeOH; vi, H,-10% Pd/C.

Li

deprotection afforded cis-2,6-dialkylpiperidine (377) which was transformed to the ketal(378) on successive oxidation and protection. Decarbomethoxylation of 378 and subsequent cyclization gave (t)-monomorine I (16a) in 60% yield (Scheme 44) (441).

The racemic stereoisomer (16b) of monomorine I has been stereoselectively synthesized (416). Thus, successive bis-alkylations of 1 -methoxycarbonyl-3- pyrroline (379) gave truns-2,5-dialkylpyrroline (381) as a I : 1 mixture of 4’- bromopentane isomers. N-Decarbomethoxylation gave the bicyclic compound

375 376

H.., &*H& ,..H

r C02Me OH C02Me P O

377 378 A

.H ___)

viii

(+)-16a SCHEME 44. Reaction conditions: i, CIC0,Me; ii, BrMgmCH(CH2)3CH,; iii, H2-F’VC; iv,

I 0 THP

H+, MeOH; v, CrO3, aq HzS04; vi, HOCHzCHzOH, P-TsOH, PhH; vii, KOH, NHzNHz, HOCHzCHZOH; viii, Pd/C, aq HCl, MeOH.


. ...

Me

1 , I l l 0- i, ii 0 Bun

COOMe COOMe 6OOMe 379 380 381

- iv, v

vi 4f.) "Bu M e "BU Me

382 (f)-16b

SCHEME 45. Reaction conditions: i, LDA; ii, "BuBr; iii, 1,4-dibromopentane; iv, TMSI; v, Na2C03-MeOH; vi, H2-Pt02.

(382) as a 1 : 1 mixture of C-5 methyl isomers. Catalytic hydrogenation afforded a single product (16b) (416). This highly interesting reduction phenomenon does appear to be general, occumng with related 3,5-dialkyl- 1,2-dehydroindolizidine alkaloids (Scheme 45) (416,442).

The first asymmetric synthesis of (-)-monomorine I , an enantiomer of the natural alkaloid, by Husson and co-workers starts with the chiral 2-cyano-6- oxazolopiperidine synthon (385) prepared from (-)-phenylglycinol (384), glu- taraldehyde (383), and KCN (443). Alkylation of 385 with an iodo ketal led to the formation of a single product (386). The cyano acetal (386) was treated with silver tetrafluoroborate and then zinc borohydride to afford a 3 : 2 mixture of C-6 epirnenc oxazolidine (387) having the (2s) configuration. Reaction of 387 with

385 386

M e CqHg M e C4Hgn

390 (-)-16a

SCHEME 46. Reaction conditions: i, KCN, pH 3-4; ii, LDA-THF; iii, ethylene ketal of 1- iodoheptane-3-one; iv, AgBF4-THF; v, Zn(BH4)2; vi, MeMgI; vii, H2-PdIC, 1% 1 M HCi-MeOH.


methylmagnesium iodide afforded a 4 : 1 mixture of the desired cis-alcohol (389) and its trans isomer (388). The major cis-alcohol (389) was reductively cyclized in the presence of aqueous acid to yield (-)-monomorine I (Ma) after the usual column chromatographic separation from its isomer (Scheme 46). Since the absolute configuration of synthesized (-)-monomorine I [16a*HCl, [ c ~ ] ~ ~ - 6 9 . 2 ~ (MeOH)] is (3S, 5R,9R), the natural monomorine I (dextrorotatory) (20) should have the (3R, 5S, 9s) configuration (443).

2. Other 3-Alkyl-5-methylindolizidines

Structures of 3-alkyl-5-methylindolizidines, found in thief ants, Solenopsis species (Table II), arrived at by gas chromatographic and mass spectral analysis were confirmed by coinjection and direct comparison with the synthetic sample. Indolizidine 15a from S. C O ~ ~ K ~ U ~ U exhibits characteristic peaks at mlz 152 (M - CH,) and 138 (M - C,H,, a base peak) as well as aparent peak at mlz 167 in the mass spectrum. It corresponds to an isomer of 3-ethyl-5-methylindolizidine (15) which was prepared as a mixture of four stereoisomers by reductive amination of triketone 391 with ammonium acetate-sodium cyanoborohydride and sodium borohydride (Scheme 47).

In order to assign the stereochemistry of the isomers, indolizidine preparations from 2,6-lutidine (351) by Sonnet (134,435) were employed. The hy- droxyalkylpyridine (392) obtained from 351 was catalytically reduced to afford

vi , vii

391 15

H ... H i 5 iii;'i> 111

M e QMe viii Me + M e M e M e M e

1 5 a Me 351 OH 393

392

n H

I

OH 394

395 1 7 a

SCHEME 47. Reaction conditions: i, "BuLi; ii, octene-1-oxide; iii, H2-Pt02; iv, CrO,-AcOH; v, HCIO,; vi, NH40Ac-NaOH, NaBCNH,; vii, NaBH,; viii, butene-1-oxide.


cis-2-methyl-6-(3-hydroxypentyl)piperidine which on oxidation with chromium tnoxide-acetic acid followed by treatment with perchloric acid gave the iminium salt (393). Catalytic hydrogenation of 393 gave as a sole product (52,92)-3- ethyl-5-methylindolizidine (15a), which had an identical gas chromatographic retention temperature with the natural alkaloid (Scheme 47) (134).

(5Z,9Z)-3-Hexyl-5-methylindolizidine (17a) from a Solenopsis sp. exhibits characteristic peaks at mlz 208 (M - CH,) and 138 (M - C,H,,, a base peak) as well as a parent peak at mlz 223 in the mass spectrum. The stereochemistry has been determined by synthesis. Racemic (5Z,9Z)-3-hexyl-5-methylindolizidine (17a) was prepared by the above-mentioned methodology, using octene- 1 -oxide instead of butene-1-oxide (Scheme 47) (134).

Monomorine VI (lS), 3-(5-hexenyl)-5-methylindolizidine, has been isolated from M . phuruonis workers (Table 11), but its stereochemistry is unknown and synthesis has not yet been conducted (22,238).

E. QUINOLINES

A predominant toxin (51) from water beetles of the genus Zlybius (Table V) shows a UV absorption corresponding to hydroxyquinoline or hydroxyiso- quinoline. The 'H-NMR spectrum exhibits, beside signals of methyl ester and phenol, signals of five aromatic protons as both ABC and AB systems, the latter indicating two protons at C-3 and C-4 in quinoline. Since electron pyrolysis of 51 gives radioactive 8-hydroxyquinoline, its structure is identified as methyl 8- hydroxyquinoline-2-carboxylate (51) and confirmed by synthesis from xanthurenic acid (52) (Scheme 48) (101). The precursor of this alkaloid was shown to be tryptophan (444).

The structure of 1-methyl-2-quinolone (57), from the aposematic beetle in the genus Metriorrhynchus (Table V), was expected from the mass spectral data and was confirmed by comparison with an authentic sample (97).

F. XANTHOMMATIN

Xanthommatin (58) and dihydroxanthommatin (59) are well-known representatives of the tryptophan metabolite, ommatine. Xanthommatin (58) shows a

OH c1

...

OH OH OH 397 R= H

52 396 51 R= CH3

SCHEME 48. Reaction conditions: i, P0Cl3; i i , H,-Pd; iii, HCl/CH30H.

6 . ALKALOIDS FROM ANTS AND OTHER INSECTS 27 1

COOH YOOH 1 CHNHZ CHNH2

I I CH

COOH COOH

___t

398 399 58

SCHEME 49. Reaction conditions: i, aq AcOH, A.

characteristic redox behavior: the yellow-brown pigment (58) is converted by treatment with sulfurous acid or sodium dithionite to the red pigment, dihydroxanthommatin (59), which is reoxidized by oxygen in air. Basic degradation of 58 by treatment with 0.5 N sodium hydroxide solution yields xanthurenic acid (52) via 3-oxykynurenine (398). The enzymatic reaction of 58 with kynureninase affords alanine. On the basis of this evidence structure 58 was proposed, and confirmed by total synthesis, which was accomplished by condensation of 3- oxykynurenin (398) with quinolinequinone (399) (Scheme 49) (445). Xanthom- matin (58) was also demonstrated to be synthesized from 3-oxykynurenin (398) in vivo.

G. PAPILIOCHROMES

One of the papiliochromes, papiliochrome I1 (142), isolated from Pupilio butterflies, is actually a pair of optical isomers, papiliochromes IIa and Ilb. Compound 142 is hydrolyzed by treatment with 10W3 N HC1 to afford L-

kynurenine and a new catecholamine (400) (71). Results of acid hydrolysis of the latter with 1 N HC1 and the mass and 13C-NMR spectra suggest that the structure of 400 is N-P-alanylnoradrenaline, which was proved by chemical synthesis. The 13C-NMR data indicate that papiliochrome I1 is represented as structure 142 in which the nitrogen of aromatic amino group of kynurenine is bonded to C-5 of the side chain of N-P-alanyldopamine. The existence of optical isomers, IIa and

5 1 7 8 +

C H - C Hz-N H - CO- C HZ C HZ N Hz

H O 7 7 H H 6 H H

400 HO

1 4 2


Ilb, is explained by rotation of the catechol ring about the axis C-5 and p-OH to the opposite side.

H . COCCINELLINES

1. Structure

The isolation of eight defensive alkaloids (99-106) (Table VII) from the ladybug (Coccinellidae) and the soldier beetle (Cantharidae) was carried out by partitioning the methanol extract between aqueous methanol and n-pentane followed by chromatographic separation (alumina) of the aqueous methanol extract (85,328,330-332,334). The mass spectrum of coccinelline (99), purified by recrystallization, shows a characteristic peak at mlz M - 16, diagnostic of an N- oxide, as well as a molecular ion at mlz 209, indicative of a molecular formula C,,H,,NO. Compound 99 shows only end-absorption in the UV spectrum, and its 'H-NMR spectrum shows the absence of olefinic protons. It is optically inactive, and the 13C-NMR spectrum affords strikingly simple signals (only eight signals). This evidence indicates that 99 is a tricyclic amine oxide possessing a plane of symmetry (85,333). The structure and stereochemistry have been established by an X-ray analysis of coccinelline hemihydrochloride (446). Reduction of coccinelline (99) under mild conditions (ferrous sulfate or catalytic hydrogenation) gives precoccinelline (loo), which is therefore a free base of 99.

Propyleine (104) is an enamine with one olefinic proton and a secondary methyl group, as assumed from the IR and 'H-NMR spectral properties. Catalyt- ic hydrogenation of 104 gives precoccinelline (100). There are three possible dehydroprecoccinellines (336). Propyleine (104) is devoid of the UV absorption typical of enamines, indicating that the lone pair on nitrogen cannot be parallel with the n-electron system of the double bond. An enamine, which in addition to this condition can lead to 100 on catalytic hydrogenation, could only be 104a of the three possible dehydrococcinellines (334,336).

Convergine (101) and hippodamine (102) are an N-oxidelfree base pair, since monoperphthalic acid oxidation of 102 gives convergine (101) and 101 can be reduced with lithium aluminum hydride to yield 102. The structure and absolute configuration of 101 and 102 have been established by X-ray diffraction analysis


99 401 103 100

SCHEME 50. Reaction conditions: i, Ac20 or CIC0,Et; ii, catalytic hydrogenation.

of convergine hydrochloride and by chemical correlation between the two alkaloids (329).

The structure and absolute configuration of hippocasine (105) and hippocasine oxide (106) have been determined by X-ray analysis of hippocasine oxide hydrochloride and by chemical correlation between both alkaloids. Pyrolysis of 106 gives 105, whereas oxidation of 105 with hydrogen peroxide affords 106. This indicates that 105 is the free base of 106 (332). Myrrhine (103) shows in its IR spectrum the Bohlmann bands (443 , possible only for an all-trans fusion of the three rings. The structure was confirmed by chemical correlation between 99 and 103, using the Polonovski reaction. Thus, treatment of coccinelline (99) with acetic anhydride or ethyl chloroformate gave an unstable enamine (401), which was reduced by catalytic hydrogenation to yield a 9 : 1 mixture of myrrhine (103) and precoccinelline (100) (Scheme 50) (330,448).

2. Synthesis

Extensive synthetic studies on ladybug defensive alkaloids have been carried out by Ayer and co-workers starting from pyridine derivatives and culminating in total synthesis of several alkaloids (336,449,450). Collidyllithium generated from collidine (402) was alkylated with P-bromopropionaldehyde dimethylacetal to give the acetal (403). Subsequent treatment of 403 with phenyllithium and acetonitrile provided, after an aqueous workup, the ketone (404) which was isolated as its bis(ethy1ene) acetal (405). Reduction of 405 with sodium in isoamyl alcohol yielded the all-cis piperidine (406) as the major product. Hydrolysis of 406 with a diluted acid gave a crystalline hemiacetal (407) which yielded a tricyclic ketone (408) on treatment with p-toluenesulfonic acid. The ketone (408) possessing the myrrhine stereochemistry was unstable and immediately converted to the thioketal(409), which was desulfurized with Raney W-2 nickel to yield myrrhine (103) in approximately 40% yield from the tricyclic acetal(407). When hemiacetal 407 was treated with AcOH-pyrrolidine, a mixture of the ketones (408 and 410) was obtained. Thioketalization of the mixture followed by Raney nickel desulfurization provided a mixture of myrrhine (103) and hippodamine (102) separable by preparative thin-layer chromatography (449). The hippo-


damine framework would arised from iminium ions A, B, and C (Scheme 51) (336,449). Oxidation of hippodamine (102) yielded convergine (101).

In a similar manner, coccinelline (99) and precoccinelline (100) have been synthesized from 2,6-lutidine (351) (336,450). Thus, treatment of the mono- lithium derivative (153) of 351 with p-bromopropionaldehyde dimethylacetal gave an acetal, which was converted to the keto acetal (412) by treatment with phenyllithium and acetonitrile. Reaction of 412 with ethylene glycol and p - toluenesulfonic acid followed by reduction with sodium-isoamyl alcohol gave the cis-piperidine (413). Hydrolysis of 413 with 5% HCl gave the tricyclic acetal (414) which was transformed to a separable 1 : 1 mixture of the ketones (415 and 416) by treatment with pyrrolidine-acetic acid. Reaction of ketone 416 with methyllithium followed by dehydration with thionyl chloride afforded the rather unstable olefin (417) which on catalytic hydrogenation over platinum oxide in methanol gave precoccineIline (100). Oxidation of 100 with m-chloroperbenzoic acid yielded coccinelline (99) (Scheme 52) (336,450).

Another elegant synthetic method to obtain ladybug defensive alkaloids, starting from perhydroboraphenalene (451), has been reported by Mueller and co-

M e M e

407 408 R= 0 103

409 R=:gJ

U

Me Me

0

R H

A B C 410 R= 0;102 R= H2

411 R=CS] S

SCHEME 51. Reaction conditions: i, PhLi-Et20; Br(CH2)2CH(OMe)2; ii, PhLi; MeCN; H 3 0 + ; iii, (CH20H)2, p-TsOH; iv, Na-isoamyl alcohol; v, aq 5% HCl; vi, p-TsOH; vii, (CH2SH)2; viii, Raney W-2 Ni; ix, AcOH-pyrrolidine.


412 413 & - v o & + & __c vi

M e H

HO 0 H H : o

414 415 416

M e Me M e

H H

417 100 99

SCHEME 52. Reaction conditions: i, BICH,CH2CH(OMe)Z, PhLi, MeCN, H30+ ; ii, ethylene glycol, p-TsOH; iii, Na-isoamyl alcohol; iv, aq 5% HCl; v, AcOH-pyrrolidine; vi, MeLi; SOCI,; vii, HZ-PtO2-MeOH; viii, m-CPBA.

workers (452-458). Hydroboration-oxidation and equilibration of 1,5,9- cyclodecatriene (418) gave perhydroboraphenalene (419) which was oxidized with ruthenium and sodium periodate to afford the triketone (420). Reductive amination of 420 yielded the all-cis amine (421). A next step involves the inversion of stereochemistry at one of the carbon atoms adjacent to the nitrogen atom. Oxidation of 421 to the known enamine (422) (455,456,459) was accomplished with mercuric acetate. Hydrocyanation of 422 gave the aminonitrile (423) which was converted to the amide (424) by fuming sulfuric acid. Reaction of 424 with mercuric acetate gave the tetracyclic amide (426) via the quaternary base (425). Catalytic hydrogenolysis of 426 afforded the amide (427) which was converted by treatment with phosphorus oxychloride to the nitrile (428) admixed with the enamine (429). Reaction of the borane (419) with N-chloro-0-(2,4- dinitropheny1)hydroxylamine and subsequent oxidation with hydrogen peroxide in aqueous sodium hydroxide gave the amino alcohol (430) (452), which was converted to the enamine (429) by oxidation. On the other hand, treatment of amino alcohol 430 with p-toluenesulfonic acid gave the amine (431) which on oxidation with mercuric acetate or by the modified Polonovski reaction on its N- oxide gave the enamine (422). Enamine 429 has the appropriate stereochemistry for conversion to all the ladybug alkaloids except myrrhine (103) (Scheme 53) .


418 419 420 421 422

H H

VL VLll

H H H

- VL

VLll H" "R

423 R= CN 425

4 2 4 R= CONH,

426 427 R= CONH2 429

428 R= CN 1 I XI

XI1

H Q E H Q H .. HQH2HQoH 422 422 431 419 430

SCHEME 53. Reaction conditions: i, BH3.MezS; i i , RuOz-NaI04; iii, NH3-Hz-Pd/C; iv, Hg(0Ac)z-EDTA; v, KCN, H + ; vi, HZSO4.SO3; vii, Hz-Pd/C; viii, POCl,-F'y; ix, ClN(H)ODNP; x, H202-NaOH; xi, CrO,; xii, p-TsOH; xiii, H202; xiv, T F A A - E t 3 N .

Hydroboration-oxidation of 429 yielded a separable 3 : 1 mixture of two alcohols (432 : 433 = 1 : 3), and subsequent oxidation of alcohol 433 gave the ketone (434). Reaction of 434 with the Bredereck reagent gave the enamino ketone (435) which was reduced to the unstable amino ketone (436) using lithium bronze. Catalytic hydrogenolysis of 436 over palladium on carbon gave the methyl ketone (437). Wolff-Kishner reduction of the ketone (437) gave a 2 : 1 mixture of hippodamine (102) and its axial methyl isomer (significant epimerization occurred during hydrazone formation). However, reduction of the derived thioketal with lithium in ethylenediamine gave hippodamine (102) as a sole product (453). Reaction of 102 with peracid gave the hydrated form of the N - oxide of 102, convergine (101) (Scheme 54) (453).

Conversion of ketone 437 to hippocasine (105) was accomplished by Bom- ford-Stevens reaction via the following reaction sequence. Successive treatments of 437 with hydrazine, p-toluenesulfonyl chloride, and then lithium tert- butylamine gave hippocasine (105). The reaction occurred exclusively in the desired direction. Treatment of hippocasine (105) with methanolic hydrogen peroxide gave hippocasine oxide (106) (Scheme 54).

Propyleine (104) also is derivable from ketone 437. Reduction of 437 with LAH gave the equatorial alcohol (438) which was converted into the corresponding mesylate (439). Clean elimination was effected by heating 439 with potassium carbonate in dimethylsulfoxide to yield a 3 : l mixture of propyleine (104) and isopropyleine (440) (Scheme 54) (455).

Coccinelline (99), precoccinelline (loo), and myrrhine (103) have been syn-


H H H n n

W o n \/**OH U U 429 432 433 434

102 436 R= CHZNMe2

437 R= Me 435

H

101

105 106 438 R= n 104 440

439 R= Ms

SCHEME 54. Reaction conditions: i, BH,; ii, H@-NaOH; iii, Cr03; iv, MeOCH(NMe2)2; v , Li- NH+BuOH; vi, H*-Pd/C; vii, 1 ,Z-ethanedithiol, BF3-Et20; viii, Li-ethylenediamine; ix, rn- CPBA; x, NH2NH2; xi, p-TsC1; xii, 'BuNHLi; xiii, LiAIH4; xiv, MsCI; xv, K2CO3; xvi, H202.

thesized from enamine 429. Epoxidation of the allylic amine (441), derived from 429, with trifluoroperacetic acid in trifluoroacetic acid gave the epoxide (442) which was reduced with lithium in ethylenediamine to afford the axial alcohol (443). Oxidation of 443 gave the ketone (416), previously prepared by Ayer and Furuichi (450) and Stevens and Lee (460). Wittig reaction of 416 and subsequent isomerization of the double bond with p-toluenesulfonic acid gave the allylic amine (417). Catalytic hydrogenation over palladium-carbon gave precoccinelline (loo), oxidation of which afforded coccinelline (99) (Scheme 55) (455).

Myrrhine (103) differs significantly from all other ladybug alkaloids in that it possesses the thermodynamically favored all-cis stereochemistry to the nitrogen atom. Hydroboration-oxidation of 422 followed by Jones oxidation afforded the ketone (445) (455). Reaction of 445 with the Bredereck reagent gave an enamino ketone which was treated with thiobutanol to yield the thiomethylene compound 446. Reduction of 446 with lithium aluminum hydride followed by treatment with aqueous acid gave the aldehyde (447). Reduction of 447 with lithium gave a good yield of aldehyde 448 along with its epimer in the thermodynamic 85 : 15 ratio. Conversion of the mixture of the aldehydes to the alcohols by hydride reduction permitted purification of the desired equatorial hydroxylmethyl com-


Q ), Q iv Q v

- - - - - - N - N - v1 QH ,,i, N -

iii H H H H H H H H

/

0 OH 0

4 2 9 441 442 443 416

M e M e M e Me

417 100 99 CHZ

444

H" *.H ''H - xviil

0 X I S CHSBu CHO R

422 445 446 447 448 R= CHO

449 R= C H 2 0 H

103 R= M e

SCHEME 55. Reaction conditions: i, MeSO3F; ii, LDA-THF; iii, EtSLi-DMF; iv, CF3C03H- CF,C02H; v, Li-ethylenediamine; vi, Cr03; vii, Ph3+CHz; viii, p-TsOH, xylene, reflux; ix, Hz- Pd/C; x, BH3.MezS; xi, H2O2-NaOH; xii, Cr03; xiii, MeOCH(NMe2)2; xiv, BUSH-p-TsOH; xv, LiA1H4; xvi, H 3 0 + ; xvii, Li-NH3; xviii, MsCI-Et3N; xix, LiBHEt,; xx, m-CPBA.

- iii Me02C CHOMe

i + CH2=CHCH0 7 MeOZC CH(OMe)2

I OMe

Me0 2C

450 451

CH(OMel2

_?) iv 0 CH(OMe)2 " ' p H ( O M e ) 2 2.-

CH(OMe)2 CH (OMe) CH(0Me) 2

452 453 454

H H H

viii H

MeOZC Me

0 0 M e 455 416 100 99

SCHEME 56. Reaction conditions: i, NaOMe; ii, CH(OMe),, H + ; iii, NaCl, wet DMF; iv, NaH, DME; v, AcONH,-NaB(CN)H3; vi, dimethyl 3-oxoglutarate, pH 1; vii, Ph3P=CH2; viii, H2-Pd/C; ix. m-CPBA.


pound (449) by crystallization. Subsequent mesylation of 449 followed by reduction with lithium triethylborohydride completed the synthesis of myrrhine (103) (Scheme 55) (455).

A stereospecific synthesis of (*)-coccinelline (99) and (?)-precoccinelline (loo), using the classical Robinson-Schopf reaction, has been reported (460). Thus, reaction of dimethyl malonate with acrolein afforded an aldehyde which was protected by treatment with trimethoxymethane in the presence of an acid catalyst to yield the acetal (450). Decarbomethoxylation of 450 under neutral conditions followed by self-Claisen condensation afforded the 6-keto ester (452) via the acetal ester (451). Decarbomethoxylation of 452 gave the keto diacetal (453) which was reductively aminated to afford the amino diacetal(454). Hydro- lysis of 454 with hydrochloric acid at pH 1 followed by addition of dimethyl 3- oxoglutarate gave the tricyclic keto diester (455) as a single isomer. Decar- bomethoxylation of 455 afforded the known ketone (416), and subsequent reaction of 416 with the Wittig reagent gave an olefin which was catalytically reduced to afford (?)-precoccinelline (100). (+-)-Precoccinelline (100) was converted to crystalline (*)-coccinelline (99) by oxidation with rn-chloroperbenzoic acid (Scheme 56) (460).

3. Biosynthesis

The framework of coccinelline-type alkaloids may be generated by linear combination of seven acetate units, as illustrated in Scheme 57 (330,336). An intermediate such as 456 would explain the existence of the different ladybug alkaloids. Support for the polyketide origin has been provided by feeding experiments ( 14CH,COONa and CH, 14COONa) with Coccinellu septempunctutu (330).

7 CHQCOOH

p-0 CH3 456 - & SCHEME 51


I. ADALINES

1. Structure

A defensive alkaloid of ladybugs in the genus Adaliu, adaline (107) (Table VII), C,,H,,NO (M+ mlz 209), isolated by alumina column chromatography of the extract, contains a carbonyl and an N-H group, as indicated by IR bands at 17 10 and 3330 cm- I . The IH-NMR spectrum shows the presence of one methyl group attached to a methylene group and one proton a to the nitrogen atom. These data suggest a bicyclic aminoketone (337). The complete structure including the absolute configuration was established by X-ray analysis of the base hydrochloride (337) and by optical rotatory dispersion measurement (338), as described by formula 107a.

H

On the other hand, a defensive alkaloid in ladybugs of the genus Cryptolaemus and Mexican bean beetles of the genus Epilachna, euphococcinine (108) (Table VII), is isolated by preparative gas chromatography or successive gel filtrations of the extract (87,89). It is resistant to catalytic reduction and contains a carbonyl group, as shown by formation of a dimethylhydrazone. The empirical formula C,H,,NO (M+ mlz 153) indicates three degrees of unsaturation and thus suggests a bicyclic aminoketone. The general resemblance of the mass spectrum to that of the adaline (107) shows 108 to be a C, lower homolog of adaline (107), namely, l-methyl-9-azabicyclo[3,3,l]nonan-3-one (87). This alkaloid (108) is identical with the known plant alkaloid from Euphorbia atoto (88).

2. Synthesis

The well-known Robinson-Schopf reaction has been applied to the synthesis of dl-adaline (107) from ketoglutaric acid (457), ammonium chloride, and keto- aldehyde (458) (Scheme 58) (3382. The second synthesis of dl-adaline (107) starts with nitrone 459 (462). Reaction of 459 with pentylmagnesium bromide gave a hydroxylamine (460) which was oxidized to yield a mixture of nitrones 461 and 462. Without separation of the nitrones (461 and 462), successive treatments with allylmagnesium bromide and then mercuric oxide gave a mixture of desired nitrones 466 and 467 and by-product 468. Nitrones 466 and 467 are capable of 1,3-dipolar cycloaddition and, on heating in chloroform, 466 and 467


were converted to the isoxazoline derivative 469. dl-Adaline can be obtained from 469 in a straightforward way via amino alcohol 470 (Scheme 58) (462).

The third synthetic route reported by Husson and co-workers (140) is as follows: Amino nitrile 472 obtained from the ketal (471) was converted to the 2,6-dialkylpiperidine (473) by catalytic hydrogenation followed by alkylation with lithium diisopropylamide and pentyl bromide. Refluxing a solution of 473 in methanol containing hydrochloric acid led to the formation of 9-benzyladaline (475) in 90% yield. Debenzylation of 475 gave dl-adaline (107) in nearly quantitative yield (Scheme 59) (140).

+ NH4C1 + C O H O - 0 A &J ‘C5Hl ln

107 C5Hl?

457 458

459 460 461 462

463 464 465

466 467 468

0 OH

A iV - H . @C5HI; - fC5H11 v_

469 470 107

SCHEME 58. Reaction conditions: i, “C5HI ,MgBr; ii, HgO; iii, allyl-MgBr; iv, Raney Ni; v, PCC.


Asymmetric synthesis of adaline has been reported by Hill and Renbaum (461). The 1 ,Caddition of pentylmagnesium bromide-copper iodide reagent to dienone 476 followed by treatment with phenylselenyl bromide gave the ketone (477). Oxidation of 477 with hydrogen peroxide-pyridine gave a dienone (478) via selenoxide. Double Michael-type addition of (R)-( +)-a-methylbenzylamine gave a separable diastereoisomeric mixture of the adduct (479). After separation, each of the diastereomers can be hydrogenolyzed to (+)- or (-)-adaline. The synthesized (-)-adaline (107) was found to be identical to the natural alkaloid (Scheme 59) (461). Euphococcinine (108) has been prepared by the groups of Husson and Hill according to the method described above.

rPh r Ph

471 472 473

474 475 107

( + ) - a d d i n e (107)

(-) -adaline (107)

is

479

SCHEME 59. Reaction conditions: i, H2-Pd/C; ii, LDA-THF; i i i , “C5H, ,Br; iv, 10% HCI; v , H2- Pd/C-HCI-EtOH; vi, C,H, ,MgBr-CuI; vii, PhSeBr; viii, H202-Py; ix, (R)-(+)-a-methylbenzylamine.

3. Biosynthesis

Biosynthesis of adaline (107) may be carried out via intermediate 456 from polyketide origin. A possible biogenetic interrelationship between adaline (107) and the coccinelline-type alkaloids (Scheme 57), suggested by Tursch et al.


(330,337) and Ayer and Browne (336), is supported by the presence of the monocyclic alkaloid 4, a key intermediate of the biosynthetic scheme, in the genus Cryptoluemus (Table I) (87).

J. PYRAZINES

1. Structure

Isolation and identification of pyrazine alkaloids (Table 111) have been achieved in most cases by a combination of gas chromatography and mass spectrometry (35,36,38,69,97,142). Methyl-, 2,3,6-trimethyl-, and tetramethylpyrazines (23a, 21a, and 22a) from the melon fly are identified by utilizing a solid sampling technique in conjunction with gas chromatography-mass spectroscopy (147). Methylpyrazines show the molecular ion as a base peak. Fragmentation proceeds mainly by the loss of HCN or CH,CN from the molecular ion (141). Eth-

____)

.. CH + rnlz 135

20b R 1 2 =R =Me, R 3 =H 480a R 1 2 =R =Me, R 3 =H

21b R 1 3 =R =Me, R 2 =H b R1=R3=Me, R 2 =H

yldimethylpyrazines (20b and 21b) exhibit an intense peak for the (M - 1) + ion owing to loss of the f3-hydrogen (32,141). The primary carbonium ion (480) would be stabilized by the pair of electrons on the nitrogen (141). 2,5-, 2,6-, and 2,3-Dimethylpyrazines having a side chain alkyl group of three or more carbons exhibit a characteristic and diagnostic peak (484, base peak) at mlz 122 resulting from a McLafferty rearrangement (35,45,141,142,145).

.

R1 + ,>C=CH2

CH2 R H

m l z 1 2 2

3 5 3 5 4

3 4 5 3 4 5 481 R =R =Me, R4=H 484a R =R =Me, R =H

482 R =R =Me, R =H b R =R =Me, R =H

483 R 4 5 =R =Me, R 3 =H c R4=R5=Me, R 3 =H


Since the mass spectra of the 3-alkyl-2,6-dimethylpyrazines (482) are almost identical to those of the 2,5 isomers (481), it is necessary to compare gas chromatographic retention times with authentic samples. The retention times of the 2,5 isomers (481) are significantly shorter than those of the 2,6 isomers (482) under isothermal conditions. Further confirmation of the 2,5 and 2,6 isomers is obtained by quaternization of one nitrogen with methyl iodide, followed by reduction of the ring with sodium borohydride to give N-methylpiperazines. 3- Alkyl-2,6-dimethylpyrazines (482) are alkylated preferentially on the nitrogen not surrounded by both methyl groups, while the 2,5 isomers (481) are alkylated on the nitrogen not surrounded by the methyl and large alkyl groups. The mono- rnethylpiperazine (485) from 2,6-dimethyl-3-n-pentylpyrazine (21g) exhibits a base peak at mlz 128, while the monomethylpiperazine (486) from 3-isopentyl-2,5-dimethylpyrazine (20h) has its base peak at mlz 72 (399,463).

H M e M e I M e

72 M e

M&i1: Me B 485 486

The mass spectrum of 3-citronellyl-2,5-dimethylpyrazine (201) exhibits a parent peak at mlz 246 and a normal base peak (484a) at mlz 122, indicative of a dimethylpyrazine having an unsaturated C,, alkyl chain without branching at the a-methylene group. The pyrazine is identified by direct comparison with the compounds synthesized on the assumption that the alkyl chain is isoprenoid (142).

The (a- and (E)-styrylpyrazine structures 20j and 20k were assigned on the base of the mass, NMR, and UV spectral data. The mass spectrum of Z isomer (20j) shows a base peak (the molecular ion) at mlz 210 with a peak at mlz 133 formed by the loss of a phenyl group from 20j. The 'H-NMR spectrum shows the presence of five aromatic and two olefinic protons in addition to one heteroaromatic proton and two methyl groups attached to the heteroaromatic nucleus. Ozonolysis of the Z isomer (20j) yields 3-formyl-2,5-dimethylpyrazine (487) and benzaldehyde, confirming the styryl moiety in 20j. The (E)-styryl derivative (20k) is readily isomerized to the Z isomer (20j) on exposure to sunlight (Scheme 60). Extraction of the pyrazines from I . humillis in the dark indicates that E isomer 20k is the naturally occurring product (144,145).

2 4 l-Butenyl)-5-methyl-3-n-propylpyrazine (23b) has a base peak at mlz 133 (M - 57) as well as a parent peak at m/z 190. This is reduced catalytically (Pt and H2) to give a mixture of two compounds (489 and 490) with molecular weights of 192 and 198, respectively. Compound 489 shows the normal


20k 2Oj 487

SCHEME 60.

McLafferty rearrangements: mlz 164 (loss of ethylene), 150 (loss of propylene), and a double-Mclafferty loss to 122. Compound 490 exhibits two major fragments at mlz 100 and 98 in accordance with the fragmentation of piperazines. An assumed structure was confirmed by synthesis (464).

23b 489 490

3-Alkyl-2-methoxypyrazines exhibit a base peak at mlz 124 in the mass spectrum. The peak corresponds to a molecular ion in 2-methoxy-3-methylpyrazine (24a) and to a fragment ion, resulting from a McLafferty rearrangement of an alkyl group, in 3-isopropyl-2-methoxypyrazine (24b) and 3-sec-butyl-2-methoxy pyrazine (24d) (97).

2. Synthesis

Alkylpyrazines are prepared by two main procedures, (1) self-condensation of a-amino carbonyl compounds and (2) alkylation (or acylation) of pyrazines at nuclear or side chain carbons. Condensation of aminoacetone hydrochloride (491) in the presence of the corresponding aldehyde gave the 3-n-alkyl-2,5- dimethylpyrazines 20e and 20g (Scheme 61) (36). 2,5-Dimethylpyrazine 20a was prepared from hydroxyiminoacetone (493) by reduction with tin and hydrochloric acid (Scheme 61) (145). 3-Ethyl-2,6-dimethylpyrazine (21b) was prepared along with 20a and 495 by condensation of aminoacetone hydrochloride (491) with 2-aminopentan-3-one hydrochloride (494) in the presence of sodium ethoxide (Scheme 61) (36).

The alkylation of either 2,5- (20a) or 2,6-dimethylpyrazine (496) with the appropriate alkyl lithium at a nuclear carbon atom affords various dimethylpyrazines (20b-20d, 20g-204 201, 21b-21d, 21g-21i) (Scheme 62) (35,36, 142,145).

The procedure involving the alkylation or acylation of dimethylpyrazines (496, 20a) gives 2-( l-butenyl)-5-methyl-3-n-propylpyrazine (23b) (Scheme 63) (464). The (2)- and (E)-2,5-dimethyl-3-styrylpyrazines (20j and 20k) are pre-


+ R C H O - , Z C H 3 *QC CH2R

+

4 9 1 492 2 0 e R= iso-Pr

2 o g R= n-Bu

20a O H 4 9 3

or - ii n”r+ kN\Y + N’ N’

H 2 N 4 9 1 4 9 4 2 1 b 2 0 a 495

SCHEME 61. Reaction conditions: i, Sn-HC1; ii, NaOEt.

pared by replacement of the halogeno substituent of 3-chloro-2,s-dimethylpyrazine (505) by either an alkenyl or an alkynyl group (Scheme 64) (465).

3. Biosynthesis

A hypothetical biosynthetic sequence has been proposed for the 3-alkyl-2,6- dimethylpyrazines (482) from various species of Odontomachus ants, as shown in Scheme 6.5. The acyloin (507), prepared by condensation of the pyruvate with “active” acetate, or the derived dione (508) may condense with the amide (509) of alanine, ultimately giving the 3-alkyl-2,6-dimethylpyrazines (482) (141). A separate biogenesis is envisaged for the 3-alkyl-2,5-dimethylpyrazines (481) such as 3-isopentyl-2,S-dimethyl(20h) and 2,5-dimethyl-3-styrylpyrazines (20j,

20a 497

4 9 6 4 9 8

SCHEME 62. Reaction conditions: i , RLi.

2 3 b 500

20a 501

503

2 3 b 504 SCHEME 63. Reaction conditions: i, LDA; ii, EtBr; iii, CH3CH2CH=CHLi; iv, n-PrLi; v,

EtCOZEt; vi, NaBH4; vii, TsC1, A .

... )yi&Ph x :Lph- AZKCI - 111 CEC-Ph

20k 505 506 20 j

SCHEME 64. Reaction conditions: i, PhCH=CHZ, Pd(PPh3),, CH,COOK; ii, Ph-H, Pd(PPh&, CH3COOK; iii, H,/Pd-CaCO,; iv, LiA1H4.

COOMe R I H N

\,/OH 2 \c=o FN

x,%,,

I

--I-

H3C

I

1 decarboxylation, e t c

1 Oxida t ion

I

C H I + C

H3C’ %J H ~ N / \ C H ~

507 509 482

reduction

R H N ‘c=o ‘c=o

,c=o C H I +

H3 H ~ N / \ C H ~

508 509

SCHEME 65


20k) from I . humilis. It seems likely that the precursors to the 3-isopentyl and 3- styryl substituents in these pyrazines may be introduced into a symmetrical intermediate arising via dimerization of alanine (141,145).

K. ACYCLIC AMINES

1 . Hannonine

A new aliphatic diamine, harmonine (121) (Table VIII), has been isolated as a diacetate (510) from ladybugs in the genera Hippodamia and Harmonia. Its structure has been identified as (Z)-1,17-diaminooctadec-9-ene on the basis of various spectroscopic analyses of diacetylhannonine (510) and the mass spectrum of the epoxide (511) of 510. The high-resolution mass, IR, and IH-NMR spectra suggest that 510 is a C,, long chain aliphatic bearing two acetylamino groups at C-1 and C-17 beside a double bond. The geometry and position of the double bond can be determined from the IR spectrum of 510 and the mass spectrum of the epoxide (511), respectively. This structure has been proved from the fact that oxidative cleavage of 510 by treatment with NaIO, in the presence of catalytic amounts of KMnO, followed by CH,N, esterification gave methyl 8- acetylaminononanoate and methyl 9-acetylaminononanoate (3 78).

2. Amines from Ants

Twelve volatile acyclic amines and amides (114-120, 125-129) (Table VIII) from ponerine ants in the genus Mesoponera have been identified by gas chromatography-mass spectrometry and mass spectral comparison with authentic synthetic samples (41). The major aliphatic amine, N-isoamylnonylamine (114), shows a molecular ion at m/z 213, a-cleavage fragments at miz 156 (M - C,H,) and 100 (M - C,H,,), and an ion at m/z 44 (CH2=NHCH3+) resulting from cleavage and rearrangement with hydrogen transfer, typical of alliphatic secondary amines.

3. Amides from Flies and Beetles

Two of amides from melon flies of the genus Dacus (Table VIII) have been identified as N-isoamylacetamide (122) and N-(2-methylbutyl)acetamide (123) by comparison of their mass spectra and chromatographic properties with those of authentic samples (103). The third amide, previously reported neither as a component of an insect secretion nor as a synthesized derivative, was assigned as N-isoamyl-2-methoxyacetamide (124) from the mass spectrum, showing a molecular ion at mlz 159 and fragment ions at miz 129 (M+ - CH,O) and 102 (M+ - C,H,), and its structure was confirmed by comparison with a synthetic au-


thentic sample. It has been suggested that the N-isoamyl and N-2-methylbutyl amine moieties originate from leucine and isoleucine, respectively (104). The 2- methoxyacetamide component (124) may arise from the sequential hydroxylation and methylation of the acetamide (122) or via a route involving glycolic acid.

3-Phenylpropanamide (130), from the aposematic beetle (genus Metrior- rhynchus) (Table VIII), has been purified by gas chromatography from the methanol extract. Its structure is presumed from mass spectral data and was confirmed by comparison with a synthetic sample (97). The co-occurrence of amide 130 and 1-methyl-2-quinolone (57) in this beetle suggests a common pathway of biosynthesis and that they may be derived from the amino acid phenylalanine.

4. Other Amines

Dimethylamine (109), putrescine (lll), and spermidine (110), isolated from various insects (Table VIII), were obtained as p,p’ -nitrophenylazobenzoyl, p - phenylazobenzenesulfonyl, and 1-dimethylaminonaphthalene-5-sulfonyl (dansyl) derivatives and picrates or were detected by high-performance liquid chromatography (HPLC) using the ion-exchange resin (106,343). N,N-Dimethyl-P- phenylethylamine (131) from spiders of the genus Sclerobunus (Table VIII) has been identified by mass spectral comparison with a synthetic sample (117).

L. PEDERIN

1. Structure

Pederin (147) contains two hydroxyl, four methoxyl, and four methyl groups and a secondary amide. It is hydrolyzed on gentle heating in aqueous solution to yield pseudopederin (148) (466), in which a hydroxyl group replaces a methoxyl group in pederin (147). Reduction of pederone (149) with lithium aluminum hydride shows it to have a ketone instead of a hydroxyl group as in pederin (147) (93). The structures of pederin (147), pseudopederin (148), and pederone (149) were initially proposed by Cardani and co-workers (93,466), based primarily on the structures of degradation products, pederolactone and meropederoic acid, which were obtained from 148 on treatment with barium methoxide in an oxygen atmosphere. On the basis of detailed NMR spectral analysis, however, Mat- sumoto and co-workers (467) suggested that the structure for pederin was better represented as 147, which has a hydroxyl group at C-13 instead of C-12 in tetrahydropyran ring. This was confirmed by two independent X-ray crystal analyses of a di-p-bromobenzoate of pederin (147) (468,469), which also established the absolute configuration. The structures of pseudopederin and pederone are therefore represented as 148 and 149, respectively (470).


1 2 3

1 2 3

1 2 3

OCH3 1 4 7 R = OCH3, R = O H , R = H

148 R = R = O H , R = H

R1 w% l3 Y O C H , OCH3 1 4 9 R = OCH3, R = R = 0

..14 OH

R3 'R2

2. Synthesis of (*)-Pederamide

Pederamide (512), an acid hydrolysis product of pederin (147) (467), has been synthesized by two research groups. In one approach (471) to 512, cis-di- methylbutyrolactone (513) was converted to the dihydroxyalkynyl ester (516) by

H no i -no ii -z P iii

OH G ; '*

513 514 '% 515

H @C02Me vi

- OH - v i i . .

'CO-Me L

516 517 518

OMe OMe OMe

F C 0 2 M e w C 0 2 M e m C O N H 2 - OAc

523 OH R~ R~ i x

R I

1 2 519 R= OH 521 R = OH, R = H

OMe 2

520 R= SePh 522 R1= H , R =OH

512

SCHEME 66. Reaction conditions: i, LDA, CH==CCH2Br; ii, LiAIH,; iii, DHP-TsOH; n-BuLi- CIC02Me; TsOH-MeOH; iv, Et,N; v, m-CPBA; vi, PhCOCI-Py; 1 N HCI-THF; PhCOCl-Py; MeON-AcC1; MeONa-MeOH; vii, TsCl; phenylselenolate anion; viii, H202-THF, Et3N; ix, MeOH-H20-Et,N, AqO-Py, 6-chloro- I-@-chlorobenzenesulfonyloxy)benzotriazole-Et,N-NH~; x, NH,MeOH.


alkylation with propargyl bromide, lithium aluminum hydride reduction, and carbomethoxylation (Scheme 66). Internal Michael addition of the unsaturated ester gave a Z-E mixture of the vinylidene furan (517) which was transformed to the bicyclic ketal (518) by oxidation with rn-chloroperbenzoic acid. The tetrahy- drofuran ring of 518 was opened with hydrochloric acid, using the benzoyl protecting group, to yield the tetrahydropyran (519). The primary alcohol of 519 was selectively selenated to give 520. Oxidative elimination of the selenide to form the exocyclic double bond afforded methyl pederate (521) together with its epimer (522) at C-2. The methyl pederate (521) yielded racemic pederamide (512) on basic hydrolysis of the ester, acetylation, amidation with a benzotriazole derivative, and deacetylation.

A second approach (472) to 512 started with trans-2-butene epoxide (524) (Scheme 67). Opening of the epoxide ring of 524 with lithium acetylide gave an acetylenic alcohol, which was converted to the acetylenic acid (525) by carbox- ylation with gaseous carbon dioxide. Partial hydrogenation of 525 followed by lactonization afforded the ol,P-unsaturated lactone (526) which was transformed to the nitrolactone (527) by a Michael addition reaction of nitromethane. The Nef reaction of 527 gave the tetrahydrofuranyl acetal (528) which was converted to

P o L+ y H iii T o .. .- *- C 0 2 H

524 525 526 CH2N02

527

C 0 2 E t vii iv Q o M e L To vi -

531 R= C(Me)20Me

532 R= H

C02Me

528 529

X

X O >6 x q C 0 2 E ? T C 0 2 ' > ~ 0 2 E t A 512

535 CHO C H 2 9 3

534 N02

533

SCHEME 67. Reaction conditions: i, C H s L i ; n-BuLi-COz; ii, 5% Pd-BaS04, A; iii, CH,NO,- Triton B; iv, NaOMe; H2S04-MeOH; v, HCI gas-HSCH2CHzSH; vi, LDA- MeOC(Me)20CH2C02Et (530), HCI; vii, acetone-P205, HgO, HgCI2; viii, NaBH4; o-NOzPhSe- CN-n-Bu3P; ix, H202; x, NH40H; HC1-MeOH.


the dithiolane lactone (529) by treatment with ethanedithiol. Lactone 529 afforded adduct 531 on treatment with the lithium enolate of 530. The alcohol protecting group was removed to give hemiketal alcohol 532 as a mixture of epimers. The dithiolane ring of the acetonide of 532 was cleaved by oxidative hydrolysis, using mercuric oxide and mercuric chloride, to yield the aldehyde (533). After sodium borohydride reduction 533 was converted to the aryl selenide (534) which afforded the exocyclic olefin (535) on oxidation with hydrogen peroxide. Olefin 535 was transformed to the corresponding amide which was treated with hydrochloric acid in methanol to yield pederamide (512).

3. Total Synthesis of Pederin

Many approaches to the synthesis of pederin have been tried (473,474). Total synthesis of (+)-pederin (147) was finally accomplished by two research groups (475-477) on the basis of a method joining pedamide, the right-hand half of pederin, and a pederic acid derivative, the left-hand half.

In the first total synthesis by Matsumoto and co-workers (475,476), (+)- benzoylpedamide (536) (478,479) was prepared through a new, remote-controlled asymmetric induction (Scheme 68). An optically active acetal ketone

P h 539 R1= R2 = 0 542 R = CH2Ph

543 R = H

1 2

1 2 1 2 537 R = R = O

538 R =OH, R = H 540 R = O H , R = H 1 2

541 R = OMe, R = H

vii HO byom 0 M e ~ ~ O M ~ R 1 ~ ~ O M e 2 _j

OMe - OMe x , x i OMe vi i i , i x

6 C O P h OH R R

1 2 R = C02Me, R =H 547 1 2

1 2 1 2 545 R = R = O

546 R = H , R = OH 548 R = H , R = C02Me

544

(+)-536 R 1 = C O N H 2 , R 2 = H

SCHEME 68. Reaction conditions: i, LiAlH4, ii, PhCH,Cl-'AmONa; m-CPBA; NaOMe-MeOH; Collins oxidation; iii, Li( +Bu0)3A1H; iv, MeI-NaH-PhH; v, 3 N HC1-acetone; CHFCHCH2BrMg; vi, Na-liq NH3; vii, m-CPBA, p-TsOH-HzO-PhH; viii, Jones oxidation, CH2N2; ix, NaBH,; x, PhCOC1, i-PrzNLi-THF, HOAc; xi, Et3N-HzO-MeOH, SOCl2; NH3.


(537) from (-)-(2R, 3R)-2,3-butanediol was reduced with lithium aluminum hydride to give the (+)-alcohol (538) having the desired (15R) configuration. Alcohol 538 was converted to a dialkoxy ketone (539) by protection of the C-15 hydroxyl group, oxidation of the double bond, opening of the epoxide group employing sodium methoxide, and Collins' oxidation. Reduction of 539 with lithium tri-tert-butoxy aluminum hydride followed by methylation of the new hydroxyl group afforded a (-)-acetal (541) having the desired (17s) configuration. Acetal541 was converted to an olefinic diol (543) by removal of the acetal group followed by Grignard reaction with allylmagnesium bromide and removal of the benzyl protecting group. Oxidation of the double bond with rn-chloroperbenzoic acid and subsequent acid treatment gave a tetrahydropyran (544) which was transformed to the (13R)-alcohol (546) by Jones oxidation followed by esterification and reduction with sodium borohydride. After protection of the hydroxyl group, stereocontrol at C- 1 1 bearing the methoxycarbonyl group was effected by enolization and subsequent kinetically controlled protonation to give the desired ester (547) and its epimer (548) in 4 : 1 ratio. The (+)-ester'(547) was converted to (+)-benzoylpedamide (536) by hydrolysis of the methoxycarbonyl group, acid chloride formation, and amidation.

Pedamide 536 was converted by treatment with trimethyloxonium tetrafluoroborate to methyl pedimidate (549) (475), which was connected by the reaction sequence shown in Scheme 69 to (+)-acetylpederic acid (550), prepared via a route similar to that to the racemic pederamide (536) from (-)-(2R, 3R)-2,3- butanediol. The ratio of the resulting (+)-pederin (147) to (+)-10-epipederin (551) was 1 : 3. This ratio can be inverted to 60 : 14 by a stereocontrolled synthesis (476) including connection of methyl pedimidate (549) and (+)-selenoacid (552)

Me0 536 - i H N % T O M e

OMe

OCOPh

549

OMe oMe 0 R1R2 WO~H - ii, iii wNk H yOMe OMe

iv OAc OH

550 6 H

1 2 (+)-147 R = OMe, R = H 1 2 5 5 1 R = H , R = OMe

SCHEME 69. Reaction conditions: i , Me30BF4; ii, SOCL-Py; iii, 549-Et3N; iv, NaBH,; 1 N LiOH .


prepared through a similar route to (+)-acetylpederic acid (550), selective conversion of the resulting (+)-dihydro-10-epipederin derivative (554) to a (+)-di- hydropederin derivative (553) by an acid-catalyzed double alkoxy exchange reaction, and generation of the exo double bond at a later step.

T C 0 2 H

?Me 0 R1 b'voMe R2

OAc O C O P h OMe

S e P h S e P h 6 C O P h

552 1 2 5 5 3 R = OMe, R = H

5 5 4 R'= H , R'= OMe

In the second synthesis to (+)-pederin (147) by Oishi et ul. (477), (+)- benzoylpedamide (536) (480) was prepared by using recently developed general methods for the synthesis of both 1,3-syn- and 1,3-unti-polyols (481) (Scheme 70). Treatment of aldehyde 555, prepared from (S)-(-)-malic acid, with i- PrC0,Et afforded P-hydroxy ester 556, which was converted into &-lactone 557 by deacetonization, silylation, and lactonization. After protection of the hydroxyl group of 557 as the ethoxyethyl ether, the lithium enolate of tert-butyl acetate was treated to give hemiacetal 558 which was transformed to a mixture of the desired 4P-alcohol (559) and 4a-isomer (560) by acetalization and removal of the ethoxyethyl protecting group. Treatment of 559 with ethanedithiol in the presence of Lewis acid caused acetal-thioacetal interchange at C-6 and subsequent lactonization between the 4P-hydroxyl group and the tert-butyl ester to give &-lactone 561. The liberated hydroxyl groups in 561 were methylated by treatment with CH,N, in the presence of silica gel to give dimethoxy lactone 562.

6a-Alcohol 565 was stereoselectively prepared by the method used in the 1,3-anti-polyol synthesis involving DIBAH reduction of 562, treatment with BrCH,OMe and i-Pr,NEt, dethioacetalization with NBS, and LiAlH, reduction of 564. The benzoate (566) of 565 was converted to a mixture of 8P- and 8a- nitriles (568) by acid treatment followed by acetylation and treatment with Me,SiCN and Lewis acid. Treatment of 568 with TiC1, produced predominately the 8P-amide (536).

The synthesis of (+)-benzoylselenopederic acid (569) (477) (Scheme 71), the left-hand half of pederin (147), began with (+)-P-keto imide 570, which was subjected to the recently developed syn-directing Zn(BH,), reduction (482) to give syn-a-methyl-P-hydroxy acid derivative 571. Imide 571, after protection of the hydroxyl group as the THP ether, was reduced with DIBAH, and the resulting aldehyde was treated with lithium enolate of tert-butyl acetate to give the P-


P h

O-(i-tBu __L

f&CHO -!+ Aop P h iii

555 556 6 H 557

561 R= H

562 R= Me

viii -

6 R R

563 R= SCH2CH2S 565 R= H

564 R= 0 566 R= COPh

"*OM. - is (+)-536

OCOPh

567 R= OAc

568 R= CN

SCHEME 70. i, LDA-Me2CHCOOEt; ii, p-TsOH-MeOH; rBuPh2SiC1-imidazole; CSA-PhH; iii, CH2=CHOEt-PPTS; LDA-'BuOAc-THF; iv, CSA-CH(OMe)3; v, HSCH2CH2SH- BF,.Et20, CH2N2-silica gel; vi, DIBAH, MeOCH2Br-'Pr2NEt, NBS-AgN03-Na2C03; vii, LiA- 1H4, PhCOCI; viii, 6 N HCI, Ac20, Me3SiCN-BF3; ix, TiC1,-aq AcOH.

hydroxy ester (572). After removal of the protecting group, 572 was converted by treatment with p-TsOH to the a,P-unsaturated lactone (573) which on Michael addition of nitromethane gave nitromethyl lactone (574). The nitro group of 574 was converted to aldehyde with TiCl, and Et,N, producing bicyclic lactone (575) which was isomerized to more stable lactone (576) with HC1 treatment. The treatment of 576 with ethanedithiol afforded thioacetal lactone (577), which was converted to the a-keto ester (578) by introduction of a glycolic acid moiety, conversion of the resulting hemiacetal to the methyl ether, deprotection of methoxy isopropyl ether, and Moffatt oxidation. Zn(BH,), reduction of 578 gave the desired 7;IP-alcohol (579). After benzoylation 579 was transformed to the selenoester (582) by dethioacetalization followed by


570 1 571 '

THPO

i i M e

Me 572

H

M e p ?Me

M e OR x, xi Me OR1 xii

y OMe COOMe Me me^ OMe OOH COOMe Me d - ix

OCOPh

s\ /s R2 S e P h u

1 2

1 2 (+)-569 579 R= H 581 R = C O P h ; R = OH

580 R= COPh 582 R = COPh; R = SePh

SCHEME 71. Reaction conditions: i, Zn(BH4)2; ii, DHP-p-TsOH; DIBAH-PhMe; LDA-r- BuOAc; iii, p-TsOH-MeOH, p-TsOH-PhH; iv, MeNO,-Triton B; v, TiClrEt3N; vi, conc HCI- CH2C12; vii, HSCH2CH2SH-BF3.Et20; viii, LDA-MeOC(Me,)OCH,COOMe, CSA-CH(OMe)3, DMSO-DCC-F'y-CF~COOH-Et20; ix, Zn(BH4)2, PhCOC1-DMAP-Py; x, HgO-HgCb-aq MeCN; Zn(BH4)2; xi, PhSeCN-Bu3P; xii, PrSLi-HMPA.

Zn(BH,), reduction and phenylselenation. The methyl ester of 582 was selectively hydrolyzed by PrSLi treatment to yield (+)-selenoacid (569) (Scheme 7 1). The total synthesis of (+)-pederin (147) from (+)-536 and (+)-569 was accomplished in a manner similar to Matsumoto's.

4. Biosynthesis

Pederin (147) has been considered to be derived via polyketide biosynthesis, based on the result of feeding experiments with [ l-14C]acetate and [2-14C]acetate in Puederus fuscipes (483).

M . ISOXAZOLES

Compound 150, one of two isoxazolinones first found in the defensive secretion of chrysomelid beetles, Chrysomelu tremulue, shows a UV spectrum (A,,,


260 nm, E = 6500) characteristic of an N-substituted 3-isoxazolin-5-one system and diagnostic peaks for the 3-isoxazolin-5-one heterocycle, namely, two doublets (J = 3.5 Hz) at 6 8.42 and 5.31 ppm, in the ‘H NMR spectrum. The presence of a glucose moiety in 150 was indicated by acid hydrolysis followed by GC analysis and fragment peaks at mlz 331, 211, 169 and 109 in the CI-mass spectrum of the tetraacetate of 150. Compound 150 was shown from this evidence to be 2-(~-~-glucopyranosyl)-3-isoxazolin-5-one, previously isolated from Lathyrus odoratus seedlings.

The general features of the various spectra of the other compound (151) are very similar to those of 150 except that two characteristic CH, signals coupled to each other appear at 13 4.70 ppm (CH,-NO,, t, J = 6 Hz) and 3.01 ppm (CO-CH,, t, J = 6 Hz) in the ‘H NMR of 151 and the 13C-NMR signals appear at 174.50 (C=O), 73 (CH,NO,) and 33.70 ppm (CH,CO), showing the existence of a 3- nitropropanoyl moiety. Acylation shift in the 13C-NMR spectrum demonstrates that the primary hydroxyl group at C-6 of the glucose is acylated by the 3- nitropropanoyl group. Thus, 151 is identified as 2-[6’-(3”-nitropropanoyl)-P-~- glucopyranosyl]-3-isoxazolin-5-one (98).

151 R= F-CH2CH2N02 0 HO

N . QUINAZOLINONES

On the basis of studies by two research groups on various spectra and electron pyrolysis, structures 60 and 61, respectively, have been proposed for glomerin and homoglomerin which have been isolated from the defensive secretion of a small millipede, Glomeris marginata (Table V) (112,181,484,485). A search of the literature showed that both glomerin (60) and homoglomerin (61) had been synthesized in connection with a study of Indian medicinal plant alkaloids such as arborine, originally isolated from Glycosmis arborea (486). The two alkaloids (60 and 61) were synthesized by reacting N-methylanthranilic amide (583) with either acetic or propionic anhydride (486) (Scheme 72).

Two similar syntheses have been reported by Ziegler and co-workers (487) and Kametani et al. (488,489). Reaction of N-methylisatic anhydride (584) with thioacetamide afforded glomerin (60) in 58% yield (487). The other synthetic route is as follows: The sulfinamide (585), prepared from N-methylanthranilic anhydride and thionyl chloride, was treated with acetamide and propionamide to afford glomerin (60) and homoglomerin (61), respectively (Scheme 72) (488,489).

Feeding or injecting 14C-labeled anthranilic acid (586) to Glomeris marginata


0

H

583

Me 60 R= Me

61 R= E t

0 0 0 QyJo- Q-f--JMe Qo0 2 KJR Me Me Me Me

584 60 585 60 R= Me

6 1 R= E t

586

Me

60 R= Me

61 R= E t

587

SCHEME 72. Reaction conditions: i, (CH3C0)20; ii, (CH3CH2C0)20; iii, CH3CSNH2; iv, CH3CONH2; v, CH3CH2CONH2; vi, Glomeris marginata; vii, 2 N NaOH, 100°C.

resulted in the biosynthesis of the radioactive glomerin (60) and homoglomerin (61). Radioactive homoglomerin (61) gave N-methylanthranilic acid (587) by an alkaline hydrolysis. From these facts, anthranilic acid has been suggested as a common biosynthetic precursor (Scheme 72) (490).

0. PTERIDINES AND PURINES

1. Guanine and Hypoxanthine

Since chemistry of pterines and purines has been already reviewed (42,48,491), only recent studies will be described here. Guanine (93) was prepared by reaction of 4-hydroxy-2,5,6-triaminopyrimidine sulfate (588; see Scheme 73) with HCONH, with removal of H,O from the reaction system in an excellent yield (492). Also, irradiation of oxygenated aqueous solutions of 6-mercaptopurine with near-UV light gave hypoxanthine (92) as a minor product (< 10%) together with purine-6-sulfinate (589). It also arises from degradation of purine-6-sulfonate obtained from photooxidation of the sulfinate (589) (493).


H X c a N H-Ph

y ““2 H+OAC

n ACO-LH I

590

P OR on ii

iii 70 R= H

SCHEME 73. Reaction conditions: i, MeOH-H20-Py; ii, I,-MeOH; iii, NH3.

2. Biopterin

Two regiospecific syntheses of biopterin (70), identified as 6-(~-erythro- 1,2- dihydroxypropy1)pterin (42), have been reported (494,495) in addition to those reviewed recently (496). Both methods are very similar and include the condensation of 4-hydroxy-2,5,6-triaminopyrimidine (588) with 5-deoxy-~-arabinose- phenylhydrazone (589) or its triacetate (590). Treatment of the pyrimidine (588) with the triacetate (590) in aqueous methanol-pyridine formed the intermediate (591) which was oxidized with I, to afford diacetylbiopterin (592). Cleavage of the acetyl groups with NH,OH led to pure L-biopterin (70) (Scheme 73). Po- tassium hexacyanoferrate(II), potassium iodide, and hydroperoxide were used as oxidation reagents in the method starting with the phenylhydrazone (588). The yield of the method using the triacetate (590) is better than the other because protection of the two hydroxyl groups in the side chain prevent its cleavage during the oxidation of the tetrahydrobiopterin derivative to L-biopterin (70).

3. Sepiapterin and Deoxysepiapterin

a. Structure. The planar structure of sepiapterin (81) has been revealed to be 6-lactoyl-7,8-dihydropterin (Scheme 74) (42). The absolute configuration of the side chain in 81 has been established as (S) by two facts as follows: (1) Natural sepiapterin (81) is synthesized by autooxidation from 5,6,7 &tetrahydrobiopterin (85), together with biopterin (70), deoxysepiapterin (isosepiapterin) (82), and other pterins (Scheme 74) (497,498). (2) The oxidative degradation of sepiapterin (81) in a sodium borate solution affords L-lactic acid beside 7,8- dihydroxanthopterin (80) (499).

Deoxysepiapterin (82) has been prepared by reaction of 7,8- dihydropterin (593) with a-ketobutyric acid (594) and thiamin (500), and sepiapterin (81) has been obtained by the same reaction in the presence of zinc chloride

b. Synthesis.


SCHEME 74. Reaction conditions: i, H2-Pt; ii, Na2S20,; iii, 25% AcOH-Nz or Sephadex P (H+ form); iv, O2 (pH 4).

using p-hydroxy-a-ketobutyric acid (595) instead of 594 (501). Both compounds are also formed by acid-catalyzed dehydration of 7,8-dihydrobiopterin (596) (502) or by autooxidation of 5,6,7,8-tetrahydrobiopterin (85) as described above (Scheme 74) (497,498,503). (6R, S)-5,6,7,8-Tetrahydro-~-biopterin (85) was prepared by catalytic and sodium dithionite reduction of L-biopterin (70), the reduction of which formed 7,8-dihydro-~-biopterin (596) together with 85. Di- hydrobiopterin (596) in acetic acid without oxygen (503) or in a Sephadex P column (H+ form) (504) converted to deoxysepiapterin (82) (Scheme 74).

The synthesis of deoxysepiapterin (82) has been recently achieved by homolytic nucleophilic substitution of the pteridine nucleus by acyl radicals (505). Since this substitution arises preferentially at the most electron-deficient 7 position, protection at 7 position is necessary for nucleophilic attack at the 6 position. 2,4-Diamino-7-methylthiopteridine (597) and 2-amino-4-n-pentyloxy-7-n-pro- pylthiopteridine (600), protected by the thio function, can be used as starting materials. Homolytic acylation of 597 with the system propionalde- hyde/Fe2 + Itert-butylhydroperoxide afforded 6-propionylpteridine (598) in good yields, which could be transformed to deoxysepiapterin (82) by selective hydrolysis followed by deprotection of the thio function (Scheme 75). Deoxysepiap- terin (82) can also be prepared by a similar procedure from 600.

0

597 598 599

SCHEME 75. Reaction conditions: i , C2H5CHO/Fe2+ it-Bu02H; ii, 6 M HCI; iii, Cu-Al-alkaline EtOH.


4. Drosopterin and Isodrosopterin

The red eye pigment of the fruit fly, D. melurtoguster, consists of six complex pteridines known as drosopterin (87a), isodrosopterin (87b), neodrosopterin (88), aurodrosopterin (89), and fraction e (90) (Table VI). Drosopterin (87a) and isodrosopterin (87b) have mirror-image circular dichroism spectra, indicating that they are enantiomers (255a), but they are separable by cellulose thin-layer chromatography. Neodrosopterin (88) is known to rearrange to a mixture of drosopterin (87a) and isodrosopterin (87b) in aqueous solutions (255~) .

Drosopterin (87a) and isodrosopterin (87b) have been prepared by treatment of 7,8-dihydropterin (593) with P-hydroxy-a-ketobutyric acid (595) or a-hydroxyacetoacetic acid (601) (506). Their initially proposed structures (507) have been revised to 87 (see Scheme 76) on the basis of detailed.lH-NMR spectral analysis of 6,7-dimethyldrosopterin (602), which was prepared by treatment of 7-methyl-7,8-dihydropterin (603) with a-hydroxyacetoacetic acid (601) (508). Structures of other drosopterins (88-90) have not yet been established.

5. Pteridine Biosynthesis

There are a number of studies on the biosynthesis of various pteridines, i.e., xanthopterin (65), isoxanthopterin (67), erythropterin (73), leucopterin (68), and pterin (62) (509-511). The most important intermediate of the proposed biosynthetic pathway from guanosine triphosphate (GTP) (604) seems to be di- hydroneopterin triphosphate (H,-NTP) (605), however, because evidence has recently been accumulated indicating that pteridines such as biopterin (70), sepiapterin (Sl), and drosopterins (87) are synthesized from GTP (604) by way of H,-NTP (605) (Scheme 76) (512).

Biosynthetic pathways of sepiapterin (81) and drosopterins (87) were recently

OH OH OH H

- 81 " 'N H H H H

'N

605

SCHEME 76


proposed as shown in Scheme 76 on the basis of detailed studies of the intermediates and the enzyme systems responsible for their syntheses (512-516). Howev- er, an alternative synthetic pathway for drosopterins (87) may also be possible; dihydropterin (593) derived from H,-NTP reacted spontaneously or en- zymatically with P-hydroxy-a-ketobutyric acid (595), found in D . melanogaster, to give drosopterins (87) (512).

P. ARISTOLOCHIC ACID

Aristolochic acid I (143), isolated from whole bodies of swallowtail butterflies of the genus Pachlioptera, is the already known substance and was identified by the mass spectrum (73). One of the two acidic components obtained from aposematic butterflies of the genus Zerynthia has been identified as aristolochic acid C (145) by direct comparison with an authentic sample. The other, first isolated from this butterfly, has been identified as aristolochic acid Ia (144) by mass spectral analysis and its derivation to aristolochic acid I methyl ester (146) (74).

2

1 2

2 1

1 2

143

145

146 R = H , R = OCH3, R3= CH3

144

R1= R3= H , R = OCH3

R = R3= H , R = OH

0

R = R3= H , R = OH

Acknowledgments

The following persons sent information, preprints, and reprints: R. Baker, M. Bopprk, A. R. Brossi, M. V. Brown, C. Cardani, K. Dettner, H.-P. Husson, T. H. Jones, J. Meinwald, R. H. Mueller, M. Natsume, M. Pavan, T. Reichstein, F. J . Ritter, P. G . Sammes, H. Schildknecht, D. Schneider, R. M. Silverstein, P. E. Sonnet, B. Tursch, and J . W. Wheeler. We thank all for their help in preparing this work.

REFERENCES

1. T. Eisner, in “Chemical Ecology” (E. Sondheimer and J . B. Simeone, eds.), p. 157. Academ-

2. J. H. Law and F. E. Regnier, Annu. Rev. Biochem. 40, 533 (1971). 3. B. Tursch, J. C. Braekman, and D. Daloze, Experientia 32, 401 (1976). 4. T. H. Jones and M. S. Blum, “Alkaloids: Chemical and Biological Perspectives” (S. W.

Pelletier ed.), Vol. 1, p. 33. Wiley (Interscience), New York, 1983. 5. M. R. Caro, V. J. Derbes, and R. Jung, Arch. Derm. 75, 475 (1957). 6. G . A. Adrouny, V. J . Derbes, and R. C. Jung, Science 130, 449 (1959).

ic Press, New York, 1970.


7. M. S. Blum and P. S. Callahan, Int. Congr. Entomol. Proc. l i th, Vienna 3, 48 (1960). 8. M. S. Blum, J. R. Walker, P. S. Callahan, and A. F. Novak, Science 128, 306 (1958). 9. L. K. Cole, Diss. Abstr. Int. B 38, 3955 (1975).

10. D. C. Buffkin and F. E. Russell, Toxicon 10, 526 (1972). 11. D. P. Jouvanez, M. S . Blum, and J. G. MacConnell, Antimicrob. Agents Chemother. 2, 291

12. J. Z. Yeh, T. Narahasi, and R. R. Almon, J . Pharm. Exp. Ther. 194, 373 (1975). 13. E. Y. Cheng, L. K. Cutkomp, and R. B. Koch, Biochem. Pharmacol. 26, 1179 (1977). 14. R. B. Koch, D. Desaiah, D. Foster, and K. Ahmed, Biochem. Pharmacol. 26, 983 (1977). 15. G . W. Read, N. K. Lind, and C. S. Oda, Toxicon 16, 361 (1978). 16. T. H. Jones, M. S. Blum, and H. M. Fales, Tetrahedron 38, 1949 (1982). 17. K. Holldobler, Biol. Zbl. 48, 129 (1928). 18. M. S. Blum, T. H. Jones, B. Holldobler, H. M. Fales, andT. Jaouni, Natunvissenschafen 67,

19. B. Holldobler, Oecologia 11, 371 (1973). 20. F. J. Ritter and C. J. Persoons, Neth. J . Zool. 25, 261 (1975). 21. F. I . Ritter, I. E. M. Rotgans, E. Talman, P. E. J. Verwiel, and F. Stein, Experientia 29,530

22. F. J. Ritter, I. E. M. Bruggeman-Rotgans, E Verkuil, and C. J. Persoons, in “Proceeding of the Symposium on Pheromones and Defensive Secretions in Social Insects” (Ch. Noirot, P. E. Howse, and G . Le Masne, eds.), p. 99. Univ. Dijon Press, Dijon, France, 1975.

23. a. E. Talman, F. J. Ritter, and P. E. J. Verwiel, “Mass Spectrometry in Biochemistry and Medicine,” p. 197. Raven, New York, 1974; b. F. J . Ritter, I. E. M. Briiggemann, P. E. J. Venviel, E. Talman, F. Stein, and C. J. Persoons, in “Scientific Papers of the Institute of Development and Behavior” (M. Kloza, ed.), p. 871. Karpacz, Poland, 1980.

24. R. J. Ritter, I. E. M. Rotgans, P. E. J. Verwiel, C. J. Persoons, and E. Talman, Tetrahedron Lett., 2617 (1977).

25. T. H. Jones, M. S. Blum, R. W. Howard, C. A. McDaniel, H. M. Fales, M. B. DuBois, and J. Torres, J . Chem. Ecol. 8, 285 (1982).

26. J. W. Wheeler, 0. Olubajo, C. B. Storm, and R. M. Duffield, Science 211, 1051 (1981). 27. J. C. Moser and M. S. Blum, Science 140, 1228 (1963). 28. J. C. Moser and R. M. Silverstein, Nature (London) 215, 206 (1967). 29. S. W. Robinson, J. C. Moser, M. S. Blum, and E. Amante, Znsectes SOC. 21, 87 (1974). 30. P. E. Sonnet, J . Med. Chem. 15, 97 (1972). 31. P. E. Sonnet and J. C. Moser, J . Agric. Food Chem. 20, 1191 (1972). 32. J. H. Cross, R. C. Byler, U. Ravid, R. M. Silverstein, S. W. Robinson, P. M. Baker, J. S. de

33. A. B. Attygalle and E. D. Morgan, J . Chem. Ecol. 10, 1453 (1984). 34. H. Schildknecht, P. B. Reed, F. D. Reed, and K. Koob, Insect Biochem. 3, 439 (1973). 35. J. W. Wheeler and M. S. Blum, Science 182, 501 (1973). 36. C. Longhurst, R. Baker, P. E. Howse, and W. Speed, J . Insect Physiol. 24, 833 (1978). 37. K. Parry and E. D. Morgan, Physiol. Entomol. 4, 161 (1979). 38. R. M. Duffield, M. S. Blum, and J. W. Wheeler, Comp. Biochem. Physiol. 54B, 439 (1976). 39. W. V. Brown and P. B. Moore, Insect Biochem. 9, 451 (1979). 40. D. F. Howard, M. S. Blum, T . H. Jones, and M. D. Tomalski, Insectes SOC. 29, 369 (1982). 41. H. M. Fales, M. S . Blum, 2. Bian, T. H. Jones, and A. W. Don, J . Chem. Ecol. 10, 651

42. R. C. Elderfield and A. C. Mehta, in “Heterocyclic Compounds” (R. C. Elderfield, ed.), Vol.

43. C. A. Brown, J. Watkins 11, and D. W. Eldridge, J . Kansas Entomol. SOC. 52, 119 (1979).

(1972).

144 (1980).

(1973).

Oliveira, A. R. Jutsum, and J . M. Cherrett, J . Chem. Ecol. 5 , 187 (1979).

(1984).

9, p. 1. Wiley (Interscience), New York, 1967.


44. J. H. Law, E. 0. Wilson, and J. A. McCloskey, Science 149, 544 (1965). 45. A. Hefetz and S. W. Batra, Comp. Biochem. Physiol. 65B, 455 (1980). 46. a. H. Ederry, J. Ishay, S. Gitter, and H. Joshua, in “Handbook of Experimental Phar-

macology” (S. Bettini, ed.), Vol. 48, p. 691. Springer-Verlag, Berlin, Heidelberg, New York, 1978; b. R. O’Conner and M. L. Peck, in “Handbook of Experimental Pharmacology” (S. Bettini, ed.), Vol. 48, p. 613. Springer-Verlag, Berlin, Heidelberg, New York, 1978.

47. E. Habermann, Science 177, 314 (1972). 48. R. K. Robins, in “Heterocyclic Compounds” (R. C. Elderfield, ed.), Vol. 8, p. 162. Wiley

(Interscience), New York, 1967. 49. M. Gates, Chem. Rev. 41, 63 (1947). 50. R. Harmsen, 1. Exp. Biol. 45, 1 (1966). 51. G. R. Pettit, R. H. Ode, R. M. Coomes, and S. L. Ode, Lloydia 39, 363 (1976). 52. W. Pfleiderer and J. Lemke, J. Comp. Physiol. 82, 407 (1973). 53. S. Tojo and T. Yushima, J. Insect Physiol. 18, 403 (1972). 54. L. P. Brower, J. V. Z. Brower, and F. P. Cranston, Zoologica 50, 1 (1965). 55. J. Meinwald, Y. C. Meinwald, J. W. Wheeler, T. Eisner, and L. P. Brower, Science 151, 583

56. M. Bopprk, R. L. Petty, D. Schneider, and J. Meinwald, J . Comp. Physiol. 126, 97 (1978). 57. T. E. Pliske and T. Eisner, Science 164, 1170 (1969). 58. J. Myers and L. P. Brown, J. Insect Physiol. 15, 2217 (1969). 59. J. Meinwald, Y. C. Meinwald, and P. H. Mazzocchi, Science 164, 1174 (1969). 60. D. Schneider, “Colloques Internationaaux du C.N.R.S. No. 265-Comportement Des Insec-

61. J. A. Edgar, C. C. J. Culvenor, and G. S. Robinson, J . Austr. Entomol. SOC. 12, 144 (1973). 62. J. A. Edgar and C. C. J. Culvenor, Experientia 13, 393 (1975). 63. J. A. Edgar, M. Boppre, and D. Schneider, Experientia 35, 1447 (1979). 64. J. A. Edgar, J. Zoot. (London) 196, 385 (1982). 65. J. A. Edgar, P. A. Cockrum, and J. L. Frahn, Experientia 32, 1535 (1976). 66. J. A. Edgar and C. C. J. Culvenor, Nature (London) 248, 614 (1974). 67. D. Schneider, M. Boppr6, H. Schneider, W. R. Thompson, C. J. Broriack, R. L. Petty, and J.

68. M. Bopprk and D. Schneider, Proc. 5th Int. Symp. Insect-Plant Relationships, p. 373. Pudoc,

69. M. Rothschild, B. P. Moore, and W. V. Brown, Biol. J . Linnean SOC. 23, 375 (1984). 70. Y. Umebachi, in “Biochemical and Medical Aspects of Tryptophan Metabolism” (0. Hay-

71. Y. Umebachi, 2001. Sci. 2, 163 (1985). 72. S . Tojo and T. Yushima, Nogyo Gijutsu Kenkyusho Hokoku C 26, 126 (1972). 73. J. v. Euw, T. Reichstein, and M. Rothschild, Israel J . Chem. 6, 659 (1968). 74. M. Rothschild, J. v. Euw, and T. Reichstein, Insect Biochem. 2, 334 (1972). 75. W. E. Conner, T. Eisner, R. K. Meer, A. Guerrero, and J. Meinwald, Behav. Ecol. Sociobiol.

76. D. Schneider, M. Bopprk, J. Zweig, S. B. Horsley, T. W. Bell, J. Meinwald, K. Hansen, and

77. M. Boppr6, U. Seibt, and W. Wickler, Entomol. Exp. Appl. 35, 115 (1984). 78. M. Boppr6 and G. Scherer, Systemat. Entomol. 6, 347 (1981). 79. M. C. J. M. de Jong, and E. Bleumink, Arch. Dermatol. Res. 259, 247 (1977). 80. W. L. Gyure, Insect Biochem. 4, 303 (1974). 81. M. Tsusue, J. Biochem. 69, 781 (1971). 82. S. Tojo and C. Hirano, J. Insect Physiol. 14, 1121 (1968).

(1966).

tes Et Milieu Trophique,” p. 353. C.N.R.S., Paris, 1977.

Meinwald, J. Comp. Physiol. 97, 245 (1975).

Wageningen, 1982.

aishi, Y. Ishimura, R. Kido, eds.), p. 117. Elsevier, Amsterdam, 1980.

9, 227 (1981).

E. W. Diehl, Science 215, 1264 (1982).


83. G. M. Happ and T. Eisner, Science 134, 329 (1961). 84. D. A. Kendall, Entomologist 233 (1971). 85. B. Tursch, D. Daloze, M. Dupont, J. M. Pasteels, and M. C. Tricot, Experientiu 27, 1380

86. J . M. Pasteels, C. Deroe, B. Tursch, J. C. Braekman, D. Daloze, and C. Hootele, J . Insect

87. W. V. Brown and B. P. Moore, Aust. J . Chem. 35, 1255 (1982). 88. N. K. Hart, S. R. Johns, and J. A. Lamberton, Aust. J . Chem. 20, 561 (1967). 89. T. Eisner, M. Goetz, D. Aneshansley, G . Ferstandig-Arnold, and J. Meinwald, Experientiu

90. a. S . Maugeri and F. Candura, Atti 2nd Congr. Naz. Med. Rurule 57 (1964); b. M. Pavan, Ind.

91. a. M. Pavan and G. Bo, Physiol. Comp. Oecol. 3, 307 (1953); b. A. Quilico, C. Cardami, D.

92. M. Pavan, Publ. Inst. Ent. Univ. Puviu 23, 3 (1982). 93. C. Cardani, D. Ghiringhelli, A. Quilico, and A. Selva, Tetrahedron Lett. 4023 (1967). 94. H. Schildknecht, D. Berger, D. Krauss, J. Connert, J. Gehlhaus, and H. Essenbreis, J . Chem.

95. H. Schildknecht, D. Krauss, J. Connert, H. Essenbreis, and N. Orfanides, Angew. Chem. Int.

96. H. Schildknecht, Angew. Chem. Int. Ed. 15, 214 (1976). 97. B. P. Moore and W. V. Brown, Insect Biochem. 11, 493 (1981). 98. J. M. Pasteels, J. C. Braekman, D. Daloze, and R. Ottinger, Tetrahedron 38, 1891 (1982). 99. K. Dettner, Proc. Acud. Nutl. Sci. Phila. 137, 156 (1985).

(1971).

Physiol. 19, 1771 (1973).

42, 204 (1986).

Lito-Tipogruf. M. Ponzio. Paviu 1 (1963).

Ghirighelli, and M. Pavan, Chim. Ind. 43, 1434 (1961).

Ecol. 2, 1 (1976).

Ed. 14, 427 (1975).

100. H. Schildknecht, Endeavour 30, 136 (1971). 101. H. Schildknecht, H. Bimnger, and D. Krauss, 2. Nuturjorsch. 24B, 38 (1969). 102. R. Baker, R. H. Herbert, and G. G. Grant, J . Chem. SOC., Chem. Commun. 824 (1985). 103. R. Baker, R. H. Herbert, and R. A. Lomer, Experientiu 38, 232 (1982). 104. T. E. Bellas and B. S. Fletcher, J . Chem. Ecol. 5, 795 (1979). 105. P. W. H. Heinstra and G. E. W. Thorig, J . Insect Physiol. 28, 847 (1982). 106. M. M. Blight, J . Insect Physiol. 15, 259 (1969). 107. L. Merlini and G. Nasini, J . Insect Physiol. 12, 123 (1966). 108. L. M. Roth and G. P. Dateo, Jr., Science 146, 782 (1964). 109. E. Stratakis, J . Insect Physiol. 25, 925 (1979). 110. E. Stratakis, J . Comp. Physiol. 137, 123 (1980). 1 1 1 . G. Berthold and M. Henze, J . Insect Physiol. 17, 2375 (1971). 112. Y. C. Meinwald, J. Meinwald, and T. Eisner, Science 154, 390 (1966). 113. J. Smolanoff, A. F. Kluge, J. Meinwald, A. McPhail, R. W. Miller, K. Hicks, and T. Eisner,

114. A. Gomes, A. Datta, B. Sarangi, P. K. Kar, and S . C. Lahiri, Indian J . Med. Res. 76, 888

115. D. A. Otieno, A. Hassanali, F. D. Obenchain, A. Sternberg, and R. Galun, Insect Sci. Appl. 6,

116. H. Schildknecht, P. Kunzelmann, D. Krauss, and C. Kuhn, Nuturwissenschaften 59, 98

117. 0. Ekpa, J. W. Wheeler, J. C. Cokendolpher, and R. M. Duffield, TetrahedronLett. 25, 1315

118. C. R. Diniz, Acta Physiol. Latinoam. 12, 211 (1962). 119. C. R. Diniz, An. Acud. Brusil. Cienc. 35, 283 (1963). 120. M. C. Pansa, G. M. Natalizi, and S . Bettini, Toxicon 10, 85 (1972).

Science 188, 734 (1975).

(1982).

667 (1985).

( 1972).

(1984).


121. K. R. Adam and C. Weiss, Nature (London) 183, 1398 (1959). 122. J . G. MacConnell, M. S . Blum, and H. M. Fales, Science 168, 840 (1970). 123. J. M. Brand, M. S . Blum, H. M. Fales, and J. G. MacConnell, Toxicon 10, 259 (1972). 124. J. G. MacConnell, M. S . Blum, W. F. Buren, R. N. Williams, and H. M. Fales, Toxicon 14,

125. J . M. Brand, M. S . Blum, and H. H. Ross, Insect Biochem. 3, 45 (1973). 126. J . G. MacConnell, M. S . Blum, and H. M. Fales, Tetrahedron 26, 1129 (1971). 127. M. S . Blum, J. M. Brand, R. M. Duffield, and R. R. Snelling, Ann. Enromol. SOC. Am. 66,

128. 3 . G. MacConnell, R. N. Williams, J. M. Brand, andM. S . Blum, Ann. Entomol. SOC. Am. 67,

129. G. W. K. Cavill, P. L. Robertson, J. J . Brophy, R. K. Duke, J. McDonald, and W. D. Plant,

130. K. Dettner, Z. Naturforsch. 38c, 319 (1983). 131. T. E. Bellas, W. V. Brown, and B. P. Moore, J . Insect. Physiol. 20, 277 (1974). 132. D. J. Pedder, H. M. Fales, T. Jaouni, M. S . Blum, J. MacConnell, and R. M. Crewe,

133. T. H. Jones, M. S . Blum, and H. M. Fales, Tetrahedron Lett., 1031 (1979). 134. T. H. Jones, R. J . Highet, M. S . Blum, and H. M. Fales, J. Chem. Ecol. 10, 1233 (1984). 135. F. J. Ritter and C. J. Persoons, “Isolation and Identification of Pheromones: Integrated Control

of Insect Pests in the Netherlands,” p. 203. Pudoc, Wageningen, 1980. 136. F. J . Ritter, I. E. M. Briiggemann, P. E. 3 . Venviel, E. Talman, F. Stein, andC. 3. Persoons,

in “Chiral Pheromones of Pharaoh’s Ant, Momomorium pharuonis, Olfaction and Taste VII” (H. V . D. Starre, ed.), p. 108. International Retrieval Ltd., London, 1980.

137. F. J. Ritter and C. J. Persoons, “Trail Pheromones and Related Compounds in Termites and Ants. Proceedings of the Eighth Congress of IUSSI,” p. 34. Pudoc, Wageningen, 1977.

138. T. H. Jones, J. B. Franko, M. S. Blum, and H. M. Fales, Tetrahedron Lett. 21, 789 (1980). 139. J. H. Cross, J. R. West, R. M. Silversteen, A. R. Jutsum, and J. M. Cherrett, J . Chem. Ecol.

140. D. H. G. Medina, D. S . Grierson, and H.-P. Husson, Tetrahedron Lett. 24, 2099 (1983). 141. J. J. Brophy and G. W. K. Cavill, Heterocycles 14, 477 (1980). 142. J. J. Brophy, G. W. K. Cavill, and W. D. Plant, Insect Biochem. 11, 307 (1981). 143. J. J. Brophy, G. W. K. Cavill, J . A. McDonald, D. Nelson, and W. D. Plant, Insect Biochem.

144. G. W. K. Cavill and E. Houghton, J . Insect Physiol. 20, 2049 (1974). 145. G. W. K. Cavill and E. Houghton, Ausr. J . Chem. 27, 879 (1974). 146. J. J. Brophy and D. Nelson, Insect Biochem. 15, 363 (1985). 147. R. Baker, R. H. Herbert, and R. A. Lomer, Experientia 38, 232 (1982). 148. a. J. Meinwald and Y. C. Meinwald, J . Am. Chem. SOC. 88, 1305 (1966); b. J A. Edgar, C. C.

149. J. Meinwald, C. J. Boriack, D. Schneider, M. Boppr6, W. F. Wood, and T. Eisner, Experien-

150. U. Seibt, D. Schneider, and T. Eisner, Z . Tierpsychol. 31, 513 (1972). 151. R. L. Petty, M. Bopprt, D. Schneider, and J. Meinwald, Experientia 33, 1324 (1977). 152. R. T. Aplin, M. H. Benn, and M. Rothschild, Nature (London) 219, 747 (1968). 153. J. Meinwald, I. Smolanoff, A. T. McPhail, R. W. Miller, T. Eisner, and K. Hicks, Tetra-

154. J. H. Dustmann, Insect Biochem. 5 , 429 (1975). 155. I. Ishiguro, T. Ikeno, and H. Matsubara, Yakugaku Zasshi 94, 116 (1974).

69 (1976).

702 (1973).

134 (1974).

Insect Biochem. 14, 505 (1984).

Tetrahedron 32, 2275 (1976).

8, 1119 (1982).

12, 215 (1982).

J . Culvenor, and L. W. Smith, Experientia 27, 761 (1971).

tia 30, 721 (1974).

hedron Lett., 2367 (1975).


156. A. Butenandt, U. Schiedt, E. Biekert, and P. Kommann, Liebigs Ann. Chem. 586, 217

157. A. Bouthier and R. Lafont, Ann. Endocrinol. 37, 537 (1976). 158. J. Meinwald, W. R. Thompson, T. Eisner, and D. F. Owen, Tetrahedron Lett., 3485 (1971). 159. A. Butenandt, P. Karlson, and W. Zillig, Hoppe-Seyler’sZ. Physiol. Chem. 288, 125 (1951). 160. K. Inagami, Nippon Sunshiguku Zusshi 24, 295 (1955). 161. 0. Imura and N. Shibuya, Appl. Ent. 2001. 14, 221 (1979). 162. R. Danneel and B. Zimmermann, 2. Nuturforsch. 9B, 788 (1954). 163. Y. Umebachi and K. Tsuchitani, J . Biochem. 42, 817 (1955). 164. A. Butenandt, E. Biekert, H. Kubler, and B. Linzen, Hoppe-Seyler’s 2. Physiol. Chem. 319,

165. T. G. Wilson and K. B. Jacobson, Biochem. Genet. 15, 307 (1977). 166. J. Ferre, F. Silva, M. D. Real, and J. L. Mensua, Chem. Biol. Pteridines, Proc. 7th Int. Symp.

Pteridines Folic Acid Deriv., Chem. Biol. Clin. Aspects, Berlin, 1982, (J. A. Blair, ed.), p. 669 (1983). Berlin, 1982 (published in 1983).

(1954).

238 (1960).

167. D. Parisi, D. D’amora, and A. R. Franco, Insect Biochem. 7, 1 (1977). 168. J. Ferre, Insect Biochem. 13, 289 (1983). 169. J. P. Phillips, H. S . Forrest, and A. D. Kulkami, Genetics 73, 45 (1973). 170. I. Ziegler and M. Feron, 2. Nuturforsch. 20B, 318 (1965). 171. V. Mitteilg, A. Butenandt, and G. Neubert, Hoppe-Seyler’s 2. Physiol. Chem. 301, 109

172. B. Linzen and W. Schartau, Insect Biochem. 4, 325 (1974). 173. N. Kokolis, Foliu Biochem. Biol. Gruecu 8, 1 (1971). 174. A. Bouthier, Compt. Rend., Ser. D 262, 1480 (1966). 175. M. D. M. MenCndez, An. Real. SOC. Espuii. Fis. Quim. (Madrid) Ser. B 55(B), 171 (1959). 176. S . Fuzeau-Braesch, Compt. Rend. 245, 2401 (1957). 177. G. Berthold and D. Buckmann, J . Comp. Physiol. 111, 33 (1976). 178. C. J. Potrikus and J. A. Breznak, Insect Biochem. 10, 19 (1980). 179. S . Johne, Prog. Chem. Org. Nut. Prod. 46, 159 (1984). 180. H. Schildknecht, U. Maschwitz, and W. F. Wenneis, Nuturwissenschuften 8, 196 (1967). 181. H. Schildknecht and W. F. Wenneis, 2. Nuturforsch. 21B, 552 (1966). 182. G. Karl and S . Gerhard, Umschuu 9, 4 (1959). 183. G. H. Schmidt and M. Viscontini, Helv. Chim. Actu 45, 1571 (1962). 184. G. H. Schmidt, A. Hotari, and H. Radtke, 2001. Juhrb., Abt. Allg. 2001. Physiol. Tiere 84,

185. G. H. Schmidt and M. Viscontini, Helv. Chem. Actu 49, 344 (1965). 186. R. Ikan and J. Ishay, J . Insecr Physiol. 13, 159 (1967). 187. H. Joshua, J . Fischl, E. Henig, J. Ishay, and S. Gitter, Comp. Biochem. Physiol. B 45, 167

188. H. Rembold and L. Buschmann, Liebigs Ann. Chem. 662, 72 (1963). 189. R. Schopf, Z Angew. Entomol. 89, 3 (1980). 190. C. Schopf and E. Becker, Liebigs Ann. Chem. 524, 49 (1936). 191. W. B. Watt, Nature (London) 201, 1326 (1964). 192. W. Pfleiderer, Z . Nuturjorsch. 18B, 420 (1963). 193. W. B. Watt and S . R. Bowden, Nature (London) 210, 304 (1966). 194. R. Harmsen, J . Insect Physiol. 12, 23 (1966). 195. S. Tojo, Seibutsu Kuguku 20, 102 (1968). 196. B. Mauchamp and R. Lafont, Comp. Biochem. Physiol. B51, 445 (1975). 197. A. Tartter, Hoppe-Seyler’s 2. Physiol. Chem. 266, 130 (1940).

(19%).

425 (1980).

(1973).


198. H. Simon, F. Weygand, J. Walter, H. Wacker, and K. Schmidt, Z . Naturforsch. 18B, 757

199. H. Simon, H. Wacher, and J. Walter, Pteridine Chem., Proc. 3rdInt. Symp., Sruttgurt, 1962,

200. G . R. Pettit, L. E. Houghton, N. H. Rogers, R. M. Coomes, D. F. Berger, P. R. Reucroft, J.

201. R. Purrmann and M. Mass, Liebigs Ann. Chem. 556, 186 (1944). 202. W. F'fleiderer, Chem. Ber. 95, 2195 (1962). 203. R. Purrmann, Hoppe-Seyler's Z. Physiol. Chem. 260, 105 (1939). 204. H. Descimon, Bull. SOC. Chim. B i d . 47, 1095 (1965). 205. H. Descimon, Compt. Rend. 260, 4637 (1965). 206. H. Descimon, C. R. SOC. Biol. 160, 928 (1966). 207. H. Descimon, Compt. Rend., Ser. D 262, 390 (1966). 208. H. Descimon, Biochimie 53, 407 (1971). 209. W. B. Watt, J . Biol. Chem. 242, 565 (1967). 210. I. Mori, M. Yamaguchi, andT. Tsumaki, Mem. Fac. Sci., Kyushu Univ., Ser. C. 5,43 (1962). 211. M. Viscontini, A. Kiihn, and A. Egelhaaf, Z. Naturforsch. IlB, 501 (1956). 212. M. Viscontini and H. Stierlin, Helv. Chim. Acta 44, 1783 (1961). 213. M. Viscontini and H. Stierlin, Helv. Chim. Acta 45, 2479 (1962). 214. A. Kiihn and A. Egelhaaf, 2. Naturforsch. 14B, 654 (1959). 215. J. L. Nation and R. L. Patton, J . Insect Physiol. 6, 299 (1961). 216. J. L. Nation and K. K. Thomas, Ann. Enromol. SOC. Am. 58, 883 (1965). 217. M. Krzyzanowska and W. Niemierko, Insect Biochem. 10, 323 (1980). 218. M. Krzyzanowska and W. Niemierko, Insect Biochem. 9, 11 (1979). 219. M. Marek, Vestn. Cesk. Spol. Zool. 43, 165 (1979). 220. a. N. Kokolis, Chim. Chronika 34, 136 (1969); b. N. Kokolis, Chim. Chronika35, 17 (1970). 221. N. Kokolis and N. Mylonas, Folia Biochim. Biol. Graeca 8, 21 (1971). 222. N. Kokolis and N. Mylonas, Foliu Biochim. Biol. Gruecu 8, 14 (1971). 223. S. Nawa and T. Taira, Proc. Jpn. Acud. 30, 632 (1954). 224. M. Tsusue and M. Akino, Zool. Mug., Tokyo 74, 91 (1965). 225. M. Goto, M. Konishi, K. Sugimura, and M. Tsusue, Bull. Chem. SOC. Jpn. 39, 929 (1966). 226. T. Tamura, Nippon Sanshigaku Zasshi 46, 113 (1977). 227. T. Tamura, Kugaku Seibutsu 16, 92 (1978). 228. Y. Hayashi, Nippon Sunshigaku Zusshi 30, 89 (1961). 229. T. Fukuda and S. Nishitsutsuji, Nippon Sunshiguku Zasshi 30, 420 (1961). 230. Y. Hayashi, Nippon Sanshiguku Zasshi 30, 427 (1961). 231. S. Tojo, Insect Biochem. 1, 249 (1971). 232. M. Pramila and R. V. Krishnamoorthy, Entomon 2, 1 (1977); cf. Chem. Abstr. 88, 19229V

233. T. Kawano and E. Matsumura, Yukugaku Zusshi 98, 663 (1978). 234. M. Eguchi, Nippon Sunshiguku Zusshi 29, 32 (1960). 235. M. Eguchi, Nippon Oyo Dobutsu Konchu-Guku Zasshi 5, 163 (1961). 236. M. M. Jezewska, B. Gorzkowski and T. Sawicka, Acta Biochim. Pol. 14, 71 (1967). 237. J. Heller and M. M. Jezewska, Bull. Acad. Polon. Sci., Ser. Sci. Biol. 7 , 1 (1959). 238. A. C. Cohen, Experientiu 39, 435 (1983). 239. A. Jacob and T. R. Subramaniam, Curr. Sci. 42, 648 (1973). 240. S. Tojo and C. Hirano, J. Insect Physiol. 12, 1467 (1966). 241. H. Ikemoto, Bochu-Kugaku 36, 59 (1971). 242. Y. P. Ramdev and P. J. Rao, Indian J . Enromol. 41, 94 (1979). 243. M. A. A. Eid and M. S. Salem, Bull. Fuc. Agric., Univ. Cairo 28, 423 (1977).

(1963).

p. 327 (1964).

F. Day, J. L. Hartwell, and H. B. Wood, Jr., Experientiu 28, 381 (1972).

(1978).


244. P. Radha and H. C. Agrawal, Arch. Int. Physiol. Biochem. 71, 605 (1963). 245. U. Laudani and C. Contini, Boll. Zool. Agric. Bachicolt. 10, 21 (1970). 246. B. Rasmuson, M. M. Green, and G. Ewertson, Hereditus 46, 635 (1960). 247. T. G. Gregg and L. A. Smucker, Genetics 52, 1023 (1965). 21 (1970). 248. M. Viscontini and E. Mohlmann, Helv. Chim. Acta 42, 1679 (1959). 249. J. D. Gearhart and R. J. MacIntyre, Anal. Biochem. 37, 21 (1970). 250. 0. Brenner-Holzach and F. Leuthardt, Helv. Chim. Acta 44, 1480 (1961). 251. M. Tsusue and M. Akino, Dobutsugaku Zasshi 74, 94 (1965). 252. R. Kiiersteiner, J. Insect Physiol. 7, 5 (1961). 253. J. V. Burcombe and M. J. Hollingsworth, Exp. Gerontol. 5 , 247 (1970). 254. C. I. I. Driver and M. J. Lamb, Exp. Gerontol. 15, 167 (1980). 255. a. K. Rokos and W. Pfleiderer, Chem. Ber. 108,2728 (1975); b. I. Schwinck and M. Mancini,

256. K. Sugiura and Goto, Tetrahedron Left. 1187 (1973). 257. K. M. Summers and A. J. Howells, Insect Biochem. 10, 151 (1980). 258. L. M. Birt and B. Christian, J . Insect Physiol. 15, 71 1 (1969). 259. K. R. France and C. L. Judson, J . Insect Physiol. 25, 841 (1979). 260. H. Briegel, Rev. Suisse Zool. 87, 1029 (1980). 261. H. Briegel, Experientia 36, 1428 (1980). 262. E. Bursell, J . Insect Physiol. 11, 993 (1965). 263. A. Grigolo, L. Sacchi, L. Cima, and A. Malacrida, Riv. Parussitol. 33, 51 (1972). 264. T. W. Goodwin and S. Srisukh, Biochem. J. 49, 84 (1951). 265. W. Mordue and G. J . Goldsworthy, Insect Biochem. 3, 419 (1973). 266. A. M. Mainguet and J. R. Le Berre, Arch. Sci. Physiol. 27, 91 (1973). 267. A. Bouthier and J . Lhonore, J. Comp. Physiol. B 154, 549 (1984). 268. P. Razet, C. R. SOC. Biol. 164, 2627 (1970). 269. L. Merlini and R. Mondelli, Gazz. Chim. Ital. 92, 1251 (1962). 270. V. Janda, Jr., Zool. Jahrb., Abt. Allg. Zool. Physiol. Tiere 74, 506 (1969). 271. M. Viscontini and H. Schmid, Helv. Chim. Acta 46, 2509 (1963). 272. A. Shimamune, R. Marin, and C. Naquira, Seikagaku 39, 29 (1967). 273. F. M. Barrett and W. G. Friend, J. Insect Physiol. 16, 121 (1970). 274. F. M. Barrett, Diss. Abstr. Int. B 31, 1725 (1970). 275. a. A. H. Bartel, B. W. Hudson, and R. Craig, Insect Physiol. 2, 348 (1958); b. H. S. Forrest,

IVPACInt. Symp. Chem. Nat. Prod., Kyoto, 1964, Abstr. Pap., p. 137 (1964). 276. H. S. Forrest, S. E. Harris and L. I. Morton, J . Insect Physiol. 13, 359 (1967). 277. M. Afza, I. Ahmad, M. H. Qazi, and T. Hameed, Pak. J . Sci. Ind. Res. 28, 104 (1985). 278. H. J. Banks and D. W. Cameron, Insect Biochem. 3, 139 (1973). 279. C. L’Helias, Compt. Rend. 253, 1353 (1961). 280. C. L’Helias, Bull. Biol. Fr. Belg. 96, 187 (1962). 281. F. Fischer, W. Kapitza, M. Gersch, and H. Unger, Z. Naturforsch. 17B, 834 (1962). 282. P. N. Srivastava and P. D. Gupta, J. Insect Physiol. 6, 163 (1961). 283. H. Bruchhaus, Zool. Jahrb., Abt. Allg. Zool. Physiol. Tiere 76, 375 (1972). 284. D. E. Mullins and D. G. Cochran, Comp. Biochem. Physiol. A 50, 501 (1975). 285. D. G. Cochran, Comp. Biochem. Physiol. A 53, 79 (1976). 286. C. L. Washington and D. Ludwig, 1. N.Y. Entomol. Sac. 73, 168, (1965). 287. D. E. Mullins and D. G. Cochran, Comp. Biochem. Physiol. A 53, 393, (1976). 288. D. G. Cochran, Cornp. Biochem. Physiol. A 46, 409 (1973). 289. D. G. Cochran, Annu. Rev. Entomol. 30, 29 (1985). 290. D. G. Cochran, Comp. Biochem. Physiol. A 64A, 1 (1979). 291. D. G. Cochran, Comp. Biochem. Physiol. A 70A, 205 (1981).

Arch. Genet. 46, 41 (1973).


292. D. G . Cochran and D. E. Mullins, J . Exp. Zool. 222, 277 (1982). 293. J. Cerkasov and J. Seifert, Vestnik Cesk. Spolecnosti Zool. 24, 130 (1960). 294. A. K. Bhattacharya and G. P. Waldbauer, Ann. Entomol. Soc. Am. 62, 925 (1969). 295. G . Farn and D. M. Smith, 1. Assoc. Ofic. Agric. Chem. 46, 517 (1963). 296. A. K. Bhattacharya and G. P. Waldbauer, J . Insect Physiol. 16, 1983 (1970). 297. C. P. Hoyt and G. 0. Osborne, Ann. Entomol. SOC. Am. 63, 1198 (1970). 298. G. A. Rosenthal and D. H. Janzen, Biochem. Syst. Ecol. 9 , 219 (1981). 299. N. Mitlin and G. Wiygul, Insect Biochem. 6 , 207 (1976). 300. J. E. Baker, Comp. Biochem. Physiol. B 53, 107 (1976). 301. R. Bernasconi, Experientiu 19, 148 (1963). 302. P. E. Spiegler, J . Insect Physiol. 8 , 127 (1962). 303. M. Nakagoshi, S. Takikawa, and M. Tsusue, Experientiu 39, 742 (1983). 304. M. Nakagoshi, M. Masada, and M. Tsusue, Insect Biochem. 14, 615 (1984). 305. J. Gregoire and F. Miranda, C. R. Seances Soc. Biol. Ses Fil. 149, 1439 (1955). 306. K. Vajropala, Nature (London) 136, 145 (1935). 307. E. Gorup-Besanez and F. Will, Liebigs Ann. Chem. 69, 117 (1949). 308. B. H. Hamdy, J . Med. Entomol. 9 , 346 (1972). 309. B. H. Hamdy, J . Med. Entomol. 10, 53 (1973). 310. U. Grossbach, Z. Naturforsch. 12B, 462 (1957). 311. H. Descimon, Ann. Soc. Entomol. Fr. 3 , 827 (1967). 312. E. Cerioni, C. Contini, and U. Laudani, Chem. Biol. Pteridines, Proc. 5th Int. Symp., Berlin,

313. M. Gogala and s. Michieli, Bid . Vestnik 10, 33 (1962). 314. M. Gogala and 5. Michieli, Bull. Scient. Cons. Acad. R.P.F. Yougosl. 7, 61 (1962). 315. W. A. Nelson, Nature (London) 182, 115 (1958). 316. R. M. Kothari, N. N. Godbole, and V. G. Vaidya, J . Univ. Poonu, Sci. Technol. 40, I (1971). 317. L. Levenbook, R. F. N. Hutchins, and A. C. Bauer, J . Insect Physiol. 17, 1321 (1971). 318. J. S . Buckner, J. M. Caldwell, and J. P. Reinecke, J . Insect Physiol. 26, 7 (1980). 319. J. S . Buckner, J . Insect Physiol. 28, 987 (1982). 320. G . K. Sharma and G. C. Rock, Experientiu 31, 930 (1975). 321. M. N. Schreiber and W. H. Mason, Spec. Publ. Ecol. Soc. Am. 1, 136 (1976). 322. G. Haggag and Y. Fouad, Nature (London) 207, 1003 (1965). 323. K. P. Rao and T. Gopalakrishnareddey, Comp. Biochem. Physiol. 7 , 175 (1962). 324. R. H. Francis, Biol. Bull. 137, 155 (1969). 325. G. Schmidt, M. Liss, and S. J. Thannhauser, Biochem. Biophys. Actu 16, 533 (1955). 326. J. F. Anderson, Comp. Biochem. Physiol. 17, 973 (1966). 327. B. H. Hamdy, J . Med. Entomol. 14, 15 (1977). 328. B. P. Moore and W. V. Brown, Insect Biochem. 8, 393 (1978). 329. B. Tursch, D. Daloze, J. C. Braekman, C. Hootele, D. Losman, A. Cravador, and R.

330. B. Tursch, D. Daloze, J. C. Braekman, C. Hootele, and J. M. Pasteels, Tetruhedron31, 1541

331. B . Tursch, D. Daloze, J. M. Pasteels, A. Cravador, J. C. Braekman, C. Hootele, and D.

332. W. A. Ayer, M. J. Bennett, L. M. Browne, and J. T. Purdham, Can. J . Chem. 54, 1807

333. B. Tursch, D. Daloze, M. Dupont, C. Hootele, M. Kaisin, J. M. Pasteels, and D. Zimmer-

334. B. Tursch, D. Daloze, and C. Hootele, Chimiu 26, 74 (1972).

1975, p. 851.

Karlsson, Tetrahedron Lett. 409 (1974).

( 1975).

Zimmermann, Bull. SOC. Chim. Belg. 81, 649 (1972).

(1976).

mann, Chimiu 25, 307 (1971).


335. R. D. Henson, A. C. Thompson, P. A. Hedin, P. R. Nichols, and W. W. Neel, Experientia 31,

336. W. A. Ayer and L. M. Browne, Heterocycles 7, 685 (1977). 337. B. Tursch, J. C. Braekman, D. Daloze, C. Hootele, D. Losman, R. Karlsson, and J . M.

338. B. Tursch, C. Chome, J. C. Braekman, and D. Daloze, Bull. Soc. Chim. Belg. 82,699 (1973). 339. H. Schildknecht and K. Koob, Angew. Chem. Int. Ed. Engl. 9, 173 (1970). 340. H. Schildknecht and K. Koob, Angew. Chem. Int. Ed. Engl. 10, 124 (1971). 341. I. S. De la Lande and J. C. Lewis, Mem. Inst. Butantan 33, 951 (1966). 342. J. Leconte, V. Bourdon, and N. Magis, Bull. Soc. R. Sci. Liege 53, 317 (1984). 343. T. Nakajima, T. Yasuhara, N. Yoshida, Y. Takernoto, S. Shinonaga, R. Kano, and H.

344. R. Jaques and M. Schachter, Br. J . Pharmacol. 9, 53 (1954). 345. K. D. Bhoola, J . D. Calle, and M. Schachter, J . Physiol. 151, 35 (1960). 346. K. D. Bhoola, J. D. Calle, and M. Schachter, J . Physiol. 159, 167 (1961). 347. J. Ishay, A. Zalman, Y. Grunfeld, and S. Gitter, Comp. Biochem. Physiol. A 48, 369 (1974). 348. S . C. Lahiri and B. Sarangi, Indian J . Med. Res. 69, 505 (1979). 349. M. D. Owen and A. R. Bridges, Toxicon 20, 1075 (1982). 350. H. Edery, J. Ishay, L. Lass, and S. Gitter, Toxicon 10, 13 (1972). 351. E. Kaplinsky, J. Ishay, and S. Gitter, Toxicon 12, 69 (1974). 352. T. Yasuhara, H. Yoshida, and T. Nakajima, Chem. Pharm. Bull. 25, 936 (1977). 353. R. G. Geller, H. Yoshida, M. A. Beaven, 2. Horakova, F. L. Atkins, H. Yamabe, and J . J .

354. J . H. Welsh and C. S . Batty, Toxicon 1, 165 (1963). 355. M. Watanabe, T. Yasuhara, and T. Nakajima, Anim. Plant Microb. Toxins, Proc. 4th Int.

Symp., 1974 2, 105 (1976). 356. M. D. Owen, Experientia 27, 544 (1971). 357. B. E. C. Banks, J. M. Hanson, and N. M. Sinclair, Toxicon 14, 117 (1976). 358. G. Nagamitu, Okayama Igakkai Zasshi 47, 3005 (1935). 359. a. M. Reinert, Festschr. E. Barell Switz., 407 (1936); b. C. Tetsch and K. Wolff, Biochem. 2.

288, 126 (1936); c. W. Neumann and E. Habermann, Arch. Exp. Pathol. Parmakol. 222, 367 ( 1954).

145 (1975).

Pasteels, Tetrahedron Lett. 201 (1973).

Yoshida, Eisei Dobutsu 34, 61 (1983).

Pisano, Toxicon 14, 27 (1976).

360. W. H. A. Schottler, Metn. Inst. Butantan 26, 7 (1954). 361. 0. Markovic and L. Rexova, Chem. Zvesti 17, 676 (1963). 362. M. D. Owen and J. L. Braidwood, Can. 1. Zool. 52, 387 (1974). 363. M. D. Owen, J. L. Braidwood, and A. R. Bridges, J . Insect Physiol. 23, 1031 (1977). 364. M. D. Owen, J . Insect Physiol. 24, 433 (1978). 365. M. D. Owen, Toxicon, Suppl. 1, 589 (1976, Published in 1978). 366. S. Grzycki and K. Czerny, Acta Anal. 82, 91 (1972). 367. E. Ostlund, Acta Physiol. Scand. 31, Suppl. 112, 1 (1954). 368. E. Ostlund, Nature (London) 172, 1042 (1953). 369. T. Piek, A . Buitenhuis, R. T. Simonthomas, J. G. R. Ufkes, and P. Mantel, Comp. Biochem.

370. E. Kaiser and W. Raab, 2. Angew. Zool. 52, 1 (1965). 371. H. Itokawa, R. Kano, T. Nakajima, and T. Yasuhara, Eisei Dobutsu 36, 83 (1985). 372. El S. Amin, J . Chem. Soc. 3764 (1957). 373. D. Ackermann, Hoppe-Seyler's 2. Physiol. Chem. 291, 169 (1952). 374. D. Ackermann, Hoppe-Seyler's 2. Physiol. Chem. 302, 87 (1955). 375. D. J. Fowler, C. J . Goodnight, and M. M. LaBrie, Ann. Entomol. Soc. Am. 65, 138 (1972).

Physiol. 75C, 145 (1983).


376. N. G. Kamyshev, E. V. Savvateeva, N. N. Kudryavtseva, andI . I. Lobacheva, Dokl. Akad.

377. D. Ackennann, Z . Biol. 71, 193 (1920). 378. M. F. Braconnier, J. C. Brackman, D. Daloze, and J. M. Pasteels, Experimentia 41, 519

379. R. J. Martin, B. A. Bailey, and R. G. H. Downer, J . Chromatogr. 278, 265 (1983). 380. M. S. Blum, J. B. Wallace, and H. M. Fales, Insect Biochem. 3, 353 (1973). 381. R. M. Duffield, M. S. Blum, J. B. Wallace, H. A. Lloyd, and F. E. Regnier, J . Chem. Ecol.

382. K. R. Adam and C. Weiss, J . Exp. Biol. 35, 39 (1958). 383. K. R. Adam and C. Weiss, Nature (London) 178, 421 (1956). 384. J. H. Welsh and M. Moorhead, J . Neurochem. 6, 146 (1960). 385. C. M. Gilbo and N. W. Coles, Aust. J . Biol. Sci. 17, 758 (1964). 386. J. L. Prado, Z. Tamura, E. Furano, I. J. Pisano, and S. Undenfriend, Hypotensive Peptides,

387. M. Beroza, Ace. Chem. Res. 3, 33 (1970). 388. K. Fuji, K. Ichkawa, and E. Fujita, Chem. Pharm. Bull. 27, 3183 (1979). 389. B. P. Mundy and M. Bjorklund, Tetrahedron Lett. 26, 3899 (1985). 390. Y. Moriyama, D. D. Huynh, C. Monneret, and Q. K. Huu, Tetrahedron Lett., 825 (1977). 391. W. Curmthers, M. J. Williams, and M. J. Cox, J . Chem. Soc., Chem. Commun. 1235 (1984). 392. D. L. J. Clive, V. Farina, A. Singh, C. K. Wong, W. A. Kiel, and S. M. Menchen, J . Org.

393. R. K. Hill and T. Yuri, Tetrahedron 33, 1569 (1977). 394. S. Sakane, Y. Matsumura, Y. Yamamura, Y. Ishida, K. Maruoka, and H. Yamamoto, J . Am.

Chem. Soc. 105, 672 (1983). 395. a. Y. Matsumura, K. Maruoka, and H. Yamamoto, Tetrahedron Lett. 23, 1929 (1982); b. K.

Muraoka, T. Miyazaki, M. Ando, Y. Matsumura, S. Sakane, K. Hattori, and H. Yamamoto, J . Am. Chem. SOC. 105, 2831 (1983).

396. M. Bonin, J. R. Romero, D. S. Grierson, and H. P. Husson, Tetrahedron Lett. 23, 3369 (1 982).

397. Y. Nakazono, R. Yamaguchi, and M. Kawanishi, Chem. Lett., 1129 (1984). 398. A. I. Meyers, P. D. Edwards, T. R. Bailey, and G . F. Jagdman, J . Org. Chem. 50, 1019

399. M. Ogawa and M. Natsume, Heterocycles 21, 769 (1984). 400. R. Lukes and 0. Cervinka, Coil. Czech. Chem. Commun. 24, 1846 (1959). 401. E. Spath and L. Mamoli, Chem. Ber. 69, 1082 (1936). 402. B. P. Mundy, K. B. Lipkowitz, M. Lee, and B. R. Lansen, J . Org. Chem. 39, 1963 (1974). 403. T. Sakan, A. Fujino, F. Murai, Y. Butsugan, and A. Suzu, Bull. Chem. Soc. Jpn. 32, 315

404. G. W. K. Cavill and D. L. Ford, Aust. J . Chem. 13, 296 (1960). 405. G . W. K. Cavill and A. Zeitlin, Aust. J . Chem. 20, 349 (1967). 406. J. D. Wuest, A. M. Madonik, and D. C. Gordon, J . Org. Chem. 42, 2111 (1977). 407. L. B. Davies, S. G . Greenberg, and P. G. Sammes, J . Chem. SOC. Perkin Trans. 1 1909

408. J. Meinwald, G . M. Happ, J. Labows, and T. Eisner, Science 151, 79 (1966). 409. H. M. Fales, W. Comstock, and T. H. Jones, Anal. Chem. 52, 980 (1980). 410. R. W. Howard, C . A. McDaniel, and G . J. Blomquist, J . Chem. Ecol. 4, 233 (1978). 411. G. J. Blomquist, R. W. Howard, C. A. McDaniel, S. Remaley, L. A. Dwyer, and D. R.

412. E. Schmitz, H. Sonnenschein, and C. Griindemann, J . Prakt. Chem. 322, 261 (1980).

Nauk SSSR 256, 1237 (1981).

(1985).

3, 649 (1977).

Proc. Int. Symp., Florence, 1965, p. 93 (1966).

Chem. 45, 2120 (1980).

(1985).

( 1959).

(1981).

Nelson, J . Chem. Ecol. 6, 257 (1980).


413. F. J. Ritter and F. Stein, U.S. Pat. 4,075,320 (1978). 414. F. J. Ritter and F. Stein, Br. Pat. P 25,286,560 C1 C07 D 207-06 (1975). 415. R. R. Fraser and S. Passannanti, Synthesis, 540 (1976). 416. T. L. MacDonalds, J. Org. Chem. 45, 193 (1980). 417. K. Shiosaki and H. Rapoport, J. Org. Chem. 50, 1229 (1985). 418. W. Gessner, K. Takahashi, and A. Brossi, Helv. Chim. Acta (submitted) (1987). 419. J. H. Tumlinson, R. M. Silverstein, J. C. Moser, R. G. Brownlee, and I . M. Ruth, Nature

420. J. H. Tumlinson, J. C. Moser, R. M. Silverstein, R. G. Brownlee, and J. M. Ruth, J. Insect

421. H. Rapoport and J. Bordner, J. Org. Chem. 29, 2727 (1964). 422. T. Sugahara, Y. Komatsu, and S. Takano, J. Chem. Sac., Chem. Commun., 214 (1984). 423. C. C. J. Culvenor and J. A. Edgar, Experientia 28, 627 (1972). 424. E. Roder, H. Wieldenfeld, and T. Bourauel, Liebigs Ann. Chem., 1708 (1985). 425. T. W. Bell, M. Bopprk, D. Schneider, and J. Meinwald, Experientia 40, 713 (1984). 426. C. C. J. Culvenor, J. A. Edgar, L. W. Smith, and H. J. Tweeddale, Aust. J . Chem. 23, 1869

427. T. Hudlicky, J. 0. Frazier, and L. D. Kwart, Tetrahedron Lett. 26, 3527 (1985). 428. L. H. Zalkow, J. A. Glinski, L. T. Gelbaum, T. J. Fleischmann, L. S. McGowan, and M. M.

429. H. Stetter, W. Basse, H. Kuhlmann, A. Landscheidt, and W. Schlenker, Chem. Ber. 110,

430. T. H. Jones, M. S. Blum, H. M. Fales, and C. R. Thompson, J. Org. Chem. 45,4778 (1980). 431. T. Katsuki and K. B. Sharpless, J . Am. Chem. SOC. 102, 5974 (1980). 432. 0. Mitsunobu, M. Wada, and T. Sano, J . Am. Chem. SOC. 94, 679 (1972). 433. S. Takano, S. Otaki, and K. Ogasawara, J. Chem. SOC., Chem. Commun., 1172 (1983). 434. J. E. Oliver and P. E. Sonnet, J . Org. Chem. 39, 2662 (1974). 435. P. E. Sonnet and J. E. Oliver, J . Heterocycl. Chem. 12, 289 (1975). 436. P. E. Sonnet, D. A. Netzel, and R. Mendoza, J. Heterocycl. Chem. 16, 1041 (1979). 437. T. Shono, Y. Matsumura, K. Uchida, and H. Kobayashi, J . Org. Chem. 50, 3243 (1985). 438. R. V. Stevens and A. W. M. Lee, J. Chem. Soc., Chem. Commun., 102 (1982). 439. M. Natsume and Y. Kitagawa, Abstr. 104thAnnu. Meet. Pharm. SOC. Jpn.. Sendai, 1984, p.

440. E. Hata, T. Matsuki, R. Yamaguchi, and M. Kawanishi, Abstr. 5ZndAnnu. Meet. Chem. SOC.

441. M. Ogawa, J. Nakajima, and M. Natsume, Heterocycles 19, 1247 (1982). 442. T. F. Spande, J. W. Daly, D. J. Hart, Y .-M. Tsai, and T. L. MacDonald, Experientiu 37, 1242

443. J. Royer and H. P. Husson, J. Org. Chem. 50, 670 (1985). 444. H. Schildknecht, G. Krebs, and H. Birringer, Chem. Zeit. 95, 332 (1971). 445. A. Butenandt, Angew. Chem. 69, 16 (1957). 446. R. Karlsson and D. Losman, J. Chem. Soc., Chem. Commun., 626 (1972). 447. F. Bohlmann, Chem. Ber. 91, 2157 (1958). 448. R. T. Lalonde, A. Auer, C. F. Wong, and P. Muralidharan, J . Am. Chem. SOC. 93, 2501

449. W. A. Ayer, R. Dawe, R. A. Eisner, and K. Furuichi, Can. J. Chem. 54, 473 (1976). 450. W. A. Ayer and K. Furuichi, Can. J. Chem. 54, 1494 (1976). 451. H. C. Brown and W. C. Dickason, J . Am. Chem. SOC. 91, 1226 (1969). 452. R. H. Mueller, Tetrahedron Lett., 2925 (1976). 453. R. H. Mueller and M. E. Thompson, Tetrahedron Lett. 21, 1093 (1980).

(London) 234, 348 (1971).

Physiol. 18, 809 (1972).

(1970).

Gordon, J. Med. Chem. 28, 687 (1985).

1007 (1977).

318 (1984).

Jpn., Kyoto, 1986, p. 1219 (1986).

(1981).

(1 97 1).


454. H. Bredereck, F. Effenberger, and G. Simchen, Chem. Ber. 98, 1078 (1965). 455. R. H. Mueller, M. E. Thompson, and R. M. DiPardo, J . Org. Chem. 49, 2217 (1984). 456. R. H. Mueller and R. M. DiPardo, J . Chem. SOC., Chem. Cornmun., 565 (1975). 457. R. H. Mueller and M. E. Thompson, Tetrahedron Lett., 1991 (1979). 458. R. H. Mueller and M. E. Thompson, Tetrahedron Lett., 1097 (1980). 459. I. Murahashi, A. Kubo, J. Saito, and J. Haginiwa, Chem. Pharm. Bull. 12, 747 (1964). 460. a. R. V. Stevens and A. W. M. Lee, J . Am. Chem. SOC. 101,7032 (1979); h. R. V. Stevens,

461. R. K. Hill and L. A. Renbaum, Tetrahedron 38, 1959 (1982). 462. E. Gossinger and B. Witkop, Monatsh. Chem. 111, 803 (1980). 463. R. J. Highet and J. W. Wheeler, in “The Alkaloids” (A. Brossi, ed.), Vol. 24, pp. 287-348.

464. J. W. Wheeler, J . Avery, 0. Olubajo, M. Shamim, C. B. Storm, and R. M. Duffield,

465. Y. Akita and A. Ohta, Heterocycles 19, 329 (1982). 466. C. Cardani, D. Ghiringhelli, R. Mondelli, and Quilico, Tetrahedron Lett., 2537 (1965). 467. T. Matsumoto, M. Yanagiya, S. Maeno, and S. Yasuda, Tetrahedron Left . , 6297 (1968). 468. A. Fumsaki, T. Watanabe, T. Matsumoto, and M. Yanagiya, Tetrahedron Lett., 6301 (1968). 469. B. Corradi, A. Mangia, M. Nardelli, and G. Pelizzi, Gazz. Chem. Ital. 101, 591 (1971). 470. C. Cardani, D. Ghiringhelli, R. Mondelli, and A. Selva, Gazz. Chem. Ital. 103, 247 (1973). 471. K. Tsuzuki, T. Watanabe, M. Yanagiya, and T. Matsumoto, Tetrahedron Lett., 4745 (1976). 472. M. A. Adams, A. J. Duggan, J. Smolanoff, and J. Meinwald, J . Am. Chem. SOC. 101, 5364

(1979). 473. a. J. Meinwald, Pure Appl. Chem. 49, 1275 (1977); b. K. Tsuzuki, Y. Nakajima, T.

Watanabe, M. Yanagiya, and T. Matsumoto, Tetrahedron Lett., 989 (1978). 474. a. G . S. Cockerill and P. Kocienski, J . Chem. SOC., Chem. Commun., 460 (1982); b. K. Isaac,

P. Kocienski, and S. Campbell, J . Chem. SOC., Chem. Commun., 249 (1983); c. P. Kocienski and T. M. Willson, J . Chem. SOC., Chem. Commun., 1011 (1984).

Pure Appl. Chem. 51, 1317 (1979).

Academic Press, New York, 1985.

Tetrahedron 38, 1939 (1982).

475. F. Matsuda, M. Yanagiya, and T. Matsumoto, Tetrahedron Lett. 23, 4043 (1982). 476. F. Matsuda, N. Tomiyoshi, M. Yanagiya, and T. Matsumoto, Tetrahedron Lett. 24, 1277

477. T. Nakata, S. Nagao, N. Mori, and T. Oishi, Tetrahedron Lett. 26, 6461 (1985). 478. M. Yanagiya, F. Matsuda, K. Hasegawa, and T. Matsumoto, Tetrahedron Lett. 23, 4039

479. T. Matsumoto, F. Matsuda, K. Hasegawa, and M. Yanagiya, Tetrahedron 40, 2337 (1984). 480. T. Nakata, S. Nagao, N. Mori, and T. Oishi, Tetrahedron Lett. 26, 6461 (1985). 481. a. T. Nakata, S. Takao, M. Fukui, T. Tanaka, and T. Oishi, Tetrahedron Lett. 24, 3873

(1983); b. T. Nakata, S. Nagao, and T. Oishi, Tetrahedron Lett. 26, 75 (1985). 482. a. D. A. Evans, M. D. Dennis, T. Le, N. Mandel, and G . Mandel, J . Am. Chem. SOC. 106,

1154 (1984); b. Y. Ito, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett. 25, 6015 (1984). 483. C. Cardani, C. Fuganti, D. Ghirnghelli, P. Grasselli, M. Pavan, and M. D. Valcurone,

Tetrahedron Lett., 2815 (1973). 484. T. Eisner and J. Meinwald, Science 153, 1341 (1966). 485. H. Schildknecht, W. F. Wenneis, K. H. Weis, and U. Maschwitz, Z . Naturforsch. 21B, 121

486. D. Chakravati, R. N. Chakravati, L. A. Cohen, B. Dasgupta, S. Datta, and H. K. Miller,

487. E. Ziegler, W. Steiger, and T . Kappe, Monatsh. Chem. 100, 948 (1969). 488. T. Kametani, C. V. LOC, T. Higa, M. Ihara, and K. Fukumoto, J . Chem. SOC. , Perkin Trans.

(1983).

(1982).

(1966).

Tetrahedron 16, 224 (1961).

I , 2347 (1977).


489. T. Kametani, C. V. LOC, M. Ihara, and K. Fukumoto, Heterocycles 9, 1585 (1978). 490. H. Schildknecht and W. F. Wenneis, Tetrahedron Left., 1815 (1967). 491. R. Shapiro, Progr. Nucl. Acid Res. Mol. Biol. 8, 73 (1968). 492. Kohjin Co., Ltd., Jpn. Kokai Tokkyo-Koho JP 59 16891 [84 168911 (C1. C07D473/18)

493. V. J . Hemmens and D. E. Moore, J. Chem. Soc., Perkin Trans. 2, 209 (1984). 494. M. Kappel, R. Mengel, and W. Pfleiderer, Liebigs Ann. Chem., 1815 (1984). 495. B. Schircks, J. H. Bieri, and M. Viscontini, Helv. Chim. Acra 68, 1639 (1985). 496. M. Viscontini, Biochem. Clin. Aspects Pteridines 3, 19 (1984). 497. W. Pfleiderer, Chem. Biol. Pteridines, Proc. 5th Int. Symp., Berlin, 1975, p. 941 (1975). 498. W. Pfleiderer, Chem. Ber. 112, 2750 (1979). 499. S. Matsuura, T. Sugimoto, C. K. Yokokawa, and M. Tsusue, in “Chemistry and Biology of

Pteridines” (R. L. Kisliuk and G. M. Brown, eds.), p. 135. Elsevier-North Holland, New York, 1979.

500. S. Nawa and H. S. Forrest, Nature (London) 196, 169 (1962). 501. K. Sugiura and M. Goto, Nippon Kagaku Kaishi 93, 206 (1972). 502. S. Katoh and M. Akino, Experientia 22, 793 (1966). 503. B. Schircks, J. H. Bieri, and M. Viscontini, Helv. Chim. Acta 61, 2731 (1978). 504. T. Fukushirna, Methods Enzymol. 66, 508 (1980). 505. R. Baur, T. Sugimoto, and W. Pfleiderer, Chem. Lett., 1025 (1984). 506. K. Sugiura, M. Goto, and S . Nawa, Tetrahedron Lett., 2963 (1969). 507. H. Schlobach and W. Pfleiderer, Angew. Chem. Int. Ed. Engl. 10, 414 (1971). 508. a. N. Theobald and W. Pfleiderer, Chem. Ber. 111, 3385 (1978); b. N. Theobald and W.

Pfleiderer, Tetrahedron Lett., 841 (1977). 509. W. B. Watt, J. Biol. Chem. 242, 565 (1967). 510. H. Descirnon, Biochim. 55, 907 (1973). 511. H. Descimon, Dev. Biochem. 4, 93 (1978). 512. M. Masada and M. Akino, Biochim. Biophys. Acta 630, 92 (1980). 513. G. M. Brown, G . G. Krivi, C. L. Fan, and T. R. Unnasch, in “Chemistry and Biology of

Pteridines” (R. L. Kisliuk and G. M. Brown, eds.), p. 81. Elsevier-North Holland, New York, 1979.

(1984).

514. D. Dorsett, J . J. Yim, and K. B . Jacobson, Biochemistry 18, 2596 (1979). 515. D. Dorsett, J. M. Flanagan, and K. B. Jacobson, Biochemistry 21, 3892 (1982). 516. G. J. Wiederrecht and G. M. Brown, J. Biol. Chem. 259, 14121 (1984). 517. J. W. Wheeler, T. Olagbemiro, A. Nash, and M. S . Blum, J. Chem. Ecol. 3, 241 (1977). 518. M. S. Blum and J. M. Brand, Am. 2001. 12, 553 (1972). 519. R. G. Riley, R. M. Silverstein, B. Carroll, and R. Carroll, J. Znsect Physiol. 20, 651 (1974). 520. A. K. Borg-Karlson and J. Tengo, J . Chem. Ecol. 6, 827 (1980). 521. R. M. Duffield, M. Shamim, J. W. Wheeler, and A. S . Menke, Comp. Biochern. Physiol.

522. R. P. Evershed and E. D. Morgan, Naturwissenschaflen 68, 374 (1981). 523. R. P. Evershed, E. D. Morgan, and M.-C. Cammaerts, Insect Biochem. 12, 383 (1982). 524. G. W. K . Cavill, P. L. Robertson, and F. B. Whitfield, Science 146, 79 (1964). 525. D. W. Thomas and J . C. Lewis, Aust. J . Exp. Biol. Med. Sci. 43, 275 (1965).

70B, 317 (1981).


- CHAPTER 7 -

PAVINE AND ISOPAVINE ALKALOIDS

BELKIS GOZLER

Department of Pharmaceutical Chemistry Faculty of Pharmacy

Ege University Izmir, Turkey

I. Introduction 11. Occurrence and Structure Elucidation

A. Pavine Alkaloids B . Isopavine Alkaloids

A. Synthesis of Pavines B. Synthesis of Isopavines

IV. Unnatural Pavines and Isopavines V. Spectral Properties

111. Synthesis

A. Mass Spectroscopy B . lH-NMR Spectroscopy C. W-NMR Spectroscopy D. UV Spectroscopy E. ORD, CD, and Absolute Configuration

VI. Biosynthesis VII. Chemotaxonomic Considerations

VIII. Homopavines and Homoisopavines IX. Aporphine-Pavine Dimers X. Pharmacology

References

I. Introduction

Pavines and isopavines are two relatively small subgroups of the isoquinoline alkaloids, being represented by 22 and 11 compounds, respectively. Few new examples have been reported in the last decade, which stands in contrast to the rapid increase in the number of known natural compounds in recent years as a consequence of improved isolation techniques and spectral methods of structure elucidation.

In the meantime, a substantial corpus of synthetic work has been reported, where novel routes have been described and conventional approaches have been reinvestigated for improved methods or yields. Enantioselective syntheses have

THE ALKALOIDS, VOL 31 Copyright 0 1987 by Academic Press, Inc.

All nghts of reproduction in any form reserved.

317

318 BELKIS GOZLER

also been successfully achieved, the significance of which should be emphasized with regard to future pharmacological studies on these compounds. Quite a few pavine and isopavine bases, so far unknown as natural products, have been obtained as a result of these synthetic efforts. It is of interest to note that a number of naturally occurring pavine and isopavine alkaloids had been synthesized prior to their isolation from natural sources. The structure of the first pavine alkaloid, argemonine (5), was elucidated by comparison with the long known semisynthetic compound, N-methylpavine. Likewise, the accumulated knowledge on synthetically derived isopavines prompted the structural elucidation of the first isopavine alkaloids, amurensine (24) and amurensinine (25). Other examples of synthesis preceding isolation from plant sources include the pavines isonorargemonine (11) and the N-metho salts of argemonine (lS), caryachine (16), and eschscholtzidine (17) and the isopavines 0-methylthalisopavine (26) and amurensinine N-metho salt (31).

Two numbering systems have been used for the pavines, represented by expressions l a and l b ( I ) . We adopt here the system represented in la. For the isopavines, the numbering sequence in 2 will be followed.

1 5

11 10

7 6

l a l b A 7

12 11

2

The pavine and isopavine alkaloids of the Papaveraceae have been discussed in Vols. 4, 10, 12, and 17 of this treatise (2-5), and only brief references have been made to occurrences outside this botanical family. Individual chapters have been devoted to the pavine and isopavine alkaloids in the two books by Shamma (6,7), covering developments until 1977, and also in Rodds Chemistry of Car- bon Compounds (8), published in 1978. A listing of naturally known pavines and isopavines up to 1975, with references to physical and spectral data, appeared in Kametani’s Chemistry of the Zsoquinoline Alkaloids (9,lO). A more recent compilation by Gozler and co-workers (11) has covered references to mid- 1982. Relevant literature has also been summarized regularly in Vols. I-XI11 of Spe-

7. PAVINE AND ISOPAVINE ALKALOIDS 319

cialist Periodical Reports, the Alkaloids (1969- 1982) and subsequently in Natu- ral Product Reports (1982-present). This chapter is designed as a comprehensive review, aimed at covering the manifold facets of pavine and isopavine alkaloid chemistry.

11. Occurrence and Structure Elucidation

A. PAVINE ALKALOIDS

The first isolation of pavine bases from a natural source dates back to 1944 when brief descriptions and empirical formulas were reported for two crystalline compounds from Argemone hispida (12), later designated as A. munita subsp. rotundata based on habitat, morphology, and alkaloidal profile (13) . Subse- quently reisolated from the same plant, one of these bases was named argemonine, while the other, possessing one less methylene, was given the trivial name norargemonine. Although no structural formulas could then be written, a tetracyclic ring system encompassing a tetrahydroisoquinoline nucleus was proposed according to the hitherto available chemical and analytical data (14). Following the erroneous assignment of an aporphinoid structure to argemonine (15), various structures were considered based on degradative and spectral evidence (16,17). In the meantime, a diphenolic base, provisionally named rotundine, was isolated from A. munita subsp. rotundata and shown to be convertible to argemonine on methylation, thus establishing the unambiguous relationship between rotundine, norargemonine, and argemonine (13). Shortly afterward, the name bisnorargemonine was adopted for rotundine since the latter was found to be already in use (15). In 1963, two groups independently reported that if optical activity were ignored, (-)-argemonine (5) was identical with the long known synthetic compound ( 2)-N-methylpavine, thus recognizing a novel ring system in nature (18,19). Confirmatory evidence was then provided by additional spectral data (20), by total synthesis (20), and by further degradative studies ( 2 1 ) .

The decade following the recognition of this novel structural framework was a prolific period for the discovery of pavine bases. Significantly, 17 of the 22 known pavine bases were reported between 1963 and 1973. With the increasing availability of spectral techniques, the structures of some already isolated bases possessing this tetracyclic nucleus, namely, (-)-norargemonine (13) (22) , (-)- bisnorargemonine (6) (23), and (-)-eschscholtzine (9) (24), were elucidated while several other alkaloids were isolated and characterized. The first “unusual” substitution pattern on a pavine skeleton was encountered with the discovery of (-)-munitagine (12) from A. munita subsp. rotundata (25) , while the same plant source also yielded another interestingly substituted pavine alkaloid, 2-hydroxy-3,8-dimethoxypavinan (10) (26). Furthermore, despite the technical

320 BELKIS GOZLER

difficulties encountered in the isolation of polar components, three quaternary bases and one N-oxide were isolated and fully described.

Since the previous reviews on the pavine group in Vol. 4, 10, 12, and 17 of this treatise, which cover references prior to 1976, five new alkaloids of the pavine series have been discovered. These alkaloids are (-)-2,3-methylenedioxy-4,8,9-trimethoxypavinane (3), thalipoline, (-)-caryachine N-metho salt (16), (-)-eschscholtzidine N-metho salt (17), and (-)-eschscholtzine N-oxide (20a).

1. (-)-2,3-Methylenedioxy-4,8,9-trimethoxypavinane (3)

A tertiary base isolated from Thalictrum strictum was assigned a pavine structure based on the spectral data (27). Three methoxyl and one methylenedioxy functions were detected with the aid of mass spectroscopy. Structure 3 was proposed as the most probable representation for this new pavine alkaloid, which indeed is the first example of a pentasubstituted pavine base. However, when the reported aromatic proton chemical shifts (6 6.23, 6.36, and 6.54) were evaluated in the light of empirical rules about the ‘H-NMR absorptions of pavine bases (Section V,B), and it seemed possible that the two upfield absorptions belong to H-4 and H-10 rather than to H-1 and H-10. Therefore, alternative structure 4 cannot presently be completely excluded from consideration.

?Me

3 4

2. Thalipoline

A recent addition to the pavine series may be thalipoline, C,,H,,NO,, which has been isolated from Thalictrum minus (28). The pavine framework was deduced from spectral data which, however, were not described.

3. (-)-Caryachine N-Metho Salt (16)

The new quaternary pavine base (-1-caryachine N-metho salt was isolated from Cryptocarya chinensis (29), previously shown to yield both the levorotatory and racemic forms of caryachine (7) (30,31). The structure 16 was derived

7. PAVINE AND ISOPAVINE ALKALOIDS 32 1

from 'H-NMR and mass spectral analyses, and was further confirmed by direct comparison of physical and spectral data with those of the methiodides prepared from synthetically derived caryachine and isocaryachine (139) (29). Recently, the presence of caryachine N-metho salt has been demonstrated in Eschscholtzia douglusii, thus representing the first occurrence of this alkaloid in the Pa- paveraceae (3Za). It was also detected in small amounts in E. culifornicu and E. glauca ( 3 1 ~ ) .

4. (-)-Eschscholtzidine N-Metho Salt (17)

The structure proof of the second new quaternary base, (-)-eschscholtzidine N-metho salt (17), isolated as its chloride from the fruits of Thalictrum revolutum, was provided by spectral analyses and direct comparison of the compound with the N-metho salt prepared from authentic (-)-eschscholtzidine (S), also present in the plant (32).

It is a general feature of alkaloid chemistry that less is known about the quaternary alkaloidal components than the tertiary bases due to the difficulties encountered in handling the isolation and analyses of these highly polar compounds. It is interesting to note, however, that in the pavine series, 5 naturally occurring N-metho salts as against a total of 15 tertiary pavine alkaloids have been recognized.

5. (-)-Eschscholtzine N-Oxide (20a)

A recent study on the Chilean Eschscholtzia culifornicu reported the presence of a polar alkaloid along with the known pavinane base, (-)-eschscholtzine (9). In the mass spectrum of the former, the fragmentation pattern following the expulsion of sixteen mass units from the molecular ion was identical to that of 9. Likewise, the 'H NMR spectrum displayed absorption signals similar to those of 9, but with the exception of a distinct downfield chemical shift of the N-methyl protons, thus suggesting an N-oxide structure. Deoxygenation of this levorotatory polar base with phosphorus trichloride yielded 9, verifying the structural assignment as (-)-eschscholtzine N-oxide (20a) (32a).

Until recently, only four plant families were known to elaborate pavine alkaloids, namely, the Papaveraceae, the Lauraceae, the Ranunculaceae, and the Berberidaceae. With the recent isolation of (-)-bisnorargemonine (6) from Chasmantheru dependens, however, the Menispermaceae have become the fifth pavine-producing plant family (33). Interestingly, with the exception of the family Papaveraceae, which belongs to the order Rhoedales, the families belong to the order Ranales. Two genera within the Papaveraceae, Argemone and Es-

322 BELKIS COZLER

chscholtzia, and two genera among the Berberidaceae, Berberis and Leontice, have been demonstrated to generate pavine bases. So far, only the genus Cryp- tocarya of the Lauraceae and the genus Thalictrum of the Ranunculaceae have been reported to produce pavines. Attention should be drawn to the fact that Thalictrum is the only genus known to produce both pavine and isopavine alkaloids. This observation, however, may be shown not to be true as further plant isolations are carried out.

Tables 1-111 present the naturally occurring pavinane alkaloids reported so far, in alphabetical order with a key to their structures. A comprehensive listing of plant sources is given in Table IV.

TABLE I Tertiary Pavine Alkaloids

~~ ~

Molecular Molecular Alkaloid formula weight R1 R2 R3 R4 R5 R6

Argemonine (5) (= N-

Bisnorargemonine (6) Caryachine (7) Eschscholtzidine (8) (=

0-methylcaryachine) Eschscholtzine (9) (=

crychine, califomine) 2-Hydroxy-3,8-dimethoxy-

pavinane (10) Isonorargemonine (11) 2,3-Methylenedioxy-4,8,9-

trimethoxypavinan (3) Munitagine (12) Norargemonine (13) (=

O-desmethylarge- monine)

methylpavine)

Platycerine (14)

C21H25N04 355 OMe OMe H H OMe OMe

H H H H H H

OMe OH OMe OH OMe OMe

327 325 339

1 sH1i”04 323 H H M H 2 4

OMe H 19H21 N03 31 1 OH OMe H H

34 1 369

OMe OH M H 2 4

OH OMe OH OMe

H H OMe H

OMe OMe OMe OMe

H OH H H

OMe H OMe OMe

327 34 1

C2&23N04 34 1 OMe OMe H OH OMe H


TABLE I1 Quaternary Pavine Alkaloids

Molecular Molecular Alkaloid formula weight R1 R, R, R, R5

Argemonine N-metho salt C2LH28N04+ 370 OMe OMe H OMe OMe

Caryachine N-metho salt CZ0Hz2NO4+ 340 M H 2 + H OMe OH

Eschscholtzidine N-metho C2,HZ4NO4+ 354 M H 2 - 0 H OMe OMe

Eschscholtzine N-metho salt C20H20N04 + 338 O-€H2+ H @-CH2-0

Platycerine N-metho salt CzlH26N04+ 356 OMe OMe OH OMe H

(15)

(16)

salt (17)

(18) (= californidine)

(1%

TABLE 111 Pavine N-Oxides

Molecular Molecular Alkaloid formula weight R1 R2 R, R4

Argemonine N-oxide (20) CziHz5N05 37 1 OMe OMe OMe OMe Eschscholtzine N-oxide (20a) CI9Hl7NO5 339 M H 2 + O - C H 2 - 4

324 BELKIS GOZLER

TABLE IV Botanical Distribution of Pavine Alkaloids

Alkaloid Family Species References

(-)-Argemonine (5 )

(+)-Argemonine (5)

(-)-Argemonine N-metho salt (15)

(-)-Argemonine N-oxide

(-)-Bisnorargemonine (6) (20)

Berberidaceae Papaveraceae

Ranunculaceae

Berberidaceae

Papaveraceae

Ranunculaceae

Papaveraceae

Lauraceae

Menispermaceae

Papaveraceae

Berberis buxifolia Lam. Argemone gracilenta

A. hispida Gray A. munita Dur. and

Hilg. A. munita Dur. and

Hilg. subsp. argentea G. B. Ownb.

A. munita Dur. and Hilg. subsp. rotundata (Rydb.) G. B. Ownb.a

A. platyceras Link and Otto

A. sanguinea Greene Thalictrum dasycarpurn

Fisch. et Lall. T. minus L. T. revolutum DC. T. strictum Ledeb. Leontice Smirnovii

Argemone gracilenta

A. platyceras Link and

Thalictrum revolutum

Argemone gracilenta

Cryptocarya longifolia

Chasmanthera depen-

Argemone hispida Gray A. munita Dur. and

Hilg. subsp. rotundata (Rydb.) G. B. 0wnb.a

Eschscholtzia californica Cham.

E . douglasii (Hook and Am.) Walp.

Greene

Trautv.

Greene

Otto

DC .

Greene

Kostermans

duns Hochst.

34 35

25 19

36

126,146

37c

38 39

28,40 32,4Ic,42= 43,44 45,46

35

47c,48c

32

35

49

33

25 13,25,26

31a,50C, 51c.52

31 a,50C




(-)-Caryachine (7)

(+)-Caryachine (7)

(-)-Caryachine N-metho salt (16)

(-)-Eschscholtzidine (8)

(-)-Eschscholtzidine (8)

(-)-Eschscholtzidine N-

(-)-Eschscholtzine (9) metho salt (17)

(-)-Eschscholtzine N - metho salt (18)

Ranunculaceae

Lauraceae

Papaveraceae

Lauraceae

Lauraceae

Papaveraceae

Papaveraceae

Ranunculaceae

Lauraceae

Ranunculaceae

Lauraceae

Papaveraceae

Papaveraceae

E. glauca Greene Thalictrum dasycarpum

Fisch. et Lall. Cryptocarya chinensis

Hemsl. Eschscholtzia califor-

nica Cham. E. douglasii (Hook and

Am.) Walp. E. glauca Greene Cryptocarya chinensis

Hemsl. Cryptocarya chinensis

Hemsl . Eschscholtzia califor-


Am.) Walp. E. glauca Greene Eschscholtzia califor-


Am.) Walp. E. glauca Greene Thalictrum minus L. T. revolutum DC. Cryptocarya chinensis

Thalictrum revolutum

Cryptocarya chinensis

Eschscholtzia califor-

Hemsl.

DC.

Hemsl.

nica Cham.

E. douglasii (Hook and Am.) Walp.

E. glauca Greene Eschscholtzia califor-


Am.) Walp. E. glauca Greene

E. oreganu Greene

31a,5OC 53

30,31

31a

31a

31a 30,31

29

31a

31a

31a 52

54

54 28 32,41c 30

32

30,31

31a,32a, 51c,55- 57, 58c

54,59c

31a,54,60 31a,56,

58c,61c 31a,54,6IC

31a,54,60,

62 61 c

(continued)

326 BELKIS GOZLER



(-)-Eschscholtzine N-ox-

(-)-2-Hydroxy-3,8-di- ide (20a)

rnethoxypavinan (10)

( - )-Isonorargemonine (11)

(-)-2,3-Methylene- dioxy-4,8,9-trirnethoxy- pavinan (3)

(-)-Munitagine (12)

(-)-Norargemonine (13)

Papaveraceae

Papaveraceae

Papaveraceae

Ranunculaceae

Ranunculaceae

Papaveraceae

Berberidaceae Lauraceae

Papaveraceae

Eschschotziu californica Cham.

Argemone munita Dur. and Hilg. subsp. rotundata (Rydb.) G. B . Ownb.*

Argemone gracilenta Greene

A . munita Dur. and Hilg. subsp. argentea G. B. Ownb.

Eschscholtzia culifor- nica Cham.

E. douglusii (Hook and Am.) Walp.

E. glauca Greene Thalictrum revolutum

Thalictrum strictum DC .

Ledeb.

Argemone gracilenta

A . munita Dur. and Greene

Hilg. subsp. rotundata (Rydb.) G. B. Ownb.'

Berberis buxifolia Lam. Ctyptocarya longifoliu

Kostermans Argemone brevicornuta

G. B. Ownb. A. hispida Gray A . munita Dur. and

Hilg. subsp. rotundata (Rydb.) G . B. 0wnb.O

A . platyceras Link and Otto

Eschscholtzia califor- nicu Cham.

E . douglusii (Hook and Am.) Walp.

E. glauca Greene

32u

26

35

36

3 l a

31 a

31 a 42c

27,44

35

25,26

34 49

63

22,25 126,146

37c ,64

31a,50C

31a,50C

31a,50C

I. PAVINE AND ISOPAVINE ALKALOIDS 327



Ranunculaceae Thalictrum dasycarpum 53 Fisch. et Lall.

Greene

Otto

DC.

(-)-Platycerine (14) Papaveraceae Argemone gracilenta 35

A . plafyceras Link and 37c

Ranunculaceae Thalictrum revolutum 32,42c

(-)-Platycerine N-metho Papaveraceae Argemone platyceras 47c,48C

( - )-Thalipolin& Ranunculaceae Thalictrum minus L. 28 salt (19) Link and Otto

a Synonyms: A. rotundata Rydb.; A. hispida Torrey; A. mexicana Torrey. b Plant was thought to be A. hispida Gray at the time of isolation. c Isolation from cultivated plants. d Structural formula not available.

B . ISOPAVINE ALKALOIDS

In 1960, the name amurensine was given by Boit and Flentje (65) to a new phenolic base isolated from Papaver nudicaule var. amurense. At that time, only an empirical formula could be assigned. A few years later, the compound was isolated by Santavf and co-workers (66) from two Papaver species and provisionally named xanthopetaline. On continuation of their investigations on Pa- paver species, the same group reisolated this compound and demonstrated its identity with amurensine (24), after which the older name was adopted (67). On methylation, (-)-amurensine was converted to a nonphenolic compound, (-)- amurensinine (25) ( 6 3 , which was found to accompany the former in all of the investigated species (68). The results of detailed spectral and degradative analyses were shown to be in accordance with those of the synthetically known compound (+)-isopavine (35) (69). This correlation established the first natural occurrence of another novel tetracyclic structure among the isoquinoline alkaloids (67,70). The position of the phenolic group in amurensine was correctly assigned according to chemical evidence and biosynthetic considerations (67,70) and was further confirmed through mass spectral analyses (71) and total synthesis (72).

(-)-Remrefine (32), the first quaternary isopavine base, isolated in 1966 from Roemeria refracta, was erroneously assigned a pavine structure (73), which was later revised according to the products of a two-stage Hofmann degradation and relevant 'H-NMR spectral data (74,75). The suggestion that (-)-remrefine was probably the quaternary form of (-)-amurensinine (25) (74,75) was later shown

328 BELKIS GOZLER

to be invalid when three novel isopavinane bases, (-)-reframidine (27), (-)- reframine (28), and (-)-reframoline (29), were isolated from the same natural source, and (-)-remrefine was demonstrated to be the quaternary analog of (-)- reframine (76). This identity was conclusively confirmed by spectral comparison of the synthetically derived N-metho salt of reframine with that of the natural compound (77).

The first occurrence of an isopavine alkaloid outside the Papaveraceae was demonstrated when (-)-thalisopavine (30) was found in Thalictrum dasycarpum (53). The proposed structure was verified through spectral analyses and total synthesis (53). Methylation yielded (-)-0-methylthalisopavine (26), which was later synthesized as a racemate (77). (-)-0-Methylthalisopavine was discovered in Papaver radicatum some years later (78), so this represents another case of synthesis preceding natural occurrence.

The aforementioned eight bases have already been reviewed in relevant sections of Vols. 12 and 17 of this treatise. However, only a brief reference has been made in Vol. 17 to amurensinine N-metho salt (31). Originally isolated as an unidentified quaternary base from Meconopsis nupaulensis (79), it was later reisolated from various species of Meconopsis and shown to be the quaternary analog of (-)-amurensinine (25) by direct comparison with the N-metho salt prepared from authentic (-)-amweminine (80). It should be mentioned that (?)- amurensinine N-metho salt had been previously prepared through total synthesis (81). Two new tertiary bases have been isolated since the previous review by Santavf (5): (-)-thalidine (21) and (-)-thalidicine (23).

1 . (-)-Thalidine (21)

A strongly levorotatory alkaloid isolated from Thalictrum dioicurn by Shamma and co-workers (82) was named (-)-thalidine (21) and assigned an isopavine structure on the basis of mass spectral analysis. The diphenolic nature of the alkaloid was evidenced by 'H-NMR data and by the bathochromic shift in the UV spectrum on addition of alkali. Diazomethane 0-methylation produced (-)- thalisopavine (30) and (-)-0-methylthalisopavine (26). Of the two probable isomeric structures, 21 and 22, 21 was slightly favored on biosynthetic grounds. Final proof to structure was provided by total synthesis (82). (-)-Thalidine has also been reported from T. polygamum (83).

21 22


TABLE V Tertiary Isopavine Alkaloids

R1 RwR:4 \ ' NMe

Molecular Molecular Alkaloid formula weight R, R2 R3 R4

Amurensine (24) (= xanthopetaline)

Amurensinine (25) 0-Methylthalisopavine (26) Reframidine (27) Reframine (28) Reframoline (29) Thalidicine (23) Thalidine (21) Thalisopavine (30)

C19H19N04 325

339 355 323 339 325 327 327 341

M H 2 - 4

M H 2 - 4 OMe OMe

OMe OMe OMe OH OH OMe OH OMe OMe OMe

O--CH2-4

OMe OH

OMe OMe OMe OMe W H 2 - 4 M H 2 - 0 M H 2 - 4 OH OMe OMe OH OMe OH

2. (-)-Thalidicine (23)

The spectral analyses of another new base from Thalictrum dioicum established its structure as a diphenolic isopavine, to which the trivial name (-)- thalidicine was assigned. The nonequivalency of the aromatic protons in the NMR spectrum led to the consideration of the two possible structures, 22 and 23, where 23 was apparently favored for biosynthetic considerations and also by analogy to the NMR aromatic proton chemical shifts of other known isopavine

TABLE VI Quaternary Isopavine Alkaloids

Molecular Molecular Alkaloid formula weight R1 R2 R3 &

Amurensinine N-metho salt (31) C21H24N04 + 354 O-CH,- -O OMe OMe Reframine N-metho salt (32) (= CZ1Hz4NO4+ 354 OMe OMe ( t C H 2 - 0

remrefine, roemefine)

330 BELKIS GOZLER

bases (84). However, since the proposed structure 23 was not verified by total synthesis, the structural determination is incomplete and open to question. In particular, it could be that (-)-thalidicine is identical with (-)-thalidine (21) (82,83) as suggested by the close resemblance of their physical and spectral data.

23

Tables V and VI include all the hitherto reported isopavine alkaloids in alphabetical order. Natural sources of the isopavines are listed in Table VII.

111. Synthesis

A. SYNTHESIS OF PAVINES

The pavine ring system was first encountered toward the end of the nineteenth century in the course of an experiment where papaverine (39) was reduced with tin and hydrochloric acid to furnish a tetrahydroisoquinoline. Along with the expected tetrahydropapaverine, a colorless base was obtained in low yield (90,91). Although this minor component was later designated as 1,2-dihydropapaverine (92), this suggestion was not found justifiable by the same investigator on chemical evidence. He then suggested the name "pavine" to avoid future discrepancies (93). In the same work, N-methylation of papaverine followed by reduction was shown to afford N-methylpavine for which a correct empirical formula, C,,H,,NO,, and some physical data were given. In an extension of his studies on the structure of pavine (94), Pyman suggested structure 33 for this compound. However, Schopf offered the alternate structures, 34 and 35 (95). The correct structure, 34, was established unequivocably as a result of extensive chemical and degradative studies (96,97).

33


TABLE VII Botanical Distribution of Isopavine Alkaloids


(-)-Amurensine (24) Papaveraceae Meconopsis rudis Prain (= xanthopetaline) Papaver alpinum L.

P. alpinum L. subsp. burs e r i

P. alpinum L. subsp. kerneri (Hay.) Fedde

P. alpinum L. subsp. tatricum Nyir

P. anomalum Fedde P. nudicaule L. var.

amurense Hort. P. nudicaule L. var.

leiocarpum Turz. P. nudicaule L. var.

rubroaurantiacum DC .

P. nudicaule L. var. xanthopetalum (Trautv.) Fedde

P. pseudocanescens M.

P. pyrenaicum (Kemeri)

P. suaveolens Lap. P. tatricum NyAr Meconopsis horridula

M. napaulensis DC. M. rudis Prain M. sinuata Prain Papaver alpinum L. P. alpinum L. subsp.

burseri P. alpinum L. subsp.

kerneri (Hay.) Fedde P. alpinum L. subsp.

tatricum Nyir P. anomalum Fedde P. nudicaule L. var.

leiocarpum Tun. P. nudicaule L. var.

rubroaurantiacum DC .

Pop.

L.

Hook. f. and Thoms. (-)-Amurensinine (25) Papaveraceae

80a 68 85

85

85

66 65

68

68

66,68

86",88"

68

68 68 80a

79,80a 80a 80" 68 85

85

85

860,87 68

68

(continued)

332 BELKIS GQZLER

TABLE VII (Continued)

Alkaloid Species

(-)-Amweminine N- metho salt (31)

(- )-O-Methylthal- isopavine (26)

(-)-Reframidhe (27)

Papaveraceae

Papaveraceae

Papaveraceae

(-)-Reframine (28) Papaveraceae

(-)-Reframine N-metho Papaveraceae salt (32) (= remrefine, roemre fine)

(-)-Reframoline (29) Papaveraceae

(-)-Thalidicine (23) Ranunculaceae (-)-Thalidine (21) Ranunculaceae

(-)-Thalisopavine (30) Ranunculaceae

P. nudicaule L. var. xanthopetalum (Trau- tv.) Fedde

P. pseudocanescens M.

P . pyrenaicum (Kemeri) L.

P. pyrenaicum (Kemeri) L. subsp. rhoeaticum (Ler.) Fedde

P . radicatum Rottb. P. suaveolens Lap. P . tatricum Nyar. P. tauricola Boiss. Meconopsis horridula

M. napaulensis DC. M. rudis Rain Papaver radicatum

Rottb. Papaver anomalum

Fedde Roemeria refracta

(Stev.) DC.c Roemeria refracta

(Stev.) DC.= Roemeria refacta

(Stev.) DC.c

Pop.

Hook. f. and Thorns.

Roemeria refracta (Stev.) DC.'

Thalictrum dioicum L. Thalictrum dioicum L. T. polygamun Muhl. Thalictrum dasycarpum

Fisch. et Lall.

68

88a

68

85

78a 68 68 89 80"

79,80" 80" 78"

86"

76"

76"

73,74,76"

76"

84 82 83 53

Isolation from cultivated plants. Synonym: Papaver nudicaule L. subsp. radicatum Rottb. Synonym: Roemeria rhoeadiflora Boiss.

The synthetic process leading to pavine formation can now be illustrated as in Scheme 1. It includes quaternization and selective reduction of the iminium bond to afford a 1,2-dihydroisoquinoline (36), which is the key intermediate in the synthesis of pavine bases. Acid-catalyzed cyclization of this enamine furnishes the pavinane framework 38 via the I ,4-dihydroisoquinolinium ion 37. Langhals

I . PAVINE AND ISOPAVINE ALKALOIDS 333

RO Me RO

36

RO

38

SCHEME 1

and co-workers (98) proposed a free radical mechanism for the Knabe reaction, drawing attention to the presence of formic acid as a radical chain inhibitor which permits the persistence of species 37, eventually cyclizing into the pavines. It has been shown that phenolic hydroxyls are more favored as directing groups than methoxyls in this cyclization process (99). On the other hand, cyclization is disfavored by bromine substitution on the lower pendant ring of the isoquinoline precursor (100,101).

1. Classical Routes to Pavines

a. Semisynthesis from Papaverine. In an attempt at structure confirmation of (-)-norargemonine (13), papaverine (39) was used as the starting material to construct the two possible isomeric structures (22). As shown in Scheme 2, papaverine hydrochloride was heated to afford a separable mixture of phenol betaine protopapaverine (40) and norpapaveriniurn betaine hydrochloride (41). The former was treated with methyl iodide, furnishing 42, which on reduction with tin and hydrochloric acid yielded the benzyltetrahydroisoquinoline (2)-

334 BELKIS GOZLER

UoMe OMe

39 4 0

Y

WMe OMe

42

Me no

OMe ,

41 “1 Me0

OMe

11

+ * l - p s e u d o l a ” d a n i n e

13

+ ( + ) - c o d a m I n e

SCHEME 2

zAQ&%&, %A%>Y&% 3 p?i$hkb>~? X& ~h mht p~&a, N\A ws pmva tb correspond to the racemic form of natural (-)-norargemonine. Reduction of 41, on the other hand, supplied another benzyltetrahydroisoquinoline, (&)-pseudo- laudanine, and also the positional isomer of norargemonine, isonorargemonine (ll), which was found in an optically active form in nature 3 years later (35).

b. Bischler-Napieralski Procedure. A different synthetic sequence was proposed for the preparation of (&)-norargemonine (13) (102) where the required appropriately substituted benzylisoquinoline was synthesized by a multistep process starting from benzylvanillin (43) (Scheme 3). The amidic intermediate 44 was cyclized by the well-known Bischler-Napieralski procedure. Subsequent reduction afforded the benzyttetrahydroisoquinoline 45. This material was subjected to catalytic dehydrogenation to afford the isoquinoline 46, which had undergone undesired debenzylation in the process. Rebenzylation was carried out prior to the application of the classical procedure (quaternization, partial reduction, acid-catalyzed cyclization) to 47 to obtain the expected (%)-norargemonine. The above sequence has also been utilized in constructing the requisite isoquinoline for a synthesis of (+)-bisnorargemonine (6) (103).

7. PAVlNE AND ISOPAVINE ALKALOIDS 335

BzO

BzO

BzO 44

""C - NaBH4 /NH. CI

no BzO NH BzO

OMe 45

1. M e 1

2. N a B H 4

3. H + no

13

SCHEME 3

c. Pictet-Gams Modifications of Bischler-Napieralski Procedure. In order to preclude debenzylation during dehydrogenation, Pictet-Gams modification of the Bischler-Napieralski reaction was applied to the construction of the required isoquinoline for the syntheses of ( t )-bisnorargemonine (6) and its isomers (1,99). (2)-Caryachine (7) and (2)-isocaryachine (139) were synthesized by the same Pictet-Gams approach (104,105) in order to differentiate between the two possible structures proposed for (-)-caryachine. Racemic eschscholtzidine (8) was also synthesized following the above sequence to confirm the structure previously deduced by chemical and spectral analyses of the natural levorotatory compound (106). Scheme 4 exemplifies the Pictet-Gams approach as applied to the synthesis of (+-)-eschscholtzidine (8) (106).

Total synthesis was used for the structure confirmation of the 2,3,7,8-tetrasubstituted pavine bases, (-)-

d. Pavinan Synthesis via Reissert Compounds.

336 BELKIS GOZLER

I POCI3

3 . H+

8

SCHEME 4

platycerine (14) (107) and (-)-munitagine (12) (108), where a different approach was used to obtain the required isoquinoline (Scheme 5). The Schiff base 50, prepared by condensation of 2,3-disubstituted benzaldehyde 48 and aminoacetaldehyde dialkyl acetal 49, was converted to 7,8-disubstituted isoquinoline 51 by a series of reactions depicted in Scheme 5 . Treatment of 51 with potassium cyanide and benzoyl chloride afforded the Reissert compound 52, which was then converted to the desired benzylisoquinoline 53, using the appropriately substituted benzyl halides. Successive quaternization, partial reduction, and acid-catalyzed cyclization furnished (+)-platycerine or (2)-munitagine. The trisubstituted pavine base, (+)-2-hydroxy-3,8-dimethoxypavinan (10) was also synthesized by a parallel route (26).

e. Double Cyclization of Benzylaminoacetaldehyde Dialkyl Acetals. A conventional method, where isopavines are obtained by an acid-catalyzed double cyclization of benzylaminoacetaldehyde dialkyl acetals 54 under nonreductive conditions, is known to produce pavines as well (Scheme 6). The initial cyclization affords the 4-hydroxybenzyltetrahydroisoquinoline intermediate 55 (109). Two processes compete at this stage, one involving an intramolecular nucleophilic substitution at C-4 by the C-1 benzyl group to afford isopavine 56, and the second involving a dehydration to the 1,2-dihydro compound 57, furnishing pavine 58 on intramolecular cyclization.

This method has been used by Dyke and co-workers (110) to synthesize the isopavine alkaloid reframoline (29) in the racemic form, while the corresponding


50 48 49

51

3 . H+

1 2 : R = H

1 4 : R = M e 53

SCHEME 5

RO

OR

' OR

OR

5 4

RO

RO W Y R \ Ra Row ' NR ,

50 OR

5 8

SCHEME 6

338 BELKIS GOZLER

OE t

1 CN Q

0J0

J

SCHEME I

pavine base, (+-)-caryachine (7) was obtained as a by-product (Scheme 7). This route was also adapted to a preparation of the isomeric isopavine base (?)-146, so far unknown as a natural product, while the by-product was the unnatural pavine alkaloid, (&)-isocaryachine (139) ( I 10).

It has been emphasized that either pavines or isopavines can be obtained selectively depending on the choice of acid conditions used in the aforementioned cyclization process (111). It is also apparent that acid-catalyzed cyclization at room temperature results almost solely in the production of isopavines, whereas application of heat at this stage, which promotes dehydration of the 4- hydroxy intermediate, affords a mixture of pavine and isopavine alkaloids in varying ratios (110,112).

2. Synthesis of Optically Active Pavines

Enantiomeric forms of pavines were initially obtained by resolution of the racemic bases constructed by total synthesis (20,113-116). Attempts to synthesize optically active pavines using enantiomers of the I ,2-dihydrobenzylisoquinoline intermediates were unsuccessful ( I 15).

b. Enantioselective Total Synthesis. In 1977, Dyke and co-workers (I 12) successfully resolved the properly substituted 1,2-diarylethylamines 59 using (+)-dibenzoyltartaric acid to obtain the (+) enantiomer in crystalline form. This

a. Resolution of Racemates.


could in turn be converted to its acetal60 without racemization. Acid treatment of the optically active acetal yielded (-)-caryachine (7) as well as the isopavine base, (-)-reframoline (29), in almost equal but relatively low overall yields (Scheme 8). This instance represents the first total synthesis of an optically active pavine alkaloid.

A more recent synthesis of optically active pavine bases has been reported by Brossi’s group (Scheme 9) (I 17). The readily available (S)-( -)-N-norreticuline (61) (118) was converted to the dextrorotatory carbamate 62 which was then treated with DDQ in methanol to furnish quinone methide 63. This reactive intermediate underwent 1,6-addition of methanol in situ to afford the stable ( +)-4-methoxy-N-carbethoxybenzyltetrahydroisoquinoline 64. Thermolysis of 64 resulted in loss of methanol to furnish (+)-1,2-dihydro analog 65. Cyclization was achieved using chlorosulfonic acid in acetonitrile. Reduction of the tetracyclic product 66 by lithium aluminum hydride gave (-)-bisnordrgemonine (6), which was readily converted to (-)-argemonine (5) through methylation. The racemates of these pavine bases have also been prepared from racemic N-norreticuline, following an analogous course of synthesis ( I 1 7 ) .

Me0 Bzo&NHMe

5 9 bO) 0

( + I - D i b e n z o y l - t a r t a r l c a c i d I

I NH,

1. C iCOOEt

2 . L i A l H q

OEt

(+)-59 B f orno a c e l a i HCI - - (-1-7 ( 1 4 % )

and bO) 0 [-)-29 ( 1 9 % )

( + ) - 6 O

SCHEME 8

340 BELKIS GOZLER

Me0 no%*H ClCOOEt * M : : s *.."

(-1 -61 (+) -62

OH

/ OMe / OMe

I

no \ . MeOH 1 \ OH

OMe ' OMe (+) -64 63

therrnolysis

C I S 0 H 3 HO

OH

OMe (-1 -66 (+) -65

L i A l H 4

(-1 - 5 (-1 - 6

SCHEME 9

3. Novel Routes

In a novel synthetic route involving the transformation of a tetrahydroproto- berberine nucleus to a pavine skeleton (Scheme 10) (119), canadine methiodide (67), was subjected to Hofmann degradation to yield styrene 68. This compound was successively oxidized with osmium tetraoxide-sodium periodate and the


Hofmann deg.

OMe OMe

6 7 6 8

I

OMe OMe

69

7 1 7 2

73

SCHEME 10

product reduced with sodium borohydride to furnish benzyl alcohol derivative 69. Treatment of 69 with methanesulfonyl chloride gave the methomesylate 70, which rearranged in the presence of phenyllithium to afford the unnatural pavine base 71. Cleavage of the methylenedioxy group by boron trichloride followed by methylation furnished (&)-0,O-dimethylmunitagine (72), so far unknown as a natural product. Another product of the base-catalyzed rearrangement was reported to be the tetracyclic base 73.

342 BELKIS GOZLER

Racemic argemonine (5) has been synthesized from the readily available tetrahydr0-6,12-methanodibenz[c,jlazocine (74) (120-122) through a sequence involving a Stevens rearrangement and in an overall yield of 53% from 74 (Scheme 11) (123). Hofmann degradation of 74 furnished the em-methylene compound 75 (120,122). An oxidative ring expansion of 75 afforded ketone 76, which was then reduced to secondary alcohol 77. A transannular reaction, effected by acetic acid-acetic anhydride, resulted in the formation of the tetra-

74 75

TIC104

OMe L I A I H ~

M e 0 OMe meO O M e Me

7 7 76

ACOH - A c p O I Meom Me

O M e Me

M e 0 m a

Q X

7 0

B u L i 1 80

I . q u a l e r n i z a I r o n

2 . B u t O K

M e 0 M e 0 , M e 0 M4m;;: M e o ~ o M e + ' O M e M e 0 3

81 N M e ,

1. H Q ( O A C ) ~ , Z . T E D A I 5

NaBH4

Me0 O M e

7 9

SCHEME I1

5


cyclic quaternary salt 78 ( X = OAc). Treatment of 78 (X = Cl) with butyllithium gave two products, the spiroindoline 79 and (&)-argemonine (5) in overall yields of 18 and lo%, respectively.

In an alternate route designed to improve the yield of argemonine (5), 78 (X =

CIO,) was subjected to Hofmann elimination. The resulting compound 80 was quaternized and allowed to react with potassium tert-butoxide to generate di- methylamino compound 81. An internal dimethylaminomercuration-demercuration procedure followed by N-demethylation then provided ( 2)-argemonine in 53% yield (123).

4. Synthesis of Analogous Structures

The synthesis of a new class of compounds possessing the general structure 4,4,8,8-tetraalkyl-2,3 : 6,7-dibenzo-9-azabicyclo[3.3. llnonane- 1,5-diol(84) de- serves mention since the basic skeleton is analogous to that of the pavines (Scheme 12) (124-129). Oxidation of a series of indeno[2,1-a]indenes 82 with chromic acid yielded dibenzocyclooctanediones 83. Treatment of these diketones with various amines resulted in a transannular reaction to afford species 84 in good yields.

8 2 83

SCHEME 12

8 4

Brief reference should also be made to indolopavine derivatives 85 which were synthesized as illustrated in Scheme 13 (130). Since the utilized process, which is the classical route leading to pavines, also represents the probable biosynthetic sequence for the natural pavine alkaloids, it has been suggested that the future discovery of naturally occurring indolopavines is not an unlikely possibility (130).

B. SYNTHESIS OF ISOPAVINES

In 1955, Guthrie and co-workers (131) erroneously assigned pyrroline structure 87 to the crystalline compound obtained by treating aminoacetal 86 with sulfuric acid (Scheme 14). The structure assignment was revised by Battersby and Yeowell (69) to 35, who named it isopavine, since the structure had already been proposed but eliminated for the isomeric compound pavine (34) (95,97). The Battersby structure was conclusively confirmed through a study of the chem-

344 BELKIS GOZLER

Pd , c y m e n e M e o q N H R - R

H H 1. L i A I H 4 I

1 2. R ’ X

H

85

SCHEME 13

ical and UV spectral characteristics of the Hofmann degradation products (69). This structural revision was also reached independently by Waldmann and Chwala (132).

1. Classical Routes to Isopavines

The method of Guthrie, further developed by Battersby and Yeowell, has since become a

a. Double Cyclization of Aminoacetaldehyde Dialkyl Acetals.

OEt

Raney NI Me0 Me0

87 /

86

35

SCHEME 14

7. PAVINE AND ISOPAVME ALKALOIDS 345

traditional approach to the synthesis of isopavines. It involves an acid-catalyzed double cyclization of an appropriately substituted benzylaminoacetaldehyde dialkyl acetal 88 under nonreductive conditions (Scheme 15). Originally it was postulated that the reaction proceeded via 1 ,Zdihydro- and tetrahydroisoquinoline intermediates, 89 and 90 (132). However, it has now been established that the cyclization initially affords the acid-sensitive 4-hydroxytetrahydroiso- quinoline 92 via the aldehyde 91 (132a). The key intermediate 92 then undergoes rapid internal nucleophilic displacement of the hydroxyl group by the 3,4-di- alkoxylated aromatic ring to afford the tetracyclic skeleton 93. The confirmatory evidence for the proposed mechanism was provided by the isolation of 4-hydroxy intermediates from the reaction medium (109,1324. Even in instances where these key intermediates were not easily isolable, they were claimed to be present by conversion to 1,2,3,4-tetrahydroisoquinols (109,133).

Following the initial cyclization to the 4-hydroxy intermediate, a competing mechanism may operate depending on the reaction conditions utilized to afford a 1,2-dihydro derivative through dehydration. This will eventually lead to a pavine skeleton (Section 111,A). As mentioned previously, temperature is one of the

QOR OR

91 92

111 H+

93

SCHEME 15

346 BELKIS GOZLER

controlling factors in the fate of the reaction, where elevated temperatures promote the dehydration process and consequently pavine formation. Both pavines and isopavines are produced simultaneously, but in varying ratios when heat is utilized during cyclization, whereas cyclization at room temperature furnishes almost solely the isopavine derivatives. It has also been shown that variations in acid conditions may have definite effects on the nature of the products, and either a pavine or an isopavine may be obtained selectively depending on the choice of acid (111). Attempts have been made to develop milder conditions where preferential formation of isopavine bases could be achieved through this classical route. Treatment of the intermediate acetal with chlorosulfonic acid at very low temperatures gave only the isopavines in high yields (134).

The isopavine bases, (k)-amurensinine (25) (81,135), (?)-O-methylthalisopavine (26) (136), (+)-reframidhe (27) (77), and (*)-reframhe (28) (77) were synthesized by the above-mentioned classical route, where deoxy- benzoins were utilized as starting materials. In some cases, some modification to the method has been introduced, particularly involving the formation of the requisite benzylaminoacetals (77,110). The synthesis of (+)-thalisopavine (30) was undertaken along parallel lines to confirm the structure of the naturally occurring base (53). Moreover, both (5)-reframoline (29) and its positional isomer (+)-146 were synthesized in an attempt to establish the position of the phenolic hydroxyl (110). The synthesis of (+- )-reframhe (28) from the properly substituted deoxybenzoin 94 has been outlined in Scheme 16 as a typical example (77).

b. Hydroboration and Oxidation of 1,2-Dihydroisoquinolines. An alternate approach to the key 4-hydroxy intermediate and subsequently to the desired isopavine has involved the hydroboration and oxidation of a properly substituted 1,2-dihydroisoquinoline, as exemplified in the synthesis of (+-)-O-methylthalisopavine (26) from 1,2-dihydropapaverine (96) (Scheme 17) (77). In an attempt to establish the position of the phenolic hydroxyl, (?)-amurensine (24) and (+)-isoamurensine (100) were prepared along parallel lines, where the requisite isoquinolines 98 leading to 1,2-dihydro derivatives 99 were obtained via the Reissert compounds 97 (Scheme 18) (72).

The same route has been utilized to confirm the structure of (-)-thalidine (21) through the total synthesis of the racemic base (82). The corresponding dihydro compound was obtained by N-methylation and subsequent partial reduction of the Bischler-Napieralski product. The following steps leading to racemic thalidine were similar to those presented in the foregoing examples.

c. 4-Acetoxytetrahydroisoquinolines as Intermediates. Since 4-hydroxy- tetrahydroisoquinolines cyclize to isopavines in relatively low yields, Hoshino and co-workers (137) described a method where the properly substituted 6- hydroxybenzyltetrahydroisoquinolines of type 101 were subjected to lead


Me0

Me0 meorno - I

H,NCH2CH(OMe), I 94

NaEH4 Me0 Me0

conc. HCI

1. HCHO

2. NaEH4 M e 0

9 5 : n o r r e f r a m i n e

SCHEME 16 28

OH

96

Me0

26

SCHEME 11

348 BELKIS GOZLER

0

2 4 : R * = R 3 = M e : R 1 =Bz ; R4:H

100: R J = R 4 = M e ; R2=Bz ; R3=H

SCHEME 18

tetraacetate oxidation to afford 4-acetoxy derivatives 102 (Scheme 19). Acid- catalyzed cyclization of species 102 afforded the isopavine bases in improved yields. Thus, (+)-reframoline (29) and (&)-reframhe (28) were obtained by this route with overall yields of 54 and 40%, respectively. (+)-O-Methylthaliso- pavine (26) and the unnatural isopavine (2)-147 were also synthesized through this sequence (137).

In further studies by the same group (138,139), the C-8 position of the 7- hydroxybenzyltetrahydroisoquinoline was blocked with chlorine to promote the


OAc

101 102

2 8 2 9

SCHEME 19

formation of isopavines at the expense of aporphines, which were previously shown to be the sole products when 8-nonsubstituted substrates were used (140- 142). As illustrated in Scheme 20, lead tetraacetate oxidation of species 103 afforded p-quinol acetate 104. Subsequent treatment with trifluoroacetic acid yielded the corresponding isopavine 106 via the transitory quinone methide 105 in low yields. Also obtained, however, were the related aporphine 107 and morphinandienone 108, both in relatively low yields. It was, therefore, concluded that the blocking of the C-8 cite was not effective in directing the course of the reaction.

2. Enantioselective Synthesis of Isopavines

The first synthesis of an optically active isopavine, (-)-reframoline (29), has been achieved by the acid-catalyzed double cyclization process described previously. The properly substituted diarylamine 109 was resolved using (+)-dibenzoyltartaric acid to afford the (+) enantiomer. Conversion to the acetal 110 was accomplished without racemization. Subsequent acid-catalyzed cyclization yielded the levorotatory alkaloid 29 (Scheme 21) (112).

It has already been mentioned that a novel synthetic process furnished racemates and optically active forms of pavine bases via unstable quinone methide intermediates (Section III,A) (11 7). In this process, isopavine formation has also been achieved by the proper choice of reaction sequence. Racemates of thalidine (21) and 0-methylthalisopavine (26) were efficiently obtained by the above- mentioned route (11 7). Moreover, the sequence provides a convenient route to

103

OR

105

i : : w o I R CI

106

Pb ( O A c )4 * OR

CF3COOH / 104

0 W M e

Me0

RO

OR

107

SCHEME 20

0

108

OEt

Bz 0

b r o m o a c e t a l -(+)-log- Me0

NHMe (+)-dibenzoyl-

t a r i a r i c ac id

109

(-1-29

SCHEME 21


optically active isopavines when the starting material is (S)-( -)-N-norreticuline (61), now readily available by optical resolution of racemic N-norreticuline (118,143). Scheme 22 illustrates the synthesis of the optically active forms of the aforementioned isopavine bases, 21 and 26. Thus, phenolic N-carbethoxybenzyltetrahydroisoquinoline 111 was subjected to DDQ oxidation to afford the quinone methide intermediate 112. 1,6-Addition of methanol furnished species 113. Cyclization of 113 under mildly acidic conditions supplied the corresponding N-carbethoxy-N-norisopavine 114. Hydrazinolysis then gave rise to the N -

OMe (-1 - 6 1

D O H OMe

(+) - 1 1 3

(-) - 11 4

ClCOOEt M e o W C O O E t HO - -.. H

[+)-Ill

MeOH P

OH

11 2

(-)- 2 1 CH2N2 /

Me0 M e o ~ o ~ ~ e

(-) - 26 SCHEME 22

352 BELKIS GOZLER

norisopavine in high yield, whereas diborane reduction proved to be the preferential method for the conversion into the N-methylated analog, (-)-21. Di- azomethane 0-methylation of (-)-21 gave (-)-26 (117).

3. Novel Routes

Kametani and co-workers used a previously demonstrated ring expansion method to construct the isopavine skeleton (144,145). The method was successfully applied to the synthesis of (+-)-reframidine (27) (Scheme 23) (145). Treat- ment of the 3-aryl-3,4-dihydroisoquinolinium iodide 115 with diazomethane furnished aziridinium iodide 116. On standing in 6 N hydrochloric acid, crude 116 underwent a one-step ring expansion-ring closure to afford (+-)-reframidhe in 20% yield. The same product could be obtained via benzazepine 118 depending on the reaction conditions. It has been postulated that the aziridinium iodide 116 may have formed a transitory quinonoid intermediate 117 which is attacked

115

27

116

SCHEME 23


(%o) 2. PC13

\

' 0 H

119 ClCOOEt

HgO - HC104 -

124

SCHEME 24

354 BELKIS GOZLER

either intermolecularly by a methoxyl group to afford a 3-benzazepine 118 or intramolecularly by the 3-alkoxyphenyl group to generate the isopavine framework (145).

In a more recent study, another novel route for the total synthesis of (*)- reframidine (27) was described (Scheme 24) (146). The requisite aziridine derivative 120 was obtained from deoxypiperoin (119) in three steps. Treatment of 120 with ethyl chlorocarbonate furnished 121 through a ring opening of the reactive quaternary aziridinium salt. Reaction of the urethane 121 with mercuric oxide-perchloric acid gave 122 and 123, the former of which could be converted to the latter in good yield by passing through an alumina column. Successive reduction and Swern oxidation gave 124, which on treatment with acid cyclized to furnish (*)-reframidine with an overall yield of 18%.

A facile acid-catalyzed double cyclization of N,N-dibenzylaminoacetaldehyde dialkyl acetals of type 125 has been known to generate 1-azadibenzo[c,Jlbicy- clo[3.3.l]nona[3,6]dienes 126 in high yields (120,121,147). A novel and convenient synthesis of (*)-amurensinine (25) and (*)-reframhe (28) (Scheme 25) proceeds from the quaternary salt 127, where proper choice of base and reaction

OEt

125 1 2 6

128 1 2 7

ButOK I 2 8 2 5

SCHEME 25


conditions results in preferential production of either isopavines or species 128, the latter shown to be the intermediate en route to pavine bases (Section 111,A). Thus, the doubly cyclized product 126 obtained from N-(3,4-dimethoxy- benzyl)-N-(3,4-methylenedioxybenzyl)aminoacetaldehyde diethyl acetal 125 was quaternized to afford 127, which was in turn heated with potassium tert- butoxide in dioxane to furnish the isomeric isopavine alkaloids, (-+)-ammen- sinine and (2)-reframine (147).

OMe VOF3 * M e 0 M e o w o : : e

1 2 9

2 6

SCHEME 26

A novel route to (*)-0-methylthalisopavine (26) involves the oxidation of the properIy substituted tetrahydro-3-isoquinolone of type 129 with vanadium oxy- trifluoride to furnish bridged lactam 130. Compound 130 was then reduced to the racemic isopavine alkaloid 26 in an overall yield of 4.4% (Scheme 26) (136).

OMe

132

M e O Meor ‘OH

133

I I . N a N 3 - H 2 S 0 4

2 . t h e r m o l y s i s

35

SCHEME 21

356 BELKIS GOZLER

A recent endeavor at the total synthesis of isopavines describes a promising novel route to these bases via functionalized dibenzocyclooctadienes (Scheme 27) (148). Dibenzocyclooctadienyl ether 132, formed from homoveratraldehyde (131) by a double Friedel-Crafts alkylation, is converted to dibenzocyclooc- tatrienol 133. Treatment with hydrazoic acid, followed by thermolysis and reduction, supplies (*)-isopavine (35) in good overall yield (53%). Subsequent attempts to prepare pavine bases by this approach have proved to be unsuccessful (148).

Polyphosphor ic acid *QpJJ 135 /

1 3 4 0% SCHEME 28

An isopavine having a methyl group at C-5, 135, was obtained as the major product when the acetylenic derivative 134 was heated in polyphosphoric acid (Scheme 28) (149).

IV. Unnatural Pavines and Isopavines

A number of pavine and isopavine bases hitherto unknown as natural compounds were encountered in the course of our literature survey. These compounds had been obtained as intermediates or by-products during synthetic studies which were designed primarily for the structural elucidations of natural compounds and for the improvement of methods or yields en route to synthetic target compounds. The resolution of racemates or alternatively successful stereoselective syntheses furnished enantiomers of known optically active alkaloids. In this section, the aforementioned compounds are compiled under the heading ‘‘Unnatural Pavines and Isopavines ,” the term specifically denoting racemic or optically active compounds not yet found in nature and optical antipodes of optically active natural pavine and isopavine alkaloids. The coverage is restricted to compounds of which natural occurrences are probable with regard to biosynthetic considerations. The references related to their syntheses and physical and spectral data presented in Tables VIII-XI1 may prove useful in the event of the future isolation of any of these compounds or their close analogs from natural sources.

TABLE VIII Unnatural Pavine Alkaloids

Molecular Molecular References formula weight R1 RZ R3 R4 R5 Alkaloid

~

327 OH OMe H

H

H

OMe

H

OH

OMe

OH

OMe

OH

OMe

OH

OH

H

OMe

i (*)-2,8-Dihydroxy-3,9-dimethoxy-N- methylpavinan (136)

(*)-3,9-Dihydroxy-2,8-dirnethoxy-N- methylpavinan (137)

(*)-8,9-Dihydroxy-2,3-meth- y lenediox y -N-methy lpavinan (138)

(*)-7 ,b-Dimethoxy-2,3-methylenedioxy-N-methylpavinan (71)

(*)-8-Hydroxy-9-methoxy-2,3-methylenedioxy-N-methylpavinan (139) [ =

(t )-isocaryachine] (*)-8-Hydroxy-9-methoxy-2,3-meth-

ylenedioxy-N,N-dimethyl pavinium salt (140)

(*)-2,3,8,9-Tetrahydroxy-N-meth- ylpavinane (141)

(-)-2,3,7,8-Tetramethoxy-N-methylpavinan (142) [= (-)-O,O-dimethylmunitagine]

methylpavinan (72) [= (2)-O,O-dimethylmunitagine]

*)-2,3,7,8-Tetramethoxy-N-

19HZ 1 N04

C19H21N04 321

311

OMe OH

M H 2 4

i

31 C18H17N04

339 119

325 104,105, I 10, 150, I51

340 H OH OMe 29

299

355

OH OH

OMe OMe

H

OMe

OH

OMe

OH

H

1

25,35,37,42

C21H25N04 355 OMe OMe OMe H OMe 119

TABLE IX Unnatural N-Norpavine Alkaloids

w VI m

Alkaloid Molecular Molecular

formula weight RI R2 R3 R4 References

(?)-2,9-Dihydroxy-3,8-dimethoxy- C1gH19N04 313 OH OMe OMe OH 117 pavinan (143) [= (*)#nor- bisnorargemonine]

methylenedioxypavinan (144) (?)-9-Hydroxy-8-methoxy-2,3- c 1 8H17N04 31 1 M H 2 4 OMe OH 112

(?)-2,3,8,9-Tetrarnethoxypavinan C20H23N04 34 I OMe OMe OMe OMe 90,91,92, (34) [= (*)-pavine] 93,95,

97

TABLE X Unnatural Isopavine Alkaloids

Molecular Molecular Akaloid formula weight Rl R2 R3 R4 References

(+)-2,9-Dihydroxy-3,8-di- 1gH2 1 N04 321 OH OMe OMe OH 143 methoxy-N-methylisopavinan (145) [= (+)-thalidine]

meth y lenedioxy-N-methylisopavinan (146)

N-methylisopavinan (147)

methylenedioxy-N-methylisopavinan (100) [= (*)-isoamurensine]

(*)-2-Hydroxy-3-rnethoxy-8,9- 1 gH1 gN04 325 OH OMe O-CH2-0 110

(*)-3-Hydroxy-2,8,9-trimethoxy- C2&3N04 34 1 OMe OH OMe OMe 137

(+)-8-Hydroxy-9-methoxy-2,3- 1 gH 1 gN04 325 M H Z 4 OH OMe 72

TABLE XI Unnatural Quaternary Isopavine Alkaloids

Alkaloid Molecular Molecular formula weight Rl R2 R3 R4 References

W o\ 0

~~

( -)-2,3,8,9-Dimethylene- C20H20N04 + 338 0 - 4 2 H 2 - 4 M H Z 4 76 dioxy-N,N-dimethylisopavinium salt (148)

dioxy-N, N-dimethylisopavinium salt (149)

methylenedioxy-N, N-dimethylisopavinium salt (150)

methylenedioxy-N, N-dimethylisopavinium salt (151)

dimethylisopavinium salt (152)

(+)-2,3,8,9-Dimethylene- C20H20N04 + 338 M H Z - 4 0 - 4 2 H 2 4 77

(?)-2-Hydroxy-3-methoxy-8,9- CzoHz2N04 + 340 OH OMe W H 2 - 4 110

(+-)-3-Hydroxy-2-methoxy-8,9- CZOHZZN04+ 340 OMe OH M H 2 4 137

(+-)-2,3,8,9-Tetramethoxy-N,N- C2zHzsN04 + 370 OMe OMe OMe OMe 69

TABLE XI1 Unnatural N-Norisopavine Alkaloids

Alkaloid

(-)-2,9-Dihydroxy-3,8-dimethoxy- isopavinan (153) [= (-)-PI- northalidine]

isopavinan (154) [= (+) -N- northalidine]

isopavinan (155) [= ( t ) - N - northalidine]

(+)-2,3-Dimethoxy-8,9-methyl- enedioxyisopavinan (95) [= (? )-N-norreframine]

(*)-2,3,8,9-Dimethylenedioxy- isopavinan (156) [= (+)-N-nor- reframidine]

pavinan (157)

pavinan (35) [= (*)-isopavine]

(+)-2,9-Dihydroxy-3,8-dimethoxy-

(+)-2,9-Dihydroxy-3 ,g-dimethoxy-

(*)-2,3,8,9-Tetrahydroxyiso-

( +)-2,3,8,9-Tetramethoxyiso-

Molecular formula

1 gH 1 gN04

c 1 sH 1 9N04

laH 1

19H 1 gN04

C18H15N04

Molecular weight

313

313

313

325

309

285

34 1

Rl R2 R3 R4 References

OH OMe OMe OH 143

OH OMe OMe OH 143

OH OMe OMe OH 117,143

OMe OMe M H Z - - O 77

OH OH OH OH 143

OMe OMe OMe OMe 69,117, 120,131, 132,134, 136,148

362 BELKIS GOZLER

V. Spectral Properties

References relevant to the spectral analyses of naturally occurring pavine and isopavine bases are presented in Tables XI11 and XIV. An exhaustive numerical compilation of spectral data of these alkaloids may also be consulted (11).

A. MASS SPECTRO~COPY

A base peak corresponding to a 6,7 (or 7,8)-disubstituted isoquinolinium ion is the prime criterion in considering a pavine or an isopavine structure. In the case of a pavine, the presence of the expected peaks may only confirm the structure deduced by other spectral and chemical means. In isopavines, however, mass spectroscopy is an exceptionally powerful tool in differentiating this group from the pavine alkaloids, as well as from other related isoquinoline bases.

1. Pavine Alkaloids

Pavines which are identically substituted on rings A and D display a single isoquinolinium ion (a), formed by cleavage of the benzylic bridge on the rearranged molecular ion (Scheme 29) (24,25). The molecular ion M + and the accompanying (M - 1) + ion may be of variable intensity depending on the inlet system (24).

Pavines which have nonidentical substituents on rings A and D furnish two different isoquinolinium ions through the same fragmentation mode, as ex-

M+ r e a r r a n g e d M i

RO

OR

RO OR RO

I ( M - 1 )+ ca) OR

(100%)

SCHEME 29

TABLE XI11 References for Spectral Properties of Naturally Occumng Pavine Alkaloids

Alkaloid ORD, CD, and

uv IR 'H NMR Mass Abs. Conf.

Argemonine (5 )

Argemonine N-metho salt

Argemonine N-oxide (20) Bisnorargemonine (6)

(15)

Caryachine (7)

Caryachine N-metho salt (16) Eschscholtzidine (8)

Eschscholtzidine N-metho salt

Eschscholtzine (9) (17)

Eschscholtzine N-metho salt

Eschscholtzine N-oxide (20a) 2-Hydroxy-3,8-dimethoxy-

Isonorargemonine (11)

(18)

pavinan (10)

18,24,25,37, 152a,153

13,3291

- 13,27,33,50,

l52c, 153, 165

31 ~ 104,110, 112

29 52,104,106,

32

24,31,51,54,

54,152e

32a 26

42

153

152d, 153

14,37,45, 152a

35

35 13,50,152c

110

29 -

-

31,152d

152e

- 26

22

18,24,25,29, 30,34,41, 45,123

29,32,35

35 1,23,25,33

29,31,104, 110,l I2

29 29,30,41,52,

104,106 29,32

24,31

-

32a 26

1,22,25,42

18,45,117, 123,154

32,35

35 1,25,33,50,

113

104,110,112

29 I54

-

24,54,154

-

32a 26

-

112,115,153, 155- 160

32,153

- 115, I53

112,115

29 115,153

32

115,153

-

32a -

42

(continued)

TABLE XI11 (Conrinued)

Alkaloid ORD, CD, and

uv IR 'H NMR Mass Abs. Conf.

- 4,8,9-Trirnethoxy-2,3-rneth- 27 - 27 27

Munitagine (12) 25,108 25 25 25,108 115 Norargemonine (13) 13,34,37,50, 14,22,37,50, 1,22,25,34 34,50,71 115,153

ylenedioxypavinan (3)

102,1526. 102,1526 153,165

Platycerine (14) 37,42,152f 37,152f 35,42 35 42 - Platycerine N-rnetho salt (19) 47 47 - 47


TABLE XIV References for Spectral Properties of Naturally Occurring Isopavine Alkaloids

ORD, CD, and Alkaloid uv IR 'H NMR Mass Abs. Conf.

Amurensine (24) 67,85,86,88, 67,152g 67,70 71 1 12,160,161

67,70,86, 71,85,86,88, 67,70,160 Amurensinine (25)

Amurensinine N-metho salt

0-Methylthalisopavine (26) (31)

Reframidine (27) Reframine (28) Reframine N-metho salt (32) Reframoline (29) Thalidicine (23) Thalidine (21) Thalisopavine (30)

152g,I 64

86,88,165 67,80,81,85, 67

81 81

53

76,86 76 76 76 75 76,110,112 76, 84 84 82 53 53

147 89,147 81 -

- 53,77,78 53,78, I 17,

77,145 77,86,162 77,147 147,162

- 74,75 -

136

10,137 110,112,137 110,112,162 12

- 82 82,117 82 - 84 84

53 53 -

emplified by the mass spectra of caryachine (7) (29) and eschscholtzidine (8) (Scheme 30) (154). The abundances of these ions in these species are relatively close (26,27,29,34,71) and sometimes of equal magnitude (110,112). On the other hand, in platycerine (14), the mlz 190 peak is only 30% of the mlz 204 peak. This exceptional situation has been interpreted as due to the lesser contribution of the o-quinonoidal fragment (a) to the stability of the mlz 190 ion (Scheme 31) (35).

Mass spectroscopy does not generally provide assistance in differentiating between isomeric diphenols, because the relative locations of hydroxyl and methoxyl groups do not significantly alter the fragmentation pattern (29). The mass spectrum of a pavine N-oxide displays a low intensity molecular ion peak from which an oxygen is readily expelled. The remaining pattern is superimposable with that of the corresponding tertiary base (32a,35). The N-metho salts of pavines exhibit mass spectra nearly identical with those of their tertiary bases. The halogen anion is detected at mass units which match the corresponding halogen halides and methyl halogenides (29,32,35,47).

2. Isopavine Alkaloids

The isopavines display only one isoquinolinium ion in their mass spectra, as do the symmetrically substituted pavines. This isoquinolinium ion is also the base peak and is formed directly from the ionized molecule as confirmed by the presence of the relevant metastable ions (162). Moreover, the molecule is

366 BELKIS GOZLER

0 M+

/ \ (%OMe &:I: /*NMe

r e a r r a n g e d M+

' OMe


1 I C m N Me

m / z 188

M e N a I I :

r n / z 204

SCHEME 30

cleaved in such a manner that it is possible to differentiate between the substituents on rings A and D, which greatly facilitates structural elucidation.

The molecular ion is relatively abundant (30-50%), as is the (M - l )+ ion. The latter may be represented as either (a) or (b) (Scheme 32) . The clue which points out unequivocally to an isopavine nucleus is the presence of the (M - 43) + ion in intensities varying from 30 to about 60%. It is formed by the retro- Diels-Alder condensation of the molecular ion, resulting in loss of a CH,=NCH, unit. This particular ion is practically absent in the spectrum of a pavine (71). An additional peak of moderate intensity is associated with the (M - 86) + ion which is formed by a subsequent loss of a methyl radical and carbon

+

\ /NMe M e o w O M e Me0 :NMe / ___)

m i z 204 m / z 190

14 Mi

Me0 Me'mNMe M e N a o M e

ta)

SCHEME 31


RO


RO

RO CH,.

( 1 0 0 O h )

SCHEME 32

monoxide from the (M - 43)+ ion (71,162). The sequence is confirmed by metastable ions (71) and also by the absence of this particular peak in the spectrum of reframidine (27) which lacks a methoxyl substituent (162).

An unexpectedly encountered peak in the spectrum of reframidine (27) is due to the (M + 14)+ ion, formed by the transfer of a methyl radical from one molecular ion to another, followed by hydrogen expulsion (77). Furthermore, an (M - 16)+ peak has been spotted in the spectrum of amurensine (24), being attributable to the elimination of a methyl radical from the (M - 1)+ ion (71). The presence of a rather unusual (M - 17)+ peak in the spectrum of amurensinine (25) remains unexplained (71).

B . 'H-NMR SPECTROSCOPY

1 . Pavine Alkaloids

The 'H-NMR spectra of pavines can provide appreciable assistance in structural elucidation. The oxygenation pattern of a pavine may be deduced from a careful examination of the methine (Ha,J and methylene (Hb,c,e,f) proton absorptions (lc). In the case of 2,3,8,9 substitution, the abc and def protons furnish two superimposable ABX patterns. A doublet integrating for two protons at the lower field end of the system at approximately 6 4.0 represents the bridgehead protons, H, and H,. At 60 MHz, it appears as if these protons are coupled to only one of the neighboring protons (J = 6 Hz) (18,20,25). Furthermore, the geminal hydrogens couple to each other with a coupling constant of 17 Hz (18,20). On

368 BELKIS GOZLER

i c

the other hand, in the 'H-NMR spectra of pavines bearing 2,3,7,8 substituents, the Ha and H, protons are represented by two doublets at about S 4.0 and 4.4, where the latter is assigned to H, which is proximal to one of the oxygen functions positioned on ring D (25). In the C-7 phenolic species, platycerine (14) and munitagine (12), the bridgehead protons will be shifted upfield by approximately 0.2 ppm on acetylation (163).

Some generalizations can be made regarding the aromatic region of pavine bases. In alkaloids with 2,3,8,9 symmetric substitution, the aromatic protons are paired into two singlets, each integrating for two protons ( I ,18,20,25), whereas asymmetric substitution, as in bisnorargemonine (6), results in four well-defined singlets (23). In a 2,3,7&tetrasubstituted pavine, H-9 and H-10 are expected to appear as an AB quartet. However, they may collapse into a singlet of two protons as exemplified by the spectrum of O,O-dimethylmunitagine (72) (25). The chemical shifts of the aromatic protons of some pavine bases have been amply summarized (25,29). A complementary and additive relationship has been formulated into a set of rules for the chemical shifts of aromatic protons in an N- methylpavine system (1,29,105,112). The determining factor has been stated to be the inductive effect of the bridgehead C-N bond, causing deshielding and consequently downfield shifting of H-1 and H-7 ( I ) . However, it has been justifiably pointed out that it is rather the anisotropic shielding by the aromatic rings which results in the upfield chemical shift of H-4 and H-10 (112).

In symmetrical pavines, the C-2 and C-8 methoxyls will appear as a singlet of six hydrogens just as the C-3 and C-9 methoxyls. The former pair, which is proximate to the bridgehead, will appear more downfield by about 0.07-0.1 ppm with respect to the latter (1,25). The methylenedioxy protons center around 6 5.8-5.9 as an AB quartet (J = 1-1.5 Hz). The N-methyl protons appear almost invariably between 6 2.49 and 2.57 in CDCl, solutions and at 6 2.35 in DMSO solutions.

Conversion to phenolates coupled with NMR analysis has been used in determining the relative locations of the hydroxyl and methoxyl groups in phenolic pavines (I ,25). Moreover, changes in chemical shifts of neighboring aromatic protons when going from a CDCl, solution to a DMSO solution had been useful in assigning the correct position of the phenol (25,112).


The general absorption pattern of quaternary pavines strongly resembles that of the tertiary analogs with the exception of the expected downfield shifts for each of the protons. In particular, the bridgehead protons will move downfield by about 1-1.5 ppm (32,35). N,N-Dimethyl protons will be observed as a singlet between 6 3.3 and 3.7 (29,32,35). The set of empirical rules deduced for aromatic proton chemical shifts in a tertiary system has been shown to apply also to the quaternary system (29). A listing of aromatic proton chemical shifts of some quaternary pavine bases has been presented as a reference for future studies on similar compounds (29).

2. Isopavine Alkaloids

The aromatic protons of isopavine alkaloids generally appear between 6 6.45 and 6.80 in CDC1, solutions as either four or three singlets. In case of the latter, it is always the most downfield absorption peak that integrates for two protons. The chemical shifts of aromatic protons are mostly reported without specific assignment to positions, because no set of rules have yet been formulated for the chemical shifts of these protons due to the asymmetrical nature of the isopavine ring system (222) . Similarly, methine and methylene protons are usually reported as an unresolved complex pattern between 6 2.2 and 3.9. It has been reported, however, that the H-12 absorption appeared as a triplet at 6 3.8-3.9 (63 , moving downfield by about 1 ppm in quaternary species to display a triplet at 6 4.8 (J = 6 Hz) (82).

The two N-methyl groups in a quaternary isopavine alkaloid display two different chemical shifts, explained by the nonsymmetrical nature of the molecule (74,75). The C-9 methoxyl group absorbs at a higher field (6 3.77-3.78 ppm) as compared to the C-10 methoxyl (6 3.83-3.86) (53 ,63 . Despite the various criteria summarized above for the 'H-NMR spectra of isopavine bases, it should be emphasized that it is difficult to assign an isopavine ring system to a compound based only on the NMR data.

C. 13C-NMR SPECTROSCOPY

Only the 13C-NMR spectrum of argemonine (5) has been reported so far, and is summarized by expression 5a (264).

111.4 33.3

Me0

5 a

370 BELKIS GOZLER

D. UV SPECTROSCOPY

A pavine skeleton may be regarded as two N-methyl- 1,2,3,4-tetrahydroisoquinoline nuclei fused together. In accordance with this observation, the UV spectrum of a pavine alkaloid demonstrates close similarity to that of an analogous tetrahydroisoquinoline (153). 2,3,8,9-Tetrasubstituted N-methylpavines generally display a broad absorption band between 287 and 295 nm in polar solvents (6,8,25,153). However, a triplet absorption has also been reported in ethanolic solutions between 280 and 295 nm, where the lowest and highest wavelength absorptions may appear as shoulders (1,102,153). The UV absorption band of argemonine-type pavine bases split into a well-defined multiplet in cyclohexane (25,33). Munitagine-type bases behave in a similar manner, but the splitting is not as distinct and the molar absorptivities are lower (25).

Some generalizations have been made about the effect of various substituents on the absorption maxima and molar absorptivities (165). As expected, the absorption band around 280 nm is displaced to lower wavelengths when two methoxyls are replaced by a methylenedioxy group. The UV spectra of pavines are slightly affected by protonation on nitrogen (153). Similarly, quaternary species furnish UV spectra which closely resemble those of their tertiary counterparts (153). In some pavine bases such as norargemonine (13), the expected bathochromic shift on addition of alkali has not been observed (102).

The absorption maximum of isopavine alkaloids appear at 290-294 nm. The shoulder at 250 nm, which is missing in the spectra ofpavines, provides complementary information in distinguishing between pavine and isopavine alkaloids (7,67,69). Additionally, the Hofmann degradation products of the two nuclei have been shown to differ greatly in their UV spectral behavior (67,69,75).

UV spectroscopy has been of little value in discriminating between positional isomers of the phenolic species. However, the UV spectra of the corresponding methine bases have been shown to behave differently on addition of alkali (110).

E. ORD, CD, AND ABSOLUTF CONFIGURATION

The determination of the absolute configuration of (-)-argemonine (5) has been of considerable importance with regard to its possible biosynthesis from the

H H

MeO- .. N Me OMe

Me0 I ’ OMe

A .\ 5 b


benzyltetrahydroisoquinoline, (+)-reticuline (158), of (S) configuration. The earliest assignment of an absolute configuration to (-)-argemonine, as illustrated in expression 5b, by Barton and co-workers (166) originated from exactly such a biogenetic hypothesis.

The first experimental attempt to establish the absolute configuration of (-)- argemonine involved an empirical method where ORD curves of this alkaloid and (+)-Troger’s base (159) of known absolute configuration (167) were correlated, as a result of which the (S) absolute configuration was reported for both asymmetric centers of (-)-argemonine (155). However, the method, not the conclusion, was challenged by Mason and co-workers, whose nonempirical analyses of CD spectra of the aforementioned two compounds, (-)-5 and (+)-159, at 80°K revealed that empirical comparisons of ORD curves may be of limited reliability in evaluating configurations (156,157). Their analyses of CD curves by means of an exciton model substantiated the previously assigned absolute configuration of (-)-argemonine (156,157).

159

A contemporaneous study on the same subject utilized a chemical correlation method where (-)-N-benzylargemonine chloride, obtained by sequential optical resolution and quaternization of (2)-N-methylpavine (5), underwent a multistep degradative process to furnish (-)-N,N-dimethyl-di-n-propyl aspartate. Com- parison of this final product with L-aspartic acid of known chirality led to the absolute configuration of (-)-5 (115,158). (-)-Eschscholtzine (9) was assigned the same absolute configuration by correlation of its ORD curve and optical rotation with those of (-)-argemonine (115).

Since other pavine alkaloids, such as (-)-norargemonine (13), (-)-bisnorargemonine (6), and (- )-caryachine (7), were already chemicaHy correlated with (-)-argemonine, they could be assigned the identical absolute configuration (115). The absolute configuration of (-)-caryachine was further confirmed by analogy of its CD spectrum to that of (-)-argemonine (112). Since (-)-eschscholtzidine (8) has been prepared by 0-methylation of (-)-caryachine, its absolute configuration was also firmly established (115). The close similarity of the ORD curves of these pavine alkaloids, all displaying positive Cotton effects centered at approximately 280, 235, and 206 nm, corroborated the previously attained conclusions (153). Further authentication was provided by a stereoselective synthesis of (-)-thalidine (21) and (-)-bisnorargemonine (6) from ( + ) - N -

312 BELKIS GOZLER

norreticuline (61) of established configuration (117) and also by an X-ray crystallographic study of (-)-argemonine methiodide, which furnished comprehensive information about structural details and the conformation of the molecule (159).

A successful application of the aromatic chirality method (6) has led to the determination of the absolute configuration of (-)-amurensine (24), thus establishing the absolute configuration of the isopavine bases as shown in expression 24a (161). This result was later verified by the correlation of optical rotations and ORD curves of (-)-argemonine (5) and (-) -amurensinine (25) (67,70,160) as well as of their first-step Hofmann degradation products (160).

4- 2 4 a

Other isopavines were also shown to possess the same (5S, 12s) configuration by virtue of the similarity of their CD spectra with that of (-)-amurensine (24) (112). The simultaneous synthesis of (-)-caryachine (7) and (-)-reframoline (29) from the same optically active precursor of known absolute configuration furnished further support for the established absolute configuration of the isopavine alkaloids (112).

Noteworthy is the fact that the sign of optical rotation at the sodium D line can be used safely for assigning the absolute configuration of pavine and isopavine bases. Molecules that have a high negative rotation will have the same absolute configuration as (-)-argemonine and (-)-amurensine, whereas their dextrorotatory counterparts will correspond to their mirror images (26,115,161).

VI. Biosynthesis

The work of Stermitz and co-workers (19) on the structure elucidation and establishment of (-)-argemonine (5) as the first representative of a novel framework also encompassed the earliest hypothesis about the biogenesis of this compound as being derived from a benzyltetrahydroisoquinoline. A probable biosynthetic sequence initiating from laudanosine (N-methyltetrahydropapaverine) was postulated, where argemonine was the primary product, converting to norargemonine (13) and bisnorargemonine (6) on successive demethylations (19).

The possibility of a biogenetic connection between (+)-reticuline (158) and

l-

l-

I - Y

I

/

m

m

374 BELKIS GOZLER

(-)-argemonine (5) was investigated by feeding experiments on mixed plants of Argemone mexicana and A . hispida (166). Attempted incorporation of 14C- labeled (+)-reticdine into (-)-argemonine resulted in an insignificant uptake of the labeled precursor, a result attributable to the paucity of (-)-5 in the plant material investigated (25,166).

The occurrence of four closely related pavine bases as well as (+ )-reticdine (158) in Argemone munita and A. hispida encouraged Stermitz and Seiber (25) to postulate a possible biosynthetic route based on the intermediacy of (+)-158 (Scheme 33). The iminium salt 160 formed by in vivo oxidation of this benzyltetrahydroisoquinoline could undergo intramolecular p - and o-phenolic couplings to produce (-)-bisnorargemonine (6) and (-)-munitagine (12), respectively (Route A). It was emphasized that 0-methylations to yield (-)-norargemonine (13) and (-)-argemonine (5), which were also shown to be present, should have taken place after the cyclization, since such a process operating prior to pavine formation would have resulted in (-)-isonorargemonine (11) via (+)-laudanidhe (161) as an intermediate (Route B), neither of which were detected in the plants under investigation.

In a later study by the same group (35), (+)-laudanidhe (161), (-)- platycerine (14), and (-)-isonorargemonine (11) were isolated from Argemone grucilentu, whereas no (-)-bisnorargemonine (6) or (-)-argemonine (5) could be detected. This finding seemed to support Route B for the biosynthesis of the three first-named alkaloids. However, attention has also been drawn to the fact that the co-occurrence of (-)-munitagine (12) in A. gracilenta could not be efficiently accounted for in terms of Route B (35). It should be remarked at this point that natural 0-methylation and 0-demethylation processes are usually very facile and could have readily occurred with Argemone alkaloids. Additionally, a phenolic function is always a better supplier of electrons than a methoxyl group so that Route A above, starting with (+)-reticdine (158) and proceeding through the intermediacy of the iminium cation 160, is a rational possibility as a biosynthetic approach to the pavinoids.

The biosynthesis of pavines from (+)-reticuline (158) through Route A has also been agreed upon by Barker and Battersby (115). They additionally suggested an equilibrium between the iminium ion 160 and the carbinolamine 162 (Scheme 34).

(+)-158- no

kon OMe

(+) - 160 (+) - 1 6 2

SCHEME 34


The fact that pavine and isopavine alkaloids have the same absolute configuration also suggests an alternative biosynthetic sequence where both nuclei are derived from a common 4-hydroxybenzyltetrahydroisoquinoline precursor (Scheme 35) (77,135). A dehydration reaction to afford a 1,2-dihydrobenzylisoquinoline, followed by cyclization, would yield a pavine. Alternatively, dis-

H '

/ 1 HO :NMe ""-0Me HO NMe

' OH '&OH

I

HO

o r

HO mew:: NMe

21

Me0

no

6 or

12

SCHEME 35

376 BELKIS GOZLER

placement of the 4-hydroxy group by the benzylic moiety would lead to an isopavine. The recent isolation of the first naturally occurring 4-hydroxybenzyltetrahydroisoquinoline, (+ )-roemecarine (163), along with the corresponding N- oxide, (+)-roemecarhe 2a-N-oxide (164), from Roemeria carica, a member of a genus known to produce isopavines, has lent some support to the above- mentioned hypothetical biogenetic sequence (168).

HO H

M e 0 " W N M e % H

M e 0 Meos M e 0

M e 0 Meoe [+I -1 6 3 (+) - 164

An interesting variation on the above theme for the biosynthesis of the pavines and isopavines has been proposed by Dyke (169). This proceeds via a quinone methine intermediate. The precursor, a 1-benzyltetrahydroisoquinoline-3-carboxylic acid 165 oxidizes to a quinone methide 166, which then decarboxylates to afford a reactive enamine 167. Cyclization then readily furnishes a pavine. Alternatively, hydration of the enamine 167 at C-4 would ultimately result in formation of an isopavine (Scheme 36).

An alternate precursor for achieving the same result may be ( +)-reticuline (1581, which would oxidize to quinone methide 168. Direct cyclization would result in an isopavine skeleton, whereas conversion to the enamine 167 would lead to a pavine. Similarly, a hydroxylation of the methide 168 at C-4 to furnish species 169 would either yield an isopavine by cyclization, or a pavine via the intermediacy of the 1,2-dihydro compound 167 (Scheme 37) (169).

Undoubtedly, work with labeled precursors is in order at this point to establish with certainty the exact biosynthesis of the pavine and isopavine bases.

VII. Chemotaxonomic Considerations

The presence of pavines and isopavines has been used to provide assistance for taxonomic classifications, and to determine intergeneric and phylogenic relationships in the genera Papaver and Argemone. The results of extensive chemical research on Papaver species demonstrated that morphologically distinct sections are also chemically distinguishable by virtue of their alkaloidal profile (170). Out of nine well-defined sections of Papaver, the Section Scapiflora, which displays

M e O q M y H

HO

1 6 5

M e o q M e HO

c y c i i z a t i o n I i s o p a v i n e

1 6 6

I d e c a r b o x y l a t t on

h y d r a t i o n ' & q h l e HO - 1 6 7

c y c l i z a t i o n I p a v i n e

SCHEME 36

i s o p a w i n e

[Ol h y d r a t i o n

OH (+]-158 -

168 169

Me0

c y c l i z a t i o n ____)

OH

' OMe

e a v l n e

167

SCHEME 37

378 BELKlS GOZLER

remarkable homogeneity with regard to qualitative and quantitative alkaloidal content (68,85), is the only section where isopavine bases, e.g., (-)-amurensine (24) and (-)-amurensinine (25), are constant components. The occurrence of (-)-0-methylthalisopavine (26) in Papaver rudicatum (Section Scapiflora) further substantiates the presence of isopavines as a chemotaxonomical characteristic of this section (78). More recent work, however, reports the occurrence of (-)-amurensinine as a minor constituent in Papaver tauricola (Section Mil- tantha); this instance represents the first occurrence of an isopavine alkaloid in a Papaver species outside the Section Scapiflora (89).

It has been suggested that the presence of (-)-amurensinine (25) as the main alkaloid in various Meconopsis species indicates the relationship of this genus with Papaver species of the Section Scapiflora (80). By way of parallel thinking, the genus Roemeria, which is known to produce isopavine bases, can be interre- lated with the Pupaver species of the Section Scapiflora as well as with Meco- nopsis species.

Since morphological characters were found to be insufficient in establishing subdivisions of the genus Argemone, the alkaloidal contents were taken into consideration. The suggestion has been made by Slavik and Slavikovh (37) that this genus could be divided into two groups depending on the presence or absence of pavine alkaloids. At a later time, Stermitz (170) combined the results of extensive chemical work on Argernone species with the hitherto accumulated knowledge based on morphological grounds to divide the genus into four al- liances. He demonstrated the correlation of this classification with that suggested according to morphological characteristics. Although not totally decisive in as- sisting taxonomic placement or identity of species (36,38), this classification proved to be of considerable aid in predicting new sources of pavine alkaloids (38,63) and in establishing phylogenetic relationships (38,170).

A tentative phylogenetic hypothesis for the evolution of the genus Argemone has been proposed within this context (170). Thus, since the Section Scapiflora is claimed to include the most primitive Papaver species, the production of pavine- isopavine alkaloids may well be considered a primitive characteristic. If the relationship of Papaver species of the Section Scapiflora and the pavine-producing genera, Argemone and Eschscholtzia, is valid, it follows that Argemone species which produce pavine alkaloids would have to be considered the most primitive in the genus. On the other hand, Argemone species which lack the capacity to elaborate pavines would have to be considered the most recently evolved.

VIII. Homopavines and Homoisopavines

The homopavines and homoisopavines constitute a very small group of unnatural bases which have been synthesized by some of the routes designed for the


synthesis of pavine and isopavine alkaloids (132a, I38,139,I71,172). The intermediates in the synthetic processes are the properly substituted l-phenethyliso- quinolines .

The first homopavine, (*)-homoargemonine (174), was synthesized in 1973 in an attempt to construct pavine analogs with improved analgesic activity (Scheme 38) ( I 71). The corresponding 1-phenethylisoquinoline 173 was obtained by a Bischler-Napieralski condensation of 2-(3,4-dimethoxyphenyl)- ethylamine (170) and 3-(3,4-dimethoxyphenyl)propionic acid (171) via the hy- droxyamide intermediate 172. Compound 173 was then successively quaternized, reduced by lithium aluminum hydride, and treated with acid to afford the tetracyclic compound (5)-174.

The acid-catalyzed cyclization of properly substituted aminoacetaldehyde dialkyl acetals was shown to be a suitable method in the construction of a homoisopavine (Scheme 39) (132a,172). Treatment of N-[ 1,3-bis(3,4-dimethoxyphenyl)propyl]aminoacetaldehyde dimethyl acetal (175) with concentrated hydrochloric acid afforded the N-norhomoisopavine 176 in 39% yield. This cyclization was also accompanied by some 0-demethylation. Product 176 could be readily N-methylated using formaldehyde and sodium borohydride to afford the homoisopavine (t)-177 (1 72).

The 'H-NMR and mass spectral data of homopavines and homoisopavines are in conformity with those of the pavine and isopavine bases, respectively. A brief note should be made, however, on a divergent mode of fragmentation in the mass

o on a 1 7 0 + ~

I

OMe

OMe

1. P 2 0 5 b: h e

1 7 2

b O M e OMe

1 7 3 171 J

OMe

Y

174

bhle

SCHEME 38

380 BELKIS GOZLER

OMe

1. H p N C H z C H ( O M e ) 2

2. r e d u c t i o n *

@OM. 175 &OMe OMe

1 7 6 1 7 7

SCHEME 39

M e o w Me0

Me0

( b I ( 4 4 % )

r e a r r a n g e d M +

I Me0

( 8 1 % )

SCHEME 40

I. PAVINE AND ISOPAVINE ALKALOIDS 38 1

spectra of the homoisopavines, where ions (a) formed by the expected retro- Diels-Alder reaction undergo further fragmentation to furnish the stable an- thracene derivative (b) (Scheme 40) (172).

IX. Aporphine-Pavine Dimers

An investigation of the alkaloidal contents of Thalictrum polygamum yielded a number of alkaloids (83) among which were the two novel type aporphine- pavine dimers, (-)-pennsylpavine (178) and (-)-pennsylpavoline (179) (163). Compound 178, readily determined to have a dimeric structure due to the mlz 680 parent peak in the mass spectrum, was ascribed a 1,2,9,10-tetrasubstituted aporphine-pavine skeleton based on the observation that the UV spectrum

230,280 sh, 288,308 sh, 320 sh nm) was essentially a combination of the UV spectrum of a 1,2,9,10-tetrasubstituted aporphine and a pavine. In the mass spectrum, prominent peaks clearly accounted for the mode of fragmentation expected of the proposed structure (Scheme 41). In particular, the presence of the mlz 649 (M - CH,NH,)+ and the mlz 648 (M - CH3NH3)+ together with a relatively small mlz 637 (M - CH2=NCH3)+ ion pointed to an aporphine-pavine rather than an aporphine-isopavine structure.

4.01 d d f J 6 H Z )

ome 4.43 dd

(-1-1 7 8 [-)-1 7 9

4 OMe at 6 3.76(6H), 3 .78(3H), 3 .88(3H) 4 OMe a t 6 3 .75 (3H) , 3 .76 (6H) , 3 .91(3H)

4 A r H a t 6 6.48(2H), 6 .52 (1H) , 6.6011H) 4 A r H a t 6 6 . 4 5 ( 1 H ) , 6 . 4 9 ( 1 H ) , 6.55(2H)

The key information on the pavinoid portion of the molecule was provided by the 60-MHz ‘H-NMR spectrum, where two one-proton doublets at 6 4.06 and 4.50 represented the bridgehead protons of a 2,3,7 ,%tetrasubstituted pavinane

382 BELKIS G6ZLER

Me ’ ? Me Me0

_____)

Me0 ‘ Me0 \ + M e t i a o M e

OMe

&OMe HZ I 1 0 0 Y o 1

Me0 ’

OH

Me0 ’ 0Me OH ( 5 % )

M f ( 3 6 % ) \ Me0

I “‘pMe Me0 + -0Me 0Me 0

( 2 6 ‘10 I

&!Me

j 2 2 010 1

’ I Me0 \

0.

I 2 0 010 I Me0

OH

SCHEME 41

(Section V,B). The upfield shift of the H-6’ to 6 4.35 and the downfield shift of H-9’ to 6 6.43 on acetylation were in conformity with what has been observed on acetylation of the phenolic monomeric pavine base, (-)-platycerine (14).

The second dimeric base, (-)-pennsylpavoline (179), was shown to correspond to C-1-demethylpennsylpavine. Specifically, its NMR spectrum was devoid of the 6 3.7 1 singlet which represents the C- 1 methoxyl absorption in (--)- pennsylpavine (178). Evaluation of CD spectra of these novel dimers and comparison with those of the aporphine (+)-N-methyllaurotetanine and the pavine (-)-platycerine led to the assignment of the absolute configurations as depicted in expressions 178 and 179. These dimers are probably derived biosynthetically from the aporphine-benzylisoquinoline dimers, (-)-pennsylvanine and (-)- pennsylvanamine, which were found in the same plant (7,173).


X. Pharmacology

Synthetic (*)-argemonine (5) has been resolved, and the enantiomeric methiodides were shown to display neuromuscular junction blocking properties as determined in vivo on cat hypoglossal nerve-tongue muscle preparations (116). The observed curarimimetic potency results from the quaternized nitrogen in the tetrahydroisoquinoline skeleton, a structural feature resembling the non- depolarizing blocking agents represented by the well-known bisbenzylisoquinoline, (+)-tubocurarine. The effect of stereochemical and configurational variations on curarimimetic potencies have been thoroughly investigated on the two compounds in question. It has been shown that there is a modest preference of the (S) configuration over the (R) configuration (about 2 : 1). The ED,, curarimimetic potency ratio is 1.7 : I for the (S) levorotatory argemonine methiodide to the (R) dextrorotatory analog (116).

Quaternization of synthetic (&)-argemonine (5) with 1,lO-diiododecane led to the bisquatemary compound, N,N'-decamethylenebis(N-methylpavinium iodide) (180), which was comparable in curarimimetic potency to (+)-tubocurarine (174). The enantiomeric and meso forms of this compound were, therefore, considered suitable probes for further pharmacological experiments. There is a significant preponderance of blocking activity by the (R,R) configuration over the (S,S) arrangement in the bisquaternary series. This is exactly the reverse of what has been established for the monoquaternary enantiomeric probes. The cause of this trend is not, however, immediately apparent. It should also be pointed out that the potency of the meso form with respect to the enantiomers was found to be dependent on the animal used for the assay (174).

M e 0 "'"QOMe

' O M e

Me M e 0

1 8 0

Various pharmacological activities have been attributed to the pavine alkaloids, but no pavinoid species has been claimed as a therapeutic agent. A

384 BELKIS GOZLER

number of naturally occurring pavines and some of their simple analogs have shown weak analgesic activity in mice ( 1 71). Alterations in aromatic substitution did not result in increased potency (171). Pain relieving and antiarrhythmic properties have been reported (38). (-)-Bisnorargemonine (6) caused slight to moderate inhibition of motor activity in mice; the central nervous system depres- sant effect was not significant enough to consider the alkaloid as a potential drug (13).

During the antimicrobial activity screening of Thalictrum revolutum alkaloids, (-)-argemonine (5) and (-)-eschscholtzidine (8) were shown to be only weakly active against Mycobacterium smegmatis (42). The isopavine analog 181 has been reported to display varying pharmacological activity (147). Likewise, Nomoto and Takayama have reported that appropriately substituted pavine and isopavine compounds exhibit specific pharmacological activity, but no details have appeared (123).

1 8 1

REFERENCES

1. C.-H. Chen and T. 0. Soine, J. Pharm. Sci. 61, 55 (1972). 2.

3.

4.

5.

6. 7.

8.

9.

10.

11. 12. 13. 14. 15.

A. Burger, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 4, p. 34. Academic Press, New York, 1954. R. H. F. Manske, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 10, p. 477. Academic Press, New York, 1968. F. Santavy, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 12, p. 370. Academic Press, New York, 1970. F. Santavy, in “The Alkaloids” (R. H. F. Manske and R. G. A. Rodrigo, eds.), Vol. 17, p. 433. Academic Press, New York, 1979. M. Shamma, “The Isoquinoline Alkaloids.” Academic Press, New York, 1972. M. Shamma and J. L. Moniot, “Isoquinoline Alkaloids Research, 1972-1977.” Plenum, New York, 1978. S. F. Dyke, in “Rodd’s Chemistry of Carbon Compounds” (S. Coffey, ed.), Vol. 4, p. 38. Elsevier, Amsterdam, 1978. T. Kametani, “The Chemistry of the Isoquinoline Alkaloids,” Vol. 1. Hirokawa Publishing Co., Tokyo, 1968. T. Kametani, “The Chemistry of the Isoquinoline Alkaloids,” Vol. 2. Kinkodo Publishing Co., Sendai, 1975. B. Gozler, M. S. Lantz, and M. Shamma, J. Nut. Prod. 46, 293 (1983). T. 0. Soine and 0. Gisvold, J. Am. Pharm. Assoc., Sci. Ed. 33, 185 (1944). L. B. Kier and T. 0. Soine, J. Am. Pharm. Assoc., Sci. Ed. 49, 187 (1960). J. W. Schermerhorn and T. 0. Soine, J. Am. Phurm. Assoc., Sci. Ed. 40, 19 (1951). L. B. Kier and T. 0. Soine, J . Pharm. Sci. 50, 321 (1961).

7 . PAVINE AND ISOPAVINE ALKALOIDS 385

16. M. Shamma, Experientia 18, 64 (1962). 17. T. 0. Soine and L. B. Kier, J . Pharm. Sci. 51, 1196 (1962). 18. M. J. Martell, T. 0. Soine, and L. B. Kier, J . Am. Chem. SOC. 85, 1022 (1963). 19. F. R. Stermitz, S.-Y. Lwo, and G. Kallos, J . Am. Chem. SOC. 85, 1551 (1963). 20. M. J. Martell, T. 0. Soine, and L. B. Kier, J . Pharm. Sci. 56, 973 (1967). 21. M. M. Abdel-Monem and T. 0. Soine, J . Pharm. Sci. 56, 976 (1967). 22. F. R. Stermitz and J. N. Seiber, Tetrahedron Lett., 1177 (1966). 23. T. 0. Soine and L. B. Kier, J . Pharm. Sci. 52, 1013 (1963). 24. R. H. F. Manske, K. H. Shin, A. R. Battersby, and D. F. Shaw, Can. J . Chem. 43, 2183

25. F. R. Stermitz and J. N. Seiber, J . Org. Chem. 31, 2925 (1966). 26. R. M. Coomes, J. R. Falck, D. K. Williams, and F. R. Stermitz, J . Org. Chem. 38, 3701

27. S. Kh. Maekh, S. Yu. Yunusov, and P. G . Gorovoi, Khim. Prir. Soedin., 116 (1976); Chem.

28. H. Dutschewska, B. Dimov, N. Mollov, and L. Evstatieva, Planta Med. 39, 77 (1980). 29. C.-H. Chen, S.-S. Lee, C.-F. Lai, J. Wu, and J. L. Beal, J . Nut. Prod. 42, 163 (1979). 30. S.-T. Lu, Yakugaku Zusshi 86, 296 (1966). 31. S.-T. Lu and P.-K. Lan, Yakugaku Zasshi 86, 177 (1966). 31a. J. Slavik and L. Slavikovi, Collect. Czech. Chem. Commun. 51, 1743 (1986); Chem. Abstr.

32. J. Wu, J. L. Beal, W.-N. Wu, and R. W. Doskotch, J . Nat. Prod. 43, 270 (1980). 32a. A. Urzba and L. Mendoza, J . Nat. Prod. 49, 922 (1986). 33. F. C. Ohiri, R. Verpoorte, and A. B. Svendsen, Planta Med. 49, 17 (1983). 34. V. Fajardo, A. Urzba, R. Torres, and B. K. Cassels, Rev. Latinoam. Quim. 10, 131 (1979). 35. F. R. Stermitz and K. D. McMurtrey, J . Org. Chem. 34, 555 (1969). 36. F. R. Stermitz, J. R. Stermitz, T. A . Zanoni, and J. P. Gillespie, Phytochemistry 13, 1151

37. J. Slavik and L. Slavikovi, Collect. Czech. Chem. Commun. 28, 1728 (1963). 38. F. R. Stermitz, D. E. Nicodem, C. C. Wei, and K. D. McMurtrey, Phytochemistry 8, 615

39. S. M. Kupchan, T.-H. Yang, M. L. King, and R. T. Borchardt, J . Org. Chem. 33, 1052

40. D. A. Murav’eva, 0. N. Tolkachev, and A. A. Akopov, Khim. Prir. Soedin., 416 (1985);

41. J. Wu, J. L. Beal, W.-N. Wu, and R. W. Doskotch, Lloydia 40, 294 (1977). 42. J. Wu, J. L. Beal, W.-N. Wu, and R. W. Doskotcb, Lloydia 40, 593 (1977). 43. P. G. Gorovoi, A. A. Ibragimov, S. Kh. Maekh, and S . Yu. Yunusov, Khim. Prir. Soedin.,

44. S . Kh. Maekh, P. G. Gorovoi, and S . Yu. Yunusov, Khim. Prir. Soedin., 560 (1976); Chem.

45. 8. G . Tkeshelashvili, S. Iskandarov, K. S . Mudzhiri, and S . Yu. Yunusov, Khim. Prir.

46. E. T. Tkeshelashvili and K. S. Mudzhiri, Khim. Prir. Soedin., 807 (1975); Chem. Nut. Comp.,

47. J. Slavik, L. Slavikovi, and K. Haisovi, Collect. Czech. Chem. Commun. 38, 2513 (1973). 48. J. Slavfk and L. Slavikovi, Collect. Czech. Chem. Commun. 41, 285 (1976). 49. I. R. C. Bick, T. SCvenet, W. Sinchai, B. W. Skelton, and A. H. White, Aust. J . Chem. 34,

50. J. Slavik and L. Slavikovi, Collect. Czech. Chem. Commun. 36, 2067 (1971).

(1965).

(1973).

Nat. Comp., 110 (1976).

106, 2882v (1987).

( 1974).

(1 969).

( 1968).

Chem. Abstr. 103, 51226f (1985).

533 (1975); Chem. Nut. Comp., 568 (1976).

Nat. Comp., 507 (1976).

Soedin., 539 (1971); Chem. Nat. Comp., 525 (1973).

823 (1975).

195 (1981).

386 BELKIS GOZLER

51. R. H. F. Manske and K. H. Shin, Can. J . Chem. 43, 2180 (1965). 52. R. H. F. Manske and K. Shin, Can. J . Chem. 44, 1259 (1966). 53. S. M. Kupchan and A. Yoshitake, J . Org. Chem. 34, 1062 (1969). 54. J. Slavfk, L. Slavfkovi, and K. Haisovi, Collect. Czech. Chem. Commun. 32, 4420 (1967). 55. W. Dopke and G. Fritsch, Pharmazie 25, 203 (1970). 56. H. Gertig, Actu Polon. Pharm. 22, 443 (1965); Chem. Abstr. 64, 39548 (1966). 57. R. H. F. Manske and W. R. Ashford, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 4, p.

58. S. A. Parfeinikov and D. A. Murav’eva, Khim. Prir. Soedin.. 242 (1983); Chem. Nut. Comp.,

59. J. Slavfk and L. Slavikova, Collect Czech. Chem. Commun. 20, 27 (1955). 60. L. Slavfkovi and J. Slavfk, Collect. Czech. Chem. Commun. 31, 3362 (1966). 61. J. Slavfk, L. Dole$, and P. Sedmera, Collect. Czech. Chem. Commun. 35, 2597 (1970). 62. J. Slavik, L. Slavfkovi, and L. DolejS, Collect. Czech. Chem. Commun. 40, 1095 (1975). 63. F. R. Stermitz, D. K. Kim, and K. A. Larson, Phytochemistry 12, 1355 (1973). 64. H.-G. Boit and H. Flentje, Narurwissenschaften 47, 323 (1960). 65. H.-G. Boit and H. Flentje, Nafurwissenschafen 47, 180 (1960). 66. M. Maturovi, B. K. Moza, J. Sitar, and F. Santavq, Planta Med. 10, 345 (1962); Chem.

67. F. Santavq, L. Hruban, and M. Maturovi, Collect. Czech. Chem. Commun. 31, 4286 (1966). 68. M. Maturovi, D. Pavlaskova, and F. Santavq, Plunta Med. 14, 22 (1966); Chem. Absrr. 65,

69. A. R. Battersby and D. A. Yeowell, J . Chem. Soc., 1988 (1958). 70. F. Santavq, M. Maturovi and L. Hruban, J . Chem. Soc., Chem. Commun., 36 (1966). 71. L. DolejS and V. HanuS, Collect. Czech. Chem. Commun. 33, 600 (1968). 72. S. F. Dyke and A. C. Ellis, Tetrahedron 28, 3999 (1972). 73. M. S. Yunusov, S. T. Akramov, and S. Yu. Yunusov, Dokl. Akad. Nauk USSR 23,38 (1966);

74. M. S . Yunusov, S. T. Akramov, and S. Yu. Yunusov, Khim. Prir. Soedin., 68 (1967); Chem.

75. M. S. Yunusov, S. T. Akramov, and S. Yu. Yunusov, Khim. Prir. Soedin., 225 (1968); Chem.

76. J . Slavfk, L. Slavfkovi, and L. DolejS, Collect. Czech. Chem. Commun. 33, 4066 (1968). 77. S. F. Dyke and A. C . Ellis, Tetrahedron 27, 3803 (1971). 78. V. H. Bohm, L. DolejS, V. Preininger, F. Santavq, and V. Siminek, Planta Med. 28, 210

79. J. Slavfk and L. Slavikovri, Collect. Czech. Chem. Commun. 41, 3343 (1976). 80. J. Slavfk and L. Slavikovi, Collect. Czech. Chem. Commun. 42, 132 (1977). 81. M. Sainsbury, D. W. Brown, S. F. Dyke, and G . Hardy, Tetrahedron 25, 1881 (1969). 82. M. Shamma, A. S. Rothenberg, S. S. Salgar, and G . S. Jayatilake, Lloydia 39, 395 (1976). 83. M. Shamma, J. L. Moniot, and P. Chinnasamy, Heterocycles 6 , 399 (1977). 84. H. Ong and J. BCliveau, Ann. Pharm. Fr. 34, 223 (1976). 85. S. Pfeifer and H. Dohnert, Phurmuzie 23, 585 (1968). 86. S. Pfeifer and D, Thomas, Phurmazie 27, 48 (1972). 87. S. Pfeifer and D. Thomas, Pharmazie 22, 454 (1967). 88. V. Novik and J . Slavik, Collect. Czech. Chem. Commun. 39, 883 (1974). 89. G. Sariyar and J. D. Phillipson, Phytochemistry 19, 2189 (1980). 90. G. Goldschmiedt, Monatsh. Chem. 7, 485 (1886). 91. G . Goldschmiedt, Monatsh. Chem. 19, 321 (1898).

82. Academic Press, New York, 1954.

240 (1983).

Abstr. 61, 9776f (1964).

1040e ( 1966).

Chem. Abstr. 65, 13781a (1966).

Nut. Comp., 58 (1967).

Nut. Comp., 193 (1968).

(1975).

. 92. F. L. Pyman, J . Chem. Soc. 95, 1610 (1909).


93. F. L. Pyman and W. C. Reynolds, J . Chem. SOC. 97, 1320 (1910). 94. F. L. Pyman, 1. Chem. SOC. 107, 176 (1915). 95. C. Schopf, Experientia 5, 201 (1949). 96. L. Schottenhammer, Angew. Chem. 62, 453 (1950). 97. A. R. Battersby and R. Binks, J . Chem. Soc., 2888 (1955). 98. E. Langhals, H. Langhals, and C. Ruchardt, Chem. Ber. 117, 1436 (1984). 99. C.-H. Chen, T. 0. Soine, and K.-H. Lee, J . Pharm. Sci. 60, 1634 (1971).

100. S.-W. Sun and C.-H. Chen, Tai-wan Yao Hsueh Tsa Chih 29, 35 (1977); Chem. Abstr. 91,

101. C.-H. Chen and H.-I. Chen, Tai-wan Yao Hsueh Tsa Chih 30, 88 (1978); Chem. Abstr. 92,

102. K.-H. Lee and T. 0. Soine, J . Pharm. Sci. 57, 1922 (1968). 103. C.-H. Chen, T. 0. Soine and K.-H. Lee, J . Pharm. Sci. 59, 1529 (1970). 104. S. Natarajan and B. R. Pai, Indian J . Chem. 12, 550 (1974). 105. C.-H. Chen, J. Wu, N. A. Saath and T. 0. Soine, Tai-wan Yao Hsueh Tsa Chih 28,43 (1977);

106. M. S. Premila and B. R . Pai, Indian J . Chem. 11, 1084 (1973). 107. F. R. Stemitz and D. K . Williams, J . Org. Chem. 38, 1761 (1973). 108. F. R. Stermitz, D. K. Williams, S. Natarajan, M. S. Premila, and B. R. Pai, Indian J . Chem.

109. J. M. Bobbitt and J. C. Sih, J . Org. Chem. 33, 856 (1968). 110. S. F. Dyke, A. C. Ellis, R. G. Kinsman, and A. W. C. White, Tetrahedron 30, 1193 (1974). 111. K. Yamada, M. Takeda, N. Itoh, H. Ohtsuka, A. Tsunashima, and T. Iwakuma, Chem.

112. S. F. Dyke, R. G. Kinsman, P. Warren, and A. W. C. White, Tetrahedron 34, 241 (1978). 113. W. J . Pope and S. J. Peachey, J . Chem. SOC. 73, 893 (1898). 114. W. J. Pope and C. S . Gibson, J . Chem. Soc. 97, 2207 (1910). 115. A. C. Barker and A. R. Battersby, J . Chem. SOC. C , 1317 (1967). 116. P. W. Erhardt and T. 0. Soine, J . Plzarm. Sci. 64, 53 (1975). 117. K. C. Rice, W. C. Ripka, J. Reden, and A. Brossi, J . Org. Chem. 45, 601 (1980). 118. K. C. Rice and A. Brossi, J . Org. Chem. 45, 592 (1980). 119. K. Ito, H. Furukawa, T. Iida, K.-H. Lee, and T. 0. Soine, J . Chem. Soc., Chem. Commun.,

120. D. W. Brown, S. F. Dyke, G. Hardy, and M. Sainsbury, Tetrahedron Lett., 2609 (1968). 121. D. W. Brown, S . F. Dyke, and M. Sainsbury, Tetrahedron 25, 101 (1969). 122. H. Takayama, M. Takamato, and T. Okamoto, Tetrahedron Lett., 1307 (1978). 123. T. Nomoto and H. Takayama, J . Chem. SOC. , Chem. Commun., 1113 (1982). 124. R. M. Lagidze, N. K. Iremadze, and M. Sh. Vashakidze, Zh. Org. Khim. 4, 2006 (1968). 125. R. M. Lagidze, N. K. Iremadze, M. Sh. Vashakidze, and B. V. Rozynov, Khim. Prir.

Soedin., 188 (1973); Chem. Nut. Comp., 183 (1975). 126. R. M. Lagidze, A. I . Dvalishvili, L. P. Chigogidze, D. R. Lagidze, and R. R. Devdariani,

Soobshch. Akad. Nauk Gruz. SSR 69, 597 (1973); Chem. Abstr. 79, 53159w (1973). 127. R. M. Lagidze, N. K. Iremadze, L. P. Chigogidze, D. R. Lagidze, and R. R. Devdanani,

Soobshch. Akad. Nauk Gruz. SSR 80, 601 (1975); Chem. Abstr. 84, 150803n (1976). 128. N. K. Iremadze, D. R. Lagidze, N. I. Chobaniani, M. 0. Lursmanashvili, R. R. Devdariani,

and R. M. Lagidze, Soobshch. Akad. Nauk Gruz. SSR 95,89 (1979); Chem. Abstr. 92,42187~ (1980).

129. R. M. Lagidze, N. K. Iremadze, L. P. Chigogidze, D. R. Lagidze, R. R. Devdariani, and B. V. Rozynov, Khim. Prir. Soedin., 43 (1979); Chem. Nut. Comp., 36 (1979).

130. H. Zinnes, F. R. Zuleski, and J. Shavel, J . Org. Chern. 33, 3605 (1968).

5389x (1979).

164130t (1980).

Chem. Abstr. 88, 89900f (1978).

12, 1249 (1974).

Pharm. Bull. 30, 3197 (1982).

1037 (1974).

388 BELKIS GOZLER

131. D. A. Guthrie, A. W. Frank, and C. B. Purves, Can. J. Chem. 33, 729 (1955). 132. E. Waldmann and C. Chwala, Justus Liebigs Ann. Chem. 609, 125 (1957). 132a. R. Elliott, F. Hewgill, E. McDonald, and P. McKenna, Tetrahedron Lett. 21, 4633 (1980). 133. J. M. Bobbitt, J. M. Kiely, K. L. Khanna, and R. Ebermann, J. Org. Chem. 30, 2247 (1965). 134. K. Kido and Y. Watanabe, Chem. Pharm. Bull. 29, 861 (1981). 135. D. W. Brown, S. F. Dyke, G. Hardy, and M. Sainsbury, Tetrahedron Lett., 1515 (1969). 136. J. W. Elliott, J. Org. Chem. 44, 1162 (1979). 137. 0. Hoshino, M. Taga, and B. Umezawa, Heterocycles 1 , 223 (1973). 138. H. Hara, 0. Hoshino, and B. Umezawa, Heterocycles 5, 213 (1976). 139. H. Hara, 0. Hoshino, and B. Umezawa, Nippon Kagaku Kaishi, 813 (1981). 140. 0. Hoshino, T. Toshioka, and B. Umezawa, J. Chem. SOC., Chem. Commun., 1533 (1971). 141. 0. Hoshino, H. Hara, N. Serizawa, and B. Umezawa, Chem. Phurm. Bull. 23, 2048 (1975). 142. H. Hara, 0. Hoshino, and B. Umezawa, Chem. Pharm. Bull. 24, 262 (1976). 143. A. Brossi, Pure Appl. Chem. 51, 681 (1979). 144. T. Kametani and K. Ogasawara, Chem. Phurm. Bull. 21, 893 (1973). 145. T. Kametani, S. Hirata, and K. Ogasawara, J . Chem. Soc., Perkin Trans. 1 , 1466 (1973). 146. T. Kametani, K. Higashiyama, T. Honda, and H. Otomasu, Chem. Phurm. Bull. 32, 1614

147. H. Takayama, T. Nomoto, T. Suzuki, M. Takamoto, and T. Okamoto, Heterocycles 9, 1545

148. M. E. Jung and S. J. Miller, J. Am. Chem. SOC. 103, 1984 (1981). 149. J. R. Brooks, D. N. Harcourt, and R. D. Waigh, J. Chem. Soc., Perkin Trans. I , 2588 (1973). 150. S. Natarajan and B. R. Pai, Indian J. Chem. 10, 451 (1972). 151. C.-H. Chen, J. Wu, N. A. Saath, and T. 0. Soine, Tai-wan Yao Hsueh Tsa Chih 29, 19 (1977);

Chem. Abstr. 91, 5388w (1979). 152. J. Holubek and 0. Strouf, “Spectral Data and Physical Constants of Alkaloids.” Publishing

House of Czechoslovak Academy of Sciences, Prague, 1965-1971. (a) Spectrum 24, (b) Spectrum 193, (c) Spectrum 32, (d) Spectrum 437, (e) Spectrum 409, (4 Spectrum 210, (g) Spectrum 704.

153. R. P. K. Chan, J. Cymerman Craig, R. H. F. Manske, and T. 0. Soine, Tetrahedron 23,4209 (1 967).

154. M. Tomita, S.-T. Lu, and T. Ibuka, Yakugaku Zasshi 86, 414 (1966). 155. 0. Cervinka, A. Fibryovfi, and V. NovAk, Tetrahedron Lett., 5375 (1966). 156. S. F. Mason, K. Schofield, R. J. Wells, J. S. Whitehurst, and G. W. Vane, Tetrahedron Lett.,

157. S. F. Mason, G. W. Vane, and J. S. Whitehurst, Tetrahedron 23, 4087 (1967). 158. A. C. Barker and A. R. Battersby, Tetrahedron Lett., 135 (1967). 159. T. Kaneda, N. Sakabe, and J. Tanaka, Bull. Chem. SOC. Jpn. 49, 1263 (1976). 160. M. Maturovk, J. Hrbek, Jr., and F. Santavy, Acta Univ. Palacki Olomuc., Fac. Med. 90, 5

161. M. Shamma, J . L. Moniot, W. K. Chan, and K. Nakanishi, Tetrahedron Lett., 3425 (1971). 162. L. DolejS and J. Slavik, Collect. Czech. Chem. Commun. 33, 3917 (1968). 163. M. Shamma and J. L. Moniot, J. Am. Chem. Sac. 96, 3338 (1974). 164. E. Wenkert, B. L. Buckwalter, J. R. Burfitt, M. J. GaSi?, H. E. Gottlieb, E. W. Hagaman, F.

M. Schell, and P. M. Wovkulich, in “Topics in Carbon-13 NMR Spectroscopy” (G. C. Levy, ed.), Vol. 2, p. 110. Wiley, New York, 1976.

(1984).

(1978).

137 (1967).

(1979); Chem. Abstr. 95, 7534x (1981).

165. L. Hruban and F. Santavg, Collect. Czech. Chem. Commun. 32, 3414 (1967). 166. D. H. R. Barton, R. H. Hesse, and G. W. Kirby, J . Chem. SOC., 6379 (1965). 167. V. Prelog and P. Wieland, Helv. Chim. Acta 27, 1127 (1944).


168. T. Gozler, B. Gozler, N. Tanker, A. J . Freyer, H. Guinaudeau, and M. Shamma, Heterocycks

169. S . F. Dyke, Hererocycles 6, 1441 (1977). 170. F. R. Stermitz, in “Recent Advances in Phytochemistry” (T. J. Mabry, R. E. Alston, and V.

171. F. R. Stermitz and D. K. Williams, J . Org. Chem. 38, 2099 (1973). 172. S. F. Dyke and P. Warren, Tetrahedron 35, 1857 (1979). 173. M. Shamma and J. L. Moniot, Tetruhedron Lett.. 2291 (1974). 174. A. A. Genanah, T. 0. Soine, and N. A. Saath, J . Pharm. Sci. 64, 62 (1975).

24, 1227 (1986).

C. Runeckles, eds.), Vol. 1 , p. 161. Appleton-Century-Crofts, New York, 1968.


INDEX

A

13-Acetoxyanagyrine, 125 Actinidine, 197, 212, 249 I-Acylisoquinolines, 3 Adaline, 202, 232, 280 Adlumidine, 23 Adlumine, 23 Albertamine , 1 3 1, 177 Albertidine, 129, 172 Albertine, 130, 177 Alkaloid LC-2, 123, 149 Alkylamines, in ants and insects, 197, 288 1 -Alkylisoquinolines, 3 Allomatrine, 129, 139, 140, 172 Allomatrine N-oxide, 139 11-Allylcytisine, 122, 149 Aloperine, 128, 167 5-Alpha,9-alpha-dihydroxymatrine, 131, 182 9-Alpha-hydroxymatrine, 13 1, 178 3-Alpha-hydroxysophoridine, 130, 180 Alpha-isosparteine, 135 4-Alpha-hydroxysparteine, 124, 156 Alteramine, 152 Amides, in ants and insects, 197, 204, 205,

Ammodendrine, 147 Amurensine, 327, 329, 331, 372 Amurensinine, 327, 329, 331, 346 Amurensinine N-metho salt, 328, 329, 332 Anabaseine, 196, 212, 248 Anhydroschumannificine, 73, 91 Antheroline, 18 Ants, alkaloids in, 194, 211 Apomorphine, Reissert synthesis, 14 Aporphine-pavine dimers, 38 1 1 -Aralkylisoquinolines, 3 Argemonine, 319, 322, 324, 340, 342, 370,

Argemonine N-metho salt, 323, 328 Argernonine N-oxide, 323

288

383

Argentamine, 127, 162 Argentine, 123, 152 Argentinine, 33, 59 Aristolactam BII, 35 Aristolactam-N-glucoside, 32, 46, 61 Aristolactams, 32, 59 Aristolochic acid I, 43, 54, 57 Aristolochic acid 11, 44, 57 Aristolochic acid 111, 31, 58 Aristolochic acid IV, 31, 58 Aristolochic acids, 31, 40, 47, 54, 57

Aristolochic amides, 31, 41, 59 Aristoloside, 3 1, 59, 60 Asimilobine, 33, 61 Aurodrosopterin, 205, 23 1

in insects, 302

B

Baptifoline, 163 1 -Benzylisoquinolines, by Reissert synthesis, 5 Beta-hydrastine, 23 Beta-isosparteine, 135 Bicuculline, 22 Biopterin, 299 Bisnorargemonine, 319, 324, 334, 340 Buchenavianine, 69, 78 Bulbocapnine, N-alkyl analogs, 15

C

Caaverine, 17 Cadiaine, 162 Cadiamine, 121, 143 Calgunnenine, 126 Calpunnenine, 161 Camoensidine, 128, 165 Camoensine, 127, 165 Canthin-6-one model, synthesis, 25 Capitavine, 70, 78 Caryachine, 320, 322, 325, 335, 339, 371

39 1

INDEX

Caryachine N-oxide, 320, 323 Catalaudesmine, 127, 162 Catalauverine, 127, 162 Catatine, 53 Cepharadion A, B, 35, 51, 52 Cepharanone A, B, 35, 59 Chamaetine, 125, 159 Chromanone alkaloids, 67

UV-Spectra, 79, 92 IR-Spectra, 80, 92 MS-Spectra, 81, 93 NMR-Spectra, 81, 95, 96, 97 biosynthesis, 83, 97

Chrysin, 76 Cinegalleine, 126, 162 Cinegalline, 126, 162 Cinevanine, 126, 162 Cineverine, 126, 162 Coccinelline, 202, 232, 272, 274 Convergine, 202, 232, 272, 274 Cordrastine, 23 Corlumine, 23 Corunnine, 17 Corydione, 52 Cryptaustyline, 103, 106, 114 Cryptowoline, 103, 106, 111 Cularine, Reissert synthesis, 11 Cuspidaline, 33 1-Cyanoisoquinolines, 3 Cyclanoline, 33

D

Danaidal, 199, 221 Danaidone, 199, 221, 259 Darvasamine, 129, 172 Darvasine, 129, 172 Darvasoline, 131, 181 Debilic acid, 31, 37, 59 Dehydrocrebanine, 48 Dehydroisoalbine, 122, 137 5,6-Dehydroisolupanine, 125 Dehydrolaudanosoline, 104 5,6-Dehydrolupanine, 124, 159 5,17-Dehydromatrine, 173 Dehydronantenine, 52 7,8-Dehydrosophoramine, 130, 176 13,14-Dehydrosophoridine, 130,139,175 11,12-Dehydrosparteine, 125

12,13-Dehydrosparteine, 125 Deoxodihydroleontalbimine, 174 Deoxomatrine, 130, 173 Deoxysepiapterin, 299 Desoxocamoensidine, 166 2,5-Diaikylpyrrolines, in ants, 256 Dihydroalbertine, 177 9,lO-Dihydroaristolochic acids, 45 Dihydroisocarbostyril, 3 Dihydrolactyllumazine, 201, 23 1 10,13-Dihydrolupanine, 126 Dihydronitraramine, 168 Dihydroxanthommatin, 201, 225, 271 Dimethamine, 123, 153 Dimethylphenethylamine, 209 4,5-Dioxodehydrocrebanine, 5 1 10,13-Dioxylupanine, 160 Ditermamine, 127, 163 10,17-Dixo-beta-isosparteine, 124, 155 Domesticine, 17 Doryfiavine, 41 Drosopterin, 205, 231, 301

E

Eillipticine, 26 Ekapterin, 202, 230 Emetine, Reissert synthesis, 24 Epiaphylline, 124, 156 Epilamprolobine, 121, 142 11-Epileontidine, 128, 167 Epilupinine, 120, 140 Epimyrtine, 121, 144 Epipederine, 293 Erythropterin, 206, 230, 301 Escholamine, 6 Escholtzidine, 322, 325 Escholtzidine N-Metho salt, 321, 323 Escholtzine, 319, 321, 322, 325 Escholtzine N-metho salt, 323 Escholtzine N-oxide, 321, 323 13-Ethoxylupanine, 126, 162 Euphococcinine, 202, 232, 280

F

Ficine, 68, 75, 84 Formylcinegalleine, 162 Fusenine, 35

INDEX 393

G

Glomerin, 208, 225 Goebeline, 131, 183

Isosophoramine, 181 Isosophoridine, 139, 170 Isotincotorine, 122 Isoxanthopterin, 199, 201, 205,230, 301 Isoxazoles, in insects, 296

H J

Harmonine, 202, 237, 288 Heliotrine, 260 3-Heptyl-5-methylpylizidine, 261 Hexahydrotinctorine, 15 1 3-Hexyl-5-rnethylindolizidine, 270 Hippocasine, 202, 232, 273, 276 Hippodamine, 202, 232, 272, 276 Hispidulin, 76 Homoglomerin, 208, 225 Homoisopavines, 378 Homopavines, 378 d-Hydrastine, 23 Hydrastine, 33 8-Hydroxyapomorphine, 14 1 0-Hydrox yapomorphine , 14 11-Hydroxyapomorphine, 14 7-Hydroxy-beta-isosparteine, 124, 155 Hydroxydanaidal, 199, 201, 221, 260 2-Hydroxy-3,8-dimethoxypavinan, 319, 322 9-Hydroxymatrine, 178 8-Hydroxyquinoline-2-carhoxylic acid, 204,

225

I

Ichthyopterin, 208, 230 Imenine, 19 Intcgenirnine, 222 Isocaryachine, 320, 335, 338 Isocinevanine, 162 Isodrosopterin, 205, 231 Isoficine, 68, 75, 84 Isokuraramine, 122, 146 Isoleontalbine, 129 Isomatrine, 129, 139, 140, 171 Isonorargemonine, 322, 326, 334, 374 Isopavine, 327 Isopavine alkaloids

spectra, 365, 369 biosynthesis, 374

Isopavines, unnatural analogs, 356 Isoschumanniphytine, 73, 88

Jacobine, 222 Jacoline, 222

K

Khombifoline, 154 Kuraramine, 122, 146

L

Lamprolobine, 120, 142 Laudanosoline, oxidation of, 110 Lemannine, 130, 175 Lemannine N-oxide, 139 Leontalhamine, 131, 177 Leontalbine, 129, 173 Leontalbinine, 129, 174 Leontane, 181 Leontidine, 127, 164 Leontifonnine, 122, 145 Leontisrnidine, 177, 179 Leontismine, 131, 181 Leucopterin, 198, 230, 301 Lindenianine, 124, 157 Lupinine, 118, 135, 140 Lycopsamine, 200, 221

M

Magnaflorine, 33 Mamanine, 121, 136, 143 Mamanine N-oxide, 121 Matridine, 181 &-Matrine, 139 Matrine, 138, 140 Matrine N-oxide, 138 Mecambridine , 2 1 9-Methoxy-ellipticine, 26 2,3-Methylenedioxy-4,8,9-trimethoxypavinan,

4-Methylpyrrole-2-carboxyiate, 257 320, 322

394 INDEX

Monocrotaline, 222, 260 Monomorine I, 263 Monomorine VI, 270 Monomorines, 196 Munitagine, 319, 322, 336 Myrrhine, 202, 232, 273 Myrtine, 121, 144

N

N-Acetylcytisine, 123, 148 N-Allylaloperine, 128, 167 N-Demethylbuchenavianine, 69, 78 N-Demethylcapitavine, 69, 70, 79 N-Ethylcytisine, 123, 148 N-Formylcytisine, 122, 148 N-Hydroxynitraramine, 128, 168 N-Methylaloperine, 128, 167 N-Methylanhydroschumannificine, 73, 91 N-Methylisoschumanniophytine, 74, 89 N-Methylschumagnine, 74, 91 N-Methylschumannificine, 72, 90 N-Methylschumanniophytine, 74, 89 N-Methyltaiiscamine, 47 N-Methyltetrahydrocytisine, 122 N-(3-Oxobutyl) cytisine, 123, 148 Nandazurine, 17, 52 Nantenine, 52 Naringenin, 77 Neodrosopterin, 205, 23 I Neosophoramine, 130, 176 Nitraramine, 128, 168 Nitropolyzonamine, 263 Norargemonine, 319, 322, 326, 334 Norpontevedrine, 54 Nuttalline, 125, 159

0

0-Demethylbuchenavianine, 69, 78 0-Methylcryptaustoline, 105, 108, 114 0-Methylcuspidaiine, 33 0-Methyldauricine, 9

Oxocampostelline, synthesis, 11 Oxocularine, synthesis, 11

P

Papilochrome 11, 200, 271 Pavine alkaloids

spectra, 362, 367 biosynthesis, 372

Pavines, unnatural analogs, 356 Pederamide, 290 Pederine, 203, 289, 292 Pederone, 203 Pennsylpavine, 381 Pennsylpavoline, 381 Petrosine, 121, 145 Petrosine-A, 121, 145 Petrosine-B, 121, 145 Phyllospadine, 69, 75, 76, 86 Piperidines, in ants, 195, 211, 238 Platycerine, 322, 324, 336 Platycerine N-metho salt, 323 Platycerine, synthesis, 13 Pohakuline, 121, 136, 143 Polyamines, in insects, 206 Polyzonimine, 208, 215, 258 Pontevedrine, 35, 52, 53 Precoccinelline, 202, 232, 272, 274 hestephanine, 34 Propyleine, 202, 232, 272, 276 Pseudopederine, 203, 288 Pterorhodin, 202, 231 Pteridines, in insects, 197, 230, 298 Pyrazines, in ants, 197, 200, 204, 218, 283 Pyrrolidines, in ants, 195, 214, 251 Pyrrolizidines, in ants, 199, 221, 259

Q

Quettamine, synthesis, 12 Quinazolinones, in insects, 297 Quinolines, in insects, 270

0-Methylthalisopavine, 328, 332, 346, 355 R 0,N-Bisdemethylbuchenavianine, 69, 78 Octahydromatrine, 173 Ommatine, 270 Ommochromes, in insects, 200 Orientalidine, 21 Orientaline, 34 349

Reframidine, 328, 329, 332, 346, 352, 254 Reframine, 328, 329, 332, 346, 349 Reframine N-metho salt, 329, 338 Reframoline, 328, 329, 332, 336, 339, 348,

INDEX 395

Reissert anion reaction, 4 Remrefine, 327 Reticuline, by Reissert synthesis, 6 Retronecine, 260 Roemecarine, 376 Robitukine, 71, 89, 99 Rosmarinine, 203 Rugosinone, 7

S

Sardosemine, 127, 162 Schumagnine, 74, 92 Schurnannificine, 72, 90 Schumanniofoside, 75 Schummaniophytine, 71, 87 Senecionine, 222 Seneciphylline, 222 Sepiapterin, 201, 208, 231, 299 Skatole, 198, 207 Solenopsins, synthesis, 238, 245 Sophocarpine, 184 Sophoranol N-oxide, 13 1 Sophorbenzamine, 13 1, 182 Sophoridine, 129, 139, 140, 169 Sophoridine N-oxides, 130, 139, 171 Sophorine, 121, 144 Stenusine, 203, 212, 246 Stephanine, 34 Subsessiline, 18 Supinidine, 260

T

Tetramethoxy aristolochic acid, 47 Thalicmidine, 17 Thalidicine, 328, 329, 330, 332 Thalidine, 328, 329, 330, 332 Thalipoline, 320 Thalisopavine, 328, 329, 332, 346 Thermopsamine, 124, 156 Tinctorine, 122, 149 Trigonelline, 74 Trimethoquinol analogs, 9 Tsukushinamine A, 124, 137, 154 Tsukushinamines B and C, 124, 154 Tubemlactam, 32, 61 Tuberosine, 33 Tuberosinone, 33, 61 Tuberosinone-N-glucoside, 33, 61

U

Urocanic acid, 199, 237 Usaramine, 222

V

Violapterin, 201, 231 Virgiboidine, 123, 149 Virgidivarine, 123, 138, 149 Virgiline, 158 Vochysine, 69, 77, 86

X

Xanthommatin, 200, 205, 225, 270 Xanthopterin, 198, 230, 301

Takatonine, 6 Taliscanine, 32, 47


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The Alkaloids Chemistry and Pharmacology, Volume 31 - (1987)