Synthesis of Marine Natural Products 2: Nonterpenoids

Bioorganic Marine Chemistry Volume 6

Edited by Paul J. Scheuer

K.F. Albizati, V.A. Martin, M.R. Agharahimi, D.A. Stolze

Synthesis of Marine Natural Products 2 Nonterpenoids

With 161 Structures and 263 Schemes

Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest

Professor Paul J. Scheuer University of Hawaii at Manoa, Department of Chemistry 2545 The Mall, Honolulu, Hawaii 96822, USA

ISBN-13:978-3-642-76840-8 e-ISBN-13:978-3-642-76838-5 DOl: 10.1007/978-3-642-76838-5

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9,1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution of the German Copyright Law.

Library of Congress Catalog Card Number 89-649318 © Springer-Verlag-Berlin Heidelberg 1992 Softcover reprint of the hardcover 1 st edition 1992

The publisher cannot assume any legal responsibility for given data, especially as far as directions for the use and the handling of chemicals are concerned. This information can be obtained from the instructions on safe laboratory practice and from the manufacturers of chemicals and laboratory equipment.

51/3020-5421O-Printed on acid-free paper

Preface

Volumes five and six of Bioorganic Marine Chemistry differ from their predecessors in two respects - they deal exclusively with laboratory synthesis of marine natural products and they represent the effort of a single author and his associates.

The rationale for these departures is readily perceived. For several decades organic synthesis has without doubt been the most spectacular branch of organic chemistry. While the late R.B. Woodward's dictum - organic compounds can undergo only four basic reactions: they can gain electrons; they can lose electrons; they can be transformed with acid or with base - is still true, the wealth and variety of available reagents which will accomplish chemical transformations has reached staggering proportions. Little wonder then, that synthetic methodology has achieved a high degree of predictability and total synthesis of natural products has been successfully directed toward ever more challenging targets. As for the second point, that of single authorship, multiple authorship would invariably have led to gaps and overlaps, thus making it difficult to assemble and assess recent research in a systematic and comprehensive fashion.

These two volumes are significant not only as a testimonial to the productivity and versatility of marine biota and to the virtuosity of synthetic chemists. As the material is presented along biogenetic principles, it is ideally suited to support research into the biosynthesis of marine metabolites. The comprehensive nature of the work makes it an easy matter to compare and evaluate different synthetic approaches prior to any synthesis of labelled precursors.

The division into terpenoid (V 01. 5) and nonterpenoid (V 01. 6) compounds is a natural one not only because of bulk. Nonterpenoid, particularly amino acid-derived, metabolites have become the fastest growing group of marine natural products. As recently as a decade ago, this position was held by di-, and earlier by sesquiterpenoids. This change parallels the current trend in research emphasis. Much early work in marine natural products was the result of serendipitous collections and separations. By contrast, most of today's research is guided by biological activity, which in tum is skewed toward those

VI Preface

activities - e.g. antitumor, antiviral, which receive funding in industrialized societies.

While reading and editing the manuscript I was struck by the large impact which marine natural product research has made on organic synthesis and indeed on contemporary chemistry. It occurred to me that these books could be valuable auxiliary texts for graduate courses in Organic Synthesis.

I am indebted to Dr. Albizati and his associates for the monumental task which this endeavor entailed. As before, I should like to express my appreciation to Springer Verlag for their prompt and expert cooperation. As always, I look forward to hearing from members of the scientific community how we can improve future volumes in the series.

August, 1991 Paul J. Scheuer

Table of Contents

3 Amino Acids and Peptides 1

3.1 Various Amino Acids 1 3.1.1 Camosadine . 1 3.1.2 Ovothiols A and C 1 3.1.3 (alpha)-Kainic Acid and allo-Kainic Acid. 3 3.1.4 Domoic Acid 9 3.1.5 Tetraacetylclionamide 13 3.1.6 Demethyldysidenin and Demethylisodysidenin 14

3.2 Brominated Tyrosine Derivatives . 17 3.2.1 Quinols 17 3.2.2 Aplysinadiene 19 3.2.3 Aerothionin, Homoaerothionin and

Aerophobin-1 20 3.2.4 Bastadins -1, -2, -3, and -6 . 20

3.3 Peptides. 25 3.3.1 Didemnins 26 3.3.2 Jaspamide. 30 3.3.3 Geodiamolides A and B. 39 3.3.4 Thiazole-containing Peptides . 43

3.3.4.1 Patellamides A, Band C 43 3.3.4.2 Ulicyclamide and Ulithiacyclamide. 51 3.3.4.3 Ascidiacyclamide and Dolastatin-3 . 54

3.3.5 Dolastatin-10 and Hexaacety1celenamide . 59 3.3.6 Teleocidin A-1 (Lyngbyatoxin A) and

Teleocidin A-2 . 63

4 Fatty Acid Derived Metabolites 69

4.1 Haloethers of Laurencia sp. . 69 4.1.1 Laurencenyne 69 4.1.2 Laurediol. 71 4.1.3 Laurediol Derivatives. 74 4.1.4 Laurencin. 74 4.1.5 Laurenyne 78 4.1.6 cis-Maneonenes A and B 79

VIII Table of Contents

4.1.7 trans-Maneonene B 79 4.1.8 Panacene. 84

4.2 Prostanoids 84 4.2.1 Clavulones 84

4.2.1.1 Clavulones I and II 87 4.2.1.2 Clavulone III 87 4.2.1.3 Desacetylclavulone II. 91 4.2.1.4 Chlorovulone II 92 4.2.1.5 Preclavulone A . 92

4.2.2 Punaglandins 96 4.2.2.1 Punaglandin 4 . 96 4.2.2.2 Punaglandin 3 and (7 E)-

Punaglandin-4 102 4.2.3 Hybridalactone . 106

4.3 C 8-C ll Algal Pheromones 107 4.3.1 Dictyoprolene 107 4.3.2 Dictyopterenes . 107

4.3.2.1 Dictyopterene A 110 4.3.2.2 Dictyopterene B (Hormosirene) 115 4.3.2.3 Dictyopterene C and

Dictyopterene C" . 117 4.3.2.4 Dictyopterene Df (Sirenin,

Ectocarpene) . 119 4.3.2.5 4-n-Butyl-2,6-Cycloheptadienone. 120 4.3.2.6 Multifidene 121 4.3.2.7 Desmarestene and Viridiene 125 4.3.2.8 Lamoxirene . 128 4.3.2.9 Aucantene 128 4.3.2.10 Fucoserratene 131 4.3.2.11 Giffordene 133 4.3.2.12 Clavularins A and B . 135

4.4 Miscellaneous Metabolites 139 4.4.1 Acarnidines 139 4.4.2 Pahutoxin. 139 4.4.3 D-erythro-l-Desoxydihydroceramide-l-

Sulfonic Acid 142 4.4.4 Phosponosphingoglycolipid from Turbo

cornutus 144 4.4.5 Metabolites of Plexaura fiava . 144 4.4.6 N otheia anomala Metabolite 146 4.4.7 Octacosadienoic Acids 147 4.4.8 Hexacosadienoic Acids 156 4.4.9 Diacetylenes from Reniera fulva 156

Table of Contents IX

5 Nitrogenous Metabolites. . . . . . 158

5.1 Indoles and Related Compounds. 158 5.1.1 Flustramine B . 158 5.1.2 Surugatoxins. . . 158 5.1.3 Various indoles. . 165

5.1.3.1 Trikentrins 165 5.1.3.2 Indoles Related to Aplysinopsin . 169 5.1.3.3 Dendrodoine. . . . . . .. 172 5.1.3.4 Tetrahalogenoindoles. . . .. 173 5.1.3.5 (E)-3-(6-Bromoindole-3-yl)Prop-2-

enoate. . . . . . . 173

5.2 Carbazoles. . . . . . . . . . . 175 5.2.1 Hyellazole and 6-Chlorohyellazole 175 5.2.2 Eudistomins. . . . . . 179

5.2.2.1 Eudistomin A . . 179 5.2.2.2 Eudistomins H, I, P 180 5.2.2.3 Other Eudistomins 181

5.2.3 Manzamine C 188

5.3 Pyridines . . . . 192 5.3.1 Navenone A . 192 5.3.2 Pulo'upone . 193 5.3.3 Ascididemin. 195 5.3.4 Aaptamine and Demethoxyaaptamine . 199 5.3.5 Amphimedine . . . . . . . .. 206

5.4 Guanidine-Containing and related Metabolites 210 5.4.1 Tetrodotoxin. 210 5.4.2 Saxitoxin. 211 5.4.3 Ptilocaulin . 217 5.4.4 Oroidin . . 220 5.4.5 Dibromophakellin . 223 5.4.6 Girolline. . . . 223

5.5 Nuc1eosides and Related Substances. 226 5.5.1 Mycalisin. . . . . . . . 226 5.5.2 Phidolopin . . . . . . . 227 5.5.3 6-Imino-1,9-dimethyl-8-oxopurine 228 5.5.4 1-Methylisoguanosine (Doridosine) . 229

5.6 Reniera Alkaloids . . 230 5.6.1 Mimosamycin . . . . . . . . 230 5.6.2 Reniera Isoindole. . . . . . . 231 5.6.3 7-Methoxy-1,6-dimethyl-5,8-Dihydroiso-

quinoline-5,8-dione and N-Formyl-1,2-dihydrorenierone 234

5.6.4 Renierone. . . . . . . . . . . 237

X Table of Contents

5.7 Zoanthoxanthins. 241

5.8 Pyrrole-Containing Alkaloids 243 5.8.1 Oscarella lobularis Pyrrole Metabolite. 243 5.8.2 5-Nonylpyrrole-2-Carbaldehyde . 243 5.8.3 Pentabromopseudilin . 245 5.8.4 Bonellin, Methyl Ester 246

6 Miscellaneous Metabolites . 249

6.1 Metabolites Related to Citric Acid 249 6.1.1 Delesserine 249 6.1.2 Leptosphaerin 250

6.2 Brominated Phenolic Esters. 253

6.3 Others 256 6.3.1 Metabolites of Delisia jimbriata 256 6.3.2 Kjellmanianone. 259 6.3.3 Pukeleimide A 259 6.3.4 Latrunculin B 260 6.3.5 Bisucaberin 262 6.3.6 Hormothamnione . 262 6.3.7 Bissetone . 266 6.3.8 (8,8)-Palythazine 267 6.3.9 Dysidin 267 6.3.10 Grateloupia jilicina Metabolite and

Related Compounds . 271 6.3.11 Didemnenones A and B. 272 6.3.12 Tridacna maxima Metabolite 275 6.3.13 Nereistoxin 275 6.3.14 3-n-Hexyl-4,5-dithiacycloheptan-5-one . 277 6.3.15 3-Methylnavenone B 277 6.3.16 Malyngolide . 279 6.3.17 Okadaic Acid 294 6.3.18 Debromoaplysiatoxin. 299

7 Summary. 311

8 References . 312

Subject Index 32)

Abstract

The growth and extent of chemical synthesis of marine natural products from the years 1960-1989 has been evaluated and reviewed in a near-comprehensive fashion for the first time. The rapid growth in the breadth and depth of this field in a comparatively short period of time mirrors the growth and interests of the synthesis community at large. Synthesis chemists are stimulated primarily by compounds which possess potential biomedical importance and/or provocative structures, of which there is an abundance among the metabolites from marine sources. Continued growth in this area is projected. The information in this review consists primarily of synthetic schemes and pathways which, after analysis, have been set to words. The metabolites synthesized have been organized according to broad biogenetic lines, including terpenes, alkaloids, fat-derived compounds, amino-acid-derived and miscellaneous.

3 Amino Acids and Peptides

A variety of unusual amino acids and small cyclic and acyclic oligopeptides have been isolated from marine organisms. These have been the subject of intense synthesis activity due to the potent and broad spectrum of activities exhibited by the various members of this class. Syntheses of a number of bromotyrosinederived metabolites are also included in this section.

3.1 Various Amino Acids

3.1.1 Carnosadine

Camosadine, a new cyclopropyl amino acid isolated [312] from the red alga Grateloupia carnosa, has been synthesized by Shiba [313] as shown in Scheme 192. Dipolar cycloaddition of diazomethane to acid 1212 gives pyrazoline 1213 which upon photolysis provides cyclopropane 1214. Conversion of ester 1214 to the amide followed by Hofmann degradation gives amine 1215. Resolution of the diastereomers and addition of guanidine to 1215 gives ( - )-camosadine in 13 steps and 6.1 % overall yield.

(-)-Carnosadine 1216

3.1.2 Ovotbiols A and C

Ovothiols A and C have been synthesized by Hopkins [314] from the parent heterocycle 1217 as shown in Scheme 193. Hydroxymethylation and chlorination of 1217 gives imidazole 1219 in two steps. Treatment of 1219 with (X

glycinyl anion equivalent 1220 affords amino acid 1221. Removal of the thiol

CO

OH

C

H2N

2 'N

hv

.. ~

H~!I\~

~ COO

Me

HOOC~NHBZ

.. M

eOH

H

!

~ C

OO

Me

PhC

H3

Me

OO

C/

NH

Bz

1212

1)6M

HC

I re

flux

2)2M

HC

I M

eOH

3)

BO

C20

66%

100%

AC

OO

H

H

= N

HB

oc

./

MeO

OC

Me

OO

C/

NH

Bz

1213

I)N

H3

/MeO

H

2) B

r2 /

aq N

aOH

69%

•

MeO

H

02N

....

78%

12

14

AC

OO

H

H

= N

HB

oc

./

~N

I)

0

Bn

oJlC

l

aqN

aOH

2) (

+)-

a-m

ethy

lbe

nzyl

amin

e D

CC

/HO

Bt

82%

AC

ON

HC

H(C

H3)

Ph

H

= N

HB

oc

./

I)H

2Pd

A

N

.

• -

II H

a

= CO

NH

CH

(CH

3)P

h 2)

N

N02

~

A';

NH

Boc

I)H

2 Pd

M

eOH

N

HA

. JlH

a

= CO

OH

-

NH

H2N

N

./

2 Z

HN

1215

(r

esol

utio

n at

th

is p

oint

)

o B

no

""'-

= Z

Jl

N-

H2N

N

H

2N

N-(

, h

H

H

N

66%

Sche

me

192.

Shi

ba S

ynth

esis

of (

-)-

Cam

osad

ine

2)6M

HC

l re

flux

63%

H

(-)-

carn

osad

ine

1216

-est

abli

shed

abs

olut

e co

nfig

urat

ion

tv i o > ~ 8- I

Me \ N

«Jl N SPMB

1217

PMB = p-methoxybenzyl

1) EtO ": Yt N~OEt 1220

TIfF -78 - 0 °C

2) aqHCl

•

Me

kDCOOH

~I NH N SH 2

{+)-Ovothiol A 1222

Me \

Various Amino Acids 3

Me \ COOH

<~D~ SH

{+)-Ovothiol C 1223

Me \

aqHCHO N~ SOCl2 N~ • (, I QH • (, I Cl

HOAc/NaOAc reflux 3.5 hr

N SPMB N SPMB

76% 1218 1219

Me Me

~~COOH Hg(OlFAh \ COOH

(~D (, r.!l. .~ N SPMB 2 N SH 2

ca 94% (+)-ovothiol A 1222 1221

48% from 1218

1) aqHCHO NaBH3CN

2) Hg(OlFAh CF3COOH

78%

Me \ COOH

(~nez N SH

(+)-ovothiol C 1223

- established structure by localizing where the imidazole Me group was

Scheme 193. Hopkins Synthesis of (± )-Ovothiols A and C

protecting group yields (+ )-ovothiol A in approximately 34% yield over 5 steps. Reductive methylation of 1221 prior to deprotection gives ( + )-ovothiol C in 6 steps and 28% overall yield.

3.1.3 rx-Kainic Acid and AUo-Kainic Acid

ex-Kainic acid is the parent member of the kainoids, a group of structurally related pyrrolidine dicarboxylic acids. It has been isolated, along with its C4 epimer ex-allo-kainic acid, from the alga Digenea simplex [315] and has also been


a-Kainic Acid 1234 a-Allokainic Acid 1228

found in the alga Centrocerus clavulatum [316]. Although a-kainic acid has been reported to possess anthelmintic and insecticidal attributes [317], it is of interest mainly due to its pronounced neuroexcitatory properties [318].

The diastereomeric a-allo-kainic acid was first prepared by Oppolzer [319] in 1978 as shown in Scheme 194. N-alkylation of the easily accessible Ntrifluoroacetylaminomalonic ester 1225 affords compound 1226 which undergoes an ene reaction upon heating to give trans-substituted pyrrolidine 1227. Hydrolysis and decarboxylation of 1227 yields (±)-a-allo-kainic acid in 6 steps and 53% overall yield. Crystallization of 1228 as its (- )-ephedrine salt provides enantiomerically pure ( + )-a-allo-kainic acid.

Oppolzer's second synthesis [320] of (+ )-a-allo-kainic acid (Scheme 195) utilizes (- )-8-phenylmenthol as a chiral auxiliary to promote a Lewis acidcatalyzed asymmetric intramolecular ene-type reaction that provides transpyrrolidine 1229 in 60% yield in 90% ee. Hydrolysis and decarboxylation gives ( + )a-allo-kainic acid (1228).

Oppolzer's synthesis [321] of (±)-a-kainic acid appeared in 1979 (Scheme 196) and follows a similar strategy to that used in his syntheses of 1228. Alkylation of ester 1231 via conjugate addition to a 2-methylthioacrylate ester

HN ,COCF3

("<C02Et

I CO~t

Et02CCH

1225

1227

,COCF3 yB' ~N ao~ 80°C

# (C02Et .. ..

NaH PhCH3

HMPA CHC02Et

25°C, 80%

1) NaOH, MeOH, reflux ..

2) HC1, Cu(OAc)z

78% 3) H2S, H20,

88%

1226 97%

YY'"C~H C02H

(±)-a-allokainic acid 1228

53% overall yield.

Scheme 194. Oppo1zer Synthesis of (±)-Cl-Allokainic Acid

I) NaOH, EtOH,

100°C ..

2) Cu(OAch, 100 °c, 73%

-35°C 60%

..

-Lewis acid-promoted intramolecular Ene reaction.


1229 (90% ee)

(+)-a-allokainic acid 1228

Scheme 195. Oppolzer Synthesis of (± )-IX-Allokainic Acid

followed by sulfoxide elimination gives diene 1232 as the .::\2,3 isomer. Heating this to 180°C causes cyclization to cis-substituted pyrrolidine 1233, presumably through an ene reaction of the thermally formed .::\3,4 isomer. Deprotection of the amine gives (±)-Cl-kainic acid 1234 in 7 steps and 41 % overall yield.

An enantio- and diastereospecific synthesis of (- )-kainic acid by Oppolzer [322] is outlined in Scheme 197. Triester 1235 derived from (S)-glutamic acid is converted to 1,6-diene 1236 in six steps and 19% overall yield. Intramolecular ene cyclization of 1236 followed by desilylation, oxidation and hydrolysis provides (- )-Cl-kainic acid 1234 in 11 steps and 4.6% overall yield.

Kraus's entry into the arena of kainic acid synthesis [323] involved (± )-Clallo-kainic acid 1228 as outlined in Scheme 198. Stereospecific 1,3-cycloaddition of 1238 and 1239 provides functionalized pyrrolidine 1240 in 65% yield. Desulfurization of 1240 with one equivalent of BU3SnH leads to ketone 1241 which is converted to triester 1242 in four steps via standard transformations. Hydrolysis and deprotection occurs with epimerization, thus completing the synthesis to give (± )-Cl-allo-kainic acid 1228 in 11 steps and approximately 11 % overall yield. In a full account of this work [324] it was disclosed that epimerization at C2 was performed after removal of the t-BOC protecting group.

The synthesis of (± )-Cl-allo-kainic acid 1228 by DeShong [325] involves the 1,3-dipolar cycloaddition of an azomethine ylid to an Cl,p-unsaturated ketone to give the functionalized pyrrolidine 1243 in one step along with < 1 % of the C2 epimer (Scheme 199). Conversion of 1243 to diester 1244, removal of the Nbenzyl group with Cl-chloroethyl chloroformate, and treatment with sodium

,CO

CP3

1)

LIC

A,

TII

F

,CO

CP 3

~tco,,"

-78

°c

y!c~

~ ..

2) =

<C

OzM

e

SMe

MeO

zC

SMe

85%

12

31

,CO

CF

3 I)

aq

NaO

H,

180°

C

RCO,M

' M

eOH

<4I6

2)

H+

60%

C

OzM

e 90

%

1233

Sche

me

196.

Opp

olze

r Sy

nthe

sis

of ( ±

)-cx-

Kai

nic

Aci

d

1) M

CP

BA

,

CH

2CI 2

, ,C

OC

F 3

-78

°c

~N

,#

4,

.. ;t

~M'

2) 1

30°C

90%

M

eOzC

J)H

IT

~ "

"C0

2 H

CO

zH

(±)-

a-ka

inic

ac

id

12

34

1232

0\ i o ~ 0-

m § 0- 1

HN

"C0 2

t-Bu

;""C

~H E~C

1235

1) B

H3,

TH

F,

-IS

°c,

57%

2)

TB

SC

l

NEt

3. D

MA

P.

CH

2C12

. rt.

92%

HN

"C0 2

t-Bu

;""

CH

20T

BS

E~C

,C0 2

tBu

1) yBf

N

aH,H

MP

A,7

7%

2) L

iTM

P, T

HF

3) P

hSeC

l 4)

30%

aq.

H20

2 48

%

C0 2

t-Bu

Y7~~'

130

°C

/40

hr

PhC

H3

70%

'"

.... Y2

OTB

S

C~:Et

I)T

BA

F, T

HF

2) J

ones

[0]

60%

3) L

iOH

. MeO

H

4) T

FA. C

HC

1 3•

56%

• N

H

.......... D·'·

'co2H

J "lC

02H

E~C 12

36

(-)-

a-ka

inic

aci

d 12

34

Sche

me

197.

Opp

olze

r Sy

nthe

sis

of (

-)-c

x-K

aini

c A

cid

~

::I. ~ i o > ~ -..

.J

i"O

H

S~

'=N

+

1239

~C~Et

~CH2C~OBn

o 12

38

1) H

2,P

dlC

2)

Jon

es 4

8%

3) C

H2N

2 4)

Ph 3

P=C

H2

TH

F

57%

Hl~" 0

S '.

-: "'"

1)

BU

3SnH

2)

HC

l, E

tOH

, n

,C0

2t-B

u

Et3

N

CH

3CN

65%

, N

';r'

0~

c~CH20Bn

3) t

-BuO

C0 2

C0

2t-B

u 67

%

';ry..co,~

C~CH20Bn

,C0

2t-B

u

'ry..~

CH

2C0 2

CH

3

1242

1240

1) K

OH

,MeO

H

2)T

FA

3) A

q,N

aOH

H

'r-Y,"c

o,H

CH

2C0 2

H

(±)-

a.-a

llok

aini

c ac

id 1

228

Ove

rall

yie

ld

11 %

1241

Sche

me

198.

Kra

us S

ynth

esis

of (

±)-c

x-A

lloka

inic

Aci

d

00

r > ~ 8- 1 f

,Bn


1) Ph3P=CH2,

79% o .....-/ C02Me U # . \/ ~OTBS N • I 175°C, 70% Bn

sealed tube

rC(c- 2) TBAF, 95%

3) Jones 4) CH2N2,

60%

..

azomethine y lid 1 ,3-di polar cyc1oaddition.

1244

1) ACE-C!, 61% ..

2) NaOH, 1'1,91%

OTBS

1243

,H 'ret "COOH

COOH

(±)-a-allokainic acid 1228 along with 45%

C-2 epimer.

Scheme 199. DeShong Synthesis of (±)-IX-Allokainic Acid

hydroxide gives a 1: 1 mixture of (± )-IX-allo-kainic acid (1228) and ( ± )-2-epi-lXallo-kainic acid. The natural product 1228 is obtained in 8.5% yield over 7 steps.

Knight's synthesis [326J of ( - )-IX-kainic acid (1234) is outlined in Scheme 200. The lithio anion of carbamate, derived from L-aspartic acid is N -alkylated with allylic chloride 1246 to give compound 1248. Lactonization of 1248 gives nine-membered azalactone 1249. The stereocontrolled enolate Claisen rearrangement of 1249 proceeds via a boat-like transition state to give substituted pyrrolidine 1250 as a single isomer. Homologation of the C3 carboxyl group, desilylation and oxidation gives diester 1251 which is converted to ( - )-IX-kainic acid 1234. Fifteen steps were required with an overall yield of 3.3%.

The most recent offering in this area is a rather lengthy enantiospecific (but not diastereospecific) preparation of both (- )-IX-kainic acid and (+ )-IX-allokainic acid by Baldwin [327J (Scheme 201). Reaction of optically pure epoxide 1252 with isonitrile 1253 provides an acyclic carbamate which upon treatment with base opens the epoxide in an intramolecular fashion to give amine 1254 after hydrolysis. Cobalt-mediated cyclization of the iodide derived from 1254 gives pyrrolidine 1255 as a 1.7: 1 mixture of diastereomers. The mixture is separated, converted to acids 1256 and then to 1257 and 1258 in a total of 17 steps.

3.1.4 Domoic Acid

The closely related domoic acid (1263) isolated from the red alga Chondria armata (Okamura) [328J exhibits similar neurobiological activities and is in

CO

zMe

( M

e2C

uLi,

TH

F .. -7

8°C

, 90%

TH

PO

A

THPO

C

OzM

e

1) t

-Bu2

AlH

, Et 2

0,

_70°

C, 9

0%

2) M

eSQ

zCl,

LiC

l,

s-co

llidi

ne,

DM

F,

0°

C,6

0%

THro~a

12

46

CO

zEtO

TIPS

Li

~ NJ",/

HO

zC 70

%

1) L

DA

, TB

SCl,

90zE

t 1)

PPT

S C

OzE

t O

TIPS

T

HF

O

TIPS

-c)~

~N)I

HO

zC

TH

PO

1248

,CO

zEt

W' .... /O

TIP

S

HO

zC

1250

MeO

H 9

5%

.. f

.'

2) 2

-chl

oro-

l-m

ethy

l-°

py

ridi

nium

iod

ide

°

MeC

N,

80°C

, 42%

12

49

1) (

CO

Cl)

z, E

t 20

, 2)

CH

2N2,

Et 2

0,

3) P

hC

0 2A

g, E

t3N

MeO

H67

%

4) H

F, T

HF

90

%

5) J

ones

(0]

, 62%

CO

zEt

, N

yZ

j"''I

COZH

I {

co

zM

e

1251

Sche

me

200.

Kni

ght

Synt

hesi

s of

(-

)-a.

-Kai

nic

Aci

d

-100

-20

°C

2) K2C~, M

eOH

,

1) T

MSI

, py

r,

CH

Cl 3

,60

oC

2) K

OH

, H

20,

20°C

, 70%

H20

, 20

°C,

55%

yZ

JH

I {_

""'CO

zH

CO

zH

(-)-

a-ka

inic

ac

id

12

34

......

o r >- ~ [ 1 f

~OH

BO

O)

1)~NCO

1'253

_

2) N

aH, T

HF

3)

NaO

H

1252

~WH

H~

) \..

. •• O

H

BoO

12

54

1) C

IC0 2

Ph

2) T

BSC

I

3) N

aI/T

FA

A

pyr

Chl

oroc

obal

oxim

e(II

I)

~N-~

1) N

a/N

H3

>r;-

~ M

eOH

, 0 D

C, N

aOH

, 2)

BnO

CO

CI

• ~_OTBS

3) T

sOH

/ M

eOH

CO

OH

NaB~

4) S

wem

5)

Ag 2

0 B

oO

BoO

CO

1255

12

56

Sche

me

201.

Bal

dwin

Syn

thes

es o

f ( -

)·ot· K

aini

c A

cid

and

(± )·

ot·A

lloka

inic

Aci

d

\-/'.

...

~C02Ph

~'N

In OTB

S )

~-B

oO

1257

~-

isop

rope

nyl

(-)-

a-K

aini

c A

cid

5 -

6 st

eps

27%

•

1258

a-

isop

rope

nyl

(+ )-

a-A

llok

aini

c A

cid

14%

-< i· r i .....

. .....

.

I) C

IC0 2

Et,

Et3

N,

0 T

HF

, _1

0°C

0

I) L

DA

, T

HF

, 0

~ 2

) N

oB'"

B

oc-N

•

Bo

c-N

•

Bo

c-N

I

:9 P

hSO

<:I

,-78

°C :9

90%

EtO

H

2) 0

3, C

H2C

I2

H0 2

C

_10°

C

TBSO

-7

8°

C

TBSO

1

26

0

3) T

BS

Cl,

DM

F,

imid

azol

e

I

1) 0

3, C

H2C

l2,

_78°

C, D

MS

,

2) C

H2N

2

3) M

e E

t ~O

0 ...

...

o~."yo

Bo

c-N

:: •

• oJ

'I

CH

P2C

C

0 2M

e

TsO

H

40%

fro

m 1

261

70%

fro

m 1

26

0

12

61

3) P

OC

, DM

F

Boc

-l-')'Y

"\

4) C

H2N

2, y

.... , 0

..../

70%

fro

m 1

261M

e02C

I C0

2Me

1) B

H3-

DM

S 2)

MeO

H, T

sOH

1261

)OT

MS

0

H

;

PhC

H, ~

• B

oc-N

I

135°

C,

OTM

S

seal

ed tu

be

TBSO

H

1) 6

0% A

cOH

,

60

°C

, 64%

2) P

h 3P=

CH

OC

H3

3) P

hSeC

I E

t3N

,

90%

~ ... J

CH

O

Bo

c-N

'"Y

.""

Se

Ph

Me

0 2C

I C

0 2M

e

I) N

BS,

T

HF

, R

T

2) A

q.

NaO

Ac,

67

%

'I')

B

OC

-Ny: •

•• ,)H

O

Me0

2C

I

1) Ph3P~OH •

Ph3P

, P

hMe,

110

DC,

35%

"\

BOC-N~:" ~

Me0

2 C M~:

1 Mc0

2C

1) 2

.5%

KO

H,

rt

2) T

FA

, rt

3) N

aOH

, 10

0%

'1"".\

HNy

.. ~

H02

C

H~:~

C0 2

Mc

2) J

ones

[01

HO

zC

3) C

H2N

2 (-

)-do

moi

c ac

id 1

263

Sche

me

202.

Ohf

une

Synt

hesi

s of

( -

)-D

omoi

c A

cid

......

N ~ t:I

0 > o. j;>..

en 8- "t:I

(11 I en


Domoic Acid 1263

short supply due to the small amounts available from marine sources. Ohfune's synthesis of 1263 is presented in Scheme 202 [329]. N-tert-Butoxycarbonyl-Lpyrroglutamic acid (1260), available from L-glutamic acid, is converted to unsaturated lactam 1261, thus setting the stage for the ensuing Diels-Alder reaction. Cyc1oaddition of 1261 with 2-trimethylsilyloxy-1,3-pentadiene sets the cis-stereochemistry of the nascent sidechains and provides the functionality needed for further elaboration. Ozonolysis and reductions complete the lower sidechain, which is protected as an ester, and removal of the amide carbonyl gives acetal 1262. Elaboration of the upper sidechain via selenoxide elimination and Wittig olefination sets the proper geometry of the diene system and completes the synthesis to give ( - )-domoic acid in 24 steps and 2.6% overall yield.

3.1.5 Tetraacetylclionamide

Ethanol extracts of the sponge Cliona celata, collected in the northwestern Pacific near British Columbia have been found to show in vitro antibiotic activity against Staphylococcus aureus. Unfortunately, all attempts to isolate and purify the active constituent of the ethanol extracts were unsuccessful. To circumvent this problem, the crude extracts were partially purified and acylated by treatment with acetic anhydride and sodium acetate. Mter isolation, the major component proved to be the 6-bromotryptophan enamide derivative tetraacetylclionamide (1268) [330]. Schmidt's synthesis [331] of 1268 is

NHAc a 'P N

"..&; OAe

I~'O ~ Br ,4P N, YOAe

H OAe

Tetraacetylclionamide 1268


illustrated in Scheme 203. The preparation of 1268 is guided at all stages by the knowledge that care must be taken to avoid deacylation and transacylation reactions. The synthesis is initiated by the conversion of the acid chloride of triacetyl gallic acid (1264) to azido ketone 1265. Azide 1265 is reduced to the amine and acylated with the pentafluorophenyl ester of S-BOC-6-bromotryptophan to give amide 1266. Reduction of the ketone and elimination to the enamide 1267 followed by deprotection gives the acylated natural product 1268 in 9 steps and 25% overall yield.

3.1.6 Demethyldysidenin and Demethylisodysidenin

(+ )-Demethyldysidenin (1275) and (- )-demethylisodysidenin (1276) (as well as dysidin cf 6.3.9) are among the very few naturally occurring compounds containing the trichloromethyl functionality. These three metabolites have all been isolated [332] from the Indo-Pacific sponge Dysidea herbacea. Demethylisodysidenin (1276) has been reported to exhibit antihypertensive activity when administered intravenously [333].

{+)-Demethyldysidenin 1275 (-)-Demethylisodysidenin 1276

The chiral building block for Williard's syntheses [334] of (+)demethyldysidenin and (- )-demethylisodysidenin (1276) (Scheme 204) is obtained by resolution of the half-acid ester of f3-methylglutaric acid with either cinchonidine or quinine. Chiral acid 1270 is converted to the dichloroaldehyde 1271 and then to a key fragment, trichloromethyl aldehyde 1272. Jones oxidation of 1272 gives a second key fragment, trichloromethyl acid 1273. Utilizing the one-flask "four component peptide synthesis" described by Ugi [335], combination of 1272, 1273, isonitrile 1274 and methylamine gives optically pure 1275 and 1276 in 17% and 13% yields. Demethyldysidenin (1275) and demethylisodysidenin (1276) are produced in 9 steps and 2.1 and 1.6% overall yields respectively.

OA

c C

IOCII

Y

"('O

AC

OA

c

1264

NHBoc

1) C

H2N

2 E

t3N

I E

t20

2) a

q H

CI I

dio

xane

3) N

aN3

I ace

tone

74%

N3

~ ~o

OA

c

. I ~

OA

c

OA

c

1265

I) N

aBH

3CN

T

IfF

I) H

2 Pd

I di

oxan

e;

aqH

CI

vY

2 )

~HB:

¢~ F

I

-..;::

~ 0

I .&

Br

.&

N

F

F

if

F

63%

NHR

.. H

~N"~O

~ O

Ac

Br V

J U

I ~

'H

OA

c

2)

o-02

NP

hSeC

N

BU

3P

/TIf

F

~N~I~OAC

Br V

J U

~ 'H

O

Ac

3) N

aI0 4

aq

MeO

H

OA

c

1266

Sche

me

203.

Sch

mid

t S

ynth

esis

of

Tet

raac

etyl

clio

nam

ide

61%

I)C

F3C

OO

H

2) A

C2

88%

OA

c

[ 12

67

R =

Bo

c

1268

R =

Ac

tetr

aace

tylc

lion

amid

e

-es

tabl

ishe

d ab

s co

nfig

urat

ion

-N

P s

truc

ture

elu

icid

ated

as

tetr

acet

y I d

eri v

ati v

e

i ~ ~ ::I o i .....

Vl

0 1)

BH

3-T

IlF

0 Jo

nes

[0]

D

2) p

cc, C

H2C

l 2 n

1) A

q. K

M"O

,. 65

'c

CC

l, 0

CC

I 3

0

CH

3.$

0

OC

H

.. C

I 0

~

.. CH3~OH

, ..

CH

3.$

H

ac

eton

e H

H

3 3)

t-B

uNH

2,

CH

3 H.

$ O

CH

3 2)

Pb(

OA

c)4,

LiC

I,

H

C6H

6, 8

0-85

DC

15 D

C

1270

C

CI 4

, 10

DC

4) N

CS,

H30

+,

1271

3)

DIB

AL

, to

luen

e,

38%

-7

8 D

C;

38%

C=N~N

s~

12

72

+

1

27

3

12

M

C~

_C

I3C

I

MeN

H

f(X-' N

'r!"(H

M

eOH

2

CH

' H

.$

, •• , C

Cl3

,rt

3 H

0

-is

onit

rile

127

4 w

as p

repa

red

in t

wo

step

s fr

om 2

-(am

inom

ethy

l)th

iazo

le

o ~N

CH'

sJ

(+)-

dem

ethy

ldys

iden

in 1

275

17%

yie

ld

+

Sche

me

204.

Wil

liar

d Sy

nthe

ses

of (

±)-

Dem

ethy

ldys

iden

in a

nd (

-)-

Dem

ethy

liso

dysi

deni

n

1272

85

%

CH

3 I

H

CI3C~N'r!"( .. C

CI3

CH3HH~O

CH

3

o ~N

sJ

(-)-

dem

ethy

liso

dysi

deni

n 12

76

13%

yie

ld

1273

......

0\ i o ~ oo [ i. g- oo

Brominated Tyrosine Derivatives 17

3.2 Brominated Tyrosine Derivatives

3.2.1 Quinols

The quinol 1279 first isolated from the sponge Verongia cauliformis exhibits broad spectrum antibiotic properties [336]. A similar quinol 1283 has been isolated from the mollusc Tylodina fungina [337]. The first synthesis of 1279 is that of Sharma and Burkholder [338] in 1967 (Scheme 205). Bromination of acid 1277 and amide formation gives bromoamide 1278 (no description of these two steps was given). Oxidation of 1278 with nitric acid provides the natural product in three steps. An improvement on this methodology was developed by Yamada [339]. Formation of the amide by reaction with aqueous ammonia and diphenyl phosphite provides 1278 in 70% yield. The natural product is obtained by thallium(III) perchlorate oxidation of 1278 in 82% yield.

B'~& H~

CONHz

&~& H><;

COzEt

Verongia Metabolite 1279 Tylodina Metabolite 1283

OH OH

~ bromination ..

'COOH

BryYBr ~.

1277

OH BryYBr ~.

CONH2

TI(Cl04h aqHCl04 0°C/8hr (Yamada)

82%

or ..

HN03/HOAc (Sharma)

COOH

o II

(PhOhPH / pyr

aq NH3

70%

o

BrnBr HX

..

1278 Verongia metabolite 1279

Scheme 2OS. Syntheses of the Verongia Metabolite 1279


0

"V" TMSCN •

Ph3P

0 100%

1281

~OLi OEt ______

-----77%

THF -100 °C

o

BrnBr

HX COOEt

Tylodina metabolite 1283 ~fu ~282 ~ Br9;° Br 1 37%

N(TMSh I I

(desilylation by AgF / aq THF) HO CONH2

Verongia metabolite 1279

Scheme 206. Evans Synthesis of Verongia Metabolites 1279 and Tylodina Metabolite 1283

Evans [340] has prepared both 1279 and 1283 from a common precursor (Scheme 206). Reaction of quinone 1281 with TMSCN affords dienone 1282 which upon reaction with the lithium enolate of ethyl acetate gives 1283 in 77% yield. Addition of the lithium enolate of N,O-bis(trimethylsilyl)acetamide to 1282 gives 1279 after desilylation with silver fluoride in 37% yield. Fischer [341], in conjunction with studies on functionalized organolithium reagents, has simplified the approach of Evans to do away with the need for monoprotection of the quinone 1281 (Scheme 207). At low temperatures, addition of ethyl

o

"V" • -CH2C(hEt,

THF

o 1281

o

"V" HO CH2COOEt

1283 59% plus 22% hydro·

quinone and 12% dienol and 6% of other dienone

"V" ::TMS. o fuV·,

o 1281

HO CH2CONH2

1279 60% plus 37% hydroquinone and 2% dienol

and I % of other dienone

Scheme 207. Fischer Synthesis of Verongia Metabolite 1279 and Tylodina Metabolite 1283

Brominated Tyrosine Derivatives 19

lithioacetate to brominated quinone 1281 provides Verongia metabolite 1283 in 59% yield. In a similar manner, addition of the lithium anion of N,Obis(trimethylsilyl)acetamide to 1281 gives 1279 in 60% yield.

3.2.2 Aplysinadiene

The rearranged dibromotyrosine derivative aplysinadiene (1287) was first isolated from the sponge Aplysina aerophoba collected near Graciosa Island, Canary Islands. The isolation and synthesis (Scheme 208) of (1287) is described by Norte [342]. Benzylic oxidation of 1284 followed by Baeyer-Villiger oxidation and methylation provides 1285 in 43% yield. Chloromethylation of 1285 sets up the transformation to lactone 1286 which is converted to aplysinadiene via aldol condensation and elimination. Aplysinadiene 1287 is obtained in 9 steps and 15% overall yield. Other isomers of 1287 were prepared in a similar manner to confirm the identity of the natural product.

o

Br

Aplysinadiene 1287

1) Cr03 / AC20 1) HCHO/HCl

"'11 2) H30+ / 25°C B'x;rOMO 100°C .. 1# ..

HO # 3) MCPBA MeO 2) KCN / DMSO

Br 4) Me2S04 / K2C~ Br 3) H+ reflux

1284 43% 1285 4) BF3 / CH2Cl2

59%

Brxrro

1 0 MeO #

NaH/THF Br

.. o

Br OHC~

Br

60%

1286 aplysinadiene 1287

Scheme 208. Norte Synthesis of Aplysinadiene 1287


3.2.3 Aerothionin, Homoaerothionin and Aerophobin-l

Aerothionin (1295) and homoaerothionin (1296) are novel tyrosine-derived metabolites containing spiroisoxazoline moieties. These substances have been isolated from the sponges Aplysina aerophoba, A . .fistularis and Verongia thiona. Their relative and absolute configurations have been determined by X-ray crystallographic analysis and circular dichroism studies [343]. Also isolated [344] from these sponges are the related spiro compounds aerophobin-1 (1294) and -2. Yamamura [345] has prepared aerothionin (1295), homoaerothionin (1296) and aerophobin-1 (1294) as shown in Scheme 209. Azalactone 1290 is prepared from aldehyde 1289 via known chemistry. Conversion of 1290 to 1291 occurs in five steps and sets the stage for formation of the spiroisoxazoline substructure. Oxidation of oxime 1291 with TI(OTFh affords the spiro compound 1292 in 27% yield. Zinc borohydride reduction of 1292 affords the key intermediate 1293 in 29% yield along with 40% of the cis isomer. Reduction with sodium borohydride gives only the cis isomer. Condensation of 1293 with histamine affords aerophobin-1 in 8 steps and 1.7% overall yield. Condensation of 1293 with l,4-butanediamine or 1,5-pentanediamine yields 1295 and 1296 in 0.37 and 0.089% yields respectively, over 8 steps. Although it is not known with certainty, it is possible that diastereomers of 1295 and 1296 may have been formed due to the coupling of racemic fragments.

HN"\. o 0

/(CHVn N ON

o ~N NH

H H

Bf Bf

OMe OMe OMe

Aerothionin (n = 4) 1295 Homoaerothionin (n = 5) 1296 Aerophobin-l 1294

3.2.4 Bastadins-l, -2, -3 and -6

Bastadins-1, -2 and -3 are dimeric tyrosine derivatives composed of four Tyr units. Bastadin-6 is a 28-membered ring lactam ether that is structurally related to bastadin-2. These metabolites were isolated from the Verongid sponge Ianthella basta by Wells [346] in 1980. They possess potent in vitro and some in vivo activity against Gram-positive bacteria. Yamamura [347] has completed syntheses of all four of these compounds in a highly efficient manner. 3-Bromotyramine (1297) and the oximes 1299 and 1300 were required for bastadin

0 0

""O

ON

* --

{ I)

KO

H

BnO

-:7

CH

O

N

aq d

ioxa

ne

•

2) N

H2O

HoH

CI

1 "~*

BnO

~

Br

1 •

aqK

OH

B

r

~

B

know

n

Br

3) B

nCI

OM

e

Br

r ch

emis

try

K2

C0

3/D

MF

O

Me

OM

e 1

28

9

I) K

2C0 3

/ M

eOH

2) H

2 Pd

di

oxan

e / H

OA

c

74%

1290

35

%

HN~

o ~N

NH

CO

OM

e

HOON *

~~~

,

BnO

T

I(O

Tt)

°

-:7

1 3

. o

Zn(B~h

~

CF 3

CO

OH

~

1 C

H2C

I 2 /

Et2

0 B

r B

r 2

5°

C /

4 hr

B

r B

r 2

5°

C /

7 m

in

OM

e O

Me

27%

CO

2 M

e ~

, H

N-"

N=

\ ~N

O~)

H2N

"'

-

• 82

%

Br

Br

Br

OM

e O

Me

1291

12

92

1293

(2

9%)

aero

phob

in-I

12

94

alon

g w

ith 4

0%

°

0 o

f the

cis

isom

er

N/ (C

Hzl

n H

'N

H

H

2N(C

H2)

4NH

2 / 2

5°C

HO

o

r

H2N

(CH

2)5N

H2

/ 25°

C

Br

OM

e O

Me

-rac

emic

pie

ces

wer

e co

uple

d; t

here

fore

tw

o di

aste

reom

ers

n =

4 a

erot

hion

in 1

295

(18%

) "m

ay"

have

res

ulte

d; a

utho

rs "

have

no

solu

tion

for

it"

n =

5 h

omoa

erot

hion

in 1

296

(4.4

%)

Sche

me

209.

Yam

amur

a Sy

nthe

ses

of (

± )-

Aer

othi

onin

, (±

)-H

omoa

erot

hion

in a

nd (

± )-

Aer

opho

bin-

l

~ I ~ (3 5' " w I· N

......


Bastadin-2 (X = Br) 1304 Bastadin-l (X = H) 1309

Br

Bastadin-3 1311

synthesis. The oximes were produced in a manner similar to analogous compounds used in Yamamura's aerothionin synthesis. 3-Bromotyramine (Scheme 210) was prepared from 3-bromo-4-hydroxybenzaldehyde. Phenolic dimerization of oxime 1299 using TI(N03h (Scheme 211) produced isoxazoline 1301 in 44% yield which was quantitatively reduced to the phenolic dimer 1310. Reaction with 1302 followed by removal of the PMB group gave bastadin-2 (1304). In a similar fashion, dimerization of 1300 with Tl(OTF Ah gave rise to a mixture of products in low yield, including 1301, 1305 and 1306. Compound 1301 was reduced to the analog 1302 to provide bastadin-1 (1309) after deprotection. To produce bastadin-3, the bis-spirooxazoline 1307 was reduced to 1310 in 8% overall yield from 1300. Reaction of this substance as before with protected 3-bromotyramine followed by phenolic deprotection led to bastadin-3 (1311). Assuming that no E -+ Z oxime equilibration took place during the procedures, these syntheses establish the E-oxime configurations in these four metabolites and presumably others in the series as well.

1) AC20 I pyr 2) NaBH41 diglyme

3) Zn/HOAc diglyme

51%

.. Br

PMBO~

~ NH2

3-bromotyramine 1297 (PMB ether)

Scheme 210. 3-Bromotyramine Synthesis (Yamamura)

C0

2M

c N

_

O

OH

I

I

:::,.. ?9

0 o

CF3

CO

OH

r

7 I

+

25

°C

/20

hr

:::,..

MeO

0

N'O

H

MeO

C

MeO

2

C0

2M

c

Br

Zn

------

THF

HO

Ac

MeO

N

'OH

~OH

N

Br

1299

x=

~r ~

Tl(N

03h

N' O

H

1300

=

X Y

= Br

(4

4%)

1301

'_

H Y

= B

r (6

%)

1310

(8

% o

vera

ll fr

om 1

300)

Zn

TH

F/H

OY

N ....

OH

/

MeO

o ,'-'

:

1305

X

-~

H

(5%

) --

1306

X

, Y

-

.... O

H I)

3-b

rom

otyr

amin

e \

(PM

B e

ther

) 13

3 2)

TF

A /

CH

1CI 1

H

~N

HO~

HO

O

Br

Br

Br

.4-

o B

r

o :::

,..'

MeO

HOY~~~~

HO~N

?9XO

H H

N

Br

3-br

omot

yram

me

I) P

MB

O,(

(:P

MB

eth

er)

7 ,

1303

:::,

.. N

H2

2) T

F A

/ C

H1C

I 1

HO~

0

~N

H

N ....

OH

N ....

PMB

= p

-mct

hoxy

bcnz

yl

OH

1302

X

= B

r (f

rom

130

1, 1

00%

) l3

08

X

= H

(fr

om l

30

5,

4R%

)

Sche

me

211.

Yam

amur

a Sy

nthe

sis

of B

asta

dins

-l,

-2 a

nd -

3

....O

H

X =

Br

bast

adin

-2 l

30

4

(30%

) X

=H

ba

stad

in-1

1309

(2

1%)

bast

adi n

-:; l

31

1

geom

etry

of

oxim

e sh

own

to b

e an

ti in

NP'

s

~OH

N

!:Ii .... 0 ~, II

I

Br

c; I=>-

>-l

'< .., 0 '" 5'

" t:I " ::I. < ~ .

< " '" N

\.;.

J


BrN:»N.OH

'.& 0 ,~

~o Br ?90 Br.& Br HO r p,OH

P, 0 Br:='" N H N'OH

Bastadin-6 1316

Bastadin-6 was synthesized [348] from the penultimate intermediate in the bastadin-2 synthesis and requires an intramolecular, and perhaps biomimetic, phenol oxidation (Scheme 212). Benzylation ofthe oxime hydroxyls of 1312 and removal of the PMB groups gave 1313. Addition of two bromines was accomplished in high yield providing 1314. Cyclization via T1(N03h oxidation gave macrocycle 1315 in 13% yield along with an undesired isomeric substance. Zn reduction of the quinol ether to the phenol and debenzylation yielded bastadin-6. Previously, this group had prepared bastadin-6 trimethyl ether via a similar route [349]. Although several of the yields in these processes were low, the directness of this biomimetic approach is laudable.

3.3 Peptides

A number of cyclic and acyclic peptides [350] isolated from marine organisms. exhibit a variety of biological activities. In particular, the anticancer properties of dolastatin-3 and -10 and various didemnins have attracted many groups to participate in this area. Synthesis has been particularly important in this area since many of the compounds are available in only very small amounts in amorphous form, making them untenable substrates for X-ray crystallography. Indeed, several of the originally proposed structures have been reassigned by synthesis. Although much of the work is comprised of well-known peptide synthesis techniques, the presence of several unusual amino acid units and nonamino acid sequences in many metabolites required more than classical amino acid coupling chemistry. We have used generally accepted acronyms in referring to the various reagents commonly used in peptide synthesis. Syntheses of marine polypeptides containing only common amino acids or > 15 residues have been omitted [351].

H

N,O

H

PM

BO

Y

0 '"

~N~

Br

I °

h B

r

Br?

9

BR

r PMBO~

9'

lOll

I

0 ~

~

N H

N 'O

H

13

12

TI(

N0 3

h / M

eOH

• 4

°C /

3-4

hr

"OR

HO

Y

0 I)

BnC

l /

K2C

03

DM

F

2)C

F3C

OO

H

CH

2Cl2

82%

~~~N

Br

I'"

o h

Br

B~B

Br

HO~

9'

lOR

~O~

N

H

N , O

R

1313

R

=H

=

Bn

')t'-~

&'

~O: '

~r ~~8r

o 9

' O

il

'"

I n

o ~

8r ~

N

I) Z

n H

OA

c/T

HF

2) H

2/H

OA

c P

d bl

ack

74%

..

OM

c H

N

13

15

13

%

, 08

n

alon

g w

ith 1

0% o

f an

iso

mer

ic m

acro

cycl

c

Sche

me

212.

Yam

amur

a Sy

nthe

sis

of B

asta

din-

6

Br2

/CH

Cl3

25

°C

/ 25

min

82%

.... 0

8n

8r~~~N

HO

Y

0 '"

B

r I

?90 B

:'" B

r B

r r

9'

HO~

IOB

n

I 0 ~

Br ~

N

H

N

1314

" OB

n

')?"-~

rS:"

~o : 8~;

9Br

HO

9

' 9

' I

OH

I

0 ~

8r ~

N

H

N , OH

bast

adin

-6 1

316

1 5: C> '" tv

VI


3.3.1 Didemnins

The cyclic depsipeptides didemnins A, Band C were originally isolated by Rinehart from the tunicate Trididemnum solidum and have subsequently been found in other Trididemnum sp. Didemnin B was the first marine natural product to enter clinical trials as an anticancer agent, hence its synthesis has engendered much interest. The original structural assignment has been corrected by synthesis. Rinehart [352] has described a route to didemnins A, B and C using classical peptide synthesis techniques to couple common amino acid and uncommon moieties which make up this metabolite. Dipeptides 1318 and 1319 were constructed (Scheme 213) via standard chemistry and then connected to give the larger fragment 1320. The mixed fragment 1323 was prepared from optically pure acid chloride 1321 which was prepared from L-Val (Scheme 214). Reaction with the half-acid 1322 gave 1323 as an inevitable mixture of isomers. It is reasonable to assume that such a stereo-labile center would exist in the thermodynamically preferred orientation in the natural product and this was borne out in the Rinehart and the later Shioiri and Schmidt work as well. The mixture of diastereomers was carried on through the synthesis. Coupling with leucine provided the larger unit 1324 which was further coupled to 1320 providing the seco-peptide 1325. Deprotection and cyclization via macrolactamization led directly to didemnin A (1326) which served as the precursor to both didemnins B and C. Modification of the leucyl side chain gave rise to didemnins Band C.

DidemninA

)"PMo RNM/;X;~o o~~

PI ~

OMe

Didemnin B R =

Didemnin C R =

~~ o 0

OH

~ o

Schmidt has also synthesized didemnins A, Band C using a different strategy [353]. The major fragment 1329 is equivalent to fragment 1324 in the Rinehart synthesis and was also built up from (S)-a-hydroxyisovaleric acid (Schemes 215 and 216). However, the similarity ends here, as the remainder of the synthesis

Boc EDC 89%

• 2) Hz, PdlC,

HOAc, 80%

.. NHS, EDC, 0 °c, 43%

I) DMAP, DCC,

o °c, 89% 1318 + 1319 ..

2) HCI, EtOAc, n, 100%

Scheme 213. Syntheses of Didemnin Fragments (Rinehart)

Peptides 27

P OMe

I Boc 0 #

Crz, ",," 1318

OMe

takes a different strategic, if not operational approach. Macrolactamization was carried out between the Pro and Leu residues on a substrate which carried an unadulterated Thr amino group to provide 1331 (Scheme 217). As before, ring closure was accompanied by slow epimerization of the methyl group at C2 of the 1st unit to provide a single peptolide isomer. Simple modification of the Thr amino group led to didemnin A and from there to didemnins Band C.

More recently, Shioiri has described a highly efficient convergent approach to didemnins A and B [354]. Two large eastern and western fragments (Schemes 218 and 219) were produced by standard chemistry. As in the Rinehart syntheses, a mixture of diastereomers at the C2 position of the Hip residue was generated (1334). Thus, methylation of the acylated Meldrum's acid 1333 (Scheme 218) proceeded without selectivity to produce 1334 as a mixture which

o

Bn

00

cI

iPr

1321

NH

Boc

VyC

OZ

H

....J

ems

DM

AP,

DC

C,

o DC,

84%

o 0

I)HO~OEl

Me

1322

2)

aq

KO

H,

61%

o 0

Bn

o0

00

H

i-Pr

Me

1323

(B

n-H

ip-O

Et)

\) r

H2N

C

02T

MS

c H

OB

t,

DC

C,O

°C

2) H

2o P

d/C

, i-

PrO

H,

71%

~HBoc

."l

o 0 L

HO~

Jl J

l Y

"(

-N

i-P

r M

e H

C

O2 T

MS

e

I) T

BA

F

; 0

0 ~ __

~ )c

'(00

~pN H

C

02 T

MS

e 2)

Fra

gmen

t 13

20

BtO

H

1-r

Me

13

24

E

DC

0 D

C,

53%

I) T

BA

F,

RT

2)

TF

A

94%

N

HB

oc

0 0 ~~Me 0

;: ~

;: 0

0

I II

' H

. :

: ~

! 0

1

NH

Me

ya'

0 N

N~:

..• "N

OH

0

i-~r

Me

0 o~

TM

Se0

2C

0

3) N

MM

, B

tOH

E

DC

,rt,

18%

1325

~

~ 4)

H2

, Pd

/C,

88%

:::::-

-

MeO

N

00

f. o ~ ~ 8- 1 ~

) O

H O~

"···PO

~

) O

H O~

"···P

o ~

M1~X

;~~~

o N

H

0 o

::c 0

NH

~1(i~~~

I)R

-OH

. D

CC

2) H

z. P

d/C

.

OM

e

Did

emni

n A

132

6 D

idem

nin

B

R =

(n

o yi

eld

data

) J)-

CY

o O

H

Did

emni

nC

(37%

yie

ld)

R=,

)y

o

Sche

me

214.

Rin

ehar

t S

ynth

eses

of

Did

emni

ns A

, B

an

d C

OM

e

dl I ~


1) i-C5H90NO, AcOH MeOH,HCl

2) DEAD, PPh3, HN3 3) H2, Pd, HCl, 60% .. 4) FmocCI, pyr 87% 5) aq HCI, dioxane 90% 6) SOClz, CH2CI2 91 %

Fmoc = 9-Fluorenylmethy1carbonyl

NHBoc 1) TBSCI, imid DMF 100%

.. i\::'C02H OH

diastereomer was separated

2) aq NaOH, diox 20°C, 100%

from the two obtained from condensation by recrystallization after the [R I step

Scheme 215. Synthesis of Didemnin Fragments (Schmidt)

1) Me02C-CHLi-C02TMS

2) NaBH3CN, AcOH ..

3) aq HCI, dioxane

4) aq NaOH, 40°C, BOC20

80%

NHBoc

~C02H OTBS

1328

was carried through the synthesis. Coupling of the large fragments via ester formation followed by macrolactamization gave didemnin A directly (Scheme 220). As in the Rinehart synthesis, didemnin B was prepared by coupling with a Lac-Pro unit followed by deblocking.

Nordidemnin B is a minor component of Trididemnum cyanophorum, differing from didemnin B by lacking a methyl group on the isostatine (1st) residue. Jouin [355J has synthesized this minor metabolite by assembling three large fragments as shown in Schemes 221 and 222. Combination of 1340 and 1341 provided the seco peptide 1342 (Scheme 223). Palladium-promoted deallylation was followed by removal of the acetonyl group and BOP-aSsisted macrocyclization and deblocking gave the peptolide ring 1343. Coupling with fragment 1338 then provided a synthetic product which was identical using several criteria to naturally-derived nordidemnin B.

3.3.2 Jaspamide

The cyclodepsipeptide jaspamide (jasplakinolide) was isolated by Faulkner [356J and by Crews [357J from Jaspis sp. (sponge). Two unusual amino acid units, ~-tyrosine and 2-bromoabrine, are incorporated into this metabolite as well as a polypropionate stretch containing methyl branching at alternating carbons. This metabolite exhibits a broad spectrum of activities including insecticidal, antiparasitic and antifungal properties. An enantiospecific synthesis of 1354 has been reported by Grieco [358]. A large fragment containing the two

XOOH

H

O

1) C

ICH

2CO

Cl,

pyr,

CH

2Cl 2

2) S

OC

I 2, 5

0°

C

79%

C:~OXO

CI 1)

MeC

(Li)

(C02

TM

Sh,

TH

F,

-60

°C

2) a

qK

HS

0 4

20

°C

, 84

%

CI~ Y

I

oo

,H

o O~

o

NH

2 ...

..... C

OzT

CE

I)

= Y

DC

C,C

H2C

I 2

90%

2) (

CH

2)sN

-C(S

)NH

2,

diox

ane,

TE

A,

85%

M; J:I

C0 2

TCE

. N

........

.......

HO

='y

°

0

1) 1

328,

DC

C,

DM

AP

,

CH

2Cl 2

, _20

°C

2) H

F,M

eCN

,

20

°C

, 90%

)JJM

~'(o

,=

NH

2 ~ 0

0 Y

13

29

Sche

me

216.

Syn

thes

is o

f D

idem

nin

Fra

gmen

t 13

29 (

Schm

idt)

d' '0 ~ IoU

.....

C0 2

Bn

ZHN\

···~OH

Fra

gmen

t 13

29

4.6-

Dim

ethy

l-2-

thio

pyri

done

-3-

carb

onit

rile

Ph3P

, CH

zCl z

, -2

0°

C,5

5%

I) 6C

O~:

? M

e

~I

OM

e

DC

C,D

MA

P

CH

zCl z

2)

HC

I, d

ioxa

ne,

90%

O

Me

o NH

I M

e

) O

H oy~

"'··PO~O

o N

H

ZH

NX

=o

OM

c

o N

H

o 0

TC

E0 2

C J..

... i-B

u

N..

,L,.

.. N

"Boc

M~ LJ

Boc

1)

H0 2C

l.)

t-B

u-N

C,

CH

zCl z

75%

2) H

z. P

d, H

CI

100%

3)

Z-C

I. A

q. N

aHC

0 3

70%

I) Z

n, a

q A

cOH

,

100%

2) D

CC

, C

6FSO

H

3) T

MS

OT

f.

CH

zCl z

• 20

°C

4) a

q N

aHC

0 3

CH

CI 3

• 2

0°

C

69%

o o

Boc

z:\)

O

Me

1331

).):J~:P

OM

e

00

lH 1

o 0

y~'-...

~~

1332

W

N > §. o > §:

'" § 0.- i

CH

3

1)~~e 0

6 S

¥C

H

CN

3

2) H

2•

Pd.

60%

) OHOy~

"···PO~O

00

IH 1

00

~

~:C>

O

Me

Did

emni

n A

13

26

D

idem

ninB

(8

5% y

ield

)

Did

emni

nC

(80%

yie

ld)

Sche

me

217.

Com

bina

tion

of

Did

emni

n F

ragm

ents

(Sc

hmid

t)

1) Z

-R-C

I .. 2)

H2

• P

d.

100%

OH

()

R=~N~

o 0

OH

R=~

o

) OHOy~

""·PO~O

OM

e

00

IH 1

00

~

~:O

l ~ ......

......

HOX"

"H

1) T

BSC

I, D

MF

rns~OX 1)

BnO

H, P

hH

rnS~""H

.. 69

%

2) a

q K

2C0 3

...

82%

H

O

0 2)

Mel

, NaH

3) M

eldr

um's

Aci

d 0

77%

0

DE

PC,

TE

A

1333

3)

H2,

Pd/

C,

13

34

TH

F T

HF

----

----

----

----

-

Bn0

2 CY

N~2-HCl +

~

V

Ho 2

e

1) D

EPC

, T

EA

, D

MF

,O°C

. t2

1 B"O'C~"V'''

1) 1

334,

DC

C,

TH

F B

tOH

I N

MM

o D

C, 7

9%

2) T

BA

F, T

HF

90%

2) H

CI,

diox

ane,

HO~O

o t

1 B"

o,C~

"V' "

east

ern

frag

men

t 13

35

Sche

me

218.

Syn

thes

is o

f D

idem

nin

"Eas

tern

" Fr

agm

ent

(Shi

ori)

VJ

~ r i § P

- I

)y-

1) (

Imid

)zC

O

TH

F

2) L

iCH

2CG

.!Et

NH

Boc

T

HF

78

% ..

) 0

1) N

aBJi

(, E

tOH

~

65%

"'"

C

0 2E

t ------

2) a

qNaO

H

NH

Boc

E

tOH

3)

TC

EO

H, D

CC

, D

MA

P, C

H2C

l2

98%

) O

H

" ••.. ~ C0

2CH

2CC

I3

NH

Boc

l) H

Cl,

diox

ane,

rt

2)

C0 2

H

\,.~OBn

Boc

NH

:

DE

PC

, T

EA

, D

MF

3) H

Cl,

dio

xane

, rt

4

) M

e

~_NJ

C02H

B

OC

y D

EP

C,

TE

A,

DM

F 7

1%

)"..

OH

.. ~C02CH2CCl3

1) T

BS

Cl,

im

idaz

ole

DM

F,

rt,

72%

2)

H2,

Pd/

C

TH

F

.. )

OT

BS

' ••••. ~C02H

Me

oo:CN

H

I B

...

. N

oc:y

~'"

lOR.

3) ¢

CO~~

z ~

Me

~I

OM

e D

CC

,DM

AP

C

H2C

l 2

4) Z

n,

aq N

H40

Ac

TH

F 8

9%

Sche

me

219.

Syn

thes

is o

f D

idem

nin

"Wes

tern

Fra

gmen

t" (

Shio

iri)

Me

0 0

yN

H

ROC:

y~"'

~(

wes

tern

fra

gmen

t 13

37

OM

e

o "z

N I Me

i. Co &l w

Vl

1335

+ 1

337

1) D

CC

, DM

AP

, C

H2C

12

78%

2)

H2,

Pdl

C T

HF

3) B

op-C

l, T

EA

C

H2C

l2

4) T

MS

OT

f C

H2C

l 2

98%

Did

emni

n A

13

26

I) )-N

9 O

Bn

C0 2

H_

Bop

-Cl,

TE

A,

2 °

c 2)

Pd,

HC

0 2H

, MeO

H,

49%

)",·P

Mo

HO~~y¥' 0

:;;7:0 0

0 O~

°

°

H

= N~

Me

?'I

~

Did

emni

n B

O

Me

Sche

me

220.

Com

bina

tion

of

Eas

tern

and

Wes

tern

Fra

gmen

ts:

Synt

hesi

s of

did

emni

ns A

and

B (S

hioi

ri)

~J:M'

1) H

2, P

dlC

,

MeO

H

2)"

°

.... N'lI'

2 BO

:: °

13

0°C

, 97%

BOC'N

JNi'

/ ;

I C

02M

e

""-.

../

Me

Sche

me

221.

Jou

in S

ynth

esis

of

Nor

dide

mni

n B

Fra

gmen

t 13

38

1) T

FA

2) N

aHC

0 3, B

OP

HO

"",C

OO

H

DM

F,7

7%

3) a

q N

aOH

, M

eOH

,90%

HOylN

JNi'

:: /

~ I

C02

H

""-.

../

Me

1338

v.:>

0\ > ~. ~ [ i

'-./

CO

MO

DD

,

TE

A,T

HF

o

Y

p-{

I) L

iCH

2C0

2E

t, T

HF

'-

./

BOCNH~OH

o D

OC

, 98

%

CO

MO

DD

=

: N

N

Me

BOCNH~ y

2) H

CI,

94%

3) N

aBH

4, A

cOH

B(~NH~OEt

MC

XM

C

TsO

H

y

2,2'

-car

bony

lbis

(3,

5-di

oxo-

4-m

cthy

l-l,

2,4-

oxad

iazo

lidi

ne)

o 0

y 1)

H2

Pd/

C 1

00%

OH

0

3R,4

R 1

3S,4

R =

5

:95

byN

MR

~

62%

BOCN~OEt

-TO

0

1) N

aOH

, M

eOH

,98

%

2)

HO

.......

.. C0

2Bn

/--.

..

B0-TCN~oyC02Bn

o 0

: /'

-..

2) C

OM

OD

D,

TE

A,

TH

F,9

7%

3)

OL

i

~StBU

TH

F

4) H

Cl,

98%

BocN

JyyO"

.L3-

-T

o

0 ~ T

S

t-Bu

UO

Me

B(~NHi

c-~

.#

°lH

TE

A,D

MA

P,

IPC

C,

CH

2CI 2

,

92%

HO

'r

R0

2C

"'N

HZ

TE

A,

DM

AP

[P

CC

98

%

R =

ally

l

J!x"O

"'

BOCNH~

O",(

o ""

NH

Z

RO

zC

&:b

eme

222.

Jo

uin

Syn

thes

is o

f N

ordi

dem

nin

B F

ragm

ents

I) T

FA

, 90

%

2)/\

0 'N~2

Bo~

0

89%

3) T

FA

4)

BO

CN

H-y

C0 2

H

Y

DIE

A,

BO

P,

CH

lCI l

,94

%

1340

~OMe

o I

"OCNH0

NJ

4'

y'v

~

Oox

R0

2C

"N

1341

H

Z I W

-..

..I

1340

+ 1

341

TE

A,

CuI

C

H20

2

85%

,)~~or

rO O-\~

H oZ

HNX,·· C

02 ally

i

~O

0;

l~~N

N0

_

\ /'

-...

. H

;

0 o

0:

1342

~ OMe

1st

I) P

d(P

h 3P)

4'

mor

phol

ine,

T

HF

2)

TFA

, 67

%

3) B

OP,

Na

HC

03 •

DM

F,5

4%

4) P

dIC

, MeO

H

) .. p~o

) .. p~o

I ('

) M

e 0 0

yNH

0 lH

1

OM

e

00 r

1 o

0 y~"""'"

~:\)

1343

1338

, N

MM

, B

OP

CH

20z,

57

%

Sche

me

223.

U

nion

of N

ordi

dem

nin

B F

ragm

ents

(Jo

uin)

o 0

H

~ N

,.L,-.

~, Ho

/nN~

C(1 N"

"~0;

c0 0

0y~"

""'"

~e

lJ

OM

e

nord

idem

nin

B

v.>

00

~ :; o > S: en

§ p.. ;p 'S. ~

Peptides 39

o

Jaspamide (Jasplakinolide) 1354

unusual amino acids was prepared (Scheme 224). Homologation of tyrosine (1345) produced the blocked ~-tyrosine 1346 while blocking and bromination of tryptophan gave bromoindole 1347. Coupling of these pieces and modification led to the primary amino acid fragment 1348. Preparation of the remaining fragment and coupling to 1348 are shown in Scheme 225. The optically active acid 1349 was routinely converted to the allylic alcohol 1350. Orthoester Claisen rearrangement was used to establish the correct E olefin geometry which was followed by connection to the Evans chiral auxiliary producing 1351. Methylation of 1351 via the sodium enolate provided the desired stereochemistry at the r:t carbon in 71 % yield. Conversion to the pyridinethiol ester and coupling with alanine led to 1352. Connection of the large fragment 1348 at this p0int produced the seco compound 1353, which was deprotected and cyc1ized with DCCjDMAP to yield (+ )-jaspamide identical to the natural product.

3.3.3 Geodiamolides A and B

Geodiamolides A and B [359], isolated from a sponge of the genus Geodia contain the same nonenoic acid fragment as jaspamide and differ only in the identity of the halogen on the tyrosine unit. Grieco has also synthesized ( + )geodiamolide B [360] (Scheme 226). An appropriately substituted tyrosine unit (1356) was prepared and brominated to give 1357. Coupling to alanine at both the carboxyl and amino groups gave 1358, ready for connection of the nonenoic acid piece. This was accomplished via formation of the amide bond which was followed by deblocking the hydroxyl and carboxylic acids prior to lactonization, which was carried out using the DCCjDMAP method as in their jaspamide synthesis. Desilylation of the phenolic ether gave ( + )-geodiamolide B.

Geodiamolide A has been produced by two groups. White [361] followed an approach similar to Grieco in the assembly of fragments (Scheme 228).

HOn ~)'C

O'H I)

Boc

-ON

, T

EA

TBSO~I

2)T

BS

CI

~

------

--3)

K2C

03,

Aq.

MeO

H

Boc

HN

C

OC

HN

2

1345

4

) C

H2N

2, C

IC0

2EI,

T

EA

, E

120,

79%

1) N

aHM

DS

, TB

SCI

2) N

aH,

Mel

~/, •..

(C0

2H

T

HF

DM

F 8

0%

~"1)

NH

Boc

3)

pyr

idin

ium

~

hydr

obro

mid

e pe

rbro

mid

e 4)

aq

NaO

H

TH

F,4

8%

~'I ....

(C0

2H

~"l,

\_Me

N,

N

Br

Boc

H

1347

Sch

eme

224.

S

ynth

esis

of

Jasp

amid

e (J

aspl

akin

olid

e) F

ragm

ent

1348

(G

riec

o)

1) P

hC

02A

g, T

EA

, TBSO~

t-B

uOH

, 61

%

I 2)

TB

SO

Tf,

CH

2Cl 2

~

.. 3)

K2C

03

, T

HF

, C

0 2tB

u A

q. M

eOH

, 70%

H

2N

1) 1

346,

DC

C,

BIO

H

TH

F,9

1%

2)

TB

SO

Tf,

CH

2Cl 2

, 2,

6-lu

lidi

ne

3) K

2C0

3, T

HF

, A

q. M

eOH

, 55

%

13

46

TB

SO

~ro","

o:c

"'~

~

I I

··r ..... o

N

Br

NH

Me

H

1348

~

> §. o R

en [ 1 ~

H~~ 1)

NaH

C0 3

, 12,

O

H

1) M

OM

C1,

i-P

r 2N

Et,

OM

OM

H20

, M

eOH

~~

CH

2C1 2

~

2) L

AH

, Et2

0,

, .. ~ ... ,

2) T

BA

F, T

HF

H~"

..

3) T

BS

Cl,

DM

AP

, 3)

Sw

ern

[0)

TE

A, C

H2C

I2,

OTB

S

4) C

H2=

C(C

H3)

MgB

r,

63%

T

HF

82

%

1349

1) N

aHM

DS

ITH

F;

Mel

2)K

OH

aq

MeO

H

3) (

PyS

h, P

h3P,

C

H2C

I 2,6

5%

OM

OM

aN

S

~ I

°

TBSO~

... I

C~'-B

" i""

'u----

---t •.

. ~o

OM

OM

V~J\B~eNyO

)-N

H

13

53

o

C0 2

TMS

,...

lNH

TM

S

TH

F,9

1%

1) T

BS

OT

f 82

%

2)K2C~, T

HF

A

q. M

eOH

3) B

F3·O

Et2

, Clh

C1 2

, H

SCH

2CH

2SH

51

%

4) D

CC

, D

MA

P, T

FA

, D

MPA

, CH

C1 3

, 5)

TB

AF,

TH

F,

95%

Sche

me

225.

Gri

eco

Synt

hesi

s of

(±

)-Ja

spam

ide

(Jas

plak

inol

ide)

1350

1) C

H3C

(OE

th,

EtC

0 2H

, 12

0°C

2) K

OH

, A

q. M

eOH

\-

3) t

-BuC

OC

l, T

EA

~

.. II

:'

.. ~

4)

0yN

r-l

0)f

'NH

, T

HF

,

°

°

° -

78°C

, 71%

OM

OM

13

51

1348

, DC

C

.. T

HF

,50%

13

52

HO~

~I

°

i""'u-

------

t"~o

0

VA

lJ\M

eN

J-

0 N

Be

H

N

H

(+)-

jasp

amid

e 13

54

ClM

OM

1 ~ ~

.-

(Y,f

o HO~

HN

'Bo

c

1) T

BS

Cl,

im

idaz

ole,

DM

F

(Y,f

o 2)

K2C

03,

TH

F,

Aq.

MeO

H

3) B

uLi /

TH

F

4) M

el

71%

TBSO~

MeN

'Bo

c

1356

1) T

BS

OT

f 2)

K2C

03,

aq

MeO

H

HN

1

Ot-

Bu

Br

in

3)+H

3N~O

t-Bu

,DC

C

cr

°

Br2

, CC

l 4

Hg(

OA

ch

O°C

, 80%

·,'!

(Y· ...

fo TBSO~

MeN

'Bo

c

1357

_ +

1

CI

H3N

.... n

°t-

Bu

°

DC

C,B

tOH

E

t3N

, TH

F

81%

HN

1

Ot-

Bu

Br

in J HO : "

yY

..... '( ~

o °

TBSO~

MeN

'Bo

c

BtO

H, T

HF

, 90%

4)

TB

SO

Tf

5) K

2C0

3, a

q M

eOH

, T

HF

,68%

'!(Y

.... "(

~-o °

T

BSO

)V

MoN

;( 2

DC

C, B

tOH

T

HF

,81%

°rO

t -Bu

HN

.••

•• ~OMO

Br

....L

~""'( ~O

TBSO

~ Mo

N;(

H

Sche

me

226.

Gri

eco

Synt

hesi

s of

(±

)-G

eodi

amol

ide

B

1) H

SCH

2CH

2SH

, T

FA

, CH

2Cl2

, 50

% •

2) D

CC

, D

MA

P, T

FA

C

HC

l 3,

refl

ux,

15%

3)

TB

AF

, T

HF

, 88

%

13

58

HN

1 °

B

r in

'!

(Y, ....

( '0

°

H

O)V

-;C

o 0

N

H

(+)-

geod

iam

olid

e B

~ i o i [ I

x = I Geodiamolide A = Br Geodiamolide B

Peptides 43

Tyrosine was iodinated and converted to the appropriately blocked substance 1363. N-methylation and coupling to two alanine units using standard chemistry produced tripeptide 1364. Connection of the nonenoic acid fragment via amide formation and macrolactonization via the DCCjDMAP method led to the natural product. The construction of the nonenoic acid fragments shown in Scheme 227 also features a [3,3] sigmatropic rearrangement strategy for setting the geometry of the trisubstituted olefin. The allylic alcohol 1360 was generated from the known optically active lactone 1359 via standard transformations. Orthoester Claisen rearrangement in this case was effected with triethyl orthopropionate, such that the methyl group at C2 did not have to be added subsequently. However, the Claisen rearrangement only proceeded with 1.5: 1 selectivity and required an HPLC separation of C2 epimers.

The Momose synthesis [362] of (+ )-geodiamolide A followed only a slightly different pathway from that of White and Grieco (Scheme 230). An analogous ala-tyr-ala tripeptide fragment was constructed, but iodination was deferred until the last stages, eventually producing 1368. Connection of the nonenoic acid fragment (Scheme 229) was analogous to the other syntheses, proceeding once again with amide formation first. Macrolactonization was accomplished using the Yamaguchi procedure [363] involving a DMAP mediated cyclization. The nonenoic acid fragment was again assembled using [3,3] sigmatropic rearrangement, as the Ireland variant and was reported to give a 77% yield of the desired isomer 1366 and only 6% of the C2 epimer. The synthesis was initiated with the known optically active (S)-propylene oxide 1365.

3.3.4 Thiazole-Containing Peptides

3.3.4.1 Patellamides A, Band C

A number of cancer-active cyclic peptides containing thiazole and oxazoline rings have been described from sponges, as exemplified by patellamides A, Band C [364]; ulicyclamide [365] and ulithiacyclamide [366]. Shioiri and Schmidt have been most active in this area, with several syntheses being accomplished.

o~

1359

OH

CY

lOT

BS

1) H

C0

2Me,

NaH

E

t20

2)

Me2

NH

, NaB

H3C

N,

HC

1,M

eOH

3) M

el,

MeO

H,

49%

4)

H2,

Pdl

C, E

tOH

, 72

%

CH

2=C

(CH

3)M

gBr

TH

F, r

eflu

x, 6

0%

0}Y

1) K

OH

, T

HF

2) T

BS

Cl,

DM

F

imid

azol

e 70

%

°

TBSO

~OTB

S 1)

DIB

AL

E

t20

/78

%

2) S

wem

[0)

75

%

OH

Yrl0

TB

S

13

60

1) C

H3C

H2C

(OE

th,

EtC

0 2H

, 11

0 °c

2) L

iOH

, TH

F,

Aq.

MeO

H,

86%

°

HO~OTBS

1361

1

.5:

1 m

ixtu

re w

ith C

2 ep

imer

67

% t

otal

yie

ld

Sche

me

227.

Whi

te S

ynth

esis

of G

eodi

amol

ide

A N

onen

oic

Aci

d F

ragm

ent

t r. o > ~ 8- l ~

I) 1

2> N

H40

H

Kl

2) S

OC

I 2,

MeO

H,

3) N

H3

(g)

I

I) N

aH, M

el, D

MF

86

%

2) L

iOH

I aq

MeO

H,

TH

F 85

%

~" •. (

C0

2H

HO~

NH

2 4)

(t-

BuO

CO

hO,

TH

F

46%

l(Y

', .. (C

02 M

e

p-Me

OC6H

4CH2

0~

NH

Boc

3)

1

D-t

yros

ine

5) p

-MeO

CJ4

CH

2CI,

(n-B

u)4N

l, K

2C0 3

96

%

C0 2

Me

HN~

I ....

l. C

02 M

e

l(Y

""'(

~.

I)

,..lNHB

OC

DC

C, H

OB

t

HO~

NH

Me

O

CH

zCl z

, 4°C

2) T

FA,

CH

2Cl z

, 25

°C, 6

0%

I) 1

361,

TP

PA

, T

EA

D

MF

, 0 t

o 2

5°

C, 5

7%

2) H

F, M

eCN

, 25°

C

3) L

iOH

, aq

MeO

H,

THF,

" 25

°c,

79%

HN~

HO

I

--L

C02

H

l(Y

""'(

~. HO

~ M)

:: H

Sche

me

228.

A

ssem

bly

of G

eodi

amol

ide

A F

ragm

ents

(W

hite

)

13

63

H

2N

C0 2

Me

DC

C,B

tOH

C

H2C

I 2

4) T

FA

, C

H2C

l z, 6

2%

~

I)()

.~ "",;

t. 0 C

02 M

e

# M

eN

yO

H

O

,A

DC

C,D

MA

P

TF

A,4

AM

S

CH

CI3

, ref

lux

20%

NH

2

13

64

, HN~O

'('r""'~O

0

HO~ -;

: H

geod

iam

olid

e A

1 ~ '" ""'"

Vl


~O 1365

I) BrMg.,.l TIIF

2) Swem [0] ..

3) Red-AI, 72% 4) /'yCl

o

Li

1) ~OLi

40 0 .. 2) LDA

3) a-CSA, -78 DC, 62%

TBSO~ Off'

o

1) DIBAL PhCH3 2) HSCH2CH2SH,

BF3·OEt2, 58%

TBsoMCHO ..

3) TBSCI 4) AgN03, NCS,

38%

1) LDA .. 2) TBSCI

HMPA TBSO~C02H

1366 77%

Scheme 229. Synthesis of Geodiamolide A Nonenoic Acid Fragment (Momose)

Shioiri has constructed patellamides A [364], B, and C [368] using common fragments and a common strategy. Scheme 231 shows a patellamide A synthesis using the strategy of constructing two tripeptides 1370 and 1371 from a common thiazole 1369. Condensation of 1370 and 1371 provides the seco compound 1372 which is closed just prior to bis-thiazole formation by formal cyclization of hydroxyls onto amide carbonyls. Patellamides Band C, differing only in the non-thiazole units were assembled using essentially the same approach (Schemes 232 and 233). These three syntheses, along with syntheses of several incorrect isomers, finally led to the correct formulation of these metabolites.

patellamide A patellamide B R = isobutyl patellamide C R = isopropyl

OTB

S CI

r"

y I)

1F

A, C

H2

~ /V

2)

~

~OTBS

oN

B

OC

NH

0

1 :

0

~

Boc

NH

BOC

,~ C

02 B

n ~

0 2

: N

.......

......

~ I

C0

2 Bn

-M

e

Me

CH

2CI2

, Et3

N,

I) H

2, P

dlC

, EtO

H

2) H

2Ny

C0

2t-B

U

78%

~OTBS

DC

C, C

H2C

I2,

72%

~

o ~

H

I

NH

20

~N~C02t-Bu

3) 1

2, H

g{O

Ach

, 78%

4)

TB

SOT

f i

~ II

i =

Me

0 =

5)aq

NH

4CI

80%

13

68

~OTBS

~

Cl

l)C

l-Q

-C

OC

I

Cl

1 1

)

1 ~J ~~~

~02H

HO.......-~~~l(

1 ~

II i

o :

Me

0 :

Sche

me

230.

Mom

ose

Syn

thes

is o

f (±

)-G

eodi

amol

ide

A

TE

A

2) D

MA

P,

C6H

6, r

eflu

x 3)

TB

AF

, T

HF

, 79

%

1) 1

366,

DC

C, H

OB

t, C

H2C

I2,O

oC

2) 1

FA

, CH

2CI2

HSC

H2C

H2S

H,

0°C

,47%

, HN~O

XX~

···· .. ~OO

HO

.#

N

0

Me"X

0

N

H

{+)-

geod

iam

olid

e A

1 ~ ~

-.l

Me0

2C (~NHBOC

S l A

1369

~

¥ S

BOCN

H\~ C

0 2M

e

1369

I) T

FA

2)NaHC~

3)

NH

Boc

I O

H

Me02C~

DE

PC

,TE

A

81

%

~~\~JYOH

./"'

...

I) H

CI,

dio

xane

2)

BOCN

~>-\

H

0 2C

DE

PC

, TE

A

98

%

-~~H

:X

S

~ NA~H

./"'.

..

0 i

1370

1) T

FA

2)NaHC~

3)

HO

BocNHl

c~Me •

DE

PC

, T

EA

66

%

3) N

aOH

,DM

F

I) H

Cl,

diox

ane

OH

0

'-../

OHO~

2)

y~

LyJl~~

~s A

->-<:::

--->

-to NH ~\~

Boc

NH

N

•

DE

PC

TE

A

C02

Me

C~Me

' 85

%

NH

Boc

13

71

'-..

/ O

H

°

~ S

1) N

aOH

,DM

F

'-..

/

2) H

Cl,

diox

ane

I) H

CI,

dio

xane

2)

137

0, D

EP

C •

TE

A,

79

%

l Jl

N~-)

° Y

-H

N--\

J-tN

H

C02

Me

BocNH~

NH

-<.

\

3) D

PP

A, T

EA

, D

MF

,55

%

4) S

OC

l2,

100%

~ IN

~~S

0/ Y

'H

N

J-(N

H

N

°

0-'rNH

NJ:-\

O~

HN

°

(~~0

r-OH

~

°

-./

"'..

. 1372

Sche

me

231.

Shi

oiri

Syn

thes

is o

f P

atel

lam

ide

A

5) A

gOM

s, P

hH

73

%

N

H

°

'S Jy N

Y-(

a °

./

"'..

. pa

tell

amid

e A

~ i o > ~ 8- 1 f

Bn :;

S

BOCN

H~~ C

02M

e

1) T

FA

· 2)

Na

HC

0 3

3)

10

H

Boc

NH

C

0 2H

DE

PC

, T

EA

, 75

%

1) T

FA

2)

Na

HC

0 3

1) T

FA

OH

0

~n

J..

Jl N~

S)

DE

PC, T

EA

, ~

'(

-H

N-\

85%

Boc

NH

C

0 2M

e O

H D

MF

4)

Na

,

;; N"''S

:-B

ocN

H

C0

2H •

e 2C

XNN

H~~S

NH

\\ II N

NH

Boc

C

02H

1374

Me

02C

\- (s~N

HBOC 3)

H02

C-:w

-NH

BO

C

HO

""

DE

PC

, T

EA

, 81

%

1) H

C1,

dio

xane

y

M 0

2)

6

Boc

NH

V N

H

N

HB

oc

Me0

2C

'(~Nn

:::,':

~~ '(>y~;ryo

1) H

C1,

dio

xane

2)

137

4, D

EP

C,

TE

A,7

9%

3) N

aOH

,DM

F

-ZH l)

:"~s#

\ o

}-r

-H

N

0

J"\NH

BOC

Y

Me

02 C\-

HN

°

1!

)y~Y

yo"

= 0

Sche

me

232.

Shi

oiri

Syn

thes

is o

f P

atel

lam

ide

B

1) H

C1,

dio

xane

2) D

PP

A,

TE

A,

DM

F,5

5%

3) S

OC

I 2, 4

°C

,

54%

94%

=

0

OH

f)

l IN

3y)

AY'H

NH~

O~

N=<

(Jl-

~Yy0

~ 0

-

pate

llam

ide

B

d' I t

Me

02Ct

NH

Boc

N

H, A

./

r ~Nlr

T

s §

0 O

H

OH

Ai

~n

-->--Z

NH ~~

~ N

HB

oc

C02 H

I) H

CI,

diox

ane

I) H

Cl,

diox

ane

BO

CN

HJ

2)

X

Boc

NH

C

0 2H

M

e02

C,)

-N

H

H

N --4

. 0 "-

ZS>y

NyY

DE

PC

,TE

A

DM

F,9

2%

.. =

0

OH

1375

OH

0

~n

I) H

Cl,

diox

ane

2) 1

375,

DE

PC

TE

A,

DM

F,

82%

~~~~

~NH

soc:?

O~

HN

0

(~~yY

s i

0 O

H

~

o =

0/ Y

'H

N

2) D

PPA

, T

EA

,

DM

F,4

4%

1 ~N

~tS

\ rN

H

N

0

~NH

HN~

0)

N~ \

3) S

OC

l 2, 4

°C

,

79%

Sche

me

233.

Shi

oiri

Syn

thes

is o

f P

atel

lam

ide

C

N

H

0

r ~N0:

S ~

0 "

pale

llam

ide

C

~ i o :> 5: '" [ { '"

Peptides 51

Schmidt also recorded a synthesis of patellamide B [369] using the thiazole 1376 as the primary building block (Scheme 234). Mitsunobu inversion of the alcohol to the azide and reduction led to an amine which was DCC-condensed with a blocked threonine to give 1377. Deblocking ofthe threonine was followed by reaction of the amino-alcohol with the imidate 1380 generating the oxazoline ring (1381) prior to final cyclization. A similar set of reactions was used to convert 1379 to a second tripeptide fragment 1381. Combination of these two led to the seco compound 1382 which was deblocked, activated and closed to patellamide B.

3.3.4.2 Ulicyclamide and Ulithiacyclamide

In their syntheses of ulicyclamide and ulithiacyclamide Shioiri and Schmidt used chemistry analogous to their respective patellamide syntheses. The Shioiri ulicyclamide synthesis [370] (Scheme 235) used a proline anchored to a polystyrene base and sequentially added two thiazole-containing units and a threonine to give 1384. At this point the resin was removed and the synthesis completed by macrolactamization and formation of the oxazoline ring. The Schmidt synthesis ofulicyclamide [371] proceeded as shown in Scheme 237 and features the coupling of two thiazole units to give the intermediate bis-thiazole 1387. Mitsunobu inversion of the alcohol to the amine and coupling with a blocked threonine unit followed by deblocking gave 1388. Coupling of 1388 with an Ala-Pro unit via oxazoline formation led eventually to the penultimate intermediate 1389 which was macrolactamized to ulicyclamide. An example of the synthesis of a thiazole-containing unit is shown in Scheme 236.

Ulicyclamide Ulithiacyclamide

Ulithiacyclamide contains a disulfide bridge of Cys units and, once again, has been synthesized by Schmidt [372] and Shioiri [373]. The Schmidt approach (Scheme 238) to this symmetric substance involved the coupling of two

1) D

EA

D.

PP

h 3•

C0 2

Mc

C0 2

Me

HN

3•

rt

r=<

r=<

2) H

2• P

d S

~N

.. B

n,X

NH

S ~N

3) H

0 2Cr N

HB

oc

Bn

XO

H

~,,\

Ot-B

u ~N

HBOC

DC

C

_20°

C

0 I3

76

.' 85

%

,\\\

Ot-B

u

HO

N:?-

Me02C~S

1) D

EA

D.

PP

h 3•

HN

3•

rt

2) H

2• Pd

Bo

cRH_

C

1378

3) H

0 2Cr N

HB

oc

""

OH

D

CC

_20

°C

68%

HN

) ......

N=(

Me02

C~S

1379

N

o :

: :

S

1) T

FA

. 0

°c

MeO

2) H

e,"} NH

Boc

CH

202•

reflu

x 63

%

1) H

O,C

H0

3

2) H

CI-

HN

Me7

NH

BO

C

1380

C

H2C

I 2, r

eflu

x

C0 2

Mc

r=<

s N

,XN

H

Bn ~N

NH

Boc

0:-

t .'

0

····

13

77

~ 13

77

,DP

PA

,TE

A

Boc

NH

0

° •

I~....

.. di

oxan

e. 0

C

N

65

%

o

HN

)",,

,,

N=(

j~

S M

e02C

-----

v 13

81

N

o :

YN~-ff

~o -

N

H

N-(C

02M

e

BO

Cy

N

NH

1 jlN~~S

~

O""_

Y'H

N

0 Y N

H

I) a

q N

aOH

/ di

ox

0)

N'" N

H

0

~S~Ny\

o 13

82

Sche

me

234.

Sch

mid

t Sy

nthe

sis

of P

atel

lam

ide

B

2) C~50H /

DC

C

3) d

ioxa

ne.

EtO

H,

4-py

rrol

idin

opyr

idin

e

20%

0)

N--N

H

0

~S>yNy\

: 0

pate

llam

ide

B

VI

N ~ ::s o ~ '" '" ::s Po ~ I

aC

02

CH

T[P

l

H

[P]

= p

olys

tyre

ne r

esin

13

83

TM

SO

Tf,

th

ioan

isol

e,

m-c

reso

l

I) H

oo

ey N

HB

oc

Bn

DEP

C,T

EA

DM

F

2)

NH

Boc

N~"'"

)-IO

OC~S

D

EPC

, TEA

D

MF

1 ~":~

h 3)

Lv

BO

CNH~

~S~

DEP

C, T

EA

DM

F

4)

OH

~COOH

NH

Boc

DEP

C, T

EA

DM

F

CO

OH

I) D

PPA

, TEA

, D

MF

,22

%

from

13

83

TFA

, CH

2CI 2

(Rem

oval

of

pept

ide

from

re

sin)

HO

0

l.---s

~ ....

....

, H

N

a: NH:

N)"~ 0

OArN~s

2) S

OC

I 2,

100%

Bn

0

HO

0

l.---s

l~":~~

........

,

H

N

[p]-

CH

i 02 C

N

HB

oc

0

Ct

H N

)""'"

oArN~S

Bn

0 13

84

~ -~,

A~~"""

0"

1 lr

\.-.-

s B

n 0

ulic

ycla

mid

e

-an

ext

ensi

ve d

eblo

ckin

g/w

ashi

ng p

roce

dure

was

use

d be

twee

n ea

ch c

oupl

ing

reac

tion

Sche

me

235.

Shi

oiri

Syn

thes

is o

f U

licy

ciam

ide

,gc ~ VI

W


R S

>---< HO NH2

Scheme 236. Synthesis of Thiazole Units (Schmidt)

R, NrC02Et

1) DEAD >---< I Ph3P H2N S

22)~ ~N~2';7 7r yd 1386 R = Me / 15% overall

~ Ph3P

PhC02H 2) aq NaOH

R, NrC02H >--< I HO S

R = (S)-sec butyl 29% overall

identical thiazoles to a sulfur-linked Cys dimer 1390. After functional group manipulation, the bis-seco compound 1391 was obtained. Sequential cyclization of 1391 gave rise to 1392 which was submitted to SOCl2 to complete an efficient pathway. The Shioiri approach is equally efficient (Scheme 239), involving dimerization of the tripeptide fragment 1394. This was followed by intramolecular disulfide formation and finished off with closure of the oxazoline rings.

3.3.4.3 Ascidiacyclamide and Dolastatin-3

Ascidiacyclamide (1395) [374] is a simpler member of this class, being essentially a cyclic dimer. Shioiri [375] assembled 1395 using previously outlined technology as shown in Scheme 240, involving as the key step the cyclodimerization. The synthesis required only 9 steps and established the absolute configuration of this metabolite.

AscidiacycJamide 1395

{(~

I) B

rCH

zCO

CO

zEt

> N

C0 2

H

1386

, Ph

': -L

N!~~

-->-

~~ I)

DE

AD

Ph

3P /

HN

3

HO

2) D

EA

D,

Ph3P

PhC

OzH

; hy

drol

ysis

29

% o

vera

ll

Ms1

HO

di

pyri

dyl

He)

S

disu

lfid

e 81

%

1387

2) H

z, P

d 75

%

-LN!

~~--

>-_,

H

2N

s

I) t-BUO~."\

S-py

r B

ocN

H

o 2)

TF

A,

89%

-L 0

~ o

vN

N

... N

\ L

, sj\

1"..)

--'

Bn

()

I) BOCNH~N~OMe

o N

H

2) A

q. N

aOH

3) C

#'sO

H, D

CC

E

tOA

c 4)

TF

A

HO

i-{

H

N

H2

13

88

o -LN

!~~-->

-~~,

1 O~~)

'..}

..N

S

TF

A,d

io,r

n"

0' I

~o

N

H

4-py

rrol

idin

opyr

idin

e d

N

HN

o

N

'.

d .,·C

, 16%=,

,11 OJy

~yZ.~'

" J..N

H,

Bo

O

0-I'

1389

,Ii,

y, "m

id,

Bn

Sche

me

237.

Sch

mid

t S

ynth

esis

of

Uiic

yc1a

mid

e

I VI

VI

~

OH

0

~

J.. J.

.N~S

) /'

'\'H

N-

-\ N

H2

C0

2Me

+

H0

2C

J ....

S B

ocN

H

"...

. 's

....... ".

. N

HB

oc

'r 13

90

C0

2H

+

1) N

-(3-

Dim

ethy

lam

inop

ropy

J)

N' -

ethy

l-ca

rbod

iim

ide

hydr

ochl

orid

e, 6

2%

2) A

q. N

aOH

. 95

%

3) C

6FsO

H. D

ec

4) H

Cl.

diox

ane

CF'CH,o,C(>v~~

y 0

o~" '

~ rl l

0

),. HN

>===

0 N

N

H

SOC

I2.

OoC

)-'k

')

HN

N

--!£

...C

0 2C

6F5

~o

NH

2-H

CI

HO

, ~

" . =

{NH

..

. t..

0

0 ..

)

... )

HN

>--

--{

HC

I-N

H2

O~

.... O

H

C6 F

5 02 C

", N~NH

~S

~-<

1391

>-~. S~

rl l

0

rtHN

O

N

NH

',.....

N

1"

"'(

H')--

< NH

1"'·<

0 o

S H

N

=)

... S >=

-->

... S ;-0

o

.... f .r ....

...

,,1

>-/

HN

O~

""O

H

O~N~

.NH

Ir---f~

S ~~

1392

Sche

me

238.

Sch

mid

t Sy

nthe

sis

of U

lith

iacy

ciam

ide

50%

HN

0

O~N~

,NH

10~

S "~

'de

ulit

hiac

ycla

ml

'"

DM

AP.

M

eCN

50

°C

. 41

% o

vera

ll

VI

0\ > ~. > ~ 8- 1 ~

I) T

FA

2) H

O

C0 2

H

)--<

NH

BO

C ..

~

~ S

BOCN

H~~

DP

PA

, T

EA

- DMF,

33%

C0

2Me

DE

PC

, T

EA

, D

MF

,71%

>-\ S~

.>--<

l °

H

N

N

H)-(O

N

H

NH

r-

-{

°

0i A~

_~~S

m~)=

'.

.. J

'" o

OH

HN~N~

/NH

o

I 7-

-(

S ~-<

I) H

Cl,

diox

ane

2)

CO

OH

) .. ,

Boc

NH

C

H2S

-Acm

D

EP

C,T

EA

~

OH

0

~

A(l~,\~

DM

F,9

1%

3) N

aOH

, A

q. M

eOH

~

<;?H

0 1

S

A(l~~~

o N

H

C0 2H

B

ocN

H

C0 2M

e 4)

TF

A

H2N

XC

H2

s-A

cm

12>

MeO

H

- 90%

Acm

= a

ceta

mid

o-

>-\ S~

.>--<

I °

HN

N

H>

-t0

r_.

(H 0

i ..... S

)=

°

J HN

~."

o O

H

HN~N

N

H

o I

H

S ~-<

1) S

OC

l 2,

CH

2CI 2

2) A

q. K

2C0

3,

71%

1394

>-~ ..

S~

.>--<

I °

H

N)=

==

o N

N

H

"'····~~NN

....

. r.r~'

1 ° o

S N

J

..... "

HN~N~ 0

/N

H

o IN

S

~-<

ulith

iacy

c1am

ide

Sche

me

239.

Shi

oiri

Syn

thes

is o

f U

lithi

acyc

1am

ide

i ~ VI

-.I

X'

Boc

NH

C

0 2H

H2N

C

0 2H

HOX

1)

DE

PC

, T

EA

D

MF

,72%

2) N

aOH

, M

eOH

,90%

Lv ~XC

02Me

BO

CN

HA

y

o HO

""

--Is

'>--

<, 1.

H2N

N

. C

0 2M

e

HC

l, di

oxan

e, 7

1%

~

'-..

/ o

; H

:

S N

N

--"y

'o

cNH

0

x" H

N~

H

O

SOC

ll> T

HF

.. o

to 5

°C, 9

3%

C0 2

Me

1) N

aOE

t, E

tOH

, re

flux

2

)™S

CH

N2

76

%

3) T

MS

OT

f,

CH

2C12

\i-(

l'"y,

S.:)

--C

0 2N

a

H2N

~

o 4)

NaO

H, D

MF

Sche

me

240.

Shi

oiri

Syn

thes

is o

f A

scid

iacy

clam

ide

~o

.... "

S-')

-C

02M

C

~ N

N

Jy

N

"o

"r("

B

ocN

H

II

DM

F,D

PP

A

K2H

P0 4

o to

5 °

c 27

%

o

oy

\.

JlN~~S!J

K

o/_.r ~

H N

0

)-\

NH

0=\

N"'""

(1y~

0-(0

::

0 ./

"'-.

..

asci

diac

ycla

mid

e 13

95

V\

00

r > g; '" [ i. l't

'"

Peptides 59

Elucidating the structure of dolastatin-3 has required extraordinary effort due to the minute amounts obtainable from the natural source (Dolabella auricularia) and the chemical instability of this substance. Several synthetic ventures failed to produce the natural peptide. Pettit finally succeeded in pinning down the structure of this cyclic pentapeptide as 1398. This was accomplished by a standard linear sequence of condensations as shown in Scheme 241. Beginning with proline, a valine unit was followed by two thiazole containing amino acids and a leucine producing the seco peptide 1397. Closure was effected in good yield to produce a substance identical to the natural ( - )-enantiomer.

(-)-Dolastatin 3 1398

3.3.5 Dolastatin-l0 and Hexaacetylcelenamide

Several acyclic marine peptides have attained importance due to their anticancer properties. The dolastatin family, in particular, seems to show much promise in the development of new antineoplastic agents. Isolated by Pettit from the sea hare Dolabella auricularia, dolastatin-lO [376] (1408) is a very promising cancer-active substance because of its in vivo assay performance. Pettit has also synthesized 1408 confirming the absolute stereochemistry of this important substance (Scheme 243) [377]. The two uncommon amino acids and the aminothiazole units were prepared as shown in Scheme 242. Dolaisoleuine was

~ M~~;\-~~~~)

o 0 Me OMe 0 OCH3 0 S

(-)-Dolastatin 10 1408

()...

co2M

e N

H

1)

X

Boc

NH

C

02H

DE

PC

, T

EA

, D

ME

•

2) T

FA

, C

H2C

l 2

3) B

ocN

H"-

-S

~{

C0

2H

DE

PC

, T

EA

, D

ME

1) T

FA

, C

H2C

l2

2)

N~

BOC~%'

~ N

{ C0

2H

DE

PC

, T

EA

, D

ME

.. 3)

TF

A,

CH

2CI 2

4)

t B

ocN

H

C0

2H

DE

PC

, T

EA

, D

ME

71

% o

vera

ll

("'y

co,M

< ~

LJ BO

CNH~

( \

N)=

O HN

~CON

H2

iH~N

~o

s H

1) a

qN

aOH

2)

HC

I, d

ioxa

ne

3) D

CC

I, D

ME

, C

6F50

H

rvCo,P

fp~

LJ H2N~

( \

N)=

O HN~CONH2

iH~N~o

4-py

rrol

idin

opyr

idin

e,

t-B

uOH

, dio

xane

cl~~

\ N

)=O

HN

~CON

H2

i~:r

o 9

5°

C 7

6%

S H

s

H

1397

(-

)-do

last

atin

3 1

398

Sche

me

241.

Pet

tit

Syn

thes

is o

f (-

)-D

olas

tati

n 3

0\ o r [ '" [ I '"

ZHN

X:H

Z

-S,S

-iso

leuc

ine

CX: 02H

N I Boc

Boc

-S-p

roli

ne

Bn

BOCN

HA

C0 2

H 1)

NaH

, C

H3!

I)

CH

2N

2,

BF

3'O

Et 2

2) B

2H6,

TH

F,

95%

3) D

MS

O,

S03

, py

r, 7

8%

ZM

eX

:

LiC

H2C

02t

-BlI,

TH

F,

-78

DC

33%

2) H

2,

Pd/

C,

~

EtO

Ac

3 t

Bu

MeO

H

ZMeN

C

O2

-3)

HC

I, E

t20

, M'H

N~Co".

"" O

Me

1) B

2Hu

I\"H

2)

DM

SO

l..

...N

'x' "

S C

HO

03

I py

r I

== 7

5%

Boc

Bn

Bn

0

PhAO

V

MgB

r2' T

HF

, 95

DC

OH

42

%

Sepa

rate

d fr

om

C-3

epi

mer

f\.,

H 1s

~(y~yOyPh

Boc

O

H

0 B

n

1400

M

ajor

pro

duct

Bn

dola

isol

elli

ne (

Dil

) 13

99

I)M

e30+

BF 4

-

CH

2CI 2

I\.,

H I

R 2)

KO

t-B

u, T

HF

'r:<~'Y0H

I 57

%

Boc

O

Me

0

3) a

q ci

tric

aci

d N

-Boc

-dol

apro

ine

(Dap

) 14

01

4) H

z, P

d/C

I) B

2Hu

BO

CN

HA

CH

O

H2

N..

./'S

H

BOCN

H~)

Mn0

2,

PhH

•

2) D

MS

O

PhH

77

% f

rom

140

2 B

oc-S

-phe

nyla

lani

ne

S0

3 I

pyr

1402

H

N

~

"OCNH~

) N

-Boc

-Dol

aphe

nine

(D

oe)

1403

Sch

eme

242.

P

etti

t S

ynth

esis

of (-

)-D

olas

tati

n 10

Fra

gmen

ts

~

~. ~ 0\ .....

ZNHX

0 2H

(CH

3hC

OC

l,

ZNH~~~

'B"

MezA

0 2Pf

P

M~'\

-~~C

~'_B

" N

MM

,CH

CI 3

• ..

Dil-

Ot-

Bu·

HC

l,

H2,

PdJ

C Z

-S-V

al

80%

o

Me

OM

e o

0 Me

OM

e di

oxan

e, 8

3%

1405

14

06

1) T

FA

, CH

2Cl 2

N

-Boc

-Doe

(1

403)

,e

('

I'

"'-I

'7~N

~N

2) N

-Boc

-Dap

(14

01)

DE

PC

, T

EA

, D

ME

B

oc

OC

H3

0 H

sJ

50

%

1) T

FA

, C

H2C

l 2

2) 1

406,

DE

PC

TE

A,D

ME

o °c,

74%

1407

~

M~~~~~~~~)

o 0 M

e O

Me 0

OC

H3 0

S

(-)-

Dol

asta

tin

10 1

408

Sche

me

243.

Pet

tit

Ass

embl

y of

(-

)-do

last

atin

10

Fra

gmen

ts

0\

tv ~ ::;

o i § p.. l ~

Peptides 63

made by 2-carbon aldol chain extension of a leucine derivative from which the e3 epimer 1399 was separated. Blocked dolaproine 1401 was similarly produced by chain extension of N-Boc-(S)-prolinal. An epimerization of the e2' center in 1400 was required in this process. The thiazole-containing dolaphenine 1403 was prepared from (S)-Phe. The remaining amino acids were common. Assembly of the fragments took a standard course. (S)-Val was connected to the extended leucyl fragment producing 1405 which was extended at the N-terminus with a second Val unit. The units 1403 and 1406 were connected by condensation producing 1407 which was then hooked on to fragment 1406 producing (- )-dolastatin-IO (1408).

OAc

AcO

o ACNH0

I N

Y o

(l0AC ~J f~'OAC

: N ! H

~ «N~Br H

Hexaacetylcelenamide A 1417

The pseudo~tetrapeptide hexaacetylcelenamide A was isolated from the Pacific sponge Cliona celata by Andersen [378] as its hexaacetyl derivative and possesses a relatively rare and fairly reactive enamide functionality. A synthesis has been reported by Schmidt [379] in which this functional group was generated in the final step of a synthesis of hexaacetylcelenamide A 1417 (Schemes 244 and 245). The (S)-6-bromotryptophan fragment 1410 was prepared by Wadsworth-Emmons reaction of the aldehyde 1409 and subsequent hydrogenation with an asymmetric catalyst producing 1411 in 98% ee. The propenamide containing group 1412 was constructed using standard chemistry, with the olefin eventually being generated by selenide oxidation and elimination. The fragments were assembled as shown in Scheme 245. The interesting phosphonate 1413 was condensed with the bromo tryptophan fragment to give 1414. Wadsworth-Emmons reaction with 2,3,4-triacetoxybenzaldehyde gave the E isomer 1415 which was connected to fragment 1412 by Dee condensation to provide 1416. Final oxidative elimination generated hexaacetylcelenamide A (1417).

3.3.6 Teleocidin A-I (Lyngbyatoxin A) and Teleocidin A-2

The teleocidins are metabolites of Streptomyces mediocidicus [380]. One of these substances, teleocidin A-I, was shown to be identical with lyngbyatoxin A,

OH

C ~

\~Br

I Boc

1409

~.OM

e C

lCH

2CO

NH

Y P'

OM

e

C0 2

t-Bu

KO

t-B

u, C

H2C

l 2,

-30°

C

1) C

H2N

2 2)

HC

l 3)

Kl,

NaN

3

t-B

u0 2

C

ClC

H2

CO

NH

tu

f ~ I

N ~

B

I r

Boc

1410

AcO

A

cO

AC

O-O

-C

OC

I

4) H

2, P

d, (

Boc

hO

AC

O---b

-cN

HB

OC

OH

5)

NaB

H3C

N

Sche

me

244.

Sch

mid

t Sy

nthe

sis

of H

exaa

cety

\ce\

enam

ide

A F

ragm

ents

t-B

u0 2

C

1) [

Rh(

I,5-

cod)

(R,R

-dip

amp)

tBF 4

-~·tu

H2,

EtO

H, 4

0 0c

~N

f ~

2) N

0

0di

• I

-plp

en

neth

ioca

rbam

ide

N ~

, I

Br

EtO

H,

80

°C

B

oc

(Asy

mm

etri

c hy

drog

enat

ion

with

Mon

sant

o ca

taly

St a

nd

clea

vage

of

chlo

roac

etyl

gro

up)

1) p

-N0 2

CJ4

SeC

N

n-B

u 3P

2) H

CI,

diox

ane

1411

98

% e

e

AcO

AC

O---b

-cN

H2

HC

l

SeC

6H4N

0 2-p

14

12

0\

oj:>

. f. > g; '" § P

o d' I

OM

e o

OP:

::'O

Me

AC

NH

0N

AC

02

H

y

AcO

14

13

1) L

OA

, T

HF

2)ACO~CHO

AcO

¥

AcO

3) H

C0 2

H, 4

0°C

OA

c

OM

e O

Ff,

OM

e

1411

,DC

C

MeC

N

o Ay

H C

O:z

t-Bu

'¢

N"""

AcN

H

~ 0 ~ro

'1

N

'"

Br

1414

I

OA

c

AcO

o A

CN

H0

N

Boc

H

Ny

C0 2

H

Y o

~ ~

\V

Br

1415

H

AcO

DC

C

N-h

ydro

xysu

ccin

imid

e

OA

c

com

poun

d 14

12

TE

A,M

eCN

o A

CN

H0

N

H

~ Yrc

rOAC

o

Se

::::::.,.

1

~0

OA

c

: N

NaI

0 4

diox

ane

o A

CN

H0

N

H

PO

AC

::::::

.,.1

~J

I O

Ac

. N

~

H

Y

o :

H

~

«N~

H

Br

14

16

H20

~

«N~B

H

r

Y

o

No

yiel

ds g

iven

in

any

step

. he

xaac

etyl

cele

nam

ide

A 1

417

Sche

me

245.

Ass

embl

y of

Hex

aace

tylc

elen

amid

e A

Fra

gmen

ts (

Schm

idt)

d' 'tI ~ 0'\

V

I

OE

t \n

o N

CO

Cl

+s

1419

~ ,

H

:tQ

o T

s

1421

Law

esso

n's

reag

ent

TH

F

65%

•

BF3

-E

t 20

Cl(

CH

2hC

l,

80%

o~

2.5%

KO

H

TH

F-H

20

95%

o~

ClC

OO

Et,

Et3

N

met

hyl

N-m

ethy

l-L

-v

alin

ate

• H

Br

Ger

anyl

mag

nesi

um

brom

ide

.. T

HF

80%

~ ,

H

Me'N

XC

OO

Me

14

23

o T

s

1420

~ ,

H

Me'N

XC

OO

Me

MeI

,DM

F, ..

25

°C

, 3 h

r

TsO

H

PhH

he

at,

2 m

in

~ ,

H

o T

s 87

%

~ ,

H

Me: N

XC

OO

Me

1422

(8

8%)

Me':

XC

OO

Me

NO

H

Br0

CO

OE

t

R,

Na2

C03

C

H2C

l2

1424

ser

ies

a R

1= vi

nyl,

R2=

Me

(37%

) pl

us 3

sid

e pr

oduc

ts

1424

ser

ies

b R

1= M

e, R

2= vi

nyl

(24%

) pl

us 3

sid

e pr

oduc

ts

0\

0\ ~ g i [ l f

~H

Me'N

.'

CO

OM

e 0

-""-

JlO

EI

.' ~ '''l

n

R!

a, 5

9%

b,6

5%

~H

Me'N

.'

CO

OM

e

OH

r' ...

R!

14

2S

a,5

1%

1

42

Sb

,53

%

AI-

Hg,

TH

F-

H20

, ft

, 4

hr

1) 1

0% K

OH

IMeO

H

2) E

t3N

eHC

l 3)

DP

PA

, E

t3N

, D

MF

~H

" 0

Me'N

C

OO

Me

R!

a, 9

2%

b,8

9%

R!

OE

I N

aBf4

, EtO

H,

heat

, 20

hr

.. "'\

OH

tele

ocid

in A

-I (

Lyn

gbya

toxi

n A

) 14

26

23%

+

31 %

of

two

othe

r di

aste

reom

ers

tele

ocid

in A

-2 1

427

21 %

+

29

% o

f tw

o ot

her

dias

tere

omer

s

Sche

me

246.

Nat

sum

e Sy

nthe

sis

of T

eleo

cidi

ns A

-2 a

nd A

-l (

Lyn

gbya

toxi

n A

)

1 f ~


~HH H Me, N

N

~ 0

Teleocidin A-I (Lyngbyatoxin A) 1426 Teleocidin A-2 1427

isolated from the blue-green alga Lyngbya majuscula in Hawaii [381]. Teleocidin A-1 is a highly inflammatory and vesicatory compound that exhibits very potent tumor promoting properties. Teleocidins A-I and A-2 have been prepared enantiospecifically by Natsume [382] in a synthesis that was very much lacking in diastereoselectivity (Scheme 246). The synthesis is initiated by the Friedel-Crafts acylation of N-tosylated pyrrole 1419 to afford ketoester-1420. Saponification of the ester, activation of the carboxyl and condensation with methyl N-methyl-L-valinate provides optically active ketoamide 1421. Addition of geranylmagnesium bromide to 1421 and elimination with TsOH affords 1422 as an inseparable mixture of diastereomers. Direct conversion of 1422 to indole 1424 is difficult, therefore 1422 is transformed into thioamide 1423 and treated with methyl iodide to give 1424a and 1424b in 37 and 42% yields respectively. Addition of the C3 substituent is accomplished by alkylation with ethyl 3-bromo-2-hydroxyiminopropanoate, reduction of the oxime, and selective reduction of the less hindered ester to give indoles 1425a and 1425b as mixtures of diastereomers. Formation of the 9-membered lactam occurs via saponification of the ester, neutralization of the excess alkali, and treatment with diphenylphosphoryl azide to give 1426 in 23% yield along with 31% of two other diastereomers and 1427 in 21 % yield along with 29% oftwo other diastereomers. Teleocidins A-I (1426) and A-2 (1427) are obtained in 0.71 and 0.47% yields respectively over 12 steps.

4 Fatty Acid Derived Metabolites

A large number of metabolites appear to have been derived at least partially from fatty acid metabolism. Included in this section are metabolites which appear to be related to this metabolic pathway, or in any case, which contain unbranched or nearly unbranched carbon skeleta.

4.1 Haloethers of Laurencia sp.

There have been a number of halogenated cyclic ethers based on a linear pentadec-3-en-l-yne skeleton isolated from red algae of the genus Laurencia. A number of related compounds that are presumed to be biogenetic precursors of these haloethers have also been described. Total syntheses of several of these have been performed. Of the biogenetic precursors, laurencenyne (1433) and neolaurencenyne (1434) were isolated [383] from Laurencia okamurai and their structures confirmed by total syntheses. The laurediols have been isolated [384] from L.nipponica (Yamada) by lrie, along with several related compounds. Another related compound, although possibly of different biogenetic origin, is the trienyne acetate 1457 isolated from L. pinnatifida (Gmal) Lamour by Gonzalez [385]. Of the halogenated cyclic ethers, laurencin was first isolated [386] by lrie from L. glandulifera (Kutzing) in 1968 and the similar oxocin laurenyne (1478) was obtained from L. obtusa. The tricyclic maneonenes (e.g. 1489) are chloroethers [387] isolated from L. pinnatifida. Panacene (1497), a brominated allene, has been isolated [388] from the sea hare Aplysia brasiliana, a large sluglike gastropod mollusc indigenous to the Gulf eoast of Florida. Although not yet found in Laurencia sp., it has been suggested that panacene is derived from dietary sources. The cis- and trans-maneonenes are bicyclic halogenated diethers isolated [389] from the bright green variety of the Hawaiian alga L. nidifica.

4.1.1 Laurencenyne

Yamada's synthesis [390] of laurencenyne is shown in Scheme 247. Coppercatalyzed Grignard coupling of diyne 1428 with magnesium acetylide 1429

~Br B

rMg

1428

OU

IP

1431

TH

F

~OnIP

cat.

CuC

I re

flux

/4

hr

1429

1) C

SA

/MeO

H

25

°C

/ 45

min

2) T

sCI

/ py

r o °

C /

4.5

hr

3) N

aI/

ace

tone

4)

Ph 3

P /

CH

3CN

72%

67%

laur

ence

nyne

1

43

3

Sche

me

247.

Y

amad

a S

ynth

esis

of

Lau

renc

enyn

e

.. ~

1432

1430

+ PPh 3

H2

OT

HP

..

Pd-

BaS

04

CJ16

qu

inol

ine

25

°C

!7 h

r

68%

1) n

-BuL

i /

TH

F

HM

PA

/ -7

8 °C

20

min

.

2)

OH

C

=

29%

1434

neo

laur

ence

nyne

(12

,13

dihy

dro)

w

as s

ynth

esiz

ed (

24%

ove

rall

) vi

a an

ana

logo

us s

eque

nce

from

:

OH

-.J o "rj

~

q ~ P- I ~ ~ ~

Haloethers of Laurencia sp. 71

13 12

Laurencenyne 1433

affords triyne 1430. Lindlar reduction of 1430 yields the all cis-triene 1431. Triene 1431 is then converted in four steps to phosphonium salt 1432 which is coupled in a Wittig reaction with propynal to afford laurencenyne (1433) in 7 steps and 9.5% overall yield. In a similar manner, neolaurencenyne (12,13-dihydrolaurencenyne) (1434) was synthesized in 24% overall yield.

4.1.2 Laurediols

A variety oflaurediols have been prepared by Martin [391]. The preparation of cis-(6S,7S)-laurediol is shown in Scheme 248. Lindlar reduction of alkyne 1436 followed by Sharpless asymmetric epoxidation enantiospecifically provides epoxide 1437. Rearrangement of epoxide 1437 to the terminal epoxide and Mitsunobu inversion ofthe secondary alcohol gives epoxide 1438. In a series of standard transformations, the terminal epoxide is converted to ketal 1439. Allylic oxidation of alcohol 1439 and transformation to the methylidene dibromide 1440 allows formation of the terminal acetylene by treatment with n-butyllithium. Methanolysis under acidic conditions produces cis-(6S,7S)laurediol in 16 steps and 16% overall yield. Using similar technology, the i\3,4-cis-isomer and the (6R,7R)-i\3,4 cis and trans isomers were also prepared.

OH

6S,7S-trans-Laurediol 1441

Masamune's synthesis of 6S,7S-trans-Iaurediol is outlined in Scheme 249 [392]. The key starting material is optically pure epoxide 1442 obtained from ( + )-tartaric acid. Acetylide opening of the epoxide provides the required trans diol geometry required in the natural product. From this point all that is needed to obtain 1441 is elaboration of the sidechains. The diene sidechain is obtained by addition of cis-allylic bromide 1443 and Lindlar reduction to afford alcohol 1444. The trans-enyne sidechain is obtained in a rather indirect fashion in an eight step process. Alcohol 1444 is converted in three steps to terminal epoxide 1445. Cyanide opening of the epoxide and DIBAL reduction affords aldehyde 1446, which is immediately submitted to Wittig olefination with TMS protected alkynylphosphorane 1447. Deprotection and hydrolysis yields the natural product in 12 steps and 12% overall yield from epoxide 1442.

Ti(

OP

r-i)

4 ~OH

H2 ~OH

t-B

uOO

H

(+)-

DE

T /

CH

2CI 2

-2

0 °C

/ 20

hr

.,,9

~OH

R

1436

I) P

hCO

OH

/ T

i(O

Pr-i

)4

2) T

sCI

/ py

r /

0 °C

/ 16

hr

3) N

aOM

e /

TH

F

4) P

h 3P

/ D

EA

D /

PhC

OO

H

CH

2CI 2

/ 0

°C /

2 hr

5)

NaO

Me

/ TH

F

65%

I) M

n0

2/ C

H2C

l2

2) P

h3P

/ C

Br4

73%

Pd-

BaS

04

87%

OH

R~

'0

14

38

I) E

VE

/ P

PT

S

CH

2Cl 2

./"'O

TH

P

2) L

i /'P

" BF 3

' Et2

0

R~

" 3)

H+

/MeO

H

73%

?+

I) n

-BuL

i /

Et2

0

R~

10 m

in

.. &

P

# B

r 2)

TsO

H /

MeO

H

1440

70

%

14

37

82%

~=R

I)

OC

H)

A

?+

CH

2CI 2

/H+

.. R~

2) L

iAIH

4 / T

HF

&

p

OH

OH

o °

C /

2 hr

93%

14

39

OH

~

65

,75

-1au

red

iol

14

41

Usi

ng s

imil

ar te

chno

logy

, th

e ,:\

3,4

-cis

isom

er,

the

C6-

R-C

7-R

,:\3

,4 c

is an

d tra

ns is

omer

s w

ere

also

mad

e.

Sche

me

248.

Mar

tin

Synt

hese

s of

tran

s an

d ci

s 6R

, 7r

and

6S, 7

S-L

aure

diol

s

-.l

tv ;: ~ [ i:

j [ ~ ~ [

[>-{"

" "O

H

0

1442

1) H

2 / P

d-B

aS04

E

tOH

2) L

i /

NH

3/ -

78 °

C

TH

F/M

eOH

94%

NaC

N /

MgS

04

aq.

MeO

H

35

°C

88%

OB

n l)u

= ~

DM

SO

20

°C

/ 1.

5 hr

""

0

.~

+ 2)

Me2

C(O

Mel

z 0

PPT

S /2

0 °

C

77%

OH

~O

1444

0

+

CN

~

OB

n

1) L

DA

/TH

F-H

MP

A

2)

Br

~

1443

73%

1) M

sCI

/ Et3

N

CH

2Ci 2

2) H

C1/

MeO

H

3) B

a(O

Hlz

C

H2C

i 2/H

2O

~O

OH

14

45

96%

Si0

2 / -

20

°C

DIB

AL

/ he

xane

CH

O

. (0

~-""

14

46

0

+

_~TMS

+P

Ph 3

TM

S

~.#'

1447

TH

F

Sche

me

249.

Mas

amun

e Sy

nthe

sis

of 6

S, 7

S-tr

ans-

Laur

edio

l

1) T

BA

F / T

HF

2) a

q. H

Cl /

MeO

H

~.#'

OH

6S,

7 S-t

rans

-lau

redi

ol

1441

27

% f

rom

nitr

ile

:I:

e:.. t ::a.. I fl -.l

VJ


4.1.3 Laurediol Derivatives

An enantioselective total synthesis of trienyne 1459 and its 3-trans-isomer has been performed by Martin [393] as shown in Scheme 250. Allylic alcohol 1449 is converted to epoxide 1450 which is then converted to a key intermediate epoxide 1451. This epoxide 1451 is homologated by addition of THP protected acetylide 1452 and manipulated via a series of four protection-deprotection steps to give 1453. An interesting use of disposable chirality provides aldehyde 1454 in three steps. For reasons unknown, non-chiral methods of epoxidation in this transformation result in much lower yields. Peterson olefination of 1454 with propargylic lithium reagent 1455 gives 1456 with cis stereochemistry. Desilylation and treatment of 1456 with Mukaiyama's reagent [394] gives the natural product 1457 in 16 steps. The trans-enyne 1459 is also a natural product. Peterson olefination of aldehyde 1454 with propargylic lithium reagent without the presence of added Lewis acid provides the trans-enyne geometry of compound 1458. Enyne 1458 is treated as the cis-enyne 1456 to provide natural product 1459 in a similar fashion.

1457

4.1.4 Laurencin

CI 1459

Laurencin has been prepared by Masamune [395] in a rather difficult synthesis (Scheme 251). Dialdehyde 1460 is prepared from 5-ethyl-2-furoic acid in four steps. In a key transformation, the dialdehyde is subjected to the RobinsonSchopf condensation to give 9-aza-3-oxabicyclo[3.3.1]nonanone, thus setting the relative configuration of two of the final four stereocenters. After acylation, the desired isomer 1461 is obtained in only 2.2% yield, along with 0.6% of the other 2,8-diastereomers. Ketone 1461 is converted to a mixture of ~,y

unsaturated ketones 1462 and 1463 in four steps via standard transformations.

(±)-Laurencin 1468

~OH

I) H

2 / P

d-B

aS04

M

eOH

:

OH

~

"0

I) P

hCO

OH

/ T

i(O

Pr-i

)4

1449

/,O

R3

1) L

i 14

52

2) t

-BuO

OH

/ T

i(O

Pr-i

)4

(-)-

DE

T /

CH

2CI 2

-2

0°

C

71%

~R3 #

' R

~

BF3

E

t20

1 I

' •

R1y~

OR

4

OE

E

2) A

C20

/ p

yr

OR

2

3) H

OA

c / M

eOH

1

45

1

4) T

BD

PS

CI

/ DM

AP

1

45

3

imid

azol

e /

DM

F

a) R

2 = C

H(C

H3)

OE

t, R3

= H,

R4

= TH

P 5)

TsO

H /

MeO

H

b) R

2 =

CH

(CH

3)O

Et,

R3 =

Ac,

R4

= T

HP

61%

c)

R2

= H

, R3

= A

c, R

4 =

TH

P

~=R1

d) R

2 =

TB

DPS

, R3

= A

c, ~ =

TH

P e)

R2 = T

BD

PS, R

3 =

Ac,

R4

= H

TB

DPS

I) T

BA

F /

TH

F

u+

l ~

~TMS

1455

Ti(

OP

r-i)

4 -&

\ R1

O

Ac ~

2)

E\ +

BF4

85

%

TH

F

14

54

-78

°c _

2

5°

C

TB

DPS

u+ ~TMS

TH

F/H

MP

A

62%

OT

BD

PS

R1

TMS

1456

~TMS

::::"..

. ~

OA

c

OT

BD

PS

14

58

Sche

me

250.

M

arti

n Sy

nthe

sis

of a

Tri

ene-

yne

from

Lau

renc

ia

N1)

Cl~O

I ~

Et4

N+

cr /

Et3

N

73%

65%

1450

1) H

2 / P

d-B

aS04

M

eOH

•

2) t

-BuO

OH

/ T

i(O

Pr-

i)4

(+)-

DE

T /

CH

2CI 2

-2

0°

C

3) H

I04

/ Et2

0

25

°C

/30

min

75%

for

fir

st

two

step

s; t

hird

ste

p no

t re

port

ed

2) T

sCI

/ py

r /

0 °

c /

16 h

r 3)

NaO

Me/

TH

F

R1 yt

CH

O

OA

c

OT

BD

PS

14

54

• ~OAC\

Cl

CH

2CI2

14

57

~/

• /~~y~OAc

14

59

C

l

::t: e. 0 S. '" '"1 en

0 -.

t-<

s:>

;::

... '" ;::< " Ei" en

'!'

-.I

Vl

n O

OH

~oAc

1) B

irch

re

duct

ion

2) e

ster

ific

atio

n ~COOEt

LiA

1l4

Et2

0 0

°C

-25

°C

20

hr

[ O

HC

C

HO

1

~OACH2

0H

1460

+

1) C

H3N

H3

Cr

o H

OO

C..

.)l.

....

CO

OH

25

°C

/pH

5

2 da

ys

2) A

C2

0/p

yr

54%

1461

2.

2%

( al

ong

wit

h 0.

6% o

f ot

her

2,8-

isom

ers)

~C~OH

1) t

osyl

hydr

azin

e T

HF

/H+

2) C

H3L

i

C~6/Et20

100%

..

0:3 /D

MS

MeO

H /

CH

2C1 2

-78

°C

( ..

1) C

H31

re

flux

/ 2

hr 0,

NM~

. 0

"." ..

.... O

H

+ Mo

,ND·· .. ,

.... OH .'

0

7%

aq,H

BF 4

n

... , ...... OH

+

O~O) I

O::O

H ..

2) 6

0-80

°c

(' (

refl

ux

(' , .. '

°

r 14

62

1463

32

%

13%

fr

om m

ethi

odid

e sa

lts

-.I

0'1 j > g; [ ~ ~ o i

1)

1\

O'

1)

("")

O,()..,,

/OH

HO

O

H

I

(~

Sy

S

(:O~

CHO

(CH

3h -

s,

C~/TsOH

+ <:~

Li

.. ..

.' 0

2) C

r03

DM

SO

/25

°C

TH

F ,,' I

pyr /

CH

2CI 2

r

1h

r r

-78

--2

0°

C

1462

10

0%

1464

66

%

2) A

C20

/ p

yr

1465

80

%

(~j B

F3oE

t20

0 Ph;P~

HgO

-()

.y-

I)

.

.. TM

S 15

% a

q. T

HF

(0

,,"

0 C

HO

T

HF

f O

Ac

S 2

5°

C

r O

Ac

2) N

}4F

/ D

MF

50

%

25

°C

1) T

sOH

aq

. ac

eton

e re

flux

2) NaB~ /

MeO

H

O°C

~

• 3

HO

'\'

# ,,'

0

f' O

Ac

1467

37

%

and

22%

of

C3

epim

er

Sche

me

2S1.

Mas

amun

e Sy

nthe

sis

of (±

)-L

aure

ncin

90%

CB

r4/ P

h3P

CH

2Cl2

/ 25

°C

14%

Sr

I"

OA

c

1466

OA

c

(±)-

laur

enci

n 14

68

-20

step

s -

0.00

47 %

ove

rall

yie

ld

..

i sa. I ~

....,J

...

.,J


Regioisomer 1462 is protected as the ketal and oxidized to give aldehyde 1464. Stereospecific conversion of the formyl moiety in 1464 to epoxide 1465 by treatment with dimethyloxosulfonium methylide sets the relative stereochemistry of the third chiral center. Opening of the epoxide with 2-lithio-l,3-dithiane and homologation of the sidechain by Wittig olefination gives trans-enyne 1466. Hydrolysis of 1466 affords a ketone, which upon reduction yields 37% of alcohol 1467 along with 22% of its C3 epimer. Conversion of 1467 to the bromide, with inversion at C3, produces a complex mixture of products from which laurencin1468 can be isolated in 14% yield. An overall yield of 0.0047 % is obtained over 20 steps.

4.1.5 Laurenyne

Overman's [396] synthesis of ( - )-laurenyne (1478) is illustrated in Scheme 252. The synthetic strategy addresses the problems of oxocane formation and the control of stereochemistry in eight-membered rings. The synthesis is initiated with the BF 3 • EtzO-assisted opening of oxetane with a silicon-stabilized organolithium reagent to afford alcohol 1470. Conversion of 1470 to allylic alcohol 1471 and Sharpless asymmetric epoxidation provides epoxide 1472 with an enantiomeric excess of 78-81 %. Titanium-assisted opening of epoxide 1472 with chloride ion gives chlorohydrin 1473 in 68% yield along with 25% of the regioisomeric product, thus setting the stereochemistry of two of the three stereocenters required in the product. Conversion of 1473 to acetal 1474 sets the stage for the key cyclization reaction. Treatment of 1471 with two equivalents of tin (IV) chloride results in cyclization to give oxocane 1475 in 37% yield after desilylation. Unfortunately, the use of more appropriately substituted sidechains resulted in lower yields of cyclized product. Once the oxocane ring system was obtained (along with the third stereocenter) all that was needed to complete the synthesis was minor refunctionalization and further homologation of the right hand sidechain. Application of standard methodology converts compound 1475 to diene 1476. Transformation of 1476 to aldehyde 1477 followed by Peterson olefination and desilyation gives (- )-laurenyne with the proper cisenyne geometry. Laurenyne (1478) is obtained in approximately 0.67% yield over 20 steps.

Laurenyne 1478

Haloethers of Laurencia sp. 79

4.1.6 Cis-Maneonenes A and B

The preparation of cis-maneonenes A and B is shown in Scheme 253. The synthesis by Holmes [397] begins with Grignard addition to the readily available lactone 1479 to afford lactoll480. This generates five of the six chiral centers needed in the products. A standard sequence of reactions yields aldehyde 1481, which is converted to the diyne 1482 by addition of 4-lithio-ltrimethylsilylbutadiyne. A mixture of four diastereomers is obtained. Lindlar reduction of 1482 gives cis-enyne 1483, as would be expected due to the steric and electronic influence of the trimethylsilyl group, along with 50% recovered starting material. Pyrolysis of the enyne bromo acetal gives a mixture of E and Z isomers 1484 and 1485. Separation of the isomers and treatment of each with the tetramethyl-cx-chloro-enamine 1486 forms the chlorides with inversion and leads to cis-maneonenes A and B in 24% yield. An overall yield of approximately 1.5% is obtained for each isomer over the course of the 9 step synthesis.

Br

cis-Maneonene A cis-Maneonene B

4.1.7 Trans-Maneonene B

Holmes has also prepared [398] trans-maneonene B (1489) as shown in Scheme 254. The mixture of minor isomers obtained from acetylide addition to aldehyde 1481 in Holmes's synthesis of cis-maneonenes A and B (Scheme 253) serves as the starting material for the preparation of 1489. Hydroxyl directed LAH reduction of the propargylic diyne system produces two trans-enynes 1488. Separation of the isomers and treatment as in the previous synthesis produces trans-maneonene B (1489) along with its isomer 1490.

trans-Maneonene B 1489

TMS

Br

I) s

-BuL

i 1 T

HF

Y

-7

8°

C

II •

2) o

xeta

ne

TMS~

II 6H

B

F3

· E

t20

1

47

0

77%

I) P

CC

1 N

aOA

c C

H2C

l 2

2)

C2

(CF 3

CH

20}z

' P"" C

02M

e

KH

MD

S 1

18-

crow

n-61

TH

F

-78

°C

53 -

62%

™Sn

Et0

2C

Dib

al

hexa

ne 1

C

H2C

l2

-78

°c

93%

T~0

OH

14

71

(+)-

DE

T /

Ti(

OP

r-i)

4 TM

S0 '"

NH

Cl/

TI(

O"'

-I),

TM

S0°

TM

SD

····

Cl

o ..

TsC

I ..

t-B

uOO

H 1

CH2C

l2

CH

2Q2

OH

py

ridi

ne

HO

"""

1 4A

Mol

. si

eves

14°

C

78%

? OTB

TPS

PP

TS

(ca

t)

CH

2Cl2

98%

OH

14

72

7

8-8

1%

ee

TMS~ •••

• Cl

II 0)

""

(1

"E

t

'bTS

OTB

TPS

1474

OH

88

%

14

73

68%

+ 2

5 %

of

a re

gioi

som

er

1)2

eq.S

nC

l4

TM

SU

····

Cl

CH

2Cl 2

/0 °

c

1.5

hr

• ""

",

•• ' 0

2) T

BA

F 1

TH

F ~~

OTs

37%

H

O

1475

HF

Pyr

idin

e 2

3°

C

83%

OTs

0 .. 0

.' 0

"""1

HO~'"

OTs

00

o i >

0.

p

. ~ [ I i

I) P

CC

/ N

aOA

c C

H2C

I 2

2) T

MS

OT

f /

Et3

N

Pd

(OA

ch /

CH

3CN

68%

O,"

'Cl

" 0

""'/

CH

O

I" 14

77

O,"

'Cl

"",,

/OT

s "

0 ;=

'"

OH

C

1476

I) D

ibal

/ -

78

°C

he

xane

/ C

H2C

i 2

2) M

sCI

/ E

t3N

C

H2C

I 2

..

3) N

aBH

4/H

MP

A

65%

_~Si

Pr-i

3

SiP

r-i 3

• O

""C

l ~Si

Pr-i

3

"" ~

¢f?

, 0

'

TH

F/H

MP

A

-78

°C

51%

I'"

Sche

me

252.

Ove

rman

Syn

thes

is o

f (-

)-L

aure

nyne

O:::.~

' ,,0

I

I~

OT

s

TB

AF

TH

F/D

MF

94%

I) N

aCN

/D

MS

O

95

°C

2) D

ibal

hexa

nes

/ C

H2C

i 2 ..

o °C

-rt,

the

n H

30+

51%

O,"

'Cl

"" ~

¢P

o ,~'

1/

(-)-

Iau

ren

yn

e 1

47

8

~ o " ;. " ~ o .., b' '" ~ ('

) E"

~

00

o &'C

OO

H n-P

rMgB~

TH

F /

-78

°e

o 76

%

o

1479

Li ~

MgB

r2

"""l!

TM

S • E

l 20

/ -7

8 °

e -2

5 °

e

o

x-r

ayo

n

alph

a br

omid

e

1482

51

%

o 1480

OH

(and

19%

of e

5 ep

imer

s)

~

o

Br2

/MeO

H

25

°e

70%

TM

S

H2

Pd -

BaS

04

MeO

H/E

tOA

c

/ he

xane

CO

OC

H3

I) L

iBH

4/T

HF

Br o

1483

30

-40%

2) p

ee

/ eH

2Cl 2

67%

~

alon

g w

ith

50%

SM

o

TM

S

Br

1481

200

0e

0.1

mm

Hg

30 m

in

00

tv

'TI ~

Q ~ 0.- tl [ ~

(I) ~ o ::-:

c; '"

o

0 O

H

Xr

1484

(E

)

0

, 14

85

(2)

Br

OH

lU'''!

o +

.1M

S elK

I)

Mez

N 14

86

2)T

BA

F IT

HF

25

°C

13

0 m

in

24%

TMS

24%

Sche

me

253.

Hol

mes

Syn

thes

es o

f ci

s-M

aneo

nene

s A

and

B

o

LiA

Il4/

TH

F

TMS

refl

ux /

90

min

65-8

0%

14

88

Sche

me

254.

H

olm

es S

ynth

esis

of

tran

s-M

aneo

nene

B

0 I)",

-..

..#

V~~Br

cis-

man

eone

ne A

0

, Br

TMS

cis-

man

eone

ne B

--- ---3 st

eps

anal

ogou

s to

ear

lier

syn

thes

is

(Sch

eme

254)

--- ---

10

-21

%

, , B

r

tran

s-m

aneo

nene

B

1489

o

, 1

49

0

::c t a f 5"

~

00

U

>


4.1.8 Panacene

Panacene (1497) is an aromatic diether containing a brominated allene substituent. Its synthesis by Feldman [399] is outlined in Scheme 255. At the onset of Feldman's synthetic planning, the relative stereochemistry of panacene was undetermined. Therefore, a strategy was developed that would allow the stereochemisry of the precursor to be transmitted to the bromoallene unit and would be flexible enough to provide both isomers for comparison purposes. Ethyl 6-ethylsalicylate is converted to benzofuranone 1491 by modification of known methods. Allylation, decarboxylation and reduction produces 1492 which is converted to diether 1493 by bromonium ion initiated cyclization. The tricyclic ring system is obtained as a 3: 1 mixture of exo: endo bromides. Aldehyde 1494 is obtained from 1493 in three steps. Addition of TMS protected acetylide to aldehyde 1494 affords a mixture of alcohols which is separated by formation of the benzoates followed by chromatography and hydrolysis. Mesylation of the cx-OH isomer of 1495 and treatment with LiCuBr2 produces 1-epipanacene 1496. Similar treatment of the 13-0H isomer provides panacene 1497 in 13 steps and a total yield of approximately 5%. The assigned configuration of the allene is based on the assumed stereochemistry of the displacement step as related to a steroidal model of known configuration [400]. Panacene can also be prepared from benzofuranone 1491 in a less stereo-rational, but perhaps biomimetic manner (Scheme 256) [401]. Conversion of 1491 to enyne 1499 occurs in four steps and 14% yield. Bromonium ion initiated cyclization of 1499 provides a 1: 1 mixture of l-epi-panacene and panacene in 8.9% overall yield.

Panacene 1497

4.2 Prostanoids

4.2.1 Clavulones

The clavulones are a series of marine prostanoids isolated [402] from the Okinawan coral Clavularia viridis. They have attracted strong synthetic interest due to their structures and their strong antitumor and antiinflammatory activities [403]. They bear a structural resemblance to a highly cytotoxic metabolite [404] ofPGD2• Biosynthetically, it has been proposed that they are

Cc~'

1) N

aB I

BrC

H2C

ChE

t

O:$-

~,

2ix

DM

F

1) N

aB I

BrC

H2C

H=

CH

2 I"

.. •

~

OH

2)

NaB

/CJf

6 ~

0 2)

HC

I/M

eOH

~

0 H

NBS

CH

3CN

81%

14

91

H

0;-

Br

W.

" 1)

KO

Ac

I DM

F

1 •

~

0 H

2)

NaO

CH

31

CH

30H

1493

3 :

1 m

ixtu

re o

f ex

o:

endo

a-O

H

13-0

H

3) (

CO

Clh

I D

MS

O

Et3

N I

CH

2Cl2

1) M

sCII

Et3

N

CH

2Cl2

2) L

iCuB

r21

TH

F

TH

F

50

%

69%

Sche

me

255.

Fel

dman

Syn

thes

is o

f (±

)-P

anac

ene

3) K

-Sel

ectr

ide

I TH

F

63%

031=

CH

O Li

~ H

0

:

1) ~TMS

" T

HF

1 ~

0 H

2)

TB

AF

I T

HF

1494

64

% f

rom

alc

ohol

25

%

1492

1495

a an

d ~-OH is

omer

s se

pam

ted

by c

hrom

atog

raph

y o

f th

eir

deri

ved

benz

oate

s fo

llow

ed b

y es

ter

hydr

olys

is

1496

l-

epi-

pana

cene

1497

id

enti

cal

to p

anac

ene

I 00

V

\

O:$-~"

#

0

1491

NB

S or

aq.H

CI

0'1.

300

84%

o B

rn

Br

BrY

Br

Br

Br

0'I.3

CN

1) L

DA

/ T

HF

; th

en

OJ ~

I T

MS

# 0

2) K

-Sel

ectr

ide

/ T

HF

3)

TB

AF

/T

HF

17%

+

62%

1

mix

ture

Sche

me

256.

Alt

erna

te E

ndga

me

for

(±)-

Pan

acen

e S

ynth

esis

Ar--

X ~~

1499

l-ep

i-pa

nace

ne

1496

pana

cene

14

97

00

0

\ ~ 4 5': p.. [ a:: '" ~ 2- :=.' '" '"

Prostanoids 87

derived from arachidonic acid via a mechanistic pathway involving a series of free radical intermediates [405].

4.2.1.1 Clavulones I and II

Clavulone I has been prepared by Corey [406J in 10 steps and 10% yield (Scheme 257). Sensitized photooxidation of substituted cyc10pentadiene 1500 followed by sodium borohydride reduction affords the cis diol 1501. PDC oxidation, Lindlar reduction of the alkyne and silylation of the tertiary alcohol gives the cyc1opentenone ring and lower sidechain with proper alkene geometry. Due to the sluggishness of cyc1opentadienone forming eliminations, the upper sidechain can be appended by an interesting aldol-coupling process of 1502 and racemic aldehyde 1503 to produce 1504 as a 1: 1 mixture of diastereomers. Selective replacement of the tertiary TBS group with an acetyl moiety followed by separation of the diastereomers produces optically pure 1505. Desilylation and acylation completes the synthesis to provide c1avulone I (1506).

° QAc

~¥ C02Me

\. -csHIl

OAc

Clavulone I 1506 (-)-Clavulone II 1510

The Shibasaki [407J synthesis of c1avulone II (1510) is shown in Scheme 258. Alkylation of an Cl-hydroxycyc1opentanone dianion with an eight carbon propargylic bromide followed by Lindlar reduction affords the lower side chain with the proper cis geometry. Formation of the cyc1opentenone via the enol triflate followed by a four-step carbonyl transposition gives the cyc1opentenone 1508 with proper regiochemistry. Coupling of 1508 with the enantiomerically pure aldehyde 1509 according to the procedure of Yamada (Scheme 262) and separation of the diastereomers produces ( - )-c1avulone II (1510).

4.2.1.2 Clavulone III

The synthesis by Hamanaka [408J enantiospecifically provides both c1avulone II and c1avulone III (Scheme 259). Selenylation-elimination and DIBAL reduction of the Corey lactone 1511 provides the multi-functionalized cyc10pentane 1512. Sharpless epoxidation of 1512 and reductive epoxide opening affords triol 1513 which is selectively protected at the secondary alcohol and oxidized to provide aldehyde 1514 in a four-step process. Wittig olefination provides the lower side chain with the proper cis unsaturation. Selective deprotection and acylation of the secondary alcohol followed by deprotection and oxidation of the primary alcohol affords aldehyde 1515. Coupling of vinyl stannane 1516

1) n

-BuL

i, T

HF

l)

hv,

Ob

-4

0°

C

0 -7

8 -

O°C

~CsHII

rose

ben

gal

.. 2)

ICH

2 =

CSH

ll 2)

NaB

H!,

MeO

H

-78

--3

0°

C

3) 2

3°

C, 4

hr

1500

1) P

DC

, 96

%

2) H

2, L

indl

ar

94

%

3) T

BSO

Tf,

2,

6-lu

tidin

e 9

6%

78 %

o ~

OT

BS

CSH

II

1502

o ~TBS

1) L

DA

, T

HF,

H

MPA

, -7

8°C

60

%

OT

BS

2) OHC~C02Me

1503

84 %

1) T

BA

F (

5 eq

uiv)

A

C20

, D

MA

P

2) s

epar

atio

n o

f is

omer

s

~'

C02

Mc

~

-C

SHll

OA

c

TB

AF

(5

equi

v)

AC

20,

DM

AP

45°C

, 6 h

r

60

%

1505

Sche

me

257.

Cor

ey S

ynth

esis

of

Cla

vulo

ne I

HO

.. ~C

'H"

OH

1501

~

~-r_H..

CO

2 Me

OT

BS

CSH

II

1504

(1

: 1

mix

ture

of

dias

tere

omer

s)

o ~Ac

~'

C02

Me

~

-C

sHl1

O

Ac clav

ulon

e I

1506

00

0

0

'T1

~ '< R

~ 2- s:::

~

III 8" ::-: " '"

1) M

eLi,

DM

E

1) T

MS

OT

f,

Et3

N

OT

MS

UO

TM

S 2)

Br..

.. _

CsH

II

3) H

2, L

indl

ar c

at. ~

o O

H

CsH

II

2) P

d(O

Ach

, M

eCN

~~"

1) N

aB14

, CeC

1 3

2) M

ll20,

py,

DM

AP

• 3)

H20

, ac

eton

e

79

%

66%

HO

~

OT

MS

OHC~C02Me

OA

c 15

09

Sche

me

258.

Shi

basa

ki S

ynth

esis

of (

-)-

Cla

vulo

ne I

I

CsH

II

61 %

0

1) C

olli

ns

.. ~

2) A

cOH

, H

2O

99 %

o ~C02Me

~-r~~ O~ACC

OA

c C

sHII

(-)-

clav

ulon

e II

15

10

OH

1508

CsH

II

~ ~ l 00

\Q

OT

HP

%-om

s o

1511

OT

HP

/-, ..•

•• ,-O

TB

S

I) L

DA

, P

hSeC

I 86

%

2)H

202,

79

%

3) D

ibal

86

%

+

1) Ph)P~CsHn-n

53 %

(p

lus

26 %

tra

ns)

OT

HP ce

OT

"

Hf( O

H

1512

OT

HP

/-, ...•

"-

OT

BS

1) t

-BuO

OH

V

O(a

cach

83

%

2) R

ed-A

I T

HF

60

% 1) T

BA

F

95 %

OT

HP ¢[;

" H

O

OH

O

H

1513

OT

HP

I) P

hCO

CI,

py

r, 6

6 %

2)

TB

SC

I,

imid

azol

e, 9

0 %

3) K

2C0

3, M

eOH

94

%

4) C

olli

ns o

xida

tion

6

4%

~CHO

TB

SO

OH

1514

2) T

BA

F,

70 %

3)

AC

20,

pyr,

96

% ~CSH[[

AcO

O

H

2) C

olli

ns

75 %

~

AcO

O

H

CsH

lI

I)

n-B

u)Sn

~OTHP

15

16

0H

O

TH

P O

Ac

/-, ...•

"~

n-B

uLi,

TH

F, 3

2 %

2) A

C20

, py

r, 4

5 %

1) S

ilica

, 43

%

2) A

C20

, py

,r

77

%

~_

OA

c O

TH

P

AcO

O

H

CsH

lI

1517

o ~C02Me

~-r~~ O~ACC

.•

OA

c C

SH

[[

(-)-

clav

ulon

e II

1510

+

2:

I

Sche

me

259.

H

aman

aka

Synt

hesi

s of

Cla

vulo

ne I

I an

d C

lavu

lone

III

1) A

cOH

, H

20

65 %

2) J

ones

3)

CH

2N

2

AcO

", ..

# o

OA

c

1515

¢C::

0 ..•

• '~C02Me

OA

c

CsH

lI

AcO

O

H

1518

C0 2

Me

CsH

II

c1av

ulon

e II

I 15

19

~

;;i1

~ [ ~ 8- a::: " s 8" ~ '"

Prostanoids 91

Clavulone 1lI 1519

(prepared from o-glutamic acid) with 1515 yields 1517 after acylation. Removal of both THP protecting groups, Jones oxidation and treatment with diazomethane produces keto-ester 1518. Acetate elimination on silica and subsequent acylation of the tertiary alcohol gives c1avulone II and c1avulone III in a 2: 1 ratio and an overall yield of 0.08% over 20 steps.

4.2.1.3 Deacetylclavulone II

An enantioselective and stereoselective synthesis of clavulone II that produces the naturally occurring 12-0-deacetylc1avulone II as an intermediate has been demonstrated by Yamada [409] (Scheme 260-262). The basic strategy involves utilizing optically pure 1526 as an acceptor to attach the lower side chain (Scheme 260). A carbonyl transposition allows the cyc10pentyl moiety to act as a donor so as to attach the optically pure upper appendage. The upper sidechain is prepared from lactone 1521 which is readily available from o-mannitol (Scheme 261). Reductive opening ofthe lactone with LAH, followed by acylation of the secondary alcohol in a three-step process yields 1522. Stepwise oxidation of 1522 and treatment with diazomethane affords ester 1523, which is converted to aldehyde 1524 by removal of the benzyl protecting group and Swem oxidation. Wittig olefination produces the unsaturated aldehyde 1525 with proper stereochemistry in 10 steps. Reaction of optically pure (8)-4-hydroxycyc1opentenone 1526 (obtained from (+ )-diethyl tartrate) with lithium t-butylacetate yields ester 1527 (Scheme 262). Protection of the alcohols, ester reduction-oxidation to the aldehyde and Wittig olefination allows atachment of the lower side chain in 91 % yield from the diol1527 to give 1528. Removal of the THP groups and PCC oxidation produces cyc1opentenone 1529, which is

Deacetylclavulone II 1531


o H~C~Me

HO ') OAe ~- 1525

~0...--=" o C5Hl1

>

(S)

Scheme 260. Yamada Basic Strategy for Synthesis of Clavulone II and 12-0-Deacetylclavulone II

coupled through aldol reaction with the optically pure aldehyde 1525 to give 1530. Mesylation produces desacetylclavulone II 1531, which upon treatment with acetic anhydride results in the formation of clavulone II. Alternatively, the diol 1530 can be converted directly to clavulone II in 87% yield by treatment with acetic anhydride in pyridine. Clavulone II (1510) is produced in 12 steps and 34% yield from lactone 1526.

4.2.1.4 Chlorovulone II

Optically pure 4-hydroxy-2-cyclopentenone is also utilized by Yamada [410] in an enantioselective synthesis of ( - )-chlorovulone II (1541) (Scheme 263). The chlorine functionality is introduced early in the synthesis by dichlorination of cyclopentenone 1533, followed by elimination to afford 1534. Sodium borohydride reduction of the ketone, TBS protection of the alcohol and LAH reduction of the ester yields the primary alcohol 1535. The lower appendage is attached by Swern oxidation and Wittig olefination to give 1537. Desilylation and Jones oxidation produces the ketone 1538, which is then coupled in aldol fashion with aldehyde 1539 to produce 1540 as a single isomer. Removal of the MOM group gives (- )-chlorovulone II (1541) in 13 steps and approximately 20% yield. When compared, the natural product 1541 was found to be of the opposite configuration.

o

Cl

(-)-Chlorovulone IT 1541

4.2.1.5 Preclavulone A

A combination of physico-chemical methods has detected the presence of preclavulone-A as an intermediate in the biosynthetic pathway utilized by certain corals in the production of clavulones [411]. The synthesis of this substance by Corey [412] allowed comparison with the small amount of the

T~OH

HO

-C-H

I

HO

-C-H

I

H-C

-OH

I

H-C

-OH

I C~OH

D-M

anni

tol

1) A

czO

, py

, rt

2) n

-BII

4N+P

-,

TIl

F, r

t

82 %

(fr

om

bute

noli

de)

1) H

z, P

d-C

2)D

MS

O,

(CO

Clh

3)

Et3

N.

I

--.. -..

----~

PhCHzO~

••.

H

0 o

15

21

PhC~O~OH

H

OA

c

15

22

o H~C02Me

H

OA

c

15

24

1) L

iAIH

4'

Etz

O,

rt

2) T

BS

Cl,

im

idaz

ole,

D

MF

, rt

1) P

CC

2)

Jon

es

3) C

HzN

z

88 %

Ph3

P=

CH

CH

O

ClC

H2C

H20

76%

fro

m B

o p

rote

cled

m

eth

yl e

ster

PhCH20~OTBS

H~

OH

PhCH20~C02Me

H

OA

c 15

23

o

H~C02Me

H'

OA

c 15

25

Sche

me

261.

Yam

ada

Pre

para

tion

of

Ald

ehyd

e In

term

edia

te 1

525

for

Syn

thes

is o

f C

lavu

lone

II

and

12-

0-D

eace

tylc

lavu

lone

~ l \0

w

"6 "~

"~

I) D

MSO

, (C

OC

lh

LD

A,

Et3

N

(5) ~

CH

3C0

2Bu-

t,

~ C

0 2B

u-t

I) D

HP,

CSA

•

.. ~

TH

F, -

78 °

C

2) L

iAIH

4 +

O

H

2)

Ph3P

,-"" C

5HlI

-n

0 O

H

OT

HP

1526

15

27

91 %

(fr

om d

iol)

o

"~

OT

HP

C5 H

lI

I) A

cOH

,H20

2) P

CC

~C

,""

OH

I) L

DA

, T

HF,

-78

°C

2)

0

H~C02Me

H

OA

c 15

28

o O

H

~C02Me

~r~~~C

OH

C

5 HlI

1530

MsC

I

Et3

N

75 %

73 %

15

29

o ~C02Me

~-r~~ O~AC

C O

H

C5 H

lI

deac

etyl

clav

ulon

e II

1531

Sche

me

262.

Y

amad

a Sy

nthe

sis

of C

lavu

lone

II

and

12-0

-Dea

cety

lcla

vulo

ne

AC

20

pyr

98 %

1525

72

%

o ~C02Me

~-r~~ O~AC

C O

Ac

C5 H

lI

clav

ulon

e II

1510

1.0 ~

"'1 '" q [ ~ ::1

. 2- 3:

~ ~

fb c; '"

HO

H

O

Q

-------~

Q~BJ

0

1526

(S

)-4-

hydr

oxy-

2-cy

clop

ente

none

°

C1~C

o,B"

OC

H2O

Me

1534

I) S

wem

oxi

dati

on

2) Ph3P~C5

Hl1

15

36

I) L

DA

, T

HF

, -7

8°

C

2) OHC~ (C

H2h

C0

2Me

"153

9

OH

1) N

aBR

!, C

eCI 3

, M

eOH

, rt

•

2) T

BSC

I, D

MF

im

idaz

ole

TB

SO

Cl

OC

Hp

Me

1537

o

Cl

OC

H20

Me

1) J

ones

•

2) C

ICH

2OM

e,

i-P

r 2N

Et

TB

SO

C1~Co,B"

OC

H2O

Me

I) d

esil

ylat

ion

2) J

ones

0 Q-"

OCH~OMe

1533

LiA

IH4

.. E

t20

93 %

(f

rom

ket

o es

ter)

o

Cl

1) C

1 2, E

t20

2) x

s E

t3N

75 %

(fr

om d

iol)

TB

SO

CI~ O

H

OC

Hp

Me

15

35

68 %

(fr

om s

ilyl

die

ne)

OC

H20

Me

HC

I (c

at)

HO

Ac

70

%

Cl

1538

o

OH

68 %

15

40

sing

le i

som

er

(-)-

chlo

rovu

lone

II

1541

[n

atur

al p

rodu

ct i

s (+

)]

Sche

me

263.

Yam

ada

Synt

hesi

s of

(-

)-C

hlor

ovul

one

II

§ § o ~

I,Q

V

I


Preclavulone-A

compound obtainable from incubation of the extract from Clavularia viridis with arachidonic acid (Scheme 264). The (-)-Diels Alder adduct 1542 was enolized and trapped as the TMS enol ether 1543. Cope rearrangement led to the cis fused bicyclic 1544. Oxidative cleavage led to the differentially cissubstituted cyclopentene 1545. Wittig reaction was used to append the lower sidechain. A sequence utilizing iodolactonizationallowed functionalization of the 5-membered ring to the desired lactone 1548. DIBAL reduction and a second Wittig olefination established the upper sidechain, with the synthesis being finished off with a Dess-Martin oxidation to give (- )-preclavulone-A (1549).

4.2.2 Punaglandins

The punaglandins are a series ofC-tO chlorinated marine prostanoids, isolated [413] from the Hawaiian octocoral Telesto riisei that show strong antitumor activity. Punaglandin 3 exhibits (Z)-7 geometry, whereas punaglandin 4 exhibits both (Z)- and (E)-7 geometry, but differs in that the 17,18-position is saturated. Syntheses of the punaglandins follow a very similar strategy. The lower sidechain is attached to a cyclopentenone intermediate, followed by coupling with an optically active aldehyde to obtain the upper side chain. In this way the problem of obtaining the correct relative stereochemistry between C-12, of the cyclopentenone ring, and C-5 and C-6, on the upper sidechain, is circumvented.

OAe

20

4.2.2.1 Punaglandin 4

The synthesis of punaglandin 4 (1562) by Mori [414] involves the coupling of two optically active fragments to give 1562 in an enantiospecific manner (Schemes 265 and 266). The chiral precursor 1551, prepared from (+ )-tartaric acid, is a common intermediate in two other syntheses of 1562. Conversion of 1551 to the iodide 1552, followed by a photo-induced radical addition to methyl acrylate affords 1553. Removal of the benzyl protecting group and Swem

OJ'''r

LD

A,

TM

SC

I

OJ .. 'f'"

•

TH

F,

-78

°C

0 9

6 %

O

TMS

15

42

1

54

3

1) M

CP

BA

H

N

aHC

0 3

crx

:H

Pb(

OA

c)4

• •

2) a

q H

F /

Et3

N

MeO

H

78%

H

72

%

15

45

o

O"""C

02M

e

""'~CsHll

I) a

q L

iOH

2) 1

2 3)

DB

U /

DM

E

~.l)

O···."

~CSHl1

1

54

7

89%

1

54

8

Sch

eme

264.

Cor

ey S

ynth

esis

of

( -)-

Pre

c1av

ulon

e A

H

PhC

H3

~OTMS

• f

I 20

0 °

C /

4 hr

se

aled

tub

e H

80%

15

44

H

ctco

2M

e

Ph3P~ C

SHll

CH

O

TH

F

H

92%

15

46

o

2)

+

Ph 3

P -

(CH

z}4C

OO

H B

r-

KH

MD

S/T

HF

1) D

ibal

/ C

H2C

l 2

).-

, "'~C02H

V::"'~CSHll

3)

OA

e .

AcO

, ••

UA

c

CGo

Pre

clav

ulon

e-A

15

49

o 89

%

~ '" § 2.

e:> '" \0

-...I


OMe CI

Punaglandin 4 1562

_o-yl;b. o

1551

1553

92%

2)DMSO, (COClh

Et3N

•

1552

40% (from 1551)

n-BU3SnCl, NaBH4 CH2=CHC~Me

hV,MeOH

60%

1554

Scheme 265. Preparation of Aldehyde Fragment 1554 for Mori Synthesis of Punaglandin 4

•

oxidation gives the aldehyde fragment 1554. The cyclopentenone fragment 1560 is obtained from hydroxycyclopentenone 1555. Acetylation and chlorinationelimination of 1555 followed by reduction and silylation affords the acetate 1556 as a mixture of diastereomers. Resolution of 1556 by enzymatic hydrolysis gives enantiomerically pure 1557. Oxidation of 1557 with PDC, addition of the lower side chain and Lindlar reduction of the alkyne 1558 yields 1559 with the proper olefin geometry. PCC oxidation of 1559 and protection of the tertiary alcohol forms the second optically pure fragment 1560. Coupling of 1560 and 1554 in an aldol condensation with elimination gives 1561 in 25% yield, along with 37% of the (Z)-isomer. Deketalization of 1561 and acylation produces punaglandin 4 (1562) in 16 steps and 0.03% yield.

The preparation of 1562 by Shibasaki [415] begins with attachment of the lower side chain during the initial steps of the synthesis to give 1568 (Scheme 268). Bis-chlorination of 1568 followed by lithium chloride-assisted thermal elimination yields the unsaturated ketone 1569. A 1,3-carbonyl migration in four steps, followed by protection of the alcohol as its MOM ether gives the fragment 1570, ready to be coupled to the optically pure aldehyde. The aldehyde fragment is prepared from ( + )-diethyl tartrate via the similar intermediate 1563

0 Q O

H

1555

TBSO

~ ..

CI-a""O

H

1557

I) n

-Bu4

N+

F

70 %

I) A

C20

..

2) C

1 2, E

t3N

50 %

PD

C

91 %

0

C1

-O

I) N

aBH

4, C

eCI 3

..

2) T

BS

CI,

im

idaz

ole

OA

c 71

%

TBSO~.

I)

LiC

H2

Li

C1

-Q

.O

2)

n-B

uLi,

n-C

5H

11 I

I) P

CC

2) H

z, L

indl

ar

HO

,

C'~o

""",

, O

H

2) M

OM

CI

i-P

r2N

Et

1559

LD

A,

TH

F

C,~CO'

M' 23

% o

vera

ll

I) 8

0 %

, A

cOH

, H

20,

60°C

2)

Acl

O,

py

3) A

cOH

,HC

I

pig

TB

SO

panc

reat

ic

C1

---G

..•

lipa

se

25 %

'O

Ac

1556

TB

SO

c'-

0°

"C

'""

OH

1558

o

c,~

OM

OM

n-

CsH

lI

1560

OA

c

CI

OH

O

MO

M

n-C

sH"

OH

C)A

c0

2M

C

o 14

% (

from

156

0)

1554

25

% (

plus

Z

isom

er 3

7 %

)

1561

Sch

eme

266.

Mo

ri S

ynth

esis

of

Pun

agla

ndin

4

puna

glan

din

4 15

62

OM

e "C

.... ~ S- ::;

o ~

1.0

1.0

OH

~~~

~c0C

OzEt -

----

-HO

0

1.-(+

)-di

ethy

l ta

rtra

te

1563

~~

0

HOyp00~OH

o

Ph~~O)

HO~~)

1)

1564

0

.. 2)

H2

.Pd

0

NaO

Me

MeO

H

72

%

(fro

m a

ceta

l) 6

3%

15

65

~~

0

HO

yp

0o

Me

o 15

66

(CO

Clh

. D

MSO

Et3

N

94

%

Sche

me

267.

Pre

para

tion

of C

hira

l A

ldeh

yde

Fra

gmen

t 15

54 f

or S

hiba

saki

Syn

thes

is o

f P

unag

land

in 4

D.3 15

54

..... 8 j ~ )? [ I

OTM

S

(X

OT

MS

LiC

l, D

MF

12

0°

C

93 %

two

step

s

66

%

Cl-!l

~O

OH

n

-CH

S

11

1568

NaB~,

CeC

l3

O~

OH

n

-CH

S

11

87 %

1569

H20

...

NC

S,

NaO

Ac

diox

ane

72

%

Cl>

fl

Cl-~

o O

H

n-C

S H11

Cl~

OH

O

H

n-C

S H11

Ms 2

0,D

MA

P

py, C

H2C

l 2,

o 1)

PD

C

Cl~

OM

s O

H

n-C

S H11

D

MS

O

HO

CI~"_c,HU

OH

2) M

OM

Cl,

i-

Pr 2

NE

t

Cl~

OM

OM

n-

CS H

11

1) L

DA

, -7

8 °C

2)

~~

0 OHCd~OMe

o 1554

Cl

70

%

(fro

m d

iol)

o

o

OM

OM

,~

0

7~OMe

all

four

dia

ster

eom

ers

wer

e ob

tain

ed

in a

I: I

: I: I

rat

io i

n 53

% t

otal

yie

ld

Sche

me

268.

Shi

basa

ki S

ynth

esis

of

Pun

agla

ndin

4

63 %

1) 8

0% a

q A

cOH

2)

AC

20

, py

, CH

2C1 2

3) 8

0% a

q A

cOH

30-4

0 %

Cl

1570

OM

e

OH

1562

pu

nagl

andi

n 4

~ en ~ 8.

~

>--

" o >-

-"


(Scheme 267). Chain extension of 1563 by Wittig olefination with 1564 and hydrogenation gives 1565. Ozonolysis and transesterification followed by Swern oxidation gives the needed chiral aldehyde fragment 1554. Aldol coupling of 1570 and 15S4 with elimination gives an equal mixture of all four diastereomers at the 7- and 12-positions. Deketalization and acylation of the proper diastereomer gives punaglandin 4 (1562) in 13 steps and O.S% yield.

The Noyori [416] preparation of puna gland in 4 provides both the (7E)- and (7Z)-isomers (Scheme 270) in an enantiospecific synthesis. The chiral aldehyde fragment is prepared from the allylic alcohol 1571 via Sharpless asymmetric epoxidation to afford the chiral epoxide 1572 (Scheme 269). Protection of the alcohol; basic opening of the epoxide, esterification with diazomethane and acetylation gives acetate 1573 in good yield. Deprotection of the primary alcohol and Swern oxidation provides the chiral aldehyde in 7 steps. Chirality at the 12-position of 1578 is obtained through the chiral cyc1opentenone 1576, which is obtained in four steps from 2,4,6-trichlorophenol using known chemistry. The lower appendage is attached via the equilibrating mixture of organolithiums obtained by lithiation of allenylstanne 1577 to give a 42% yield of 1578 (along with 22% of the cyc10pentyl allene). Lindlar reduction affords the desired cis geometry in the sidechain. The complete punaglandin skeleton is obtained by aldol condensation of the enolate from 1579 with aldehyde 1574. Acylation and desilylation yields a mixture of (7 E)- and (7 Z)-punaglandin 4 in a 2: 5 ratio. This ratio can be reversed to 7: 3 by irradiation with light.

4.2.2.2 Punaglandin-3 and (7E)Punaglandin 4

Yamada's [417] synthesis of (7E)-punaglandin 4 (Scheme 271) involves the coupling of the usual optically pure aldehyde 1582 with the enantiomer of an intermediate utilized in his synthesis of chlorovulone II (Scheme 264). Coupling of 1582 with 1538 in an aldol reaction followed by acylation and elimination gives the ketal 1583 as a mixture of 7,S-double bond isomers. Deketalization of the (7E)-isomer, acylation, and removal of the MOM protecting group affords (7 E)-punaglandin 4 (1562) in what might be called an "off the shelf" synthesis.

Cl

Punaglandin 3

Punaglandin-3 was assembled in an entirely analogous manner (Scheme 272). Wittig reaction of the unsaturated phosphorane with aldehyde 1585 established the lower sidechain. Desilylation and Jones oxidation led to enone 1587. Attachment of the upper sidechain as in the punaglandin-4 synthesis eventually yielded punaglandin-3 (1588).

HO~C02Me

1571

1) C

H2N

2 82

%

-2)

AC

20,

DM

AP

9

6%

Ti(

i-P

rO)4

. (+

)-D

ET

o ,:0

';

1) D

HP

. PPT

S 9

4%

t-B

uOO

H HO~C02Me

2) N

aOH

.H20

OH

THPO~C02H

HO

57

%

1572

OA

c 1)

PPT

S. M

eOH

O

Ac

~C02Me

88 %

OHC~C02Me

TH

PO

.. A

cO

2) D

MS

O.D

CC

7

5%

A

cO

1573

15

74

Sche

me

269.

Pre

para

tion

of C

hira

l A

ldeh

yde

Fra

gmen

t 15

74 f

or N

oyor

i Sy

nthe

sis

of (7

Z)-

and

(7E

)-P

unag

land

in 4

l 1 .....

o w

Cl

~

4 st

eps

TB

SO

1) M

eLi,

SnM

e3

=ec

=( n

-C5H

[[

1577

VO

H

Cl

1#

(k

now

n ch

emis

try)

Cl-

{).o

2) n

-Bu4

N+

F

Cl

1) H

2, L

indl

ar

98 %

2) P

DC

, 91

%

3) T

MS

OT

f i-

Pr2N

Et,

86 %

1) A

C20

, D

MA

P

2) H

OA

c, H

20

41 %

15

76

o

Cl~

TM

SO

n-C

5 Hll

15

79

OA

c

Cl

OH

42 %

LD

A,

TH

F,

-78

°C

OA

c OHC~C02Me

AcO

15

74

58 %

OM

e

(7E

)-pu

nagl

andi

n 4

15

62

HO

~-

Cl~n-C5H[[

HO

1578

OA

c

Cl-

-{"

~

OT

MS

1580

o

o O

Me

Cl

OH

(7Z

)-pu

nagl

andi

n 4

1581

2 :

5 7 E

: 7

Z r

atio

; ir

radi

atio

n w

ith

ligh

t gi

ves

7 :

3 7

E :

7 Z

rat

io

Sche

me

270.

Noy

ori

Syn

thes

is o

f (7

Z)-

and

(7E

)-P

unag

land

in 4

.- 0 -I'>-

"Tj

III ~

;>

~ tJ

(I) ~.

0- a: (I) iii

'J'

OM

e 0 ~ '"

H

0

HOYl~C02Me

'~0-r

o

I)D

MS

O

(CO

Clh

2) E

t3N

89

%

a~

OM

OM

C

SH

ll

1538

1) H

OA

c,H

20

2) A

C20

, P

y

3) H

Cl

(cat

) H

OA

c

Sche

me

271.

Yam

ada

Syn

thes

is o

f (7

E)-

Pun

agla

ndin

4

H

0

OHC~~C02Me

~0-r

K2C

03

H

0 OHC~~C02Me

H ~0-r

MeO

H

95 %

15

82

1) L

DA

, 15

82

2) A

C20

, DM

AP

~HO

Cl

,'I" ~C

02Me

\ 0

i -

OM

OM

C

SH

ll

1583

m

ixtu

re o

f ol

efin

iso

mer

s

OA

c

OM

e C

l

(7E

)-pu

nagl

andi

n 4

1562

~ ~ ~ '" .....

o VI


OTBS

Cl~CHO OMOM

1) Ph3P=V=V

HMPA, THF, -42°C

2) n-Bu4N+F • CI~

3) Jones OMOM

1585

• • Cl

pllnaglandin 3 1588

Scheme 272. Yamada Synthesis of of Punaglandin 3

4.2.3 Hybridalactone

1587

Hybridalactone (1593) is a macro cyclic lactone isolated from the marine alga Laurencia hybrida [418]. An enantiospecific synthesis of 1593 by Corey [419] is illustrated in Scheme 273. Problems that need to be addressed in the synthesis of 1593 include control of stereochemistry at the seven chiral centers and the problem ofmacrolactonization. These difficulties are mitigated somewhat by the fact that all seven chiral centers are contiguous and the number of degrees of rotational freedom in the ring-opened lactone are restricted due to the two cis double bonds and the fused five-membered ring. Four of the seven chiral centers are obtained by the coupling of tosylate 1587 and cyclopropylstannane 1588, both of which are optically pure. Fluoride-catalyzed fragmentation of 1589, followed by reduction with L-Selectride provides the fifth chiral center (as a 6: 1 mixture of the epimeric carbinol) along with the necessary functionality to further elaborate the upper sidechain. The final two stereo centers are obtained via Sharpless epoxidation to afford 1590. Lithiation of acetylene 1590, conversion to the Gilman reagent and 1,3-addition to the iodoallene 1591 yields the diyne 1592 which upon Lindlar reduction affords the cis stereochemistry in the

Hybridalactone 1593

C8-Cll Algal Pheromones 107

upper appendage. The carbinol stereochemistry is corrected by an oxidationreduction sequence followed by deprotection of the latent carboxyl functionality. Macrolactonization is achieved by the double activation method in 83% yield to give (- )-hybridalactone (1593) in 13 steps and 10% overall yield.

4.3 C8-Cll Algal Pheromones

A variety of Cll and C8 hydrocarbons have been isolated from brown algae of the genera Dictyopteris, Ectocarpus, and Cutleria. These metabolites are often important in algal reproduction, acting as pheromones and chemotactic agents. They possess linear unbranched structures, either cyclic or acyclic, characterized by varying degrees of unsaturation.

4.3.1 Dictyoprolene

Dictyoprolene (1598) is the acetate of one ofthe undec-l-en-3-ols that have been implicated as possible key biosynthetic intermediates leading to many of the C11 hydrocarbons [420]. It has been isolated from the brown alga Dictyopteris proliferra by Yamada, who determined its absolute stereochemistry through synthesis (Scheme 274) [421]. Condensation of acrolein with I-bromooct-2-yne in the presence of activated zinc yields allylic alcohol 1595. Esterification with optically pure steroidal acid chloride 1596 and separation of the diastereomers on silver nitrate impregnated silica provides optically pure adduct 1597. Lindlar reduction, reductive cleavage of the ester and acylation provides (+)dictyoprolene in 5 steps and 5.0% overall yield.

(+)-Dictyoprolene 1598

4.3.2 Dictyopterenes

Dictyopterene A (1601) is a cyclopropane-containing diene first isolated [422J in 1968 from a mixture of the brown algae Dictyopteris plagiogramma and D. australis. The related triene dictyopterene B (1628) has been isolated from the essential oils of an unidentified Dictyopteris sp. by Moore in 1970 [423J. It was later found in a variety of other brown algae by Jaenicke and co-workers and named hormosirene. Dictyopterene B has an intense "ocean smell" and has been

H

CAo

H

n-B

u4N

+ F

TH

F,H

2O

78

%

H

O".",-

¥~ '~ .... ,

,~OTB.

~ H

}\

7\

H

1590

1) N

aH

t-B

u02C

H

2) T

sCI 45

%

H

~

, .

0

~ ... "V

H

H

H

Ct=(

ar,

H

0

1587

L-S

elec

trid

e

92 %

..

(6 :

1 m

ixtu

re a

t ca

rbin

ol c

arri

ed o

n)

n-B

uLi,

-78

°C

BU3S:~

H

H

1588

78

%

H

~

, :

H

~'''

''~

H

H

H

%-

~ f'

O

Ts

~ O

H

H

j '.:.

H

H

1589

VO

(aca

ch

t-B

OO

H

TB

SO

Tf

2,6-

luti

dine

84 %

I) n

-BuL

i, C

uCN

2) H

I

0:\

o H

_

0:\

~.~CH2

=

(CH2h~'2

"-i ..... ,t)

;(-.OOTT

BJ.~

1) H

z, L

indl

ar

2) n

-Bu4

N+

F

.: -;

H

H

92

%

>= C

=< (CH

2h -{ 0

'2

H

0 15

91 86

%

1592

.....

o 00

~ .:;- [ ~ 0.. :::: ~ ~ o ~ !i

~~

... v

H

(CH

V3

H ...... )

;(-H

'yJ

> j

',.

oJ)

H

H

I) P

CC

2) L

-Sel

ectr

ide

75 %

~. ;

OH

-

(CH

2hC

O H

o~

... lJ

H··

· .. ~H.~

,

PH

Sche

me

273.

Cor

ey S

ynth

esis

of (

-)-

Hyb

rida

lact

one

0..

. lJ

~VO~ (CH~

J> j

',.

oJ)

H

H

I) N

aH

S0 4

• H

20

2) L

iOH

3) H

+

96

%

t-Bu

i-P

r

N

J;'>-

Sh

Ph3P

, to

luen

e

83 %

H

(-)-

hybr

idal

acto

ne

1593

..

(j

00

I Q

.....

. i=::

~ ~ ~ o ~ .... @


Zn, THF, 60°C

17%

1597

Separated from diastereomer by AgN03-Si02 preparative TLC.

38%

1595

I) Hz, Pd, CaC03,

quinoline, PhH,

RT,90%

2) LAH, THF, 0 °c 3) AczO, pyr, n,

77%

Scheme 274. Yamada Synthesis of (+ )-dictyoprolene

DWH, coC!

H H AcO ~

1596

DMAP, toluene, 50°C

H OAc

~

(+ )-dictyoprolene 1598

shown by Jaenicke to act as a sperm attractant [424]. Dictyopterene C (1606) is a common constituent of many marine brown algae. It was first isolated from the Pacific seaweeds Dictyopteris plagiogramma and D. australis collected near Hawaii [425]. It has also been found to occur in several North Pacific representatives of the same genus [426]. The closely related dictyopterene D' (1629) (variously known as sirenin and ectocarpene) has been obtained from the brown alga Ectocarpus siliculosus and shown to be a sperm attractant of the female gametes [427].

4.3.2.1 Dictyopterene A

The first synthesis of dictyopterene A was that of Ohloff [428] in 1969 (Scheme 275). Separation of 1599 from a mixture of the cis and trans isomers, followed by oxidation with activated manganese dioxide produces aldehyde 1600 with the needed trans stereochemistry at the cyclopropane ring. A non-stereoselective Wittig reaction yields dictyopterene A (1601) along with its (Z)-isomer in a 2: 3 ratio, favoring the unwanted (Z)-isomer.

Dictyopterene A 1601

C8-Cl1 Algal Pheromones 111

Later in the same year a second synthesis of dictyopterene A was described by Weinstein [429]. Addition of ethyl diazoacetate to butadiene, followed by hydrolysis and treatment with thionyl chloride produces the acid chloride 1603 as a mixture of cis and trans isomers (Scheme 276). Reduction of 1603 to the aldehyde and cis-selective Wittig olefination affords 1601 as a 1: 1 mixture of the cis and trans cyclopropane isomers. Dictyopterene A is secured by preparative GC in 5 steps.

Dictyopterene A has been prepared in low yield, along with dictyopterene C' as the major product by Billups [430]. Treatment of 1604, prepared by reaction of trans-dec-3-ene and dichlorocarbene, with potassium t-butoxide in DMSO affords a mixture of all possible isomers of 1605 in 80- 90% yield (Scheme 277). Pyrolysis of the mixture at 80°C gives dictyopterene A (1601) in 4% overall yield along with dictyopterene C' (1606) produced via Cope rearrangement of the cyclopropyl cis-isomers. Pyrolysis of 1601 at 175°C gives 1606 as the sole product in 30% overall yield.

Yamada [431] has prepared dictyopterene A in a biomimetic fashion (Scheme 278). Beginning with the alcohol portion of the ester dictyoprolene, thiol 1608 can be prepared in three steps. Solvolysis of the mesylate of 1608 in aqueous acetone and potassium acetate affords cyclopropane 1609 via a biogenetically patterned homoallyl-cyclopropylcarbinyl rearrangement. Due to the lability of cyclopropylcarbinols under acidic conditions, the elimination of the hydroxyl was performed with sodium hydride and Me02CN-SOiNEt3, giving a 1: 1 mixture of the cis and trans olefins 1610. Elimination of the sulfide and separation of the diastereomers affords dictyopterene A in 8 steps and > 6% overall yield.

An enantiospecific (but not diastereospecific) approach (Scheme 279) that produces {+ )-dictyopterene A and unnatural {+ )-dictyopterene C' has been developed by Genet [432]. Lithiation, transmetallation and acylation of commercially available silylacetylene 1611 affords ketone 1612. Introduction of chirality is achieved by enantioselective reduction of 1612 with {S)-Alpine borane producing the {S)-propargylic alcohol 1613 in 96% yield with 85% ee after desilylation. Desilylation of 1613, silylation of the hydroxyl and hydroxymethylation to give 1614 is achieved by application of standard methodology. Acylation, desilylation and Lindlar reduction of 1614 affords the cis-alkene 1615. Treatment of 1615 with sulfone in the presence of DBU and a palladium catalyst results in alkylation and concomitant isomerization of the alkene to the {E)-isomer. Benzoylation affords 1618, which is the critical intermediate needed for transfer of chirality from C-O to C-C via cyclopropanation. Palladium-catalyzed cyclopropanation of allylic benzoate 1618 gives 1619 as a mixture of diastereomers with exclusive {E)-geometry at the alkene. Desulfonylation, ester reduction and PCC oxidation gives the aldehydes 1620 and 1621 as a 3: 2 mixture of cis/trans diastereomers at the cyclopropane ring. Wittig olefination ofthe mixture followed by Cope rearrangement of the cis-isomer produces ( + )-dictyopterene A (1601) (85% ee) and unnatural ( + )-dictyopterene C' (1606) via a 15 step synthesis.

Mn

02

, C

H2C

I 2

(CJi

S)3

P =

CH(C~3CH3

~:-

......

~H

~H

......

.. ..

N

H\\\

' .,

'/ CH

20H

rt

,80%

H

\\\'

.,'/ C

HO

T

HF,

Et 2

0

~

1599

16

00

j S

epar

ated

fro

m a

(±

)-di

ctyo

pter

ene

A 1

601

mix

ture

of

cis-

and

> 26

% y

ield

by

GC

; pre

sent

wit

h O

. tra

ns i

som

ers.

Z

-iso

mer

wit

h (E

IZ)

= (

2 :

3)

t:lo I(

Sche

me

275.

Ohl

off S

ynth

esis

of (

±)-

Dic

tyop

tere

ne A

::I

. 8. a:: ~ 1'1

a'

0 1)

r\

"-c.H,~

~ N20oc~CH3

CIOC~

1) L

iAI[

OC

(CH

3hh

H

'" ..

.. 2)

Hyd

roly

sis

2) Ph3P=CHC4~

3) S

OC

I 2

1603

(4

8% b

y G

C)

(±)-

dict

yopt

eren

e A

1

60

1

Sche

me

276.

Wei

nste

in S

ynth

esis

of (

±)-

Dic

tyop

tere

ne A

~ K

Ot-

Bu,

D

MSO

~

.. 80

°C

25°C

, --- C

C4

~+ ~

1604

15

hr

80-9

0%

1605

(±

)-di

ctyo

pter

ene

A 1

601

(±)-

dict

yopt

eren

e C

' 16

06

4%

ca

60%

I 17

5°C

t

Sche

me

277.

Bill

ups

Synt

hese

s of

(±)-

Dic

tyop

tere

ne A

and

(±

)-D

icty

opte

rene

C'

OH

~

I}P

CC

, CH

20

2,

OH

rt

,41%

I

2) P

hSH

, tol

uene

. 42

%

"~SPh

1) M

sCl,

pyr,

O

°C

~

1609

SP

h A

lcoh

ol d

eriv

ativ

e o

f D

icty

opro

lene

. 3)

NaB

H4,

MeO

H,

92%

1608

+

Me0

2C-N

S02N

Et3

NaH

, DM

E, 8

0°C

nB

u"",

A

~SPh

16

10

Sche

me

278.

Yam

ada

Syn

thes

is o

f (±

)-D

icty

pter

ene

A

2) A

cOK

,

1) CF3S~CH2C~Et

MeC

N.

rt

2) D

BU

,DM

F,

50°C

, 86%

aq.

acet

one,

80

°C, 9

1%

'-B"~

(±)-

dict

yopt

eren

e A

160

1

Sepa

rate

d ch

rom

atog

raph

ical

ly

from

geo

met

rica

l is

omer

.

(") 'l" g .... ~ r '" . . IoU

1) T

BA

FT

HF

1) B

uLi,

H

=

SiM

Cj

Etz

O,

-20

°C

C4H

9 -

C

=

SiM

c3

------...;_

...

II

(S)-

Alp

ine

Bor

ane I

C4 H

9 '7

SiM

e3

HIl

i'

2) T

BSC

I, I

mid

D

MF

, rt

3) E

tMgB

r, D

MF

o

1611

2)

Mnl

z 3)

C4H

9CO

CI

TH

F,

n, 9

6%

HO

1612

16

13

4) H

2CO

, n

(80%

)

1) P

hS

0 2C

H2C

O M

C 4H

9

TB~~

) C

HzO

H

1) A

C20

, DM

AP

, N

Et3

' C

H2C

I 2, r

t

2) B

U4N

+F, T

HF

, rt

CH

>

f\-

DB

U

2 e,

~PhS02 C0

2 Me

4 ~\...

. O

A

Pd{d

ppe)

2 n

C4~

"'-

C

' ,

H""

~

OH

•

23

% f

rom

161

3 0

, C

I

1615

2)

C

I ?C

A

1614

3)

H2

, Pd

, L

indl

ar,

MeO

H

C4~

Pd{d

ppen

.. ~ S

02Ph

Intr

amol

ecul

ar

C0 2

Me

Pd c

ycli

zati

on g

ives

1

61

9

cxcl

usiv

ely

E.-

1619

.

1) N

a{H

g),

Na2

HP0

4, r

t

2) D

IBA

H

3) P

CC

, C

H2C

l 2

C4H9~ .. ''

''1

-=

(+)-

Dic

tyop

tere

ne A

16

01

• +

T-=\

o

ll.#

-CIOC~CI

CI

C4~~CHO

16

20

(R

,R)

60%

16

21

(R,S

) 40

%

HO

C4H

9

1618

Ph3P

=CH

2

(+)-

Dic

tyop

tere

ne C

' 1

60

6

Via

Cop

e

Sche

me

279.

Gen

et S

ynth

eses

of (

±l-

Dic

tyop

tere

ne A

and

{±

l-D

icty

opte

ren

C'

......

...... ~

'TI ~ 5': 0- ~ <i 0- S!::

~ ~

9.- ~.


A shorter enantiospecific synthesis of dictyopterene A (1601) (Scheme 280) has been developed by Jaenicke [433]. The optically pure ester 1623 is obtained by resolution of the acid and esterification. Condensation of 1623 with pentylidenediphenylphosphine oxide affords the ~-ketophosphine oxides 1624. Reduction of 1624 to the alcohol and treatment with sodium hydride gives an 85: 15 (E/Z) mixture of isomers. Separation on silver nitrate-impregnated silica produces (+ )-dictyopterene A (1601) in 19% overall yield.

Dictyopterene A has also been obtained enantiospecifically by Jaenicke [434] as an intermediate in the preparation of dictyopterene C (Scheme 284).

4.3.2.2 Dictyopterene B (Hormosirene)

The first synthesis of dictyopterene B (1628) was developed by Weinstein [435] (Scheme 281). Hydrogenation of 1625 over Lindlar catalyst, followed by treatment with phosphorus tribromide and then triphenylphosphine dibromide produces the phosphonium bromide 1626. Wittig olefination of 1626 with the isomeric mixture of aldehydes 1627 gives dictyopterene B as a mixture of isomers. Upon heating, the cis-isomer is transformed by Cope rearrangement into 1628 and dictyopterene D' (1629) in 6 steps.

Dictyopterene B 1628

Dictyopterene B (1628) has been prepared enantiospecifically by Jaenicke (Scheme 282) [436]. The optically pure ester 1623 (a common intermediate in the synthesis of dictyopterene A, Scheme 280) is obtained by resolution of the acid and esterification. Reduction of the ester to the alcohol 1631, oxidation to the aldehyde and olefination with (formylmethylidene)triphenylphosphorane yields the (X,~-unsaturated aldehyde 1632 with a 93: 7 E/Z ratio. A second Wittig olefination unfortunately gives a 1: 1 cis/trans ratio. Selective Diels-Alder cycloaddition of the trans isomer with 4-phenyl-1,2,4,-triazoline-3,5-dione allows separation of the two isomers to yield ( - )-dictyopterene B (1628) optically pure in 4 steps, after resolution of the starting material.

Dictyopterene B (1628) has also been prepared by Schneider [437] from fucoserratene (Scheme 302, see p. 134).

Helmchen [438] has developed the highly enantio- and diastereoselective synthesis of dictyopterene B (1628) shown in Scheme 283. The key transformation in this synthesis involves a novel diastereoface-selective intramolecular alkylation to construct the cyclopropane ring of 1628. Alkylation of the acetate of camphor derivative 1633 with (E)-1,4-dibromo-2-butene yields 1634. Treatment of 1634 with potassium t-butoxide produces cyclopropane 1635 in 85% yield and a diastereomeric purity of 96.5%. Reduction of 1635 with LAH, PCC oxidation and reaction with the formylphosphorane 1636 affords aldehyde

°

" ~

$\

(C6H

shP=

CHC4

~ _

0.,

"Ph

..

~~P"'"

• !

\ Ph

C0 2

Me

1HF

, -78

°C

__

rt

1) N

aB14

, EtO

H

2) N

aH,D

MF

, se

aled

tube

, 50

°C

(19.

1 %

ove

rall

)

.. :; ~ ..

~""

(-)-

1623

R

esol

ved

from

ra

cem

ic S

.M.

3~8%

° 16

24

Sche

me

280.

Jae

nick

e Sy

nthe

sis

of D

icty

opte

rene

A

1) H

2, L

indl

ar

+~

2) P

Br3

..

Ph3P

H

O,

Br'

"-3)

Ph 3

P

1625

16

26

Cop

e

~+

1628

Sche

me

281.

Wei

nste

in S

ynth

esis

of

(±)-

Dic

tyop

tere

nes

Ban

d D

'

1) n

BuL

i ..

2) OHC~

1627

~

16

01

(E

fZ)

85 :

15

~

(±)-

dict

yopt

eren

e B

162

8

No

yiel

d gi

ven.

dict

yopt

eren

e D

' 1

62

9

. .- 0\ j ~ ~ [ ~ ~ ~

(-) 1623 Resolved from racemic S.M.

~ ,,::< -H 0

(E/Z) 93 : 7

1631

•


2) (C6HshP=CH-CHO

C6H6, reflux, 41 %

..

(-)-dictyopterene B 1628

Scheme 282. Jaenicke Synthesis of (- )-Dictyopterene B (Hormosirene)

1637 with an EjZ ratio of 93: 7. Salt-free Wittig olefination and removal of the unwanted 3-E isomer by reaction with 4-phenyl-l,2,4-triazolidine-3,5-dione provides pure dictyopterene B (1628) in 7 steps and 19% overall yield.

4.3.2.3 Dictyopterene C and Dictyopterene C'

Dictyopterene C' has been prepared as the major product in a dictyopterene A synthesis by Billups [439] (Scheme 277).

(-)-Dictyopterene C 1641 (+)-Dictyopterene C' 1606 (the unnatural isomer)

Dictyopterene C' (1606) (the unnatural isomer) has been prepared as a mixture with dictyopterene A in an enantiospecific synthesis by Genet [440] (Scheme 279).

An enantioselective synthesis of dictyopterene C, by Jaenicke [441], is shown in Scheme 284. Lactone 1638 is obtained optically pure by separat~on of the diastereomeric amides obtained by reaction with (S)-phenylethylamine. DIBAL reduction of 1638 and immediate addition of the salt-free Wittig reagent 1639 provides 1640 with a ZjE ratio of ~ 97: 3. PCC oxidation of the alcohol 1640 and Wittig olefination provides dictyopterene A (1628) in 24% yield. Cope rearrangement of 1628 provides dictyopterene C (1641) quantitatively and with 97% ee.

-f;fx N-

SO '"

~2

OH

I) M

eCO

CI,

CC

I 4

2) L

ICA

, T

HF

, B

r 1 89

%

Br

1633

I) L

AH

, E

t20,

87

%

2)

CrO

rPyr

2,

OH

C

CH

2 Cl2

~

.. 3)

Ph 3

P=

CH

CH

O,

-16

36

~'

~

C6H

6, r

eflu

x,

52%

16

37

E/Z

= 9

3:7

1635

96

.5%

ee

X'N

'So

,,"

~\O

"Yo

1634

~

Br

Ph3P

=CH

CH

2CH

3

TH

F,

-80

°C

, 59%

Sche

me

283.

Hel

mch

en S

ynth

esis

of

Dic

tyop

tere

ne B

(H

orm

osir

ene)

KO

t-B

u, H

zO,

TH

F,

-80

°C

85%

~

dict

yopt

eren

e B

162

8 E

/Z =

7:

93

.....

.....

00

~ Q 5': Q..

~ ~ Q..

a:: " g. ~ '"


1638 (resolved)

1) DIBAH, toluene, -78 DC

1639

(45% overall)

-=100%

-

dictyopterene A 1628

1640 Z!E ~ 9713

1) PCC

2) Ph3P=CH2

TIfF (53% overall)

-

(-)-dictyopterene C 1641

Scheme 284. Jaenicke Synthesis of R-( - )-Dictyopterene C

4.3.2.4 Dictyopterene D' (Serenin or Ectocarpene)

The first synthesis of dictyopterene D' was that of Mueller [442] (Scheme 285). Wittig olefination of a mixture of cis- and trans-2-vinylcyclopropanecarboxaldehyde 1643 gives a mixture of all four possible geometric isomers 1644. Cope rearrangement followed by Lindlar reduction affords 1629 in 30% yield after separation by preparative Gc.

Dictyopterene D' 1629

Another synthesis of dictyopterene D' has been performed by Jaenicke [443] (Scheme 286). Reaction of butadiene with dibromocarbene and subsequent monodehalogenation of the adduct affords the bromovinylcyclopropane as a

1643

""=="''IN$-55----'/ _C_H_3C_H.;.2 ___ C_Hz_=_P_(C_6H_s_h__ ~-N'

C~6,51% ~ Cope

MeOH

1644 Mixture of 4 isomeric

cyclic C11HI4 hydrocarbons

-(±)-dictyopterene D' 1629

(30% by GC)

Scheme 285. Mueller Synthesis of (±)-Dictyopterene D' (Serenin)

-


( \) CHBr3, KO'Bu

~Br • 2) BU3SnH

1645 (No yield given.)

~CHO (C6H5hP~

1647

75: 25 cis / trans

.. EtOH

\) BuLi 2) CO2 ~C02CH3 .. 3)CH2N2

1646 (No yield given.)

~ 180°C .. (Cope)

47% 1648

Scheme 286. Jaenicke Synthesis of Dictyopterene D' (Ectocarpene)

\) LAH, Et20 reflux, 83% ..

2) Mn02, CH2CI2, reflux, 60%

Ch--dictyopterene D' 1629

mixture of isomers 1645. Metalation of 1645 followed by carbonation and esterification with diazomethane produces 1646. Reduction of the ester with LAH, oxidation to the aldehyde 1647, and Wittig olefination produces the divinyl cyclopropane system 1648. Cope rearrangement by heating to 180°C yields dictyopterene 0' in 8 steps.

Dictyopterene 0' has been prepared by Weinstein [444] as a mixture with dictyopterene B (Scheme 281).

Oictyopterene 0' (1629) has also been prepared by Schneider [445] from fucoserratene (Scheme 302, see p. 134).

4.3 .2.5 4-n-Butyl-2,6-Cycloheptadienone

A compound related to the Cll hydrocarbons is 4-n-butyl-2,6-cycloheptadienone (1653). It has been isolated from the essential oil of Hawaiian Dictyopteris and shown to have a dihydrotropone structure. It is structurally related to dictyopterene C (1641), and has been prepared by derivatization of 1606 [446]. The only complete synthesis of 1653 has been by Asaoka [447] (Scheme 287). Copper-catalyzed l,4-addition of butylmagnesium bromide to 1650 in the presence of TMSCI, followed by desilylation of the silyl enol ether

o

6 \ n-Bu

(+ )-4-n-Butyl-2,6-cycloheptadienone 1653

(R)- 1650

2) FeCI3, DMF

I) BuMgBr, cat. CuBr, TMSCI, HMPT

93% 2) KF,MeOH

o

.. 6 , ~ 3) NaOAc; 44% Bu

1653

1651

(+)-4-n-Butyl-2,6-cycloheptadienone 19% overall yield


1) CuCI2, DMF, 85% ..

2) LDA, TMSCI, 84%

[

OTMS 1 6.,. 1652

Scheme 287. Asaoka Synthesis of (R)-( ± )-4-n-Butyl-2,6-cydoheptadienone

yields ketone 1651 stereospecifically. Oxidative removal of the remaining TMS group to afford the en one, followed by treatment with LDA and TMSCI gives the TMS dienol ether 1652. Cyclopropanation of 1652 followed by oxidative ring opening with ferric chloride and dehydrochlorination furnishes 4-n-butyl-2,6-cycloheptadienone 1653 optically pure in 7 steps and 19% overall yield.

4.3.2.6 Multifidene

Multifidene (1659) has been isolated from the anisogamous brown alga Cutleria multifida, and identified as the male-attracting sex attractant [448]. The major structural aspects of multifidene that must be considered when designing a synthesis are the 1,2-cis stereochemistry of the two substituents on the cyclopentene ring and the (Z)-olefin geometry.

Multifidene 1659

The first synthesis of multifidene (1659) was that of Jaenicke [449] in 1978 (Scheme 288). The synthetic strategy involves using the norbornene ring system of cyclopentadiene dimer 1654 to control the relative stereochemistry bf the two cis substituents on the cyclopentene ring. After elaboration of the sidechains, the norbornene system is removed via a retro Diels-Alder reaction. Thermal [2 + 2] cycloaddition of dichloroketene affords 1655 as the major regioisomer in a 4: 1 ratio. Treatment of ketene adduct 1655 with base, esterification and reduction produces dichloroalcohol 1657. Silver-assisted hydrolysis of 1657 and Wittig

1) H

+, C

H30

H,

~

~-

CC

1 4,

refl

ux

C~C=C=O

NaO

H, H

20

3A

MS

79

%

• ~o

• C

C4

di

oxan

e, r

t 58

%

Cl

82%

2)

LA

H,E

t20

CH

Cl 2

93

%

Cl

1654

16

55

1656

Maj

or [2

+ 2)

pro

duct

; 4

: 1 w

ith o

ther

isom

er

~OH A

gN~,H20

~O P

h 3P=

CH

2

~H

• •

diox

ane,

rt

TH

F,5

8%

98

%

CH

0 2

1657

1) P

CC

, CH

2C12

,75%

2) C

H3C

H2C

H=

P(C

6HSh

C

6H6,

72%

~

Sche

me

288.

Jae

nick

e S

ynth

esis

of (

±)-

Mul

tifi

dene

OH

16

58

50

0°

C

- (48%)

...• ,"

O .... ,,

~ (±

)-m

ulti

fide

ne

1659

..... ~ j > g; ~ [ I ~


olefination of the resulting lactol gives alkene 1658. A second Wittig olefination and thermally induced retro Diels-Alder reaction completes the synthesis to give multifidene (1659) in 9 steps and approximately 8% overall yield.

The second synthesis ofmultifidene (1659) byJaenicke [450] begins with the isomerically pure acid 1656, available from dicyclopentadiene and dichloroacetyl chloride in two steps (Scheme 289). Esterification of 1656 and monodechlorination with tri-n-butytin hydride affords 1661. Treatment with silver nitrate gives the lactone 1662 which is converted to diene 1663 by DIBAL reduction and Wittig olefination under salt free conditions. Silylation of 1663 followed by a thermally induced retro Diels-Alder reaction and desilylation yields cyclopentene 1664 with the required 1,2-cis substitution pattern. Conversion of 1664 to 1659 is achieved by PCC oxidation and Wittig olefination to give multifidene (1659) in 10 steps and 26% yield overall. It was subsequently found that intermediate alcohol 1664 could be resolved via carbamate formation with (+)- or (-)-1-phenylethylisocyanate and chromatographic separation of the diastereomeric mixture [451].

Jaenicke has also prepared multifidene via an enantiospecific route beginning with meso-diol 1665 (Scheme 290) [452]. Enzymatic oxidation of the diol 1665 with horse liver alcohol dehydrogenase (HLADH) gives lactone 1666 in 90% yield with an enantiomeric excess of 97.5%. Reduction of the lactone with DIBAL and Wittig olefination provides the lower sidechain with the required cis-stereochemistry 1667. Further oxidation and methylenation produces (+ )-multifidene in five steps and an overall yield of 25%. The unnatural enantiomer was also synthesized in an analogous manner.

The strategy followed by Paquette [453] takes advantage of the stereocontrolled anionic oxy-Cope ring contraction of all cis-2,4,7,-cyclononatrienol (1668) to provide the required 1,2-cis disubstitution pattern (Scheme 291). Treatment of alcohol 1668 with potassium hydride followed by trapping with TMSCI affords the rearranged product 1669. Selenylation of 1669 produces the selenoaldehyde 1670, which upon treatment with ethylmagnesium bromide gives ~-hydroxy selenide 1671 in a stereoselective fashion. As ~-hydroxy selenides are not known to undergo cis elimination, which is required in this case to obtain the cis olefin, a double displacement process is utilized to obtain the correct olefin geometry. Formation of epoxide 1672 by internal displacement of phenylselenide by oxygen, followed by opening of the epoxide by diphenyl phosphide and elimination of methyldiphenylphosphine oxide yields isomerically pure multifidene (1659) in seven steps and 18% overall yield.

A preparation of multifidene (1659) by Crandall [454] in which there are several problems in controlling stereochemistry throughout the synthesis, is shown in Scheme 292. Dichloroketene adduct 1674 is transformed in three steps to cyclobutanol1675. MCPBA oxidation of 1675 to the sulfone and opening of the cyclobutanol to the aldehyde occurs with concomitant trapping of the aldehyde with methylidene triphenylphosphorane to give a mixture of cis and trans isomers 1677. Epimerization of the aldehyde occurring before olefination jeopardizes the needed cis stereochemistry. A 9: 1 cis/trans ratio of 1677 can be

~~H

1) B

F300

Et2

, MeO

H

~~M'

~o

refl

ux,

92%

AgN~,H20

1) D

iba!

-78

°C

.. ..

2) B

U3S

nH,

105

°c

TH

F,

refl

ux

2) P

h3P=

CH

Et

CH

Cl 2

C

H2C

l 96

%

1656

tto! O

H

1663

90%

16

61

I)M~NTMS

2) 5

00 0c

...

~OH

3) M

eOH

/ T

MSC

l ( c

at.)

-

1) P

eC, C

H2C

l2

2) P

h3P=

CH

2 T

HF

,52%

(87%

ove

rall)

16

64

coul

d be

res

olve

d vi

a ca

rbam

ate

ronn

alio

n w

ith

(+)-

or (

-)-l

-phe

nyle

thyl

isoc

yana

te

Sche

me

289.

Jae

nick

e Sy

nthe

sis

of (±

)-M

ulti

fide

ne

1662

3)

HC

l (7

4% o

vera

ll)

CC

-(±

)-m

ulti

fide

ne

1659

- ~ j ~ o [ I


HLADH .. 0;0 90%

1) DIBAL, -78°C ..

2) CH3CH2CH=PPh3

55%

1665

1) PCC

1667

o 1666

..

(+ )-multifidene 1659

Unnatural (-)-Multifidene was also synthesized in an analogous manner.

Scheme 290. Jaenicke Synthesis of Natural ( ± )-Multifidene

obtained by ring opening of the sulfide followed by oxidation. However, the synthesis is continued with a 4: 1 cis/trans mixture of 1677. Treatment of this mixture with n-butyllithium and then propionaldehyde gives 1678, which is converted to a 3.5: 1 cis/trans mixture of ketones 1679 by Jones oxidation. Reductive elimination of the phosphonate derivative 1680 yields an alkyne which can be reduced under Lindlar conditions to afford multifidene 1659 with the proper cis-alkene stereochemistry. After separation from the 4: 1 cis/trans mixture, 1659 is obtained in 2.6% overall yield.

4.3.2.7 Desmarestene and Viridiene

The chemical messengers desmarestene (1682) and viridiene (1688) are discharged [455J by the mature eggs of the Northern Atlantic seaweeds Desmarestia aculeata and D. viridis. Both pheromones have been prepared by Boland [456]. Desmarestene (1682) (Scheme 293) is prepared in two steps from the readily available ester 1681. DIBAL reduction of 1681 followed by cisselective Wittig olefination of the resulting aldehyde gives 1682 in 26% yield. Viridiene (1688) is prepared via two different routes from dibromoester 1684 (Scheme 294). The first pathway involves monodebromination of 1684 followed by silver promoted lactonization to afford 1685. DIBAL reduction of the lactone 1685 and Wittig olefination of the resulting aldehyde gives alcohol 1686, which is converted to 1687 by PCC oxidation and Grignard addition of the lower side chain. LAH reduction of the alkyne gives a mixture of geometric isomers. The

Desmarestene 1682 Viridiene 1688

OOH

1668

I)K

H,-

78

°C

,Et z

O ~

~OSiM~

-78

°c

1669

PhS

eCI,

Etz

O 0:

;: o

• \.

eRO

-7

8 C

, 64

% f

rom

16

68

S

ePh

1670

1) E

tMgB

r,

Etz

O,

-116

°c

2) H

OA

c,

-78

°C;

76%

~ 1)

(C

2HS)

30+B

F4-,

DM

E,

rt

2) K

H,

DM

E,

71 %

~

" I)

Ph2

PL

i, 1

HF

~

~2)CH3I;51%

• ~

o -

SeP

h

1671

1

67

2 a

long

wit

h (±

)-m

ulti

fide

ne

16

59

ci

s ep

oxid

e is

omer

Sche

me

291.

P

aque

tte

Synt

hesi

s of

(±

)-M

ulti

fide

ne

.....

IV

0\

"rj ~ '< >

~ ~ Ci 0- s::: I ::;." '" '"

o=(C

I BU

3SnH

0=

(0

PhSN

a

74%

fro

m

1674

0=(0

C

l

1674

o=(0

H SPh

1675

Ph3P

+CH

3Br-

t-B

uOK

,75%

I MCPBA

OH

o=(S

",. Ph

3P+C

H3B

{

t-B

uOK

16

76

Cl

CC

Ph

+

9

H

~

~SPh

I MC

PBA

77

%

(9:

1)

H

SPh

~ ~

~S02Ph

+ ~S02Ph

1677

76

% v

ia 1

67

6,3

: 2

LiA

IH4

70%

1) B

uLi,

4 :

1 16

77

2) C

H3C

H2C

HO

~

S02P

h

16

78

1678

Jo

nes

[0]

• ~

S02P

h

I) K

H,

TH

F,

HM

PA

,O°C

2) (

Me2

N)2

POC

I, n;

74%

s:c I)

NaH

P0 4

, N

a(H

g),

\ n

,36

%

OP(

O) (

NM

ezh

_ 2)

H2,

Lin

dlar

, Ph

S02

hexa

ne,

45%

C

C-

(±)-

mul

tifi

dene

16

59

Sep

arat

ed f

rom

16

79

(cIt

) =

3.5

: 1

Sch

eme

292.

Cra

ndal

l Sy

nthe

sis

of (±

)-M

ulti

fide

ne

1680

4

: 1

(cIt)

mix

ture

.

(j 6 ..... { f o ~ .- tv

-.l


1) DIBAH, hexane, toluene, -78 "c ..

aoo,E, 1681

2) (C6HshP~

THF, OoC; 26%

(SM was available in bulk quantities.)

Scheme 293. Boland Synthesis of (±)-Desmarestene

(±)-desmarestene 1682

unwanted (E)-isomer is removed via selective Diels-Alder reaction by treatment with 4-phenyl-l,2,4-triazoline-3,5-dione to give viridiene (1688) in seven steps. A second pathway to 1688 (Scheme 294) involves initial reduction of the dibromoester 1684 followed by silver promoted solvolysis and ring closure to form the lactol 1689. Addition of the alkynyl Grignard 1690 and LAH reduction yields alcohol 1691. Conversion of 1691 to viridiene (1688) is achieved by PCC oxidation and Wittig olefination to give a mixture of isomers which are separated as in the first route to give 1688 in six steps and 10% overall yield.

Boland [457] has also developed a stereospecific synthesis of (+ )-viridiene (Scheme 295). Enzymatic oxidation of 1692 with horse liver alcohol dehydrogenase yields enantiomerically pure 1693. Reduction of lactone 1693, addition of Grignard reagent 1690 and LAH reduction of the alkyne affords a 3: 2 ratio of the EIZ isomers. Removal of the unwanted isomer by selective Diels-Alder reaction with 4-phenyl-l,2,4-triazoline-3,5-dione gives pure 1694. Conversion of 1694 to the final product is achieved by oxidation of the aldehyde to the alcohol and Wittig olefination to afford 1688 in 6 steps from the racemic dio11692.

4.3.2.8 Lamoxirene

Lamoxirene has been prepared by Jaenicke [458] (Scheme 296) as an extension of the desmarestene synthesis of Boland and Jaenicke (Scheme 293). Epoxidation of desmarestene (1682) with MCPBA gives a mixture of four diastereomers. Lamoxirene can be separated from this mixture by column chromatography. No yield or stereochemical configuration information is provided.

Lamoxirene 1696

4.3.2.9 Aucantene

Another chemical signal compound isolated [459] from the brown alga Cutleria multifida is the Cll triene aucantene (1698). The first synthesis of (± )-aucantene

QC

02 M

e A

q. A

gN03

, TIl

F

OjO

1) D

IBA

H, T

IIF,

-78

°c

~

• •

rt,9

0%

2)

Ph3P

=C

H2

CH

20H

1 C

H2B

r 1

68

6

1685

T

IIF,

0 °

c, 4

2%

I B

U3S

nH 8

6%

1) P

CC

, CH

2C1 2

I 2)

BrM

g-C

=C

-C~OCH3

TII

F, 0

°c

t Q

C0

2 Me

~

LA

H

~

.. C

HB

r2

Et 2

O,0

°C

16

84

49

%

HO

O

CH

3 (±

)-vi

ridi

ene

1688

1

68

7

Sepa

rate

d fr

om m

ixtu

re

"-A

1H3,

Et 2

O,

of E

and

Z is

omer

s

0°

C,8

9%

1)

PC

C, C

H2C

l 2, 7

1 %

2) P

h 3P=

CH

2

[ T

IIF,

0 °

c, 4

6%

) Br

Mg-C

=C-C

H20n

IP~

1 16

90

QC

H2 0

H

Aq.

AgN

03, T

IIF

0;)0

TII

F, O

°C, 8

4%

~

.. •

rt,8

9%

2) L

AH

, E

t 20

, 0°

C,7

9%

CH

Br2

H

O

H

1689

16

91

Sche

me

294.

Bol

and

Synt

hesi

s of

(±

)-V

irid

iene

(j 'l" Q ~ l 3 o ~ '" .....

~


enzymatic oxidation .. ~OH

\,JAOH

1692 1693

1) BrMg = CHzOTHP

THF, 0 °c 1690 •

2) LiAIl4, THF,

(27% from 1693) ~ 1694

(FlZ)=3:2

Scheme 295. Boalnd Synthesis of ( + )-Viridiene

MCPBA

desmarestene 1682

•

DIBAL • Toluene, -78°C

1) PCC, CH2Cl2

2) Ph3P=CH2 •

THF, rt (12.5%)

~CHZOH

~CHO

(+)-viridiene 1688 (>99% ee)

lamoxirene 1696

Separated from 4 diastereomers by column chromatography.

No yields or stereochemical configuration given.

Scheme 296. Jaenicke Synthesis of Lamoxirene

(+)-Aucantene 1698

is that of Jaenicke [460J in 1975 (Scheme 297). Diels-Alder reaction of methyl 2E,4E-hexadienoate with butadiene gives the desired cycloaddition product 1697 in 5.2% yield, along with a mixture of three other isomers. Reduction and oxidation of 1697 to the aldehyde followed Wittig olefination gives 1698 in 1.2 % yield over four steps.

An enantiospecific synthesis (Scheme 298) of aucantene (1698) was later developed by Boland and Jaenicke [461J, which utilized a strategy similar to their synthesis of (+ )-viridiene (Scheme 295). Enzymatic oxidation of diol1700 with horse liver alcohol dehydrogenase yields lactone 1701 with an enantiomeric excess of96%. Reduction to the lactol and Wittig olefination followed by PCC oxidation affords aldehyde 1702. Epimerization with base and treatment of the aldehyde 1702 with carbon tetrabromide and triphenylphosphine yields

1697 Plus 3 other isomers.

Scheme 297. Jaenicke Synthesis of (±)-Aucantene


I) LAH. Et20. 68%

2) crO}. pyr. CH2CI2• rt. 60%

..

3) Ph3P=CH2 Et20. pentane. rt.57%

(±)-aucantene 1698

1703. Treatment of 1703 with n-butyllithium results in elimination to the bromoalkyne and metallation to give the alkynyllithium. Addition of methyl iodide yields alkyne 1704 as a 3: 2 mixture of cis/trans isomers. Birch reduction with sodium in ammonia gives ( + )-aucantene 1698 in 8 steps and 1.8% overall yield.

A short and elegant synthesis of (± )-aucantene is that by Schneider [462] shown in Scheme 299. Epoxide 1705 is readily available through singlet oxygenation of cyc10pentadiene followed by thermal rearrangement and base catalyzed isomerization. Diels-Alder reaction of 1705 with butadiene gives aldehyde 1706 in good yield with correct stereochemistry and suitable functionalization for further elaboration. Wittig olefination, followed by trimethylsilyl iodide mediated deoxygenation provides 1698 isomerically pure in 3 steps and 62% overall yield.

4.3.2.10 Fucoserratene

Fucoserratene (1712), a simple conjugated triene, has been isolated [463] from the mature eggs of the marine brown alga Fucus serratus. It exhibits enormous chemotactic activity on the mobile spermatozoa of this alga. Similar activity is displayed by ectocarpene 1629, isolated [464] from the female gametes of Ectocarpus siliculosus. The first synthesis offucoserratene (1712) is that Jaenicke [465] in 1975 (Scheme 300). Control of stereochemistry of the 3,5-diene system is obtained by cis hydrogenation and E-selective Wittig olefination. Propargyl alcohol is protected as the THP ether, alkylated with ethyl bromide and deprotected to give 1708. Lindlar reduction followed by allylic oxidation affords the aldehyde 1709. Olefination with the stabilized ylide gives aldehyde 1711 which can be converted to fucoserratene 1712 by reduction, allylic oxidation and Wittig olefination. The ten step synthesis yields 1712 in 4.4% overall yield.

Fucoserratene 1712

enzy

mat

ic

~

CCO

H

oxid

atio

n •

OH

17

00

17

01

96

%

ee

~B'

CB

r4, P

(C6H

Sh •

CH

2C12

, -10

DC

65%

1

70

3

Br

(tic

= 3

: 2

)

Sch

eme

298.

Bol

and

Syn

thes

is o

f ( +

)-A

ucan

tene

oHe/O

1705

( S

eale

d T

ube,

90 D

C, 9

2%

(0 ,.'

0:"

I C

HO

17

06

+

Dia

ster

eom

er i

n a

1 :

1 ra

tio

1) D

lBA

H,

~CH20H

~CHO

tolu

ene,

-70

DC

1)

PC

C.

.. ..

CH

2C1 2

2)

(C

6Hsh

P=

CH

z T

IfF

, rt

2)

KO

H,M

eOH

1

70

2

(75%

) re

flux

tl

c=

3:2

56%

BuL

i /

CH

31

~ ~

TII

F,D

ME

U

Na

NH

3 ..

• -7

8 DC

-re

flux

E

t20

64%

(2

1 %

) (t

ic =

3 :

2)

(+ )-

auca

nten

e 16

98

(0

I( P

h 3P

=C

H2 •

-78

DC,

82%

I .. ,

Me3

SiC

l, N

aI .

. 0;

,' 0;

M

eCN

, rt

, 82

%

(±)-

auca

nte

ne

16

98

Sch

eme

299.

S

chne

ider

Syn

thes

is o

f (±

)-A

ucan

tene

.....

w

tv

"rl ~ ~ 5': p.. ?? ::1.

< '" p.. ~ '" Ei g ~ <b

'"

HO,

I)DHP

2) NaNH2, Fe(N03h NH3

3) CH3CH2Br, 80% 4) H+, rt, 83%

1) (C6Hs)3P~ 1710 C02C2Hs,

..

1708

CH2CI2, reflux, 90% .. ~ 2) LAH, Et20, 84% OHC 3) Mn02' Et20, 65% 1711

Scheme 300. Jaenicke Synthesis of Fucoserratene


1) H2, Lindlar, MeOH,81% .. OHC~

2) Mn02' Et20 55%

.. Et20,30%

1709

fucoserratene 1712

Hopf [466] has prepared fucoserratene (1712) in a short three step synthesis as shown in Scheme 301. Diyne 1713, readily available from 1,5-hexadiyne, is isomerized to 1714 by treatment with potassium t-butoxide and dicyclohexyl18-crown-6. Lindlar reduction of 1714 affords 1712.

Fucoserratene (1712) has also been prepared by Schneider [467] in three steps from (E)-2,4-pentadienoic acid (1716) in a stereospecific manner (Scheme 302). Reduction of 1716 with LAH, followed by PCC oxidation gives the aldehyde 1717 in 50% yield. A Z-selective Wittig reaction, employing the silazide method, affords fucoserratene (1712) in three steps and 39% yield overall. The synthesis can be extended to give dictyopterene B (1628) and dictyopterene D' (ectocarpene) (1629) by 1,3-dipolar cycloaddition of 3-diazo-lpropene to give 1718. Heating 1718 in refluxing hexane produces dictyopterene B (1628) and dictyopterene D' as a mixture in a 1: 1.2 ratio. Nitrogen extrusion produces 1628, which can be converted completely to 1629 via Cope rearrangement by heating to > 125°C.

The most recent synthesis of fucoserratene (1712) is a second approach by Schneider [468], shown in Scheme 303. Z-selective Wittig olefination, via the silazide method, of (E)-3-oxiranylprop-2-enal 1719 followed by reaction with thiourea yields thiirane 1720. Desulfuration of 1720 by treatment with triphenylphosphine results in the formation of 1712 in three steps and 69% overall yield.

4.3.2.11 Giffordene

Giffordene (2Z,4Z,6Z,8Z)-2,4,6,8-undecatetraene) has been isolated from laboratory cultures the brown alga Giffordia mitchellae. Confirmation of its structure was obtained through its synthesis by Boland [469] (Scheme 304) in a very simple manner. THP-protected enyne alcohol 1722 is transformed into diendiyne 1723 in five steps. Reduction of 1723 with Zn(CujAg), a reagent that is

tBuO

K /

tBuO

H

/ /

" •

Dic

ydoh

exyl

-18

-Cro

wn-

6 17

13

(No

yiel

d re

pone

d.)

Sche

me

301.

Hop

f Sy

nthe

sis

of F

ucos

erra

tene

~C02H

1716

1712

+ ~N2

I) L

AH

, E

t20 ~o

2) P

CC

/ C

H2C

l2

50%

H

1717

4°

C - 55%

H

H

~

N=N

~l.

1718

Dec

ompo

ses

abov

e 0

°c

1714

Ph3P

= CH

CH

2CH

3

TII

F, _

78°C

, 780

/:

hexa

ne

refl

ux

H2,

Lin

dlar

~

.. M

eOH

,51%

fuco

serr

aten

e 17

12

~

Fuc

oser

rate

ne

1712

~

~

VoL

+

For

med

in a

I :

1.2

rat

io v

ia t

herm

olys

is

Dic

tyop

tere

ne' B

16

28,

an N

2 ex

trus

ion

prod

uct

Dic

tyop

tere

ne D

' (E

ctoc

arpe

ne)

1629

fr

om C

ope

rear

rang

emen

t o

f a

side

pro

duct

of t

he N

2 ex

trus

ion

step

Sche

me

302.

Sc

hnei

der

Synt

hesi

s of

Fuc

oser

rate

ne, {

±)-

Dic

tyop

tere

nes

Ban

d D

' (E

ctoc

arpe

ne)

.....

w ~

.." ~ '< [ ~ ::l . ., '" 0- ~

s:l. ~ ~ en

1719

1720


~ thiourea NaHCO:J

rt, >95% ..

o

.. rt,85%

fucoserratene 1712

Scheme 303. Schneider Synthesis of Fucoserratene

Giffordene 1724

specific for the reduction of internal alkynes, gives -giffordene 1724 in five steps and 2.8% overall yield.

Related to giffordene are the four metabolites 1734-1737 isolated from D. plagiogramma [470] and Spermatochnus paradoxus. Naf [471] has prepared these metabolites from the sulfolene 1725 by making use of the RambergBacklund reaction (Scheme 305). Treatment of 1725 with KOtBu proceeded with ring-opening to the anion 1726, which was alkylated with allyl bromide to give sulfones 1727 and 1728. 1,6-Addition of either di-n-butylcuprate or the l-butenylcuprate 1729 to this geometric mixture led to the corresponding addition product mixtures 1730-1733 in moderate yield due to competing polymerization processes. These were among the first cuprate additions to unsaturated sulfones. Classical Ramberg-Backlund reaction of each of these mixtures led to mixtures of the natural products which were not further purified.

n-Bu~

1734

n-Bu~

1735

4.3.2.12 Clavularins A and B

1736

1737

Clavularins A and B were originally isolated from the soft coral Clavularia koellikeri by Endo [472] and, although not algal pheromones, bear a structural resemblance to members of this class. Subsequently, clavularin A was isolated


1) BuLi 2) CH3CH2Br .. HO~ THPO, I'

1722 3) PPTS, MeOH

62%

.. OHC~ 91%

• 19%

Zn (CulAg), aq. MeOH

• rt,26.5%

Scheme 304. Boland Synthesis of Giffordene

o

q-< Initially proposed structures for Clavularins A and B

Clavularin A (cis) 1739 Clavularin B (trans) 1740

1723

giffordene 1724

Revised Clavularin A and B Structures

Clavularin A (cis) 1748 Clavularin B (trans) 1745

[473] from a second soft coral, C. viridis. Both compounds show significant cytotoxicity. On the basis of extensive NMR studies the cyc1ononanone structures A and B were proposed for the epimeric c1avularins A and B. Subsequently, the initially proposed structures were revised [474]. The new structure of c1avularin B (1745) was confirmed through its synthesis by Urech' [475] (Scheme 306). Conjugate addition of LiCuMe2 to cyc1oheptadienone 1741 and trapping with TMSCI affords dienyl ether 1742. Regeneration of the enolate with methyllithium and treatment with silyl substituted MVK 1743 provides the diastereomeric Michael adducts in good yield. Use of the silyl substituted Michael acceptor retards further Michael additions of the adduct under the

(n-B

u)zC

uLi

~

(~

1729

et

her

o {fS~

°

°

1725

t-B

uOK

, ~S02K

DM

SO

1726

o~

{f0

n-Bu~S~

1730

+

n-Bu~S~

~~

1731

°

°

O~

{f0

S~

~

1732

+

~S~

1733

oq

~O

Sche

me

305.

Naf

Syn

thes

is o

f B

row

n A

lgal

Met

abol

ites

Br~

--

.. D

MSO

KO

H,

t-B

uOH

,

H20

,CC

4

KO

H,

t-B

uOH

,

H20

,CC

I4

O~

{f0

~S~

1727

+

O~

{f0

~S~

1728

n-Bu~

+

1734

n-Bu~

1735

~

+

1736

~

1737

(j

00

I Q

>

dQ

~ ;q ~ 3 o ::; '" '" ......

W

-..l


0 I) Me2CuLi,

(5 6 THF, -20 DC ..

2) Me3SiCI, HMPA,

1741 Et3N, -78 to 20 DC

1742 93%

EtOH SiOz .. 62%

from 1742

~ U""Me

Me

(±)-clavularin B 1745

Scheme 306. Urech Synthesis of (±)-Clavularin B

0 0 I) MeLi, THF, rt

.. 6::t 0 Me

2) ==<- 1744 SiM~

1743 -78 to -20 DC

basic aprotic conditions. Ethanolysis of 1744 gives c1avularin B in three steps and 58 % overall yield.

The epimeric c1avularin A (1748) has been synthesized by Still [476] as outlined in Scheme 307. Cyc1oheptenone (1746) is converted to unsaturated ketone 1747 by a standard series oftransformations. Hydrogenation, introduction of the endocyc1ic double bond and deprotection of the ketal provides c1avularin A (1748) in seven steps and an overall yield of 19%.

I) CH3MgBr, CuI; 1\ 0 1\ o MsO 1\ 0

6 o 0 e;::x OHC....x a'-X A12~ (basic) .. ..

-10 to 25 DC 42% overall 2) CH3S02Ci, py,

1746 Oto 25DC

I) H2, 10% PdlC,

EtOAc, rt, 99%

2) LiTMP, THF,78 DC

3) PhSeBr, 0 DC

.. ~ -'---J-..

Scheme 307. Still Synthesis of clavularin A

1747

I) 30% H202, HOAc, 0 0

o to 25 DC, 55% over~1 ' ~

2) FeCi3-SiOz, CHCi3, ~ rt, 85%

clavularin A 1748

Miscellaneous Metabolites 139

4.4 Miscellaneous Metabolites

4.4.1 Acarnidines

A series of N-substituted polyamines known as acarnidines have been isolated [477] from the red-orange encrusting sponge Acarnus erithacus. All of these have the homospermidine skeleton, differing mainly in the alkyl chain lengths and positions of unsaturation. The acarnidines exhibit mild activity against Herpes simplex virus Type I, as well as broad spectrum antimicrobial activity. The only member of the class that has been subjected to total synthesis is 1754. The only major problem to be handled in the synthesis of acarnidines is differentiation between the two amine groups in the 1,5-diamino functionality.

NH 0

H N)lN ..... (CH~s~N....cCH2h_N~ 2 I I I

H .,-CllH23 H o

N -(5-Guanidinopentyl)-N -[3-(3-methylbut-2-eneamido )propyl]dodecanamide 1754

The synthesis of 1754 by Golding is shown in Scheme 308 [478]. Monoderivatization of 1,5-diaminopentane occurs by reaction with 1750 to give 1751, where protection of the guanidino functionality with an N -nitro group reduces its reactivity and basicity. Once the two amino groups have been differentiated, the synthesis proceeds in a straightforward fashion. Reductive amination of 1751 with 1752 gives the homospermidine skeleton 1753. Acylation with pnitrophenyl laurate followed by electrolytic removal of the guanidino nitro group affords 1754, which was isolated as a dimethylpyrimidine derivative. The synthesis required approximately six steps and had a 14% overall yield.

A similar procedure was followed by Munro [479] as shown in Scheme 309. The problem of guanidine reactivity and basicity is circumvented by construction of the molecule in the reverse direction (as compared to Golding, Scheme 308), so that the guanidine moiety is attached last. Acylation of 3-aminopropanol and Swern oxidation gives aldehyde 1755. Reductive amination of 1755 with the mono-BOe protected diamine 1756 affords the homospermidine skeleton 1757. Acylation followed by Boe deprotection gives 1758, which upon reaction with methylisothiouronium iodide yields the acarnidine 1754. Synthesis of 1754 is completed in seven steps and 20% overall yield.

4.4.2 Pahutoxin

Pahutoxin is an ichthyotoxic and hemolytic substance isolated [480] from the epidermal mucus of the Hawaiian boxfish Ostracion lentiginosus. An enantiospecific synthesis by Tai [481] is shown in Scheme 310. Optical activity is

02N

,

Me

02N

-N

YJ .""" ''c

-N

, -"

'"

H2N

Me

1750

H2N

(CH

2)sN

H2

diox

ane

64 %

N

0

H2N

)l N

'" (C

Hz}

s. N

" (

CH

2h. N

~

I I

I H

H

H

1753

elec

trol

ytic

red

ucti

on

Hg

cath

ode

H2S

04

• T

HF

55 %

02N

-N " ,C

-N

H(C

H2ls

NH2

H2N

1751

02

N-Q

-02

CC

IIH

23

I-h

ydro

xy b

enzo

tria

zole

80 %

o 0

)JNH~H

I)

1752

2) N

aBl-'

4. M

eOH

50

%

°2N, N

0

H2N

)l N

'" (C

Hz}

s. N

" (C

H2

h. N

~

I )-

I H

H

o

CII

H23

NH

0

H2N

)l N

'" (C

Hz}

s. N

" (

CH

2h. N

~

I )-

I H

H

o

Cll

H23

. N-(

5-gu

anid

inop

enty

l)-N

-[3-

(3-m

ethy

lbut

-2-e

neam

ido )

prop

yl]d

odec

anam

ide

17

54

Sche

me

308.

Gol

ding

Syn

thes

is o

f N

-(5-

guan

idin

open

tyl)

-N-[

3-(3

-met

hylb

ut-2

-ene

amid

o)pr

opyl

]dod

ecan

amid

e

~ ~ '< > R

~ ::I. ei Po a:: " g. §;. " '"

~NH2

HO

o 1

)C

1M

E

t3N

, 83

%

2) D

MS

O,

(CO

Clh

-6

0 cC

, 84

%

o 0

H~NU

I H

1755

BO

C...

"

(CH

2ls

N

'N~

~ 17

56

1) 4

A m

olec

ular

sie

ves

.. 2)

NaB

14, E

tOH

, 71

%

BO

C...

"

(CH

2ls

... (C

H2)

3 ~...

"..I

N

'N 'N~

1) C

l1H

23C

OC

l, E

t3N

, 73

%

2) C

F 3C

02H

, 95

%

o H

2N" (

CH

vs. N

'" (C

H:z

}3. N~

o}-Cll~

~ I

I I

H

H

H

1757

•CH

3 S

H2N~NH.m, E

tOH

60 %

NH

0

H2N

)l N

" (C

H2 ls

. N '"

(C

H2h

. N ~

I )-

I H

H

o

CII

H23

N-(

5-gu

anid

inop

enty

l)-N

-[3-

(3-m

ethy

lbut

-2-e

neam

ido)

prop

ylJd

odec

anam

ide

1754

Sche

me

309.

Mun

ro S

ynth

esis

of

N-(

5-gu

anid

inop

enty

l)-N

-[3-

(3-m

ethy

lbut

-2-e

neam

ido)

prop

ylJd

odec

anam

ide

1758

~

00' a § " o ~ ~

~

l>l <:r 2- ~.

......

.j:>.

.....

.


1) AC20, py AcOH,87%

2) (COClh, C6~ •

1) H2, NaBr, Raney-Ni, (S, S)-tartaric acid 85 % ee

• 2) saponification

(purified to >99 % eel

62%

3) -""- _W(CH) Cl-HO'''''' 3 3

(S)-(+)-pahutoxin 1762 40-56 %

Scheme 310. Tai Synthesis of (S)-( + )-Pahutoxin

(S)-(+)-Pahutoxin 1762

obtained in the first step by enantio-differentiating hydrogenation of ~-ketoester 1760 over (S,S)-tartaric acid-sodium bromide modified Raney nickel_ Saponification of the ~-hydroxyester followed by multiple recrystallizations of the dicyc1ohexylammonium salt of 1761 affords optically pure 1762. After acetylation of the alcohol, the acid is converted to the acid chloride and treated with choline chloride to provide (+ )-pahutoxin in five steps and 34% yield overall.

4.4.3 n-erythro-l-Deoxydihydroceramide-l-Sulfonic Acid

The sulfolipid D-erythro-1-deoxydihydroceramide-1-sulfonic acid (1769) was isolated [482] from the alkali-stable lipids in the non-photosynthetic marine diatom Nitzschia alba. The only total synthesis of 1769 is that of Kamikawa [483], shown in Scheme 311. Selective acetalization of galactose (1763) followed

OH

C15H3~S020H :

C\SH3\yNH

o

D-erythro-l-Deoxydihydroceramide-l-sulfonic acid 1769

H~

HO

O

H

HO

Gal

acto

se

1763

I) M

sCI,

Et3

N,

97 %

2)

NaN

3, 5

7 %

3) P

h3P

, T

HF

, H

zO,

98 %

NB

S,

BaC

0 3

CC

l 4

72

%

..

I) C

14H

z9P-

'-Ph3

Br

I) P

hCH

O,

OH

t-

BuO

K,

TH

F

ZnC

l z

Ph O~

• --

..LO

C

HO

2)

Per

ioda

te

2) h

v, P

hSS

Ph

Oxi

dati

on

1764

56

%

Ph --..L0~ NH

2 H

-~C13 2

7

I) N

02

-o0

2C

C1

5H

31

py,

98 %

2) H

z, R

h-al

umin

a 93

%

1766

o )l

o Ph

C15H

31~

C

: Be

15H3

1y

NH

o

I) N

'azS

03

, n-

Bu4

N+B

r

CH

3CI,

HzO

, 59

%

2) N

aOH

, M

eOH

, 68

%

OH

Ph O~

• --

..LO

,

C13H

27

1765

o Ph

--.

.L~N

HCOC

15H3

1 C

14H

29

1767

OH

~S020H

C15

H31

~ N

H

C1

5H

31

Y

o

1768

D

-ery

thro

-l-d

eoxy

dihy

droc

eram

ide-

l-su

lfon

ic a

cid

1769

Sch

eme

311.

K

amik

awa

Syn

thes

is o

f D

-ery

thro

-I-D

eo

xyd

ihyd

roce

ram

ide

-l-s

ulfo

nic

aci

d

s:::

~. f o 1il s:::

~

I» cr

o =: <t '" .- +=

w


by periodate oxidation gives aldehyde 1764, which is subjected to a Wittigphotoisomerization sequence to afford the trans olefin 1765 in 56% yield. Mesylation of the axial alcohol, inversion with NaN3 and reduction of the azide by treatment with triphenylphosphine yields the equatorial amine 1766. NAcylation of 1766 by treatment with p-nitrophenyl palmitate and catalytic hydrogenation of the alkene produces 1767. Ring opening of the acetal with NBS provides the bromo benzoate 1768. Treatment with sodium sulfite under phase transfer conditions and subsequent saponification of the benzoate affords 1769 in 8% overall yield via a 12 step synthesis.

4.4.4 Phosphonosphingoglycolipid from Turbo cornutus

A variety of phosphonosphingoglycolipids have been isolated from the tissues of marine Mollusca and Protostomia. Hayashi has isolated [484] several new phosphonosphingoglycolipids from the muscle tissues of the marine snail Turbo cornutus, the simplest of which is 1776. Kamikawa [485] utilizes the protected ceramide 1771 from an earlier synthesis (Scheme 311) to develop an enantioselective synthesis of 1776 as shown in Scheme 312. The overall strategy involves coupling two optically pure fragments, both derived from galactose, to give 1771. Hydrolysis of 1771 followed by silylation, benzoylation and desilylation affords the secondary benzoate 1772. Glycosidation of 1772 with IX-D-bromotetraacetylgalactose gives a mixture of components that can be converted to 1773 in 42% yield by treatment with trimethylsilyl triftate. The phosphonosphingoglycolipid 1776 is obtained by acetate saponification and ultrasound assisted coupling of 1774 and 1773 using carbodiimide 1775. An overall yield of 3% is obtained in 15 steps from galactose.

Phosphonosphingoglycolipid from Turbo comutus 1776

4.4.5 Metabolites of Plexaura flava

The butyrolactone containing metabolites 1779 and 1780 have been isolated [486] from the Gorgonian coral Plexaura fiava. Font [487] has developed a diastereoselective enantiospecific synthesis of both 1779 and 1780 (Scheme 313). Acylation of commercially available ethyl (S}-lactate and intramolecular condensation yields lactone 1777. Hydrogenation of 1777 provides compound 1778 in 76% yield (along with 13% of the trans-isomer). The cis-isomer can be

Ph-.

....

L0~

o N

HC

OC

1SH

31

~

C13H

27

17

71

pr

epar

ed i

n ea

rlie

r K

amik

awa

synt

hesi

s

1)

Br ~

OAC

.0

Ac

AcO

OA

c

Hg(

CN

)z, C

H3N

02

2) T

MS

OT

f 42 %

HO

2N

HC

l H2

7CI3

~OH

.. T

HF

H

31C

1S y

NH

0 7

2%

o

Ph

)lO

O

Ac

~O~~

H27

C13

1~1H

Ac

OA

c H

31C

1S Y

o 17

73

HO

~ ~O ... ?~

H2WC

H3

H27

C13

:

0 0

P

: H

' "

H31

C1S

Y NH

H

OO

H

0

o

I) T

BD

PSC

I 0

imid

azol

e P

h)lO

67

%

.. H27C13~OH

2) P

hCO

Cl,

py

H3

1C

lSy

NH

88

%

3) n

-Bu4

N+

F

0

90 %

17

72

1) N

aOM

e, M

eOH

, 95

%

2) u

ltra

soun

d, p

y, 7

2 %

Et-N:C:N~NMez

1775

HO

~H

3 H

O, 'f.

__

Ny

OC

H2C

CI 3

o 0

1774

a ph

osph

onos

phin

gogl

ycol

ipid

fro

m T

urbo

cor

nutu

s 17

76

Sche

me

312.

Kam

ikaw

a Sy

nthe

sis

of P

hosp

hono

sphi

ngog

lyco

lipi

c fr

om T

urbo

cor

nutu

s

:::: tn· ~ g o ~ :::: ~ ~ '" .- .j::..

V

l


HO 0 00Et AC20 / pyr ..

'"

1) 2.2 eqLDA

TIIF / -78°C .. 2) R-I

o

1779 R = C16H33

1780 R= C14H29

LiHMDS ~ >-0 0\..-z

i OEt

---...., .. -001 : OH

'" 1777

0 0

ob.:R AC20 / pyr ob.:R .. i 'OH i 'OAc

'" '"

R = n-CJ6H33 53% R = n-C16H33

= n-C J4H29 = n-CJ4H29

Scheme 313. Font Synthesis of Plexauraflavus Metabolites 1779 ans 1780

1778 76%

+ 13% trans isomer

1779 93%

1780

converted in a straightforward manner to either 1779 or 1780 in a total of 6 steps.

4.4.6 Notheia anomala Metabolite

Williams et al. have developed methods for the stereocontrolled transformation of orthoester intermediates into substituted tetrahydrofurans. An interesting marine natural product suitable for demonstrating the utility of this methodology is the trisubstituted tetrahydrofuran 1787. Metabolite 1787 has been found [488] as a constituent of the brown alga N otheia anomala. Its structure has been unambigously confirmed by single-crystal X-ray analysis. Williams's synthesis of 1787 [489] begins with the conversion of homopropargylic alcohol to the


Notheia anomala Metabolite 1787

protected cis-alkene diol1782 (Scheme 314). Standard transformations provide a diastereomeric mixture of alcohols 1783, which is separated to give alcohol 1784. In the key transformation, oxidation of 1784 with NBS Stereospecifically provides substituted tetrahydrofuran 1786 via dioxenium cation intermediate 1785. Desilylation, Swern oxidation and addition of 8-nonenylmagnesium bromide affords the natural product 1787 in 11 steps.

An enantiospecific synthesis of the N otheia anomala metabolite 1787 has been developed by Takano [490] and is presented in Scheme 315. Acetylide ring opening of diepoxide 1788, available optically pure from (L)-diethyl tartrate, affords diyne 1789. Conversion of 1789 to alcohol 1790 and treatment with phenylsulfenyl chloride gives substituted tetrahydrofurans 1791 and 1792 as a 3: 1 mixture. Diimide reduction 1791 and 1792 and selenoxide elimination affords compound 1793, which is oxidatively cleaved to give aldehyde 1794. Separation of the diastereomers and Grignard reaction of the ~-H isomer with 8-nonenylmagnesium bromide provides the natural product as a 3: 1 mixture of diastereomers. The overall yield can be increased by inversion of the minor product (ex-OH) in 80% yield. Metabolite 1787 is obtained in 11 steps.

4.4.7 Octacosadienoic Acids

Most marine sponges contain large amounts of long-chain C24-C30 fatty acids. A variety of structural types are found, including examples of straight or branched carbon skeletons with both terminal and internal methyl branching. The synthesis of one example of this class of lipids, 22S-methyl-5,9-octacosadienoic acid (1801) from the sponge Api ysina fistularis by Djerassi [491] is shown in Scheme 316. The synthesis of 1801 begins with 1,5-cyclooctadiene (1796). In four steps 1796 is converted to mono-THP protected diol 1797. Tosylation of the free hydroxyl group and cuprate mediated coupling of the tosylate with 5-(trimethylsiloxy)pentylmagnesium bromide gives alcohol 1798. A second tosylation and cuprate mediated coupling reaction with optically pure Grignard reagent 1799 (available from (+ )-pulegone) affords THP ether 1800. Elaboration of the other sidechain proceeds via formation of the aldehyde and

~C02Me

I i {CHz}9---l.

. '{CHz}sCH3

22R-Methyl-5,9-octacosadienoic acid 1801

OH

I)

OS

04 /

NM

MO

I~OB

' 1)

H2

/ P

d-B

aC0 3

/ E

tOA

c ac

eton

e /

aq.

t-B

uOH

2)

Na

/ N

H3

/ i-

PrO

H

(C

0T

BD

PS

2)

PhC

HO

/ T

sOH

..

.. 3)

TB

DP

SC

I /

CH

2C12

O

Ac

4) A

C20

/ p

yr

n-Pe

ntyl

3)

NaO

CH

3 / C

H30

H

1782

n-

Pent

yl

74%

84

%

OT

BD

PS

sepa

ratio

n_

Ph

-;tti

NB

S/C

HC

I 3

[ am

DPS]

Ph~°

ti

_ ..

H

0 n-

Pent

yl

2 hr

/2

2 °

C

o n-

Pent

yl

I) T

BA

F /

TH

F

2) S

wer

n ox

idat

ion

1784

BzO

~CHO

n-p

entY

l,l-

0 ~~

1785

BrMg~

-78

°C

Et2

0

45%

n-Pe

ntyl

OTB

DPS

Ph~°

ti

H

0 n-

Pent

yl

1783

BZO

XK

OTB

DPS

n-Pe

ntyl

0

H 17

86

90%

78

%

Not

heia

ano

mal

a m

etab

olit

e 17

87

Scbe

me

314.

Wil

liam

s S

ynth

esis

of

Not

heia

ano

mal

a M

etab

olit

e 17

87

- "'" 00

~ '< [ ~ 8- ~ ~ g- ~ '"

! L

i ./

17

88

fro

m (

L)

diet

hyl

tart

rate

BF3

oEt2

0 T

HF

• P

haIO

TsO

H/P

hH

1) H

2/

Pd-

Pb

CaC

03

• 2)

Dib

al /

CH

2C12

91%

17

89

7

2%

fro

m d

iepo

xide

B~no

~ O

H

~

PhS

eCl

aI2

Cl2

-7

8°

C •

Bee

no H

o

+

~

SePh

Bfrn

o

H

.. ~ o

' ~

~ePh

1) d

iim

ide

TH

F

2) H

20z

TH

F

BnO

nCSH

ll~

17

93

80

%

as a

mix

ture

at

ClO

17

90

1) O

S04

/ N

MM

O

aq a

ceto

ne

2) P

b(O

Ac)

4 T

HF

BnO h

,H

nCSH

l1 ,A

.O

XC

HO

17

94

3

: 1

~: a

-H

(~-H

iso

mer

sep

arat

ed

and

carr

ied

on)

1791

3

:

1 1

79

2

89%

(m

ixtu

re c

arri

ed o

n)

1)

(CH

zh-.

?'

BrM

g-

lHF

2) L

i /N

H3

Sche

me

31S.

Tak

ano

Syn

thes

is o

f N

othe

ia a

nom

ala

Met

abol

ite

1787

OH

Not

heia

ano

mal

a m

etab

olit

e 17

87

as a

3 :

I ~ /

a-O

H m

ixtu

re

in 7

5% y

ield

-

maj

or i

som

er (~-

OH i

s N

P)

-m

inor

iso

mer

(a-

OH

) co

uld

also

be

conv

erte

d to

NP

by

inve

rsio

n in

80%

yie

ld

t !i I .... ~

0 M

CPB

A

0°

1) H

s106

C::0

H

OH

P,H

+,

C::0

TH

P

• •

• C

H2C

l2,4

0%

2) N

aBI-

4,

OH

E

t20,

49%

O

H

64%

1

79

6

1) T

sCl,

py

C=

0T

HP

1)

TsC

l, p

y •

• 2)

Li 2

CuC

I 4,

2) L

i 2C

uCl 4

T

MS

O(C

H2)

sMgC

I (C

H2)

60H

~

3) K

2C0

3, M

eOH

, 89

%

1798

MgB

r

1) P

OC

, CH

2Cl 2

~OH

~(CH2)

9 ~ (CH 2)s

CH

3

2) B

r-Ph

3P+(

CH

2)4C

02H

K

H,O

MS

O

3) C

H2N

2, E

t20,

35%

1797

C=

0T

HP

T

sOH

MeO

H

(CH

2)9 --!.

. (CH

2JsC

H3

18

00

84

%

C0

2Me

C::Z:"

'CH'

22S

-met

hyl-

5,9-

octa

cosa

dien

oic

acid

18

01

.......

Vl

o "r'l ~

Q 5': p. ~ 8. a:: ~ ~ o :=: !!

~OTHP

~OH

1) T

sCI,

py

2) L

i 2C

uC4,

T

MSO

(CH

2)6M

gBr

~OTHP

~(CH

2hOH

1)

TsC

l, py

2) L

i 2C

uC4

c::O

TH

P

I -;

(CH~

9-'.

. (CH~5CH

3 3)

K2C

0 3, M

eOH

, 88%

B

rMg /'

0..

.../

' (C

H2)

5CH

3 86

%

TsO

H,

MeO

H c:

OH

I

1 (C

H2 )

9 --

-....

.. (C

H2)5

CH

3

1) P

DC

, CH

2Cl 2

2) B

r-Ph

3P+(

CH

v4C

0 2H

K

H,D

MS

O

3) C

H2N

2, E

t20,

35%

Sche

me

316.

Dje

rass

i S

ynth

esis

of

22R

-an

d 2

2S-M

ethy

l-5,

9-oc

taco

sadi

enoi

c A

cid

C0 2

Me

c:7

(C

H2 )

9 -'-

., (C

H2ls

CH

3

is:: t o !il is:: g ~ Ii ,....

v. ,....

OM

e O

Me

0 1)~,MeOH

C::O~

I O

Ts

n-C

13H

27M

gBr,

C::"'"

•

.. 2)

TsO

H,

rt

Li2

CU

CI4

,76%

.

C13

H27

-n

3) N

aBH

4, -

10 °

c

1796

35

%

1802

HC

I, ac

eton

e c:::

HO

Ph

3P+(

CH

v4C

OO

H B

r-

I •

.. rt

,98

%

Ct3

H27

-n

KH

, D

MS

O, r

t, 8

0%

1804

OM

e

~OMe

~C13

H2Tn

M

CP

BA

,O°C

CH

2CI2

,90%

HC

I, ac

eton

e

rt

~CHO

~C13H27-n

OM

e

~OMe

O~Ct3H27-n

1806

Ph3

P\C

Hv4

CO

OH

Br-

KB

r, D

MS

O,

rt

76%

1803

~ COOH

1805

OM

e

LiP

Ph2

, rt

l

CH

3I,8

0%

~OMe

~Ct3H27-n

~COOH

~C13

H2Tn

18

07

......

VI

N ~ '< R

~ [ =:.: ~ ~ '"

OM

e O

H

~OMe

~C\3H2Tn

I) H

CI,

ace

tone

2) C

H2=

CH

MgB

r,

rt,

2 hr

, 86

% ~~'" C

H3C

(OC

Hsh

,

CH

3(C

H2h

CO

OH

14

0°C

, 95%

18

03

~COOCH3

~C13H2Tn

1809

I) L

AH

, E

t20,

90%

2)

MsC

I, E

t3N

, 93

% 18

08

• 3)

NaC

N, D

MS

O, 9

0%

4) K

OH

, E

tOH

, re

flux

~COOH

~C\3H2Tn

1810

OM

e

~OMe

~C13H27-n

I) H

CI,

ace

tone

~

CH

3C(O

CH

3h,

CH

3(C

H2h

CO

OH

14

0°C

-2)

CH

2=C

HM

gBr,

~C

13H2

Tn

1811

~COOCH3

~CI3H2Tn

rt,

2 hr

I) L

AH

,Et2

0

2) M

sCI,

Et3

N

3) N

aCN

, D

MS

O

4) K

OH

,EtO

H

Sche

me

317.

Dje

rass

i S

ynth

esis

of

5,9-

Hex

acos

adie

noic

Aci

ds

~COOH

~C\3

H2Tn

1812

~ [ § CI

> o ijl ~

g.

~

r:r ~ -U'o W

Me(

CH

2lsC

== C

Li

+

Br(

CH

2hC

H20

H

HM

PA

...

Me(

CH

2ls

-C=

= C

-(C

H2l

9 -C

H20

H

1) P

CC

M

e(C

H2l

sC ==

C(C

H2l

9CH

(OH

lC ==

CH

2)

LiC

==C

H

1) c

r03,

H2S

04

H"

pH

1)

EtM

gBr,

TM

SC

I M

e(C

H2l

sC ==

C(C

HV

9 --

C -

C ==

CH

~

H

OH

'.

~ M

e(C

H2l

sCH

= C

H(C

H2l

9 .-c

-C

== C

TMS

cis

+

2) 9

-BB

N,

(+)-

a-pi

nene

,

2) H

2, L

indl

ar

H

OH

".

"

Me(

CH

2lsC

H=

CH

(CH

2l9

-C -

CH

= CH

TMS

cis

cis

AgN

03

H

OH

H

O

H

"'. "

Me(

CH

2lsC

H=

CH

(CH

2l9

-C -

C ==

CH

I) C

U2C

l2,

NH

20H

, H

CI,

EtN

H2,

H20

'.

~

Me(

CH

vsC

H=

CH

(CH

2l9

.-C -

(C ==

C)2

CH

zOH

ci

s

1) C

U2C

I2, N

H20

H,

HC

I, E

tNH

b H

20

2) B

IC==

CC

0 2H

2) B

IC ==

CC

H20

H

cis

5

o II M

e(C

H2l

sCH

= C

H(C

H2l

9 -.,

C -

(C ==

C)2

ci

s

[ H

O

H

1 Me

(CH2

lsCH

~ CH(C

H2l9':

'C~-(c

== C

) C

O H

C

u(N

H3)

4S0 4

C

1S

2 2

H~ p

H

Mn

02

t M

c(C

H2l

sCH

= C

H(C

H2l

9 -C

-(C

== C)

2 ---"'-

---'

cis

CH

2CI2

. u.. ~

"TI ~

q [ t:1

(1) ~ ~

(1) g. ~ '"

PC

C

Me(

CH

z}p

= C

Li

+

Br(

CH

vlO

CH

20H

H

MP

A..

M

e(C

H2)

s -C

=C

-(C

H2)

IO-C

H20

H

_ M

e(C

H2)

s -

C =

C -

(CH

2ho-

CH

O

CB

r4 ..

PP

h 3

I) B

uLi

I) H

2,

Lin

dlar

M

e(C

H2)

S -

C=

C-

(CH

2)IO

-CH

= C

Br 2

..

M

e(C

H2>

S-. C

= C

-(C

H,)

.n-C

==

CT

MS

Me(

CH

2)S

-C

H=

CH

(CH

2)IO

-C =

= C

H

cis

2) E

tMgB

r,

2) A

gN03

T

MS

CI

1) C

U2C

I2, N

H20

H,

HC

l, E

tNH

2, H

20

2) B

rC=

CC

H20

H

Me(

CH

2)S

-C

H=

CH

(C

H2)

1Q -

(C ==

C)2C

H20

H

cis

Sche

me

318.

Tha

ller

Syn

thes

is o

f C

n an

d C

23

D

iace

tyle

nes

from

Ren

iera

fulv

a

a:: [ ~ o ~ a:: S a' ~ '" . VI

VI


Wittig olefination to produce the methyl ester of 22S-methyl-5,9-octacosadienoic acid in 13 steps and 3 % overall yield. The enantiomer of 1801 is prepared in a similar fashion.

4.4.8 Hexacosadienoic Acids

Djerassi has also prepared [492] the fatty acid (5Z,9Z)-5,9-hexacosadienoic acid (1805) as shown in Scheme 317. Selective ozonolysis of 1,5-cyclooctadiene (1796), tosylation, and reduction gives tosylate 1802 in which the two alkene substituents have been differentiated and the stereochemistry of the 9,10-double bond has been set. Cuprate catalyzed coupling of tridecylmagnesium bromide with tosylate 1802 yields the saturated sidechain. Wittig olefination of aldehyde 1804 provides the second double bond with correct geometry, thus giving 1805 in six steps and 21 % yield. The cis-trans isomer was prepared in a similar manner, involving olefin isomerization via the epoxide 1806. Treatment of 1806 with lithium diphenylphosphide using a standard sequence gave the trans isomer which was carried on to 1807 via a similar sequence. Scheme 317 also shows syntheses of the other two diene isomers. Intermediate 1803 was converted to the allylic alcohol 1808. Claisen rearrangement provided the trans geometry about the new olefin in 1809. Chain elongation led to the desired 1810. Finally, the all trans isomer 1812 was prepared from the trans acetal 1811 by an analogous sequence.

1805

~COOH

~C13HzTn 1807

4.4.9 Diacetylenes from Reniera fulva

1810

Several long-chain diacetylenes containing a single propargylic stereocenter from the sponge Reniera fulva [493] have been synthesized by Thaller [494] in pure optically active form to confirm the assigned absolute configuration. The routes are shown in Scheme 318 and require very little comment. The


° II Me(CH2hCH =CH(CHz}9- C-(C=C)2

cis

H" pH Me(CHz}sCH = CH(CHz}9 - ·C-(C =C)2CH20H

cis

Me(CH2ls-CH=CH(CHz}1O-(ClEC)2CH20H cis

asymmetry at the carbinol carbon (70% ee) was produced by reduction of an ex,~-alkynyl ketone with 9-BBN-(+)· ex-pinene complex. Based on the known R-selectivity of this reagent, the absolute configuration was confirmed.

5 Nitrogenous Metabolites

5.1 Indoles and Related Compounds

5.1.1 Flustramine B

Flustramine B (1818), along with several other brominated indole derivatives, has been isolated from the bryozoan Flustra foliacea [495]. Hino's synthesis [496] of 1818 is illustrated in Scheme 319. Acid-catalyzed cyclization of tryptamine derivative 1814 gives 5-nitropyrroloindole 1815. Reduction to the amine, bromination and deamination provides the 6-bromo derivative. Ring opening of 1816, prenylation, and ring closure gives the diprenylated Ncarbomethoxy compound 1817. Hydrolysis for 100 hours with sodium ethoxide in reftuxing ethanol gives the free amine, which is converted to ftustramine B by methylation. An overall yield of less than 0.5% is obtained over 9 steps.

Br

Flustramine B 1818

5.1.2 Surugatoxins

The Japanese ivory shell Babylonia japonica elaborates a class of alkaloidal glycosides which exhibit potent toxicity upon ingestion. These spirooxindoleand pteridine ring-containing metabolites have been named surugatoxins [497]. Neosurugatoxin and prosurugatoxin have been characterized as the causative agents responsible for the toxic event. Inoue has described a basic approach to

O:zN

'()::J'

l1 I

NH

"~

C0 2

Me

1) H

2S0 4

• 2)

AC

20

H

1814

H

02

NY

)-h

~N+N)

CH

3Y

""B

r

CH

3

I H

C0

2Me

Ac 18

1S

~NH

Br

N

C0 2

Me

if pH

= 2

.7, r

t, 7

1%

Sche

me

319.

Hin

o Sy

nthe

sis

of (±

)-F

lust

amin

e B

H

1)H

2 ~

2) N

BS,

DM

F" Br~N+N)

3) i

soam

yl n

itrite

I

H

I T

HF

Ac

CO:zM

e

16%

1817

1) N

aOH

, EtO

H

39%

2) M

el K

2C03

ac

eton

e

18%

1816

...

H:z

S04

... M

eOH

(±)-

flust

ram

ine

B

1818

b' go if [ ~ * p

..

Q

~ c:;

::I ~

. Vl

\0

Jja

(NPh

Th

Ra~ a

pipe

ridi

nium

ac

etat

e

NH

3+ C

I-

a '-'

:: E

tOH

'-':

: a

~ 1

820

Br~NJ=a

1819

'H

~o:

~Th 1) N

",S

,O,

I a

----

----

----

--h

2)N

H2N

H2

Br

N,

TH

F /

MeO

H;

H

HC

I w

orku

p

~aa

I h

N ,

Br

H

PhH

ref

lux

81%

Br'

""

MeS

GhC

H2

=R

aB

n

N.J- N

J.

.:,..J

l E

tSa 2

' I"

-a

Bn

N

a2

1822

NaH

C0 3

TH

F /

MeO

H;

33%

from~

IBJ!"

Ac

1821

aB

n

~N

1,Jl

H

'N' ~

-aB

n

iJ N

a2

Ra

2c

a

'-'::

a I

h N

, B

r H

1823

Zn

.. H

OA

c/T

HF

o

°C 1

10 m

in

94%

Ac

Br

~1;YO'"

~~1;YO,"

,...

\ /.

N

Ra

2c

\ /.

N

N

NaB

H3C

N

~ a

Bn

..

I

H

aB

n

a H

Cl I

EtO

Ac

I '-'::

a

I'

h N

82

%

Br

• \

18

25

A

c

H

aB

n

, N

-/

N

=\

-\.\

)'1

I/N

J-!<

. \

aB

n

H

a

a

ClA

y a

PhH

/ 2

5°

C

92%

B

r

AC

20 I

pyr

70 °

el 2

hr

50%

.....

g ~ g ~ ~ g, Ii

1826

OBn

O

Bn

N.)

...

N.)

...

<;?

-\-

Ac,

~

Ac,

~

O:X

:X

:H

~OB'

N

~

I

pyri

dine

N

I)

A,,

ol N

.OA

, ~ O

B,

• r

0 •

r 0

MO

MO

25°C

/1O

hr

1829

RO

OC

OH

2)

MC

PBA

H

OO

C O

Ac

85%

,0

" "'6

3)

pH

10.

2 bu

ffer

,0

" ..... "

pi

cryl

chl

orid

e ac

eton

e I

25

°C

I

0 py

r I

25

°C

I 1.

5 hr

B

h N

h

N

r \

46%

Br

'A

c Ac

18

27

OBn

o \ ~

Ac

N.)

...

-\

\ ~

17 /\I

o:y:' 0

N ~

\..J

\ ~

N

OBn

o "1

, 0

OO

CI ,

,·3

MO

MO

0'·

···

Br~N \ A

c

1) a

q K

OH

I M

eOH

2) P

b(O

Ac)

41 H

OA

c 3)

NaB

H3C

N I

HO

Ac

55%

(5~%

as a

I :

I

mix

ture

at

C3)

H

0

<;?H

H

'N"~l(

H

O:

,~r~H

y'y

0H

N

~

HO"Y'-O~N

~ O

H 0~.

'eO

H

Br~N

1831

'H

90%

CF 3

CO

OH

25

°C

11 h

r

Sche

me

320,

Ino

ue S

ynth

esis

of (

± )-

Suru

gato

xin

1828

OBn

o \

N

-\-

H

N.)...

-=

N~

ii Q

O:Y

:' O~: OBn

o

"" r

0 O

oc

OH

MO

MO

0'·

···

"6 Br~N

9O%

CF 3

CO

OH

6

0°

C 11

hr

\ Ac

18

30

o

H'W

·l(

OH

H

N

-H

HO

~

OH

'N

"-~

r y'y

"fl~'~o

HO~""O:'(

N'rO~

OH

,0

, .... 15

%

I al

ong

with

70%

Br

h

N

reco

vere

d 18

31

'H

(±)-

suru

gato

xin

1832

f [ i { .... 0'\

....

162 Nitrogen Metabolites

o H, .Ji..

HO '0 4 OH

OH V "'" I 0 B ~ N

r \ H

o R H /I

HO I 'N-,\ , 0 H~_H H0i1- N, ~"'~O (,&N 0

HO HO 0 OH

0'·~ '.~~ B~N r \

H

Surugatoxin 1832 Prosurugatoxin 1853 R = H OH

HO ~ Neosurugatoxin 1843 R = n

HO"'",+-\.

all three metabolites involving (as one might expect) production of separate aglycone and xylopyranosyl-myo-inositol components followed by coupling. Their approach is built around an acid-promoted equilibration late in the route. The synthesis of racemic surugatoxin [498] is shown in Scheme 320. Condensation of the isatin 1819 with 1820 yields 1821 as a single isomer. The amino group is freed and added to the highly functionalized pyrimidine 1822 resulting in substitution product 1823. Reduction of the nitro group was accompanied by cyclization to 1824. Oxidative dehydration led to 1825 in 50% yield. Construction of the final ring of the aglycone began with imine reduction and acylation to 1826. Base-induced ring closure occurred to give 1827, possessing the correct relative configuration at two of the eventual four centers of the aglycone. Acetylation and removal of the carboxyl protecting group produced 1828, ready for the myo-inositol unit. Esterification with racemic 1829 was accompanied by olefin migration and the product mixture was characterized as a 55% yield of C3 epimers. Saponification of the acetyl groups and an oxidation-reduction sequence provided the desired isomer 1830. Treatment with 90% CF 3COOH at 25°C for 1 hour removed the various inositol and pteridine protecting groups providing the dehydro compound 1831. Further treatment with TF A at 60°C for 7 hours resulted in an equilibrium mixture from which a 70% yield of 1831 and 15% yield of racemic surugatoxin could be obtained.

Neosurugatoxin was produced using a similar strategy beginning from the previously synthesized adduct (Scheme 321) [499]. Construction of the remaining three rings began with Grignard addition to the ketone 1823 and refunctionalization to 1834. Treatment with MCPBA to oxidize the sulfide in the carboxyl-protecting group to the sulfone and acetylation gave 1835. Osmylation of the alkyne and reductive work-up in the presence of pyridine effected aldol cyclization of the presumed (X-diketone intermediate giving 1836 as a mixture of

OB

n O

Bn

OB

n

J.

N'"

N

.J..

N

.J..N

H

h,.

.Jl

N'

T

-OB

n

d N

02

B

rMg

N

I

~¥OBn

N

I

~~OBn

OH

N0

2

OH

N0

2

R0

2C

0 ,

~

21%

I

0 as

a d

iast

ereo

mer

ic

Br

.&

N.

mix

ture

B

r H

1823

R

=M

eScH

2cH

2-

I)O

S0

4 T

HF

/p

yr

OB

n

H

1834

.J..N

1

,Jl

~-:y-

-OB

n

N0

2 I)

SO

Cl2

/ py

r o

2)Z

n/H

OA

c

I) M

CPB

A

CH

2CI 2

2)

AcC

l /p

yr

83%

•

Br

H

1835

R =

MeS

02C

H2c

H2-

OB

n

H

N::

:ZN

N~

,i' (

rO

Bn

2) N

aHS

03

aq p

yr

57%

3) C

SA

/ C

H2C

I 2

mooc

""'O

H

I~

0 B

r .&

N

.

82%

B

r H

1836

R =

MeS

0 2C

H2C

H2-

AC

20

/TH

F

DM

AP

72%

..

OB

n

H

N::

:ZN

N~

Ii' ( .<

rOBn

mOO

C

OA

c

I~

0

Br

.&

N. A

c 18

38 R

= M

eS0 2

CH

zCH

,-as

a s

ingl

e is

omer

(un

assi

gned

)

H

18

37

R =

MeS

OzC

H2C

H,-

pH 1

0.2

buff

er

acet

one

25

°C

/3 h

r

95%

as a

mix

ture

of

4 is

omer

s

..

OB

n

H

N::

:Z

(-V-

mooc

. ...

.,N

OB

n

OA

c

I~

Br

.&

N

0

Ac

18

39

as

a s

ingl

e is

omer

(u

nass

igne

d)

Sche

me

321.

Ino

ue S

ynth

esis

of

Neo

suru

gato

xin:

Agl

ycon

e F

ragm

ent

~ CD

'" [ if ~ p..

(j ~ o 8- '" ..- 01

W


four isomers. Dehydration of 1836 and reduction followed by brief treatment with CSA promoted cyclization and led to 1837 as a mixture of four isomers containing the basic neosurugatoxin skeleton. Acetylation and equilibration of the mixture at approximately pH 10 led in 95% yield to a single unassigned isomer 1839 with a free carboxyl group. At this point the optically active sugarderived unit 1840 (Scheme 322, synthesis not divulged) was attached to the racemic aglycone fragment in low yield, providing a mixture of 1841 along with the all-epi aglycone isomer with two stereocenters still unassigned. Basic hydrolysis of the acetates and further equilibration led to an equilibrium mixture of four isomers, from which the desired isomer 1843 was separated (18%) for succeeding steps. Recycling of the three unwanted isomers improved

1839

OAc

AcO '

ACO:Q

ci11'OH MOMO

1840

picryl chloride / pyr

12%

1842 as an equilibrium mixture of 4 isomers; this isomer separated .

(18%) and carried on

..

OAc

ACON' 0 OBn

AcO" MOMO Nd.. o):;~ 0 ~~,7 a ""0 ( r--"OBn

°MOMO 0 OAc w. . .....: N

1'<:::: 0 .6

Br N, Ac

1841 as a I : 1.3 diastereomeric mixture with the a11-epi aglycone isomer; I isomer separated and carried on

OH

1) aqKOH MeOH

2) NaOMe MeOH

neosurugatoxin 1843

Scheme 322. Inoue Synthesis of Neorsurugatoxin: Glycosylation

..

Indoles and Related Compounds 165

the overall yield somewhat. Final cleavage of the myo-inositol and pteridine protecting groups led to neosurugatoxin in 77% yield, completing a somewhat tortuous pathway. An alternative pathway to an intermediate in this process was recently described by Okada and Inoue [500] and is shown in Scheme 323. The Diels-Alder adduct 1845 was oxidatively cleaved and recyclized to the cyclopentene aldehyde 1846. Conversion to the amine 1847 was straightforward and coupling to the pyrimidine 1822 as before yielded 1848. OS04 oxidation of the olefin to the diol and selective protection with chloroacetic anhydride gave the mixture 1849. Dehydration and removal of the chloroacetate gave 1850. Oxidation of 1850 with phenylseleninic anhydride gave the diastereomeric mixture of (X-hydroxyketones 1851. Cyclization as before led to 1837 as a mixture of four isomers. Treatment with excess Ac20 in THF with DMAP at 25°C resulted in the neosurugatoxin intermediate 1838 in 72% yield. Presumably, equilibration of the tertiary carbinol center is occurring via a retroaldol process under the basic conditions.

Finally, racemic prosurugatoxin could be obtained from the intermediate 1839 as shown in Scheme 324 [501]. Combination of 1839 (as one stereoisomer) with the racemic myo-inositol unit 1829 resulted in a low yield of a product mixture characterized as 1852 and its all-epi aglycone isomer. From this point the same technology that had been used in the neosurugatoxin synthesis was utilized with nearly the same results, eventually giving racemic prosurugatoxin. Interestingly, when prosurugatoxin was kept in 1 % aqueous HOAc solution at room temperature for two days, surugatoxin was obtained. An O 2 oxidation was mechanistically implicated by running the reaction in 180 2 such that a 40% yield of surugatoxin was obtained carrying the 180 label at the C4 position.

5.1.3 Various Indoles

5.1.3.1 Trikentrins

From the sponge Trikentrion flabelliforme come a series of simple indoles containing a cyclopentane ring fused to the C6-C7 position. Some of these trikentrins [502] have been produced as the end products of three completely different approaches. A radical cyclization was used by MacLeod [503] (Scheme 325) in a synthesis of racemic cis-trikentrin A. 2-Bromoacetophenone was

(-)-cis-Trikentrin A (-)-trans-Trikentrin A cis-Trikentrin B

CH

O

I) N

aBJ-

4 P

(OE

th

2) M

sCII

Et3

N

.. ~

3) N

aN3

/DM

F

m. I)

0, I

M"'

H ~

I~

0 2

)0

1

.&

0 B

r .&

N

. +

Br

~

4) Z

n/H

OA

c

.Br

1845

H

N

'OA

c H

H

2 R

=E

t T

IfF

I P

hH

1846

=

H

50

°C

/3h

r =

MeS

02C

H2C

H2-

ca.

62%

OB

n

H

N.d

-, -

<...,

,~

N~

RO

OC

-..

;:: 2

NaHS~ I

py

r

I ~

2) (

CIC

H2C

Oh

O

1847

OB

n

N.d

-H

N

, ~

,~'

NO

R' r

--"O

Bn

I)

SO

CI 2

1 py

r N

02

2) u

rea

I MeO

H

refl

ux 3

hr

~NO

O

Bn

I) O

S04

;

.&

0 py

r B

r N

. B

r N

H

H

1848

51

% f

rom

azi

de

1849

R

' = C

OC

H2C

I

OB

n O

Bn

H

N.d

-N

.d-

, --)J

ZN

H

N

N ~,

N~'

OB

n

N.d

- N

Et02S~

/,'

r--"

OB

n

1822

N

0 2

...

OB

n

H,

N.d

-

N~

,~

£#.O

Hr--"

RO

OC

~

N0

2 O

Bn

I~

Br

.&

N

0

H 18

50

OB

n

N.d

-H

N

N~

,~'

(PhS

eOhO

. o

N0

2 C

H C

I ...,

N

AC

20

( rO

Bn

diox

ane

180°

C

91%

:c#. O

Bn

I)Z

n/H

OA

c

~-YOBn

exce

ss

RO

OC

~

OH

2

2 ..

RO

OC

O

H

DM

AP

~

2) C

SA

I C

H2C

l2

~

TH

F I

25

0C

~OO

C ""

OA

C

I~

0 I

0 2

5°

C I

10 m

in

I -

0 fu

.&

~

fu

.&

N

H

H

72%

1851

18

37

a m

ixtu

re o

f 4

isom

ers

Sch

eme

323.

Ok

ada

Syn

thes

is o

f N

eosu

ruga

toxi

n In

term

edia

te 1

838

Br

.&

N. A

c

1838

R =

MeS

QzC

H2C

HZ

a si

ngle

iso

mer

.....

0\

0\ ~ a g ~

~

I»

0- ~ '" '"

Br

OB

n

Nd..

H-y

N

~

I O

Bn

,-:N

f"

OA

c

~

OB

ri

~ O

.

O~

Nd..

ON (rac

emic

) ~

0 H

-z., I

~ f'

.L

"'O

H

oN

N ~

\...

.)'0

0

""0

(

OB

n

MO

MO

w.

' ,-:N 18

29

0 ..

M

OM

O

0 O

Ac

picr

yl c

hlor

ide

/ py

r -..::

::: I

0 11

.8%

b

N

Br

\ Ac

1839

(o

ne s

tere

oiso

mer

, ra

cem

ic)

1852

as

a 1

: 2 d

iast

ereo

mer

ic

mix

ture

with

the

all-

epi

agly

cone

isom

er;

1 is

omer

se

para

ted

and

carr

ied

on

\ __

_ O

Bn

o 1) a

qKO

H

MeO

H

2) N

aOA

c M

eOH

q~

Nd..

O~O

~~ I

~ O

oH"o

( ~rO

B'

MO

MO

O~OH

90%

CF3

CO

OH

25

°C

/1 h

r

75%

HO

H

, H

HO

N~ OH

~-z:-'

\r~H

HO

.••

'~O

( ,-:

~O V'~'~'

Br

b N

, H

as a

n eq

uilib

rium

m

ixtu

re o

f 4 is

omer

s;

this

isom

er s

epar

ated

(7

0% a

fter

5 re

cycl

es)

and

carr

ied

on

HO

0

OH

0'····

... ~,

Br~N \ H

(±)-

pros

urug

atox

in

1853

Sche

me

324.

Ino

ue S

ynth

esis

of (

±)-

Pro

suru

gato

xin

from

183

9

..

! ." 8- i (') ~ o ~ -0'1 --l

~ C

H,,

QJC

H,M

gIk

~

Br

~

..

Br

~

Et 2

O,7

5%

~

° O

H

1855

1) A

cCI,

AIC

I 3,

Et

CH

2CI 2

-<9 C

H3O

CH

CI 2

2)

NaB

14, M

eOH

T

iCI 4

..

3) H

2, P

dlC

, C

H2C

I 2

CH

CI3

,67%

74

%

Et

Et

C0 2

Et

~

I) P

hCH

3 /

heat

N

3

1858

2) a

qK

OH

di

oxan

e

74%

Sche

me

325.

Mac

Leo

d S

ynth

esis

of (±

)-ci

s-T

rike

ntri

n A

1859

.....

0'1

00

1) B

U3S

nH,

~

~ A

IBN

, C

6H6

... 0 OC> '" ::s

2) H

+,C

HC

I 3

~

~

3) H

2, P

dlC

, I'

l cr'

CH

CI 3

; 88%

18

56

@; '" '" E

t -aC

HO

Et0

2CC

H2N

3

I~

.. N

aOE

t,E

tOH

95

%

1857

Et

C0 2

H

60

0°

C

-0

~

N

FV

P

H

(±)-

cis-

trik

entr

in A


allylated to 1855. Generation of the benzene-type free radical resulted in cyclization to an intermediate aromatic which was dehydrated to an endocyclic olefin (not shown) and hydrogenated to produce the symmetrical cis isomer 1856. Sequential functionalization of the aromatic ring established the ethyl group and the beginnings of a pyrrole. Condensation of the aldehyde 1857 with ethyl azidoacetate gave 1858, which was thermally cyclized and saponified to the indole carboxylic acid 1859. Decarboxylation via flash vacuum pyrolysis produced racemic cis-trikentrin A.

Syntheses of both cis- and trans-trikentrin A has been described by Natsume [504] beginning from ( + )-pulegone (Scheme 326). Oxidation to the adipic acid 1860 and Dieckmann cyclization gave 1861 and 1862 as diastereomeric mixtures. Separation of 1861 and conversion to the mixture of cis and trans TMS enol ethers gave intermediate 1863. Reaction of 1863 with the pyrrole endoperoxide 1864 promoted by SnCl2 gave the ketone 1865. Carbonyl addition of the N,N-dimethylhydrazone 1866 and acidic cyclization led to a 45% yield of the correctly substituted indole 1867, still as a mixture. Saponification led to both cis- and trans-trikentrin A as the (- )-antipodes.

An interesting strategy has been reduced to practice by Kanematsu [505] in a synthesis of racemic cis-trikentrin B (Scheme 327). The racemic allenic ester 1869 was treated with cyclopentadiene to produce adduct 1870. A series of routine transformations provided allenic dienamide 1871. Intramolecular [4 + 2] cycloaddition and aromatization produced indole 1872. Oxidation to the aldehyde and olefin osmylation led to 1873. Wittig olefination gave a 2: 1 (EjZ) mixture which was carried on to cis-trikentrin B prior to separation.

5.1.3.2 Indoles Related to Aplysinopsin

Several compounds related to aplysinopsin have been isolated from Dictyoceratid and Dendroceratid sponges. Pietra has described interesting photoisomerizations [506] ,involving metabolites in this class, which precipitated straightforward syntheses of the alkaloids 1875 and 1878 (Scheme 328). Condensation of the imidazolone 1874 with indole-3-carboxaldehydes gives the Z-isomers as the exclusive products. The Z-isomers undergo photochemical isomerization to mixtures enriched in the E isomers.

x

X =H 1825 X=Br 1876

A6,~

'I

0 N 1 S02

Ph

o ~

".

1 "~

S

02Ph

7%

o O

TMS

I)H

+

0

HO~002C

MeO

H

MeO

c~

__

__

~ ..

-

2

" ••

,1. ,

2) N

aNH

2 ..••

+ _c

j:J 1)

NaO

Me

/ M

eOH

M

el

2) A

q. H

Br,

71

% ~ "."''-''

+ 18

60 hv

Oz,C

H2C

I 2

0 m

ethy

lene

blu

e .. 0

-1

-0

-63

to -

40°C

S

02Ph

1864

~I'

~

N

'. S0

2Ph

."''''

18

67

45

%

-" 18

61

(sepa

rated

and

18

62

carr

ied

on)

4 is

omer

s

0

18

63

/ SnC

l 2 ~

.. N

E

tOA

c .

1 .•••

" S

02Ph

37%

18

65

DM

E/M

eOH

aqK

OH

".~

..... , ... ,

4) L

DA

, T

IfF;

T

MS

CI

90%

L·+·N·NM~

1)

1

~

1866

P

hCH

3, E

t20

2) H

+, i

-PrO

H,

refl

ux

+

1863

(-)-

cis-

trik

entr

in A

52

%

(-)-

tran

s-tr

iken

trin

A

37%

Sch

eme

326.

Nat

sum

e S

ynth

esis

of

( -)-

cis-

and

( -

)-tr

ans-

Tri

kent

rin

A

..... c5 ~ i E::

: ~

!l>

cr' ~ C1

> '"

1) T

rCl,

NE

t3

NEt

3 Tr

O

HO

, C

H2C

1 2/9

4%

Tr

O

CH

03

~.~

, "

.. 2)

BuL

i, T

HF

C

0 2E

t 10

0%

3) B

F3"O

Et2

; N

2CH

C0 2

Et,

43%

~OT'

HC

HO

O

Tr

I)L

AH

, TH

F

i-P

"NH

~

2) P

CC

, CH

2CI 2

, 78%

C

uBr

II ..

~

. ..

diox

ane

NJ

3) p

ropa

rgyl

amin

e,

N--

./ 4

A s

ieve

s, E

t20

4)N

aH,D

ME

5)

I-B

uCO

O,

45%

HO

OH

1873

t-B

uCO

' 79

%

I)P

h 3P

=C

HC

H2C

H3

,

60%

2)

Nal

04

aqT

HF

3) D

IBA

L,

4) M

sO

NEt

3 58

%

Sch

eme

327.

Kan

emat

su S

ynth

esis

of (±

)-ci

s-T

rik

entr

in B

t-B

uCO

' 1871

MsO

MsO

C0 2

Et

1869

1) T

olue

ne

16

0°

C

74%

..

2)

chlo

rani

l

54%

3)

CSA

, MeO

H,

90%

Zn

l N

aI

DM

E

29%

0 kO

T'

.. Q

;H6,

80

°C

93%

C

0 2E

t

1870

OH

~

1)~C

:::::,..

C

H20

2 .....

N

po

'. \

:::::,..

...

CO

t-Bu

2) O

SO.4

' NM

MO

aq

dio

xane

3)

NaO

H,

1872

aq

MeO

H

60%

(±)-

cis-

Tri

kcnt

rin

B

(sep

arat

ed f

rom

a 2

: 1

(E

/Z)

mix

ture

)

~ " '" [ ~ [ ("l

o .§ o § g. .....

-.J .....


° .Me N

CHO

~ piperidine

A N NH2

xV--/ H

1874 reflux 4hr

•

x

X =H 1875 X = Br 1876

nearly quantitative

Scheme 328. Pietra Synthesis of Aplysinopsin-like compounds from Dendrophyllia sp.

5.1.3.3 Dendrodoine

The marine tunicate Dendroda grossular (Styelides) found along the North Brittany coast provides the cytotoxic metabolite dendrodoine (1879). Although incorporation of the indole unit of tryptamine is common among metabolites, the further elaboration of the· sidechain into a 1,2,4-thiadiazole moiety is rare [507]. Sainsbury's synthesis of 1879 is short and to the point (Scheme 329) [508]. Warming of indole with oxalyl chloride and copper(I) cyanide yields the acyl cyanide 1878 via corresponding acid chloride. The 1,3-dipolar cycloaddition of

~ kNyNM~ U) 'S_N

N H

(b N H

DMF

·12%

Dendrodoine 1879

(COClho CuCN, QiO CN • ~ A ,

Et20, CH3CN N

•

53% H

1878

~NyNM~ U) S-N

N H

dendrodoine 1879

Scheme 329. Sainsbury Synthesis of Dendrodoine


1878 with N,N-dimethylaminonitrile sulfide (generated in situ through the thermolysis of 5-(N,N-dimethylamino)-1,3,4-oxathiazol-2-one) provides dendrodoine in two steps and 6.4% overall yield.

5.1.3.4 Tetrahalogenoindoles

Crude extracts of the New Zealand marine alga Rhodophyllis membranacea (Harvey) exhibit strong antifungal activity. This activity is due to the presence of a variety of poly halogenated indoles [509]. Several of the 2,3,4,7-tetrahalogenated members of this class have been prepared by Somei [510] (Scheme 330). Oxidation of 4,7-dihalogenated indole 1880 with sodium chlorite in the presence of tert-butanol gives acid 1881. Decarboxylation of 1881 affords key intermediate indole 1882. Bromination with NBS yields the 3,4-dibromo compounds 1883a and 1883b, whereas chlorination with sulfuryl chloride provides the 3,4-dichloro metabolites. Sequential chlorination and bromination of 4,7-dibromoindole 1882a yields 3-chloro-2,4,7-tribromoindole (1884).

X I= X2= Cl XI = Cl, X2= Br XI= Br, X2= Cl X I= X2= Br

XI = X2= Br 1883a XI = X2= Cl 1883b

5.1.3.5 (E)-3-(6-Bromoindole-3-yl) Prop-2-enoate

1884

Bromoindole 1888 has been isolated from a sponge of the genus Iotrochota, collected off Freemantle, Western Australia. Sargent isolated, characterized and confirmed the structure of 1888 through synthesis (Scheme 331) [511]. Condensation of 4-bromo-2-nitrotoluene with N,N-dimethylformanide dimethyl acetal followed by catalytic reduction gives 6-bromoindole (1886). Formylation of 1886 and reaction of the resulting aldehyde 1887 with monomethyl malonate

I""" (co,M< BrM )

H

1888

¢1Xl

CH

O

I ~

" #

N

H

X 2 18

80

NaC

I02,

t-

BuO

H,

H20

84

%

~

~

V{

Br 18

82a

Xl

CO

OH

M

py

,20

hr,

V{

ref

lux,

75

;

x 2 18

81

~

V{

X2

1882

I NB

S,

t 63%

Xl

Br

¢:?-~ " Br

# N

H

X

2

Xj=

X2=

Br

1883

a X

j=

X2=

CI

1883

b

S~CI2

ethe

r 88

%

..

S02C

I2

ethe

r 63

%

M

V{ N

BS - 81%

Br

Cl

¢:?-~ " Br

# N

H

B

r B

r

1884

Sche

me

330.

Som

ei S

ynth

esis

of

Tet

raha

loge

noin

dole

s

Xl

Cl

¢:?-~ " Cl

# N

H

X 2

Xj=

X2=

CI

Xj=

CI,

X

2= B

r X

j=

Br,

X

2= C

I X

j= X

2= B

r

--.) "'" ~ ,.., o g ~ " p; CT

£.

S-"

'"

Carbazoles 175

r('(Me

BrMNoz

.. reflux

)):CH=CHNMez ~

I ~ ------I ....

Br NOz Raney Ni ~ Br~NI

H

fonnylation .. 95%

CHO

M Br~/ H

1887

pyr I piperidine, heat, 22 hr

62%

37% 1886

COzMe

I~( BrU )

H

1888

Scheme 331. Sargent Synthesis of an Indole from Asutralian Iotrochota

under the conditions of the Doebner reaction gives (E)-3-(6-bromoindole-3-yl)prop-2-enoate (1888) in four steps and 22% overall yield.

5.2 Carbazoles

5.2.1 Hyellazole and 6-ChlorohyeUazole

The unusual carbazole alkaloid hyellazole (1894) has been isolated from the Hawaiian blue-green alga Hyella caespitosa [512]. All four syntheses of hyellazole that have appeared involve construction of the substituted C ring onto a pre-existing indole ring system. The first of these syntheses, by Kano [513] (Scheme 332) begins with the condensation of lithio-N-(benzenesulfonyl)indole 1889 with propiophenone to yield alcohol 1890. Elimination of the alcohol and formylation of indole 1891 gives aldehyde 1892. Wittig olefination provides conjugated triene 1893 which undergoes cyclization and aromatization, upon heating in the presence of palladium on carbon. Hyellazole is obtained in five steps and 14% overall yield. The overall yield is lowered somewhat by the poor yield of the cyclization step.

Hyellazole 1894


10% NaOH,

00 I) LDA

~ EtOH, dioxane,

N 2)

I

S02Ph

1889

Oo-r N Ph H

1891

1893

.. 0 reflux, 88%

Ph~ 7 HO Ph

86% S02Ph

1890

DMF,POCI3

45 °C, 85% OSrCHO ~ r' f N

5% PdlC

xylene 150 - 200°C

21%

H Ph

1892

OCH3

'M-N Ph H

hye\lazole 1894

6-Chlorohyellazole was also synthesized in an analogous manner

Scheme 332. Kano Synthesis of Hyellazole

..

..

Takano's [514] synthesis of 1894 is initiated by the formation of enamine 1897 from 2,3-disubstituted indole 1896 (Scheme 333). Cyclization of 1897 by treatment with acetic anhydride and acetic acid affords acid 1898, after saponification. Conversion of the carboxyl group to a methoxy group requires three steps. Formation of the isocyanate by reaction with diphenylphosphoryl azide (DPPA) and addition of water yields urea 1899. Hydrolysis of the urea gives amine 1900, which is converted to the natural product by diazotization in the presence of methanol. Hyellazole is obtained in 5.5% overall yield in a total of 6 steps from indole 1897. The low overall yield can be attributed entirely to the poor yield obtained in the final step. 6-Chlorohyellazole is prepared in a similar fashion.

Sakamoto [515] begins the synthesis ofhyellazole with the Wittig reaction of 1902 with 3-methoxyindolin-3-one 1901 to give indole 1903 (Scheme 334). Conversion of 1903 to the 3-buta-l,3-dienylindole sets the stage for electrocyclic ring closure, giving a 4: 1 mixture of 1904 and 1905. Treatment of this mixture with tetrabutylammonium fluoride provides 1905 in 56% yield. Methylation of 1905 gives hyellazole in a total of five steps and 24% yield.

Moody's synthesis [516] of hyellazole is initiated by Diels-Alder reaction of ethyl 3-trimethylsilylpropynoate with indole 1907 (derived from commercially available indol-3-ylacetic acid) occurring with concomitant loss of carbon dioxide to give 1908 (Scheme 335). The resulting carbazole is reduced to 2-methylcarbazole 1909 and subjected to mercurio-desilylation yielding

1896

10%

aq.

NaO

H,

heat

, 76

% f

rom

189

7

CO

Me

EtO

CH

=( C

0 2E

t

100%

[--

.... \-

CO

HO

(CH

2hO

H,

NaO

H,

heat

, 77%

1899

Sche

me

333.

Tak

ano

Synt

hesi

s of

Hye

llazo

le

H

N ~COMe

~

C0 2

Et

=-18

97

DP

PA

, he

at, ..

CH

3CN

AC

20

- AcOH

1898

as

a m

ixtu

re o

f R

J=H

, R

2=E

t R

J= C

OM

e, R

2= E

t

N=C

=O

H20

94%

Me

NaN

Ob

H2S

0 4,

.. M

eOH

/hea

t

~ 10

%

=-

1900

hy

eUaz

ole

1894

~ if

.....

-...l

-.

..l


P~~O 0

o I'Me CQJ Qi" Ph 1902 ~" -----::..:....:.~. ~ N' H Me ...""". OMe dioxane, reflux, - v

~c 7 hr, 74% Ac OMePh

TMSI, HMDS, fI "I 0:))-....... OTMS

• 1 ~ N' , Me CH2Q2,80%

AcOMePh

1901 1903

_de_CaI_;_:_:_fl_U_X'_. [og: ]-oP.: + O::ff~ 1904 (53%) 1905 (13%)

•

hyellazole 1894

Scheme 334. Sakamoto Synthesis of Hyellazole

1907

TMS = C~El •

PhBr, reflux 62%

1908

BIl4N+F', 0 °C t aq. THF, 81%

LAH, dioxane •

reflux, 92%

AcOH

~SiMI:J

~N,L(-Me Hg(OAch

• Qj:f-= HgOAc

"V~#Me N

• aIkaline H2~

41% from 1085 H Ph

1909

• acetone, reflux

92%

Scheme 335. Moody Synthesis of Hyellazole

H Ph

1910

~OMe

~Ni(-M< H Ph

hyellazole 1894

Carbazoles 179

arylmercury compound 1910. Hydroboration-oxidation of 1910 and methylation provides hyellazole in five steps and 22% overall yield.

5.2.2 Eudistomins

A series of interesting carbazoles exhibiting diverse antiviral and antimicrobial activity (including potent activity against Herpes simplex virus type I) have been found in the Caribbean tunicate Eudistoma olivacea [517]. Many members in this family possess the simple carbazole structure shown below in which R may be pyrrole, phenylacetyl or some other structurally simple group. The benzene moiety may contain no further substitution or may hold hydroxy and/or bromide groups. The more interesting metabolites in this series resemble eudistomin L, possessing an unusual heterocyclic ring system.

Br

1911 Eudistomin L

5.2.2.1 Eudistomin A

Murakami [518J utilizes Fischer indolization as a key reaction in the preparation of eudistomidin-A (Scheme 336). The regioselectivity of the cyclization step is improved by tosylation of the free hydroxyl. Thus, treatment of 1912 with polyphosphoric acid yields indole 1913 in 41 % yield. Decarboxylation, formylation, and condensation with nitromethane provides 3-(nitrovinyl) indole 1914. Conversion of 1914 to the amide 1915 and Bischler-Napieralski reaction followed by dehydrogenation in low yield gives the tosyl-~-carboline 1916. Hydrolysis of 1916 affords eudistomin A in 10 steps and 2.0% overall yield.

Br

Eudistomin A


Br'V I --# NHz

HO

Br'V I Me # ,N=(

~ COzEt

TsO

PPA -41%

1912

2) Cu-Cr, quinoline r" ~ . z I)LAH I)H2S04,AcOH BrwNo -3)-P-O-C-13-, -D-MF---- -- ~

4) CH3NOz, 70% TsO ~ 2) hoc-pro-OH,

(EtO)zP(O)CN 63%

1) PPE

2) Mn02 11%

Br

1914

KOH,EtOH

100%

1916

Scheme 336. Murakami Synthesis of Eudistomin A

5.2.2.2 Eudistomins H, I, P

B'~

rN~COzEt TsO H

1913

Br~

Tr~)06{INH NBoc

1915

eudistomin A

Hino [519] has prepared eudistomins H and I by utilizing the Bischler

Napieralski reaction of N-(N-tert-butoxycarbonylpropyl)tryptamine 1918 to

obtain dihydro-~-carboline 1919 (Scheme 337). Dehydrogenation of 1919 with

1919

t-BuOOC

DDQ PhH

90%

~ ,COOH

GH -74%

eudistomin I 1920

Scheme 337. Hino Synthesis of Eudistomins H and I

r\-(\NH "=Z. )\(5 .,/1 74%

N 0 ,H H .' NCOOBu-t

1918

PPE

Br

NBS .. 80%

eudislomin H 1921

Carbazoles 181

DDQ provides eudistomin I (1920) in three steps and 63% overall yield. Bromination of 1920 with NBS yields eudistomin H (1921) with an overall yield of 50%. Preparation of eudistomin P requires 6-bromo-5-methoxy-tryptamine (1922) as the Bischler-Napieralski precursor (Scheme 338). This is prepared in five steps utilizing standard methodology. Reaction of 1923 with N-benzyloxycarbonyl-L-prolyl chloride followed by treatment with phosphorus oxychloride gives the eudistomin ring system 1924. Elimination of the N-benzyloxycarbonyl protecting group, dehydrogenation and demethylation provides eudistomin P in 10 steps and 7.6% overall yield.

5.2.2.3 Other Eudistomins

Rinehart [520] has synthesized six of the seventeen known eudistomins. Eudistomins H and I are prepared in an identical fashion starting with either 1-cyano-~-carboline 1926a or 6-bromo-1-cyano-~-carboline 1926b respectively (Scheme 339). Grignard addition to 1926 and sodium borohydride reduction of the intermediate imine provides amino acetal 1927. Deprotection of the acetal and cyc1ization to the imine provides isomeric eudistomin 1928. Removal and reinsertion of the double bond in its proper position gives eudistomin H 32% over five steps. Eudistomin I is obtained in a similar fashion in 20% overall yield. The synthesis of eudistomin M begins with 1-cyano-6-methoxy-~

carboline (1929) (Scheme 340). Grignard addition to the nitrile and mild hydrolysis affords ketone 1930. Formation of the pyrrole, by reaction of 1930 with ammonium acetate and acetic acid, followed by demethylation yields eudistomin M in three steps and 36% overall yield. The preparations of eudistomins N, D and 0 are outlined in Scheme 341. Eudistomin N can be prepared in one step from ~-carboline by treatment with bromine in THF. In similar fashion, bromination of 6-methoxy-~-carboline and demethylation with BBr3 gives eudistomin D in 54% yield. The synthesis of eudistomin 0 requires a more circuitous route. In four steps, 4-amino-2-nitrotoluene is converted to 6-bromoindole 1932. Alkylation with aziridinium tetrafluoroborate gives amine 1933 which is converted to eudistomin 0 by glyoxylation and dehydrogenation. The natural product is obtained in eight steps and 7.2% overall yield.

Eudistomin I along with eudistomin T have been prepared by Cardellina [521] as shown in Scheme 342. Acylation of N-protected indole isonitrile 1934 with phenylacetyl chloride followed by treatment with silver tetrafluoroborate affords dihydro-~-carboline 1935 in 92% yield. Treatment of 1935 with elemental sulfur at 200 °C for four minutes results in deprotection and dehydration to give eudistomin T. Eudistomin I is prepared by modification of this procedure in 12% yield.

Wasserman [522] utilizes a flexible synthetic strategy that provides eudistomins T and I, along with the methyl ether of eudistomin M (Scheme 343). The key transformation in these syntheses is the condensation of the 1,2,3-tricarbonyl component 1937 with tryptamine 1938 in the presence of trifluoro-

HO

~

~)

~H

N

C0 2

Me

H

1) H

3P0

4

2) A

C20

, py

72

%

MeO

ACO~

U)--.

f'<Xl

"'O

Ac

1) K

2C03

, M

eOH

M

el,

96%

2) N

BS

HO

Ac

96%

MeO

MeO

~

Br~ ).

..-~

N

'C

02M

e A

c

1922

KO

H,E

tOH

,

-t>-D

1) c

!0C

l

NC

0 2B

n

.. B

r _

_ ~NH

refl

ux,

62%

N

2

AIC

I 3, M

eN0 2

55%

MeO

Br

Sche

me

338.

Hin

o Sy

nthe

sis

of E

udis

tom

in P

2) P

OC

I 3

H

75%

1923

MeO

NBS

-B

r 70

%

., B

r

1924

HO

BB

r3

-B

r 64

%

eudi

stom

in P

.- 00

N

~ 8' g s::: I ~

R~N

~Nk~

H

1926

a R

=H

b

R=

Sr

H3S

eNM

e 3

AcO

H,T

HF

I)Br

Mg~:

) T

HF

,O°C

2) NaB~, M

eOH

R

a R

= H

(75

%)

b R

= S

r(62

%)

R

1927

a R

= H

(78

%)

b R

= S

r (7

9%)

1) N

aOC

I

2)Na2C~

R

aq.H

Cl0

4

TH

F

R

1928

a R

= H

(74

%)

b R

= S

r (5

0%)

R=

H

eudi

stom

in I

19

20 (

75%

) R

= S

r eu

dist

omin

H

1921

(8

0%)

Sche

me

339.

Rin

ehar

t Sy

nthe

sis

of E

udis

tom

ins

H a

nd I

I .....

00

w


MeO

I) BrMg..,.,-<:) THF, 0 °C

•

MeO

reflux, 72%

NH

~

Scheme 340. Rinehart Synthesis of Eudistornin M

~OAc,AcOH, .. reflux, 67%

HO

..

eudistomin M

acetic acid. Condensation at the central carbonyl to form the imine, PictetSpengler cyclization, and subsequent decarboxylation affords dihydro-~-carboline 1939. D«hydrogenation of 1939a affords eudistomin T (1940a) (four steps and 40% overall yield), while dehydrogenation of 1939b and reaction with hydrazine gives eudistomin I (five steps and 44% overall yield). Conversion of 1940c to eudistomin M methyl ether requires reduction, Swern oxidation to form the y-ketoaldehyde, and treatment with ammonia to form the pyrrole 1941. Demethylation to give the natural product has already been reported. Methyl ether 1941 is obtained in 7 steps and 32% overall yield.

Eudistomins T and S have been prepared by Still [523] from tryptamine 1943a and 5-bromotryptamine 1943b, respectively (Scheme 344). Pictet-Spengler cycIization of 1943 with glyoxylic acid and esterification gives 1944. Aromatization of 1944 by heating with elemental sulfur and addition of benzylmagnesium chloride in the presence of lithium chloride provides the eudistomins in 4 steps. Eudistomins T and S are obtained in 39% and 25% yields, respectively.

Nakagawa's [524] strategy for the preparation of (- )-eudistomin Land ( - )-debromoeudistomin L is outlined in Scheme 345. By careful control of reaction conditions optically active nitrone 1946 can be cyclized to either the normal Pictet-Spengler product 1947 or to the tetracyclic adduct 1948. Thus, cyclization of optically active nitrone 1946 with trifluoroacetic acid at low temperatures provides Pictet-Spengler product tetrahydro-~-carboline 1947 with high diastereoselectivity. Oxidation of 1947 with NCS yields the oxathiazepine 1948 in poor yield. Deprotection of 1948 gives ( - )-debromoeudistomin L in four steps and 6.1 % overall yield. Cyclization of 1949 at room temperature for five minutes gives tetracyclic hydroxylamine 1950 in 70% yield, along with 21 %

~

~~N

N

H

Brl>

TH

F,

78%

Br

Br~

V~N

N

H

eudi

stom

in N

M<O'Q

-CN B

r2, A

cOH

,

71%

w.D'O-

c N H

OW

: ~ _

__

__

__

__

_ ~~_

1 ~

N

refl

ux,

90%

.--

::;

~ ~

BB

r3,

(CH

2Cl h

,

N

H

N

H

N

H

eudi

stom

in D

~Me

H2N~ N0

2

1) N

aN02

, H

Br,

-1

°C

2) C

uBr,

70

°C

, 88

%

~Me

Br~

1)

HC({»

)3 B

r-lli

11

0°

C

2) T

iCI 3

, H

20,

63%

H2 N+

L.

:::,.

, BF

4

100

°C, 4

3%

-Q-(

'NH

2 B

r .--

::;

N

H

1933

1) H

CO

CO

OH

, pH

4-5

2) H

+, r

eflu

x, 7

5%

N0

2

0-{

'NH

Br~

)\-.

Jl

N

H

Sche

me

341.

Rin

ehar

t Sy

nthe

sis

of E

udis

tom

ins

N,

D a

nd 0

Ph2S

e(O

CO

CF 3

h

40%

N

H

1932

~N

Br~ )-

Jl

N

H

eudi

stom

in 0

~ ~ o if .....

00

V

l

vrC

l

Q)N

C

1) I

"=:: ~

°

':?W

N

..

I 2)

AgB

F 4, -

20

°C

N

~

CH

302C

92

%

I

CH

,O?C

°

19

34

1935

°

Q)N

C

1)O:

::N~

Cl

°

.. N

N

I

2) A

gBF4

, -2

0°

C

I C

H30

2C

52%

C

H30

2C

°

Sche

me

342.

Car

dell

ina

Synt

hesi

s of

Eud

isto

min

s I

and

T

S8

200

°C

73%

°

eu

dist

omin

T

1921

1) S

8, 2

00 °

C

2)H

2NN

H2,

M

eOH

,23%

" '\

eudi

stom

in I

-00 0'1 ~ g s:::

(1) g. o ~ en

0

o 0

0 0 R

OJ

0 rO

t-Bu

R)lC

l Go

! -

NH

2 T

FA,

PhH

P

(Phh

..

RY

Ot-

Bu

-R

YO

t-B

u +

~

J \

.. Ph

H

12 h

r P

(Phh

0

N

H

a R

=CH

2C6H

S a

94%

19

37a

64%

19

38a

R'=

H

b R

= (C

H2h

NPh

th

b 96

%

b 78

%

c R

= (C

H2h

C02

Et

c 96

%

c 84

%

b R

'= O

Me

R~

R' [OJ~

NH

2NH

2 N

..

.,N

-

N..

.,N

E

tOH

,PhH

H

H

86

%

o R

o

R

1939

a 76

%

1940

a eu

dist

omin

T

88%

b

82%

b

83%

19

21

eudi

stom

in I

1940

c L

AH

, TH

F •

78%

c 84

%

c 88

%

Meo~

-~

OA

c A

cOH

~

J N

\ ...,

N

2) N

14 8

1 %

1) S

wer

n [0

], 8

4%

H

OH

( CH

2hC

H2

HO

Sche

me

343.

Was

serm

an S

ynth

esis

of

Eud

isto

min

T,

I an

d M

MeO

H

O

-----------~

1941

eu

disl

Om

in M

19

42

(j a. ~ o if .....

00

-.

J


1943a R= H b R=Br

a R=H (92%) b R= Br (96%)

1) H~CCHO Rt):Q, 2) MeOH, HCI:--= N ~ NH

heat

S8, xylene,

heat

R

BnMgCl, .. LiCI, ether

H COzMe

1944a R= H (71%) b R= Br (65%)

R= H eudistomin T (59%) R= Br eudistomin S (40%)

Scheme 344. Still Synthesis of Eudistomins S and T

..

of the normal Pictet-Spengler product. Acylation, bromination and deacylation of 1950 provides the brominated heterocycle 1951. Rearrangement of 1951 with trifluoroacetic acid gives the Pictet-Spengler product 1952, which is converted to ( - )-eudistomin L in poor yield. The natural product is obtained in 0.69% yield over 6 steps.

Still has prepared the N(10)-acetyl derivative of eudistomin L, but unfortunately was unable to remove the acetyl protecting group to obtain the natural product (Scheme 346). Bromoindole 1953 is converted to hydroxylamine 1955 via nitroolefin 1954 in four steps. Coupling of 1955 with aldehyde 1956 (prepared as shown in the upper half of the scheme) yields nitrone 1957. Treatment of 1957 with trifluoroacetic acid gives the Pictet-Spengler product 1958. Cyclization of 1958 occurs via a sila-Pummerer reaction of the diastereomeric mixture of sulfoxides obtained upon treatment of 1958 with MCPBA. N(10)-acetyleudistomin L is obtained in eight steps and 1.9% overall yield.

5.2.3 Manzamine C

Manzamine C is a novel ~-carboline alkaloid bearing an azacycloundecene ring. It is the simplest member of the manzamine family and has been'isolated from an Okinawan sponge [525]. Manzamine C exhibits potent antitumor activity. Hino's synthesis [526] of 1963 is shown in Scheme 347. The azacycloundecenyl portion (1961) is prepared via Lindlar reduction of alkyne 1960 and cyclization of the ditosylate to give 1961 in 28% overall yield. Acylation of tryptamine followed by Bischler-Napieralski cyclization leads to substituted ~-carboline

Q)N

HO

H

N

OHC

BOCH

N~SM

e 90

%

Q)f-a

1FA

~:8 °C

N

~SMe

SMe

H

HB

ocH

N

1946

NC

S,C

C4,

1F

A,

I

8%

lRA

-400

, 94

%

S

Boc

HN

1948

,OH

"'--

I'ii

-a

1FA

, CH

2Cl2

V)

~~H

25

°C

N

~SMe

HB

ocH

N

70%

~

~ k

N,

SMe

N

::. ,

H

H

Boc

1949

19

50

O-d

eace

tyla

tion

Br~'OH

V "

~"H

.-

. .

N

SMe

N

:. ~

H

H

Boc

75

% (

3 st

eps)

Br

1FA

33%

1951

19

52

Boc

HN

1947

N-

" ...

H

H.)

....

. __

S

H2N

(-)-

debr

omoe

udis

tom

in L

1) a

cety

latio

n I

2) N

BS,

rt

SMe

, OA

c

Br

iN.:..

~sMe

~k~,

NC

S

4%

Br

N

if B

oc

H

S

H2N

(-)-

eudi

stom

in

L

Sche

me

345.

Nak

agaw

a Sy

nthe

sis

of (-

)-E

udis

tom

in L

and

(-

)-D

ebro

moe

udis

tom

in L

f .....

00

\0

o

Me

OY

SH

NH

2

"''Q

) .-

-::;

~

N

H

1953

Zn,

NH

4Cl ..

80 -

85%

TF

A - 24%

1) N

aHC

0 3, H

20,

CH

2Cl2

> 65

%

2) C

lCH

2TM

S,

K2C

03,7

5%

1) P

OC

l 3

DM

F

95%

o

Me

OY

S/'

-.T

MS

NH

2

1) A

C20

, E

t3N

2) D

ibal

45

%

85%

o

HyS

/'-

.T

MS

NH

CO

Me

, N

aB

Rt,'

.. 2)

NR

tOA

c, M

eN0 2

", "'

'0-(

: ~NO

.. ¥

~N02

.--::;

N

2

TH

F, 8

0%

.--::;

N

70

%

Br~

U ~

.. ~,NH

.--::;

N

H

O

H

1955

Br

1958

H

1954

o H

YS

""T

MS

NH

CO

Me

1956

H

MgS

04' C

H2C

1 2

Br'O

-(:

¥ '~

~-O

.--:

; ~ /

'-. T

MS

N

S

H

H

1) M

CP

BA

70

%

2) 0

.02

M i

n M

eCN

23

-8

0°

C (0

.5 h

r)

80

°C

, 1

hr

17 -

20%

Br

NH

Ac

1957

AcH

N

S

N(1

0)-

Ace

tyle

ud

isto

min

L

Sche

me

346.

Stil

l Sy

nthe

sis

of N

(lO

)-A

cety

leud

isto

min

L

.. \0

o ~ i ~

C1> g. o s: C1> '"

OTB

S

u~

~

alky

latio

n I)

H2

Lin

dlar

w

ith

.. 2)

TSN

H,

~

TB

AI

PhH

1960

3)

Red

-AI

I

Qf'"

";,

N=

( 98

%

O:S:tN

-H ~

'-C

OzE

t

1) P

OC

I 3

2) P

d/C

49%

H

0

CO

zEt 1)

am

ine

1961

Ph

CH

3 re

flux

2)L

iAll

4

34%

Sche

me

347.

Hin

o S

ynth

esis

of

Man

zam

ine

C

~'

--N

..

&

,

N

H

""""

"'""

C

, •

• , 0

H o

1961

28

% o

vera

ll

O:f

{ ~

CO-z

Et

1962

f . \0

.-


Manzamine C 1963 o 1962. Coupling of 1962 with amine 1961 provides manzamine C in six steps and 16% overall yield.

5.3 Pyridines

5.3.1 Navenone A

Huang's synthesis [527] of navenone A is shown in Scheme 348. Due to a variety of complications involved in the use of normal phosphonium salts in the preparation of conjugated E-polyenes, triphenylarsonium salts were used in the preparation of navenone A. Reaction of triphenylarsonium salt 1965 with 3-pyridinecarboxaldehyde in the presence of potassium carbonate and a trace of

o

Navenone A 1967

r"YCHO

~.J N

+ _ 1) K2C03, 25°C, 12 hr + Ph3As~CHO Br __ E_t2_O_'_THF __ '_H_2_O __ ..

1965 2) 12, CH2C12, 82%

~CHO

~_J N

1964 1966

o

• 2) 12

56% navenone A 1967

Scheme 348. Huang Synthesis of Navenone A

Pyridines 193

water gives a mixture of isomers, treatment of which with iodine in sunlight gives the (E,E)-isomer 1966 in 82% yield. Repeating this sequence with the triphenylarsonium bromide prepared from 5-bromo-3-penten-2-one gives navenone (1967) in four steps and 46% overall yield.

5.3.2 Pulo'upone

Pulo'upone (1976) is a minor metabolite of the Hawaiian opisthobranch mollusk Philinopsis speciosa. It is an uncommon pyridine derivative substituted at C2 by a bicyclic C16-polyketide. The natural product most closely related to 1976 is navenone A (1967) (Scheme 348). As only small quantities of Pulo'upone could be isolated, biological testing was not possible [528]. Pulo'upone has been synthesized by three different groups. In all three cases, the general strategy utilized involves formation of the hydrindene nucleus followed by addition of the pyridine moiety.

Pulo'upone 1976

Burke has prepared Pulo'upone beginning with aldehyde 1969 (Scheme 349) [529]. Homologation of 1970 gives diene 1971 in four steps and 56% yield. Reduction of diene 1971 gives 1972a and 1972b in 69% and 29% yields respectively. Separation and conversion of each to lactone 1973 proceeds with a combined yield of 88%. In the key transformation, formation of the trimethylsilyl ketene acetal of 1973 followed by heating gives hydrindene 1974 via a retro hetero Diels-Alder-intramolecular Diels-Alder pathway. Hydrindene 1974 is obtained as a 4.2: 1 mixture of diastereomers, reflecting the endo and exo cycloaddition modes. The synthesis is completed by transformation of the carboxyl to secondary alcohol 1975 and homologation of the vinyl iodide to give the pendant pyridyl moiety. Pulo'upone (1976) is obtained in 14 steps and 14% overall yield.

Oppo1zer's approach [530] to (- )-Pulo'upone involves a bomane-10,2-sultam-directed, Lewis acid-accelerated, intramolecular Diels-Alder reaction (1981 -. 1982) as the key transformation (Scheme 350). Homologation of aldehyde 1977 provides acetate 1978 with the needed (E,E) geometry. Further

C0

2iPr

C

02i

Pr j:o 1)

NaH

/ TI

-lF~

I 1)

Jon

es [

0]

.. °

')

) 2)

/HO

2) (

CO

CI)

z, P

hH

3) M

eP(O

)(?M

eh

0"

OH

C

n-B

uLl

p 1

96

9

1) N

aOH

aq

TI-

lF /

MeO

H

2) P

h 3P,

DE

AD

Ph

Me3

63

%

(for

19

72

a)

or

1) N

aOH

aq

TI-

lF /

MeO

H

2) c

arbo

diim

ide

DM

AP

/ C

HzC

l z,

88%

(f

or 1

97

2b

)

I 62

%

(OM

e)2

19

70

H

Ow

19~'

1 91

%

1) L

HM

DS

/ TM

SCI

2) x

ylen

e; 1

40°C

, 12

hr

1975

Sche

me

349.

Bur

ke S

ynth

esis

of

Rac

emic

Pul

o'up

one

(197

6)

.#

°

1971

H

19

74

71

%

4.2

: I

mix

ture

wit

h 2,

3-di

-epi

iso

mer

1) ~"'

" N

.& Z C

uCN

Li 2

T

HF

, -7

8 °C

2) (

CO

CI)

z, D

MS

O

Et3

N

71 %

(ov

eral

l)

NaB

I-L!,

CeC

I 3

I"",~

MeO

H,2

5°

C

/"

98%

1972

a, X

= O

H,

Y=

H

(69%

) 19

72b,

X=

H,

Y=

OH

(2

9%)

1) i

-Bu2

AIH

, PhM

e

2) (

CO

Clh

, DM

SO

E

I3N

3)

MeM

gBr,

E

lzO

I~

N

72%

(±)-

pulo

'upo

ne

19

76

.......

1.0

.j:>.

Z -.., 0 ~ ::s ~

~

s:o

cr" S.

::;.' " en

Pyridines 195

homologation, by cuprate-assisted displacement of the acetate with Grignard reagent 1979 and addition of chiral acylphosphonate 1980 provides sultam 1981 and gives the required (E)-geometry about the newly formed double bond. Addition of the mild Lewis acid Me2AICI affords the endo-cycloaddition product in 71 % yield and 93% d.e. The diastereomeric excess is raised to 100% by recrystallization. Desilylation and intramolecular displacement of the sultam provides lactone 1983 which is ring-opened and converted to nitrile 1984. Reduction of the nitrile and Wittig olefination leads to acetate 1985 which in turn provides the natural product 1976 upon displacement with lithium di-(2-pyridyl)cuprate. Pulo'upone is obtained in 2.6% yield over 20 steps.

Takano [531] utilizes an approach to (- )-pulo'upone (Scheme 351) that is very close to that of Oppolzer (Scheme 350). The key step is the preparation of the trans-hydrindene nucleus from chiral trienimide 1991 by Evans's asymmetric Diels-Alder reaction [532]. Treatment of the aldehyde derived from 1987 with lithio triethyl4-phosphonocrotonate gives diene ester 1988 with (E,E)-geometry. Homologation of 1988 by cuprate displacement and addition of methyl diisopropylphosphonoacetate to the deprotected aldehyde from 1989 gives triene acid 1990. Addition of 3-lithio-(S)-( + )-oxazolidinone, available from (S)phenylalanine, to the acid chloride of 1990 gives chiral triene 1991. Treatment of 1991 with 1.3 equivalents of Me2AICI gives the trans-hydrindene 1992 in 57% yield. Removal of the chiral auxiliary by the normal methods was unsuccessful due to steric crowding. However, oxidative removal of the p-anisyl group with ceric ammonium nitrate and intramolecular displacement of the chiral auxiliary affords lactone 1993, which is transformed into aldehyde 1994. The synthesis is completed with a lack of diastereoselectivity in the final Wittig reaction to give ( - )pulo'upone in 11 % yield along with 34 % of the undesired cis-isomer. Pulo'upone (1976) is obtained in 0.16% yield over 18 steps.

5.3.3 Ascididemin

The pentacyclic alkaloid ascididemin (1999) is isolated in low yield from a Didemnum sp. of an Okinawan tunicate. It is of interest due to its antileukemic properties [533]. The only synthesis of 1999 to-date is that of Bracher [534], outlined in Scheme 352. Dichromate oxidation of quinoline 1995 gives quinone 1996 which is converted to tetracyclic quinone 1997 via regioselective oxidative amination with o-aminoacetophenone. Reaction of 1997 with dimethylform-

o

Ascididemin 1999

TBSO~H

o

(EtO)20P~ C

OO

Et

1977

TBSO~I ~OAC

1978

O~

TBSO~

~5&N

: S

02

TB

SO

~

~ H

1982

47

% o C )--

-/' Mg

Bt

o 19

79

Li z

CuC

I 4

62%

k N

-./' p

(OE

" ~ n

il

S02

0

0 19

80

DB

U, L

iCl,

MeC

N

89%

I) B

F 3·E

t zO

, C

HzC

l z

2) L

iH,

DM

F

89%

TBSO~I ~COO

Et

(0

TBSO

~

~

TB

SO

19

81

%

H 19

83

I) D

ibal

hex

ane/

Etz

O

2) A

C20

, py

r

94

%

I) H

CI

aq a

ceto

ne ..

2) T

BS

CI,

NE

t3

63%

Mez

AIC

l, C

HzC

l z

-20°

C, 8

0 hr

63%

I) M

eLi

/ E

tzO

, -7

8 °C

, 30

min

2) T

sCI,

pyr

80%

-1.0 0\ ~ 8 g ~ " g. o ::::: ~

T~O~ ...

.-...M

e X; _

"U

>

H

OA

c

19

85

1) N

aI,

acet

one

2) n

-Bu4

N+C

N

CH

2C1 2

80%

NC ~

Me

~

~~

H

1) l)-

.::: CuL

i I

2 ~

2) S

wer

n [0

]

81%

1984

Sche

me

350.

Opp

olze

r Sy

nthe

sis

of (-

)-P

ulo'

upon

e

1) D

ibal

/ E

t20

75%

2) P

h3P=

CH

C02

Me

3) D

ibal

4)

AC

20

/py

r

79%

(-)-

pulo

'upo

ne

1976

~

::I. r- ......

\0

.....:a

ArO

A

rO

ArO

A

rO

(0

\ I)

TsO

H /

MeO

H ~

I)D

;OO

IlE

"O

~OA'

O~

\2=>

.-.-

MgB

r 2)

PC

C /

CH

zClz

1

2) A

czO

/ py

r .-

1,&

O

TH

P 3)

(MeO

)zPO

,&

L

i zC

uCl 4

-~COEt

C0

2Et

97%

3

0°

C /

2 hr

1987

2

1988

74

%

1989

A

r =

p-an

isyl

T

HF

44%

A

rO

ArO

A

rO

I) H

OA

c

~ ~

\(b

aqT

HF

I)

(C

OC

I)z

/ P

hCH

3 M

ezA

1C1

.-.-

... 2)

(iP

rOlz

· p"'

;'" C

O M

e 1,

&

2) ol~

CH

zCl z

\I

2

1,&

-3

0°

C /

5 hr

0

~

~ I

Ph

1991

57

%

19

90

L

i H

T

HF

/ -2

0°

C /

5 hr

ol~

3) a

q N

aOH

/ M

eOH

T

HF

/ -7

8°

C

19

92

42%

62

%

r(~

+ Ph

Q

=

N

N":

I) C

AN

aq

CH

3CN

2) 1

equ

iv n

-BuL

i T

HF

0 °

C /1

hr C&

I) D

ibal

/T

HF

.-2)

MeL

i T

HF

/E

tzO

3)

PC

C

OHC'l(

b ~

~

~.....: _

fPh3

TH

F /

0 °C

/ 5

hr

45%

72

%

H

H

1993

42

%

1994

(-

)-pu

lo'u

pone

1

97

6

H

as a

I :

3

tran

s/ci

s ix

ture

Sch

eme

351.

Tak

ano

Syn

thes

is o

f { -

)-P

ulo'

upon

e (1

976)

.....

\0

00

~ ... o g a:::

~ ~

o ;:r- '" '"

ex? Cr20 7"2

~N ,;

OH

1995

o

0

• ex> 0

1996

HOAc reflux I 10 min

94%

•

+

Nl4C1 I HOAc

reflux 11 hr

59%

Pyridines 199

~ CeC13 • 7 H20

o I,; .. EtOH I air 120 °C

78%

o

DMF/120 °C

1997

o

•

NM~

1998

ascididemin 1999

Scheme 352. Bracher Synthesis of Ascididemin

amide diethyl acetal yields enamine 1998 which is cyclized directly to ascididemin (1999) by treatment with ammonium chloride in reftuxing acetic acid. Ascididemin is obtained in four steps, from quinone 1996 in 43% overall yield.

5.3.4 Aaptamine and Demethyloxyaaptamine

The aqueous ethanol extracts of the Okinawan sponge Aaptos aaptos yield an unusual heterocycle given the name aaptamine (2006). This bright yellow compound is the first example of the 1H-benzo[de]-1,6-naphthyridine ring system. Also isolated from the ethanolic extracts of A. aaptos, is the related

MeO:s9" "I N MeO

HN",

Meoxa~ I N o ~

I N '"

Aaptamine 2006 Demethyloxyaaptamine 2009

•


demethyloxyaaptamine (2009). Aaptamine exhibits IX-adrenoceptor blocking activity, while demethyloxyaaptamine possesses antitumor and antimicrobial activity [535].

The first reported synthesis of aaptamine (2006) is that of Cava [536] in 1985 (Scheme 353). Selective nitration of dihydroisoquinoline 2001 provides compound 2002. Heating 2002 with the monoethyl ester of malonic acid followed by re-methylation of the free hydroxyl gives ester 2003, which can be converted to lactam 2004 by hydrogenation under acidic conditions. Removal of the amide carbonyl and dehydrogenation gives aaptamine in 38% yield along with 45% of imine 2005. Isolation of aaptamine as its hydrochloride gives an overall yield of 12% in eight steps. The saIl)e synthetic strategy is also used for the preparation of demethyloxyaaptamine (2009) (Scheme 354). Instead of methylating the free hydroxyl group before cyclization, nitro compound 2007 is reduced and cyclized under acidic conditions and then doubly protected to give lactam 2008. Removal of the amide carbonyl and dehydrogenation with concomitant debenzylation gives demethyloxyaaptamine (2009) in a total of nine steps and 5.2% overall yield.

Kelly's synthesis [537] of aaptamine (Scheme 355) begins with the ortholithiation of veratrole and treatment with trimethylsilylmethyl azide to afford amine 2011. Conjugate addition of 2011 to methyl propiolate followed by thermal cyclization gives quinolone 2012. Chlorination of 2012 and reaction with aminoacetaldehyde dimethylacetal affords compound 2013. Although the original synthetic strategy was based on inducing 2013 to undergo an intramolecular Pomeranz-Fritsch type reaction, this proved not to be viable. Treatment of 2013 with a mixture of chlorosulfonic acid and antimony pentatluoride produces a 1: 1 mixture of aaptamine and pyrrole derivative 2014. Aaptamine is obtained in 8.5% yield over five steps.

The synthesis of aaptamine by Yamanaka [538] is iterative in nature. It begins with the conversion of aldehyde 2015 to nitrile 2016 (Scheme 356). Palladium-catalyzed coupling of trimethylsilylacetylene with 2016 gives acetylene 2017 which is converted to chloroisoquinoline 2018 in four steps. A second palladium-catalyzed coupling with trimethylsilylacetylene followed by cyclization gives aaptamine as its hydrochloride in four steps. Aaptamine is obtained in 6.6% yield over 12 steps.

Tollari's synthesis [539] of aaptamine involves intramolecular cyclization of a 1-vinylnitrene isoquinoline to obtain 2006 very quickly. Condensation of nitromethane with aldehyde 2020 and elimination gives vinyl nitro compound 2021 in 85% yield (Scheme 357). Treatment of 2021 with retluxing triethylphosphite gives aaptamine (2006) in 49% yield over 2 steps. The intermediate nitrene is presumably obtained as a mixture of E/Z isomers that undergo thermal isomerization before cyclization. Conjugation of the nitrene reduces the amount of rearrangement products.

Most recently, Raphael [540] has prepared aaptamine (2006) as shown in Scheme 358. Conversion of nitro aldehyde 2022 to silyl protected cyanohydrin 2023 followed by reduction gives amine 2024. Condensation of 2024 with

Meo~

Meo~N

48%

HB

r,..

Meo

Y'(

l 9

5°

C,6

7%

HO~N

20

01

40%

HN

O),

• N

aNO

b 0

°C,

60%

Meo~1

~

"",N

HO

N

0 2

2002

1) H~CCH2C~Et

120

°C, 7

4%

2) C

H2N

2> E

t20,

C

H2C

I 2,9

5%

Meo

w

10%

Pd/

C, H

2

~ I

N

H

AcO

H,7

7% .

. Me

O N

02

CO

OE

t

Meo

=ss

~ I

N

H

MeO

HN

B2H

6, T

IIF,

refl

ux,

95%

• Me

°tr~

I

NH

Me

O H

N

2003

1) 5

% P

d/C

, xy

lene

M~:s:9

re

flux

~ I

N

H

+

• 2)

HC

I Me

O N~

2005

(45

%)

Sche

me

353.

Cav

a Sy

nthe

sis

of A

apta

min

e

o 20

04

M~~

I N

Me

O ~

"'" H

N#

aapt

amin

e 20

06

(38%

, se

para

ted)

HC

I -Me°tr~

~ I

""

,NH

Cl

MeO

HN

#

~

::1. e: ~ '" ~ -

Meo

w ~

I NH

A

cOH

, 10

0%

HO

N02

C

OO

Et

2007

5% P

dlC

, H2

Me0V

' I

NH

~

HO

HN

°

1) B

OC

20, C

HC

l 3,

refl

ux,

88%

2)

BnB

r, K

2C0

3,

acet

one,

ref

lux,

86%

MeO M~-'_BOC

2008~Y

°

TF

A,H

20

,

25

°C

,96

%

Me0V

' I

NH

~

RnO

HN

B2!f

t" T

HF

, .. 25

°C

, 69%

Meo

w I N

H

~

RnO

HN

5% P

dlC

, xy

lene

, .. re

flux

, 35

%

Me0))9~

I ,&

N

°

I N

#

°

dem

ethy

loxy

aapt

amin

e 20

09

Sche

me

354.

Cav

a Sy

nthe

sis

of D

emet

hylo

xyaa

ptam

ine

s ~ 8 g f a' §: 1i

~

Me

oA

.(

MeO

n-B

uLi

Me3

SiC

H2N

3

78

%

I •

V I)

=

C0 2

Me

MeO

#

-N

H2

2) (

Ph

hO

he

at

MeO

7

2%

2011

........

....

HN

C

H(O

Mej

z

°

M

Meoy~)

MeO

H

2012

~

CF3S~H

, M

eo

Y N

)

Sb

Fs,

TF

A f/1

' I ~ ~

MeO

#

-N

""'"

+ M

eO

MeO

M

eO

MeO

I) P

OC

I 3

86%

2) H

2NC

H2C

H(O

Me)

z

52%

2013

20

14

33

%

34

%

aapt

arni

ne

2006

Sche

me

355.

Kel

ly S

ynth

esis

of

Aap

tam

ine

~

::I.

Q..

~.

'" ~

VJ

HOX;(

M

el

~vB'

MeO

I

# C

RO

K2C

03

1)H

2NO

H M~vB'

.. ..

88%

M

eO

# C

RO

2)

AC

20

MeO

#

CN

96

%

N0 2

N

02

N0

2

2015

20

16

~WO'"

H2~'

M~~O"

N~

I ..

I #

OM

e O

Me

67%

M

eO

# C

N

Na2

C03

,75%

M

eO

CO

NR

2

N0

2 N

02

I~ M

eO

MeO

TM

S

1) N

aOM

e, 6

3%

PdC

l 2 •

(Ph 3

Ph

85%

MeO

2)

H2,

.Pdl

C, 9

4%

N0

2 III T

MS

Sche

me

356.

Yam

anak

a S

ynth

esis

of

Aap

tam

ine

MeO

OM

e

/T

MS

1!P

M~~

.. Pd

C1 2

• (

Ph 3

Ph

M

eO

# C

N

83%

N

02

2017

1) T

sOH

90%

I

N

M~W

.. 2)

PO

Cl 3

92

%

MeO

#

6

HO

- 45%

N0

2 C

l

2018

I #

6N

H

O

MeO

Me

ow

,,<

::::

::

HN

#

aapt

amin

e 2

00

6

(hyd

roch

lori

de s

alt)

tv

TMS

0 .j:

>.

~

::t

0 OCI

Cl> = a:: ~ Pl c:r

0 ~

c;;

en

I N Meox:Q~ MeO ~ .& Et2NH, 1 hr

eRO

2020

Meo:g:~ I N MeO ~ .&

°2N OR

Pyridines 205

AC20, py, .,

o °C, 14 hr 85%

Me07"~ I N MeO ~ .&

?'

N02

(EtOhP, heat, ., 150 min, 58%

Meow~ I N MeO ~ .&

,N # R

aaptamine 2006 2021

Scheme 357. Tollari Synthesis of Aaptamine

MeO

~:& 02N ~ I eRO

2022

MeO

Meo~ ~ I OTBS

H2N

CN 2024

MeO

TBSCl,KCN, ., ZnI2, CH3CN,

83%

CH(OCH3)3, reflux, 92%

.,

MeO

MeO

M~~ ~ I OTBS 02N

eN 2023

OMe

°XhM17 ~ I OTBS

HN ,

~O eN

0=\+ 2025

Me0t6 HN ~ I OTBS

~ eN o

Raney Ni, .,

H2,91%

Meo~ HN ~ I OTBS

~ 0 NH

TsOH HMDS ..

sonication 51%

2

2026

Scheme 358. Raphael Synthesis of Aaptamine

Raney Ni ., Hz, 95%

Ph20, reflux .. 88%

MeO

Me6)0 HN ~. I -HCl

~ ::,.. I N

aaptamine 2006 (hydrochloride salt)


trimethyl ortho formate and Meldrum's acid affords enamide 2025 which cyclizes to the quinolone 2026 upon heating. Reduction of the nitrile 2026 and intramolecular condensation gives aaptamine2006. Isolation of aaptamine as its hydrochloride provides the natural product in six steps and 30% overall yield.

5.3.5 Amphimedine

In 1983 Schmitz reported the isolation of the pentacyclic alkaloid amphimedine (2033) from an Amphimedon sp. sponge found near Guam island [541]. Amphimedine exhibits general cytotoxicity and is distantly related to the mimosamycin-type family of antibiotics [542].

Amphimedine 2033

Kubo [543] utilizes a non-regioselective approach to prepare amphimedine, as shown in Scheme 359. Condensation of 2,5-dimethoxyaniline (2028) with ~ketoester 2029 affords amide 2030. Cyclization of 2030 followed by chlorination of the resulting 2-quinolone gives 2-chloroquinoline 2031. Oxidative demethylation of 2031 with eeric ammonium nitrate and a non-selective Diels-Alder reaction with 2-aza-1,3-bis(tert-butyldimethylsilyloxy)-1,3-butadiene leads to 7% of the desired adduct 2032, along with 8% of the other regioisomer. Hydrogenation of 2032 occurs with cyclization and loss of chloride to give amphimedine (2033) in seven steps and 0.25% overall yield.

A somewhat similar approach is followed by Stille [544] in the preparation of 2033 (Scheme 360). Conversion of 4-quinolone 2034 to triflate 2035 followed by palladium-catalyzed cross-coupling with organostannane 2036 provides quinoline 2037. Exchange of protecting groups to give 2038 and monodemethylation gives 2039. Bromination of 2039 and oxidative demethylation with ceric ammonium nitrate yields bromoquinone 2040. The presence of the bromine solves the problem of regioselectivity. Diels-Alder cycloaddition of 2040 with azadiene 2041 gives a 48% yield of quinone 2042 as the only regioisomer, after treatment with pyridihium hydrofluoride. Interestingly, the use of dry acid-free chloroform as solvent gives spiro compound 2043, a heretofore unprecedented mode of reactivity in these types of cycloadditions. Acid-catalyzed cyclization of

c~ +

f>~

# N

H2

0

CH

30

EtO

0

2028

CA

N

aq C

H3C

N

77%

2029

N0

2

CI

o

tolu

ene,

C

H30

'r

~~-~

o ..

pyr,

100

%

CH

30

1) TBSO~

N~

TB

SO

2) C

H3I

, K

2C0

3

2030

o

-N0

2 o

2032

1) 8

0% H

2S0

4

53%

2) P

OC

I 3 /

PC

I s 6

6%

N0

2

CI

10%

Pdl

C

Et3N

13%

7% p

lus

8% o

f ot

her

cycl

o-ad

duct

Sche

me

359.

Kub

o S

ynth

esis

of

Am

phim

edin

e

CH

30 o

N0

2

Cl

2031

o

amph

imed

ine

20

33

~

:3. S- (I

) '" N o -...J

MeO

0

¢¢

# N

H

MeO

2034

I

MeO

2038

TBDMSO~

1)

_ N~

2041

O

TB

DM

S

TH

F,

23

°C

2) P

yr·

HF

48%

..

Ql

MeO

O

Tf

.&

NH

C0 2

t-B

u

Tf 2

0,

2,6-

luti

dine

,

¢6 M

e3Sn

20

36

.. ..

DM

AP,

92-

95%

#

6 P

d(P

Ph 3

)4,

87%

N

MeO

M

eO

2035

NH

CO

CF 3

-N

HC

OC

F 3

LiI

, 2,

6-lu

tidi

ne

I) B

rb A

cOH

..

.. 14

0-14

5 °C

, 64%

2)

CA

N,

59%

HO

2039

NH

CO

CF

3

o

o

20

42

HC

I, - THF,

86%

o

o

Sche

me

360.

Stil

le S

ynth

esis

of

Am

phim

edin

e

~

00

NH

C0 2

t-B

u

I) T

FA

, 94

-100

%

~ •

0

2) T

FA

A,

(i-P

rhE

tN

~ =

100%

~

(1)

2037

p;- er

0 ~ '"

n ~

-NH

CO

CF

3

Bf

0

2040

M~S04'

o

- K2C~,

96%

o

amph

imed

ine

2033

Pyridines 209

2043

2042 and N -methylation completes the synthesis to afford amphimedine (2033) in 11 steps and 12% overall yield.

A different approach to amphimedine (2033) is followed by Prager [545], as illustrated in Scheme 361. Addition of 4-pyridyllithium to silyl-protected tluorenone 2045 gives tluorenol 2046. Treatment of 2046 with hydrazoic acid gives substituted quinoline 2047 via migration of the more electron-rich aromatic ring. Chlorination of 2047 yields 2048 which is converted to pyridone 2049 by Nmethylation and oxidation of the pyridine ring. Nucleophilic displacement of

~-' o 1P I

o N H

2045

PC1s,DMF, .. 180°C, 90%

CuCN,DMSO

1) TMSCl, Et3N

2) ~ N~Li

87%

2048

..

..

150 °C, 70% 0

2050

45°C,69%

2046

1) MeS0:3F

2) KOH, K3Fe(CN)6 20 °C, 61%

..

PPA, 90°C

5 hr, 35% ..

Scheme 361. Prager Synthesis of Amphimedine

..

o

o amphimedine 2033


chloride to give nitrile 2050 and cylization and hydrolysis with polyphosphoric acid gives amphimedine (2033) in eight steps and 8.1 % overall yield.

5.4 Guanidine-Containing and Related Metabolites

5.4.1 Tetrodotoxin

The history of tetrodotoxin (2064) is as interesting as it is convoluted [546]. A major food toxin, 2064 is found in several species of puffer fish (genus Spheroides) as well as a number of diverse organisms. This suggests a microorganismic source of this toxin, which has been identified as Pseudomonas [547]. The substance is an extremely powerful neurotoxin and is a useful neuropharmacological tool. On the dark side, several fatalities are recorded each year in countries where the puffer is considered a delicacy.

0-

=

OR

OR

Tetrodotoxin 2064

The general strategy followed by Kishi in the synthesis of tetrodotoxin is outlined in Scheme 362. Lewis acid-catalyzed Diels-Alder reaction of quinone 2051 and butadiene leads to bicyclic oxime 2052 [548]. Beckmann rearrangement of the oxime, regio- and stereospecific reduction of the less hindered carbonyl, and epoxidation leads to tricyclic decalone 2053. Further transformations provide triacetate 2057, containing all six stereocenters of tetrodotoxin with the correct relative stereochemistry. Triacetate 2057 is then converted in four steps to the acetylated tetrodoamine equivalent 2060 [549, 550]. The synthesis is completed by addition of the guanidine and hemiortho ester functionality [551] to give tetrodotoxin in a total of approximately 38 steps from commercially available starting materials.

The detailed stepwise conversion of tricyclic decal one 2053 to the acetylated tetrodamine equivalent 2060 is illustrated in Scheme 363. Standard transformations stereospecifically provide acetate 2054 in four steps from 2053. Allylic oxidation and -epoxidation are key steps that lead to the formation of ketone 2055. Epoxidation of enol ether 2056, obtained through elimination of the diethyl ketal, provides triacetate 2057. Baeyer-Villiger oxidation of 2057

2051

2057

Ouanidine-Containing and Related Metabolites 211

o

w~ N~O I OH

2052

o

2060

- HQlOH l CH "i' 3

I HO...... i

AcNH o

2053

Tetrodotoxin 2064

Scheme 362. Kishi's General Synthetic Strategy for the Preparation of Tetrodotoxin

regiospecifically provides the seven-membered ring lactone 2058 which rearranges via saponification and intramolecular epoxide opening to give sixmembered ring lactone 2059. Acetylation and thermal elimination provides acetylated tetrodamine equivalent 2060 in approximately 18 steps.

H~O H " H # CH20Ac

o ..... 0 ..... i H

o IAcNH OA AcO c

2058

Conversion of 2060 to tetrodotoxin occurs as shown in Scheme 364. Deacylation of the amide functionality in 2060 provides amine 2061 which is converted to diacetylguanidine 2062 in two steps. Treatment of 2062 with ammonia followed by osmylation yields the monoacetylguanidine diol 2063. Quenching of the excess oxidant with ethylene glycol followed by hydrolysis with aqueous ammonia gives the guanidine functionality and hemiortho ester, thus providing tetrodotoxin in 8 steps from 2060.

5.4.2 Saxitoxin

Saxitoxin (2075), one of the most toxic nonprotein substances known, has been isolated from a variety of sources. Among these are the Alaska butter clam

WQtl

.•• ,H

HU':

; I

HQ

'" ~ NH

I

0.

Ae

2053

l) S

e02,

180

°C,

xyle

ne,

60 m

in

2) N

aBf4

, CH

30H

di

oxan

e, 0

DC,

100

%

1) C

r03,

aq.

py

50 °

C, 9

0%

2) H

OC

H2C

H20

H,

BF

3-E

t20(

cat.

)

100%

H ..

·· 1) C

H(O

Eth

, CSA

, Q

Ae

EtO

H,

80

°C

2055

1) M

CP

BA

, rt,

C

H2C

I2;

100%

2) K

OA

c, A

cOH

, 9

0°

C, 2

hr,

100

%

2) a

cety

lati

on

3) h

eat,

CH

2Cl 2

H

AeQ

u,·

0.

2059

WQ,;,

.•• ,H

HIt.

o '!'

C'Q

AH

I I

0.

Ae

1) M

CPB

A, C

H2C

I 2,

QH

9

0°

C, 9

5%

.. 2)

ace

tyla

tion

, 10

0%

0.

EtQ

2056

1) a

cety

lati

on,

100%

2) 2

90-3

00 °

C 8

0%

Sche

me

363.

Kis

hi S

ynth

esis

of

an E

quiv

alen

t of

Ace

tyla

ted

Tet

roda

min

e

1»)

Mee

rwin

-Pon

dorf

V

erle

y re

duct

ion

2) a

cety

lati

on

>95%

0.

HIl

i'

QA

e 1)

MC

PBA

, K2C

03

2) A

cOH

, rt

, 70

%

from

205

5

0. 20

60

I .. QA

e

0.

HII

.'

2054

1) C

F 3C

OO

H,

70

°C

, 30

min

2) a

cety

lati

on,

80%

0.

0'

2057

QA

e

IV -IV f I i

1) E

t30+

BF4

S,

S-di

ethy

l N

-ace

tyl-

CH

20A

c

Na2

C03

C

H20

Ac

imin

odit

hioc

arbo

nim

idat

e,

··"H

..

120°

C,

12 h

r 2)

aq.

AcO

H,

92%

II 0

0

2060

20

61

Y.H

C

H3C

ON

H2

1) N

H3,

CH

2CI 2

, C

H20

Ac

150°

C, 6

0 m

in

CH

pA

c

MeO

H, r

t ..

AcN

H(N

HA

c)C

=N

.".

• 0

20%

fro

m 2

06

0

2) 0

50

4, T

HF,

-2

0°

C

'" III 2.

0 S-

O

'" (j 0 20

62

0 g. 0 S·

()Q

H

III 0 P-

I) N

aI0 4

TH

F

~ '"

30 m

in,

0 °C

C

H20

H

[ C

H20

Ac

• 2)

HO

(CH

2hO

H,

a:: 3)

N

H40

H

a III <T

25%

fro

m 2

06

2

0_

0 0

~ '" 2

06

3

(±)-

tetr

odot

oxin

2

06

4

Sche

me

364.

Kis

hi T

otal

Syn

thes

is o

f (±

)-T

etro

doto

xin.

tv

0

-w


Saxitoxin 2075

(Saxidomus giganteus), toxic mussels (Mytilus californianus), and axenic cultures of Gonyaulax catenella [552]. It has also been found in aged extracts of scallops collected during a G. tamarensis bloom and in soft shell clams (Mya arenaria) collected during red tide blooms on the New England coast [553]. Although initially purified [554] in 1957, its molecular structure was not completely elucidated until 1975 when it was subjected to X-ray analysis [555]. The first synthesis of 2075 is that of Kishi [556] (Scheme 365). Conversion of thioamide 2066 to vinylogous carbamate 2067 occurs upon treatment with CH3COCHBrC02CH3 followed by elimination. Condensation of 2067 with benzyloxyacetaldehyde and silicon tetraisothiocyanate yields gives thiourea ester 2068. Ester 2068 is converted to urea 2069, the ketal exchanged for the more acid stable thioketal group, and the saxitoxin ring system obtained by warming 2070 with acetic acid to obtain cyclic urea 2071. At this point, three tactical transformations must be achieved to obtain saxitoxin. The thiourea unit must be converted to a guanidine moiety, the 1,3-dithiane must be removed to give the carbonyl hydrate, and the benzyloxy group must be transformed into the carbamoyl functionality. The diguanidine 2072 is obtained by sequential treatment of 2071 with Et30+BF3 and ammonium propionate. Removal ofthe benzyl and 1,3-dithiane protecting groups gives hydrate 2073. Addition of chlorosulfonyl isocyanate to 2074 followed by workup with hot water and isolation via ion exchange chromatography yields saxitoxin (2075) in 17 steps and about 6.5% overall yield.

Jacobi's synthesis [557] of saxitoxin is outlined in Scheme 366. Hydrazide 2076 (derived from 2-imidazolone) upon treatment with methyl glyoxylate hemiacetal gives pyrazolidine derivative 2078 via kinetically controlled 1,3-dipolar cycloaddition of the intermediate azomethine imine 2077. Epimerization of 2078 and sodium borohydride reduction of the ester provides intermediate 2079, containing all of the stereocenters of the product with the correct relative configurations. Removal of the amide carbonyl is achieved by treatment with borane dimethylsulfide complex to give pyrazolidine 2080. Ring expansion of 2080 is achieved by conversion of 2080 to thiourea 2082. This occurs via intermediate carbamate 2081 by treatment with sodium in liquid ammonia. Acylation of the free hydroxyl and completion of the synthesis using the same methodology as Kishi (Scheme 365) provides saxitoxin (2075) in ten steps and about 13% yield from compound 2076.

0

HN~~

P 2

S 5,

.. Ph

H,

80

°C

CH

20C

H2C

6Hs

s I)

CH

3CO

CH

BIC

ChC

H3

NaH

C0 3

, ref

lux

.. HN~~

2) K

OH

, CH

30H

, 50°

C,

CH'&

HN

O~

2066

I) N

H2N

H2o

H20

, rt

2) N

OC

I, -5

0°

C

50%

(ov

eral

l)

2067

H

CH

20C

H2C

6Hs

I) C~5CH2OCH2CHO

Si(N

CS)

4, P

hH,

rt ..

2) I

to D

C, 7

5%

CH

20C

H2C

6Hs

;/~"

I C

02C

H3

sAN ~

3) 9

0°

C, P

hH

4) N

H3,

PhH

,rt,

75%

(ov

eral

l)

A

I E

t30+

BF4

-, r

t, 63

%

HN/~"

NH

CO

NH

2 H

SCH

2CH

2CH

2SH

s N

~

;/~"

I N

HC

ON

H2

sAN ~

o 20

68

AcO

H, T

FA

I

HN

~

N-

50

°C

, 18

hr

H~~

CH20

C~2C

6Hs

A

H'>

=O

s N

s~

HX;2~~

HN:(

or~

2073

20

71

50

% p

lus

10%

o

f its

C-6

epi

mer

I) N

BS,

15

°C

aq

. C

H3C

N

2) C

H30

H,

100°

C,

30%

Sche

me

365.

Kis

hi S

ynth

esis

of (

± )-

Saxi

toxi

n

o 20

69

1) E

t30+

BF4

-' N

aHC

03, r

t

2) E

tC0 2

NH

4,

13

5°

C,3

3%

HX;2~\CH2C6HS

HN:(or~

H~'

•. CH2

~H H

N

N

HNA

H

,>=

NH

N

N

OH

O

H

2074

2072

I) C

IS0 2

NC

O,

HC

OO

H,

5 °C

2) h

ot w

ater

w

ork

up

I

BC

I 3, O

°C,

75%

s 20

70

H~'.

CH2~

ONH2

H

N'

N

A

H,>

=N

H

HN

N

N

O

H

OH

(±)-

saxi

toxi

n 20

75

~ S. 0- Er

~ ~ a ~. e. Jg

[ ~ [ a:::

~ i &l N ......

Vl

H

N

0-1

WN

H",

~

• Ph

N

S

NH

H

\

0 S~

2076

1) N

aOM

e.

2) N

aBH

4•

MeO

H.

72%

(ov

eral

l)

20

80

MeO

CH

OH

CD

zMe I

BF

3eE

t20

Na.

NH

3

-78°

C

75%

H

C0

2Me

N

+~

Me

02C

H

N

S N-

Ph

O='...~N"

H

\

N

----

-..;

__

0

='..

. N

H

S~

0

2077

BH

3-D

MS

---

.. 98

%

H H

,,

-OH

o~:t\.s

~:

S O

Ph

S ~.

I--

oJ'

2081

~H

.• "

OH

H

.

N ..

....

. Ph

N

"'H

N

O=

'...N

s~

H

s0

20

79

2078

65

-75%

1) P

d. H

C0 2

H

S

2) P

hO

)lC

I

80%

H

H=

t=

,"

"'O

H 1

) A

C20

. py

N,

NH

O=

<

. ~S 2

) E

t20+

BF3

-N

:

N

KH

C0

3

-s~

.,sl

99

%

I--~

2082

o

= .

' 0

NH

rI.f1·'·"

'O

N

~ N

I

V

I A

c EtO~N

: N

)lS

Et

~=

EtC

0 2-N

H/

130°

C, 3

0 m

in

40-5

0%

..f>

<,"

'OH

H2N-

(~NJ

NH2

NB

S. a

q.C

H3C

N

ClS

02N

CO

HrIll .", )l

N·

NH

2

HN

=<

~

-2H

Cl

~uj N

NH

S ::

. S

I--

,,'

Sche

me

366.

Jac

obi

Syn

thes

is o

f (±

)-S

axit

oxin

~:

S ::

. S

I--

,,' H

O:=

HO

"

(±)-

saxi

toxi

n 20

75

IV -0\ ~ 8 g ~

~ ~

@;.

&!J

Guanidine-Containing and Related Metabolites 217

5.4.3 Ptilocaulin

Ptilocaulin 2087 is a guanidine-containing marine natural product isolated [558] from the rope-like orange sponge Ptilocaulis aff. P. spiculifer. It exhibits significant antileukemic and antimicrobial properties and, not surprisingly, several syntheses have been reported. Snider described the first synthesis of this substance, proceeding through the bicyclic enone 2086, a biomimetic strategy which was subsequently adopted by Hassner, and Uyehara, but not by Roush. After a preliminary report [559] by Snider, a full account, including an improved version of the synthesis was given [560]. The first synthesis is shown in Scheme 367. Sequential alkylation and aldol reaction of t-butyl acetoacetate produced a keto-aldehyde as a mixture of isomers. Aldol cyclization produced enone 2085, still as a mixture. Conjugate addition of a terminal butenyl group proceeded with good stereoselectivity with respect to the methyl group producing the required trans arrangement. Ozonolysis and aldol cyclization produced the key enone 2086, still as a 1: 1 mixture at the butyl-bearing (X-carbon. Treatment with guanidine for a day at reflux produced ptilocaulin with all four stereocenters intact. The groundwork had now been laid for successive work. Once the relative stereochemistry at C5a and C7 had been established, the thermodynamically more stable arrangement at C3a and C8b was assured by this strategy. The improved Snider synthesis utilized the cuprate from compound 2088 thus circumventing an ozonolysis since the adduct of 2088 and enone 2085 could be directly cyclized to bicyclic enone 2086. Optically pure ( - )-2087 was also produced via a similar route by this group. This served to establish the absolute stereochemistry of naturally-occurring (+ )-ptilocaulin.

Ptilocaulin 2087

Hassner [561] has described a route to 2087 based on intramolecular nitrileoxide cycloaddition (Scheme 368). Ketone 2090 was added to the oxime dianion of hexanal to produce 2091. Treatment of the oxime with sodium hypochlorite produced the oximidoylhalide, the precursor to the nitrile-oxide which underwent cycloaddition to produce adduct 2092 stereo chemically homogeneous at the ring fusion and C3a. Elimination of the alcohol and reductive cleavage of the isoxazoline gave ~-hydroxy ketone 2093. Birch reduction gave rise to 2094 possessing all of the stereocenters in the correct relative orientation. ~-Elimination of the alcohol produced the key enone 2086 which underwent guanidination as before to produce ptilocaulin.


o 0 1) Na I dioxane; II II nBuI 55% ~Ot-Bu -------.~

2) CH3CH=<lICHO

2084 16 hr, -40 °C 39%

~MgBr ..

2085

~ aqHOAc

OHC~ -•

HCl,25°C 17 hr, 58%

81%

1) 03, MeOH, -78°C, (CH3hS, 100%

2) HC1, THF, 70%

+ -NH2 N03

HN)lNH

..

guanidine, 24 hr

~ .. reflux, PhH, 35%

2086 as a 1 : 1 mixture

Scheme 367. Snider Synthesis of (±)-Ptilocaulin

Sa 7

(±)-ptilocaulin 2087

Co O~UMgBr

2

2088

The Uyehara racemic synthesis [562] began with the known conversion of tropolone to the bridged bicyclic compound 2095 (Scheme 369). Alkylation processes led to 2096. Acid-promoted rearrangement led to ketone 2097, which was irradiated to induce 1,3-rearrangement to 2098. Refunctionalization of this substance gave way to the familiar enone 2086 from which racemic ptilocaulin was produced as before.

Roush [563] opted for strict control of stereochemistry at all four stereocenters in a synthesis of (- )-2087 (Scheme 370). (+ )-3-Methylcyclohexanone was converted by a standard series of nine operations to olefinic aldehyde 2100. Using a similar key process to that of Hassner but on a different substrate, compound 2100 was treated with N-benzylhydroxylamine with heating to produce an intermediate nitrone which underwent intramolecular cycIoaddition to give the cycloadduct 2101 with the correct relative stereochemistry at all 4 centers. Conversion to the ~-aminoketone 2102 took 3 steps, which was followed by trans-guanidination to produce ( - )-ptilocaulin.

-ON

~

~nBU •

TIl

F,

0-20

°C

6

hr,

90%

2090

O-N

SOC

I 2, py

r

C:(x

~"

40 m

in,

95%

(I :

I m

ixtu

re)

OH

0

HO

N

oX~"

O

H

2091

H2,

Ra-

Ni,

B(O

Hh

40 °

C, 6

0%

o

NaO

CI,

CH

2CI 2

• 5

hr,

80%

OH

0

6:X

B"

20

93

6:X

B"

TsO

H,P

hH

40-4

5 °C

, 30

min

10

0%

c{(

" gu

anid

ine

PhH

, 24

hr

2094

20

86

Sche

me

368.

H

assn

er S

ynth

esis

of

(±)-

Pti

loca

ulin

O-N

6:XB

"

OH

2092

Li,

EtN

H2,

-7

0°

C

30 m

in

85%

NH

-R

N0

3

HN

)lN

H

6:X~"

(±)-

pti

loca

uli

n

2087

o ~- 9: =

C1> n § ~: =

0<1 § 0- 1;' ~

<> 0- ~

C1> ~ ~.

tv

.....

\0


rJ} 'rl? ~ LDA,THF n-BuLi, -80°C TsOH,PhH .. .. -78°C. Mel THF I hexane nBu

80°C 63% OMe

89% 0

2095

~ hv

64%

° 2097

1) TBSCI/ imid 99% .. 2) (CH3hS-BH3 81% 3) Collins [0] 97% 4) tBuOK 92%

0

.. ~Xy 0

2098

° 2086

Scheme 369. Uyehara Synthesis of {±}-Ptilocaulin

5.4.4 <>roidin

OH

2096 87% (3% of other diastereomer)

Li(sec-BuhBH

".Xy .. 85%

OH

PhH. reflux. 50% ~-NH2 N03

guanidine, 25 hr • ..

+ (±)-ptilocaulin 2087

A series of interesting multi-nitrogenous metabolites have been isolated from a variety of sponges in the genus Agelas. A central substance in this family is oroidin, originally misassigned by Minale [564], but corrected by Garcia [565]. Ahond and Poupat [566] have produced oroidin by two closely related pathways, one of which is shown in Scheme 371. 4-Hydroxymethylimidazole (2103) was N-tritylated and oxidized to aldehyde 2104. Chain extension to the protected amine 2105 occurred in a standard fashion. Deprotonation between the nitrogens and addition to phenyl azide produced the azo compound 2106.

Oroidin

..

0 6 ....

0 0

I) L

DA

, T

HF;

"'C)

I) L

DA

, H

MPA

, PH

zSz

Ph

'" S

'.

-78

to -

20

°C

..

.. 2)

MC

PBA

, -'I

, 2)

n-B

uI,

80%

65%

o

" ~BU

I) L

DA

, H

MPA

T

HF,

-7

8 °

C

Ph

0 0 "'0

", S

B

u he

at, C

CI 4

,

".",

CaC

0 3,6

5%

I) 9

-BB

N, T

HF;

H

Z02,

NaO

H

90%

~BU

U·· ..

" ~-nBu (

maj

or)

a-nB

u (m

inor

)

Bu

~SiMe3

TiC

I 4,

-78

°C

>9

5%

IN··

.. ,' 2)

CIP

O(O

Eth

, 77

%

• u

):0PO

(OE

t h

I ~

Bu

'. ·"1

2) L

i/E

tNH

z tB

uOH

99

%

HOl

0..

~"'"

PC

C,N

aOA

c

CH

zCl z

, 90%

./""

-.N

H

OH

'"~:

" LV

···"

H

t:(X

BU

'" 21

00

I) C

r03,

H2S

0 4

AcO

H, a

q.H

CI

2) P

d/M

eOH

H

CO

OH

94%

Sche

me

370.

Rou

sch

Synt

hesi

s of

(-

)-Pt

iloca

ulin

Ph

-NH

OH

PhH

, he

at,

80%

'"/

'-~.'"

LV

···"

~BU

LV···

." H

21

02

H

2101

+

N

H2

N0

3

H2N

AN

-N

~

145-

155°

C,

58-6

5%

Zn,

AcO

H

55

°C

, 3.5

hr

95%

NH

2N

03

HN

)lN

H

~B"

LV···

." H

(-)-

ptil

ocau

lin

2087

o '" J. (') o ~ ~: (I

t> [ if a 8.. s:: CD

El'

cr'

o t=: !i tv

tv ....

H

Tr

+

PBU

3 I

I N

~

N

1) t

rity

lati

on..

j)

HaJ

) 2)

Mn

02

a

HC

N

N

aH

/TH

F

2103

Tr

I

2104

H2N~ j>-

-N= N

-N

HP

h

2106

Scbe

me

371.

Aho

nd S

ynth

esis

of

Oro

idin

a ~N

.H

a

Br

1)

h Br

-'~~

Cl

H

a C

H2C

l 2

2) c

onc.

HC

l

Tr

I 1)

n-B

uLi I T

HF

; N

P

hN3

... PhthN~)

2) N

H2N

H21

EtO

H

2105

-?uBr

~ f

H

N

Br

I I

f r

NH

2 N

N~N

I H

a

oroi

din

N

N

N ~ 8' ~ ::>

~

~ g. ~

Guanidine-Containing and Related Metabolites 223

The amine was freed and acylated with the appropriate pyrrole on the pathway to the final product. Their second synthesis simply used a different series of protecting groups.

5.4.5 Dibromophakellin

A more complex substance in this family is dibromophakellin, which has been produced in an efficient biomimetic route by Biichi [567]. Scheme 372 shows the conversion of ( + )-citrulline to the aminoimidazole 2108 in four steps in good yield. Treatment with base followed by the acylating agent 2109 produced dihydrooroidin (2110). Treatment with bromine yields a compound which may be 2111, but in any case, on treatment with t-BuOK dibromophakellin is produced quantitatively.

O~N9N ')-NH2

?" N N H H

~

Br Br

Dibromophakellin

5.4.6 Girolline

The unrelated aminoimidazole girolline from the sponge Pseudaxinyssa cantharella has been synthesized by Ahond (Scheme 373) [568]. The tritylated imidazole aldehyde 2104 produced in the earlier oroidin synthesis was treated with vinylmagnesium bromide and the alcohol was silylated to give 2112. Vicinal oxyamination provided 2113 as a mixture of diastereomers. The chloride 2114 was produced from 2113 presumably by an inversion process, still leaving a mixture of isomers. Removal of the protecting groups left 2115 which was aminated between the imidazole nitro gens to give a mixture of final products. The erythro isomer was found to be identical to the natural product.

OH

r=li NH2

HNyN Cl e2HCl

NH2

Girolline

Oy0

NH

' N

H2

C02

H Br2

HO

Ac

50%

1) E

tOH

/HC

I

2) N

a/H

g

3) N

H2C

N

4) 1

5% a

q H

CI

73%

° (

J N

Y

,H I'J

( -HC

I

NH

2 ~

NH

2 H

2108

o ~H Nt\

-NH'

'7

N

H

N

_ -H

Br

Bf

Bf

tBuO

K

tBuO

H

100%

2111

Sche

me

372.

Buc

hi S

ynth

esis

of (

±l-

Dib

rom

opha

kell

in

I) 4

N N

aOH

2) 0r

~Cl3

qH

Bf

Bf

2109

N

a2C

03

O~"Y\_

NH'

'7

NH

N

\ _

H

Bf

Bf 21

10

0~1;}-

N~ B

f B

f

(±)-

dibr

omop

hake

llin

IV

~

a-; g g ~ ~ o ~

,=

('O

H

I) t

rity

lati

on

r=<

HN

VN

HC

I 2)

Mn

02

Ph3C

_N

VN

2104

OTB

S

CH

O

I) ~MgBr

94%

2) T

BS

CI

/ im

id

100%

OTB

S

OTB

S

~

Ph3C

_N

VN

2112

Os0

4,B

ocH

,

t-B

uOC

ON

H-C

I,

74%

ove

rall

~NHBOC

Ph

3C

_N

VN

O

H

Ph 3

P, P

20S

CC

I 4,1

00

%

~NHBOC

Ph

3C

_N

VN

C

I

2N

HC

I,

refl

ux,

100%

21

13

m

ixtu

re o

f er

ythr

olth

reo

isom

ers

r -""" NH

2

t=<

b -H

G

N

HN

V

2115

p-br

omoa

nili

ne ..

NaN

0 2,H

CI

Sche

me

373.

Aho

nd S

ynth

esis

of

Gir

olli

ne

OH

~NH2

HN

N

C

I Y

-H

CI

+ N

2-P

h-pB

r

cr

23%

21

14

Pt0

2, H

2

MeO

H

~H

,(y'N

H2

HN

N

C

I Y

-2

HC

I

NH

2

girr

olin

e er

ythr

o is

omer

fou

nd t

o be

id

enti

cal

to n

atur

al p

rodu

ct

[ S· '" Q I: !J

Q 8- ~ [ ~

~

I>J ~ ~

N

N

VI


5.5 Nuc1eosides and Related Substances

5.5.1 MycaIisine A

The lipophilic extracts of a marine sponge M ycale sp., collected in the Gulf of Sagami, Japan, inhibit the cell division of fertilized starfish eggs. One of the active components was found to be mycalisine A, a pyrrolo[2,3-d]pyrimidine nucleoside with unsaturation between the 4' and 5'-positions of the ribose moiety [569]. Townsend's synthesis of mycalisine A is outlined in Scheme 374

NH2 CN

N~ H1] HO OH

2117

NaI°4 •

H2O,THF

-SnCl2

N~ ~ .. J-~I

~ CH30 OH

Mycalisine A

NH2 CN

N~ ~ J-/ t) ()-N~PhSeCN HO •

o BU3P

CH30 OH

2118 plus 2'-O-methyl

isomer

~ CN

N:)) ~N N Et3N, 50°C

~~1J • ' 0 5 hr, 35% 0

from 2119

CHP OH

Scheme 374. Townsend Synthesis of MycaIisine A

2119

N~

~ CH30 OH

mycalisine A

Nuc1eosides and Related Substances 227

[570]. Methylation of nucleoside antibiotic toyocamycin (2117) yields a mixture ofthe 2'-O-methyl and 3'-O-methyl isomers. The two isomers were separated by acetylation, recrystallization and deacylation to give 2118 as a single isomer. Phenylselenylation of the primary hydroxyl followed by selenoxide elimination provides mycalisine A in 35% yield from 2119.

5.5.2 Phidolopin

Phidolopin (2123) is a xanthine derivative isolated from the "lacey" bryozoan Phido[opora pacifica, collected in Barkley Sound, British Columbia [571]. It shows in vivo antifungal and antialgal activity [572] and is of interest because it is of animal rather than plant origin and it contains a nitro group which is relatively rare in natural products. Hirota's synthesis [573] of 2123 is shown in Scheme 375. Bromination of the protected cresol 2120 affords the benzyl

Phidolopin 2123

o H

CH3'N~N OH OMOM OMOM ~ I q

<rN~ <roo' <rN~ o N N

CH3OCH2Cl NBS CH3

~I • ~I - ~I • NaH,85% AIBN K2C03, DMF, 99%

CC4 CH3 CH3 CH2Br

2120 2121

I hr, heat, 79%

phidolopin 2123

Scheme 375. Hirota Synthesis of Phidolopin


bromide 2121. Coupling of 2121 with theophylline in the presence of potassium carbonate affords 2122, which upon treatment with acid gives phidolopin (2123), in a total of four steps.

5.5.3 6-Imino-l,9-Dimethyl-8-0xopurine

The adenine derivative 6-amino-l,9-dimethyl-8-oxopurine (2128), has been isolated from the English Channel sponge H ymeniacidon sanguinea Grant in the form of its acetyl derivative [574]. The synthesis of the parent base, by Fujii, [575] is outlined in Scheme 376. Bromination of I-methyladenine (2125)

:SeN t I ~ N N

\

Me

2125

NH

~'Cx>=o N \

Me

6-Imino-l.9-dimethyl-8-oxopurine 2128

N:SeN Br2,H2O • ~ I N'}-Br pH 4, 87%

N \ Me

2126

NH

Mel .. AcNM~

99%

NH

~, :\N t I N'}-Brem

N \ Me

2127

,COMe N

10% Na2C~ Me'N:J:NL ---.. ~ I I }-Br

80% ~N N

NaOAc -AcOH

Me, ~~ + tL.LN>=o

N \

OR

\

Me

I.:\:}-B< N . ,

Me

2126

6-imino-l,9-dimethyl-8-oxopurine 2128

(36%)

NH

_1)_M_e_I,_A_cNM_~-; .. ~ Me, 7~~ NNH>= 0

2) pH> 7. 75% ~ .. L N ,

Me

2128

Sebeme 376. Fuji Synthesis of 6-Imino-l.9-Dimethyl-8-0xopurine

Me

2129 (34%)

Nucleosides and Related Substances 229

followed by methylation gives the methylated bromide 2127 as its hydroiodide. Hydrolysis of 2127 gives a 36% yield of 2128 (25% overall) along with 34% of the N 6-acetyl derivative 2129. Alternatively, methylation of2126 and hydrolysis under basic conditions yields 2128 directly in two steps and 65% yield.

5.5.4 I-Methylisoguanosine (Doridosine)

The aqueous ethanolic extracts of the sponge Tedania digitata Schmidt, collected off Newport Reef, Sydney, Australia, exhibit muscle relaxant, anti-inflammatory and other pharmacQlogical activities. The active component has been found to be a new methylated purine nucleoside, I-methylisoguanosine (2134) [576]. The preparation of 2134 by Cook [577] begins with the acetylation of 5-amino-4-carbamoyl-ll3-o-ribofuranosylimidazole (2130) to afford triacetate 2131 (Scheme 377). Conversion of 2131 to the nitrile 2132 and reaction with

t:rnz CH3 , ~N

N,~.~ ) O,lN6 N

HO~ HO OH

I-Methylisoguanosine 2134

HZNOCXN I )

H\:IN N AC20/Pyr HO a

o 94%

HZNOCXN)

H\:IN N AcO o

NCXN

I )

~\:} a 2 hr, 55%

HO OCONHz AcO OAc AcO OAc

2130 2131 2132 NHz

MeNCO,DMF

NCXN

=~.:.r A<OA ~'N5=N~

N}4CI, MeOH, O)-.N odI N

--- H°-tOOJ 100 °C 32%

a

AcO OAc

2133

5°C, 18 hr, 87% H HO OH

I-methylisoguanosine 2134

Scheme 377. Cook Synthesis of I-Methylisoguanosine


NHz

HZNOCX.N~ HzNOCXN

I)DCC H,C, ::eN MeNCS 25°C / 24 hr .. s I ~ ... N ~

HzN r-; DMF, 80°C MeHNAN r-; 2) NaOH O~N& N

R 12 hr H R EtOH, rt \

R

2136 2137 68% doridosine 2134

HO HO

Scheme 378. Townsend Synthesis of I-Methylisoguanosine (doridosine)

methyl isocyanate produces the bis(methylcarbamoyl) adduct 2133. Treatment of 2133 with aqueous ammonium chloride induces cyclization to give 1-methylisoguanosine (2134) in four steps and 14% overall yield. Alternatively, 2133 can be cyclized without isolation to give 2134 in 22% overall yield.

Using a similar starting material, Townsend [578] also prepared 2134 using a shorter sequence consisting oftwo steps (Scheme 378). Treatment of 2136 with methylisothiocyanate gave the thiourea 2137. Dee mediated cyclization and saponification gave 2134 in good overall yield.

5.6 Reniera Alkaloids

5.6.1 Mimosamycin

Mimosamycin was first isolated from the culture filtrate of Streptomyces lavendulae No. 314. It exhibits antibiotic activity towards mycobacteria, including streptomycin resistant strains of human tubercle bacilli [579]. It is the first example of a naturally occurring "isoquinoline quinone" to be reported. Mimosamycin has also been isolated as a minor metabolite from a bright blue sponge Reniera sp. [580].

Mimosamycin 2141

Reniera Alkaloids 231

The structure elucidation and first synthesis of mimosamycin (2141), by Fukumi [581], appeared in 1977 (Scheme 379). The synthesis begins with the conversion of benzaldehyde 2138 to isoquinoline 2139 in eight steps using standard transformations. Air oxidation of 2139 in the presence of morpholine and copper (II) acetate affords morpholino-substituted o-quinone 2140, containing all the functionality needed to complete the synthesis. Hydrolysis and methylation completes the right hand portion of the molecule. Reduction of the newly formed p-quinone and protection as the diacetate allows N-methylation of the isoquinoline and hydrolysis to the corresponding N-methyl pyridone. Oxidative methanolysis provides mimosamycin 2141 in 14 steps and 5.2% overall yield.

Parker's synthesis [582] of mimosamycin (2141) begins with the highly functionalized benzonitrile 2143 (Scheme 380). Allylation of the phenol, Claisen rearrangement, and methylation provides hexasubstituted benzene 2144. Permanganate oxidation reveals the latent acetic acid moiety in 2145 which is esterified to give ester 2146. Reduction of the nitrile in the presence of acetic formic anhydride provides amide 2147 which cyclizes to lactam 2148 upon treatment with diborane. Oxidative demethylation of 2148 with silver oxide yields mimosamycin 2141. Difficulties in reduction of the nitrile and problems with isolation of the final product lessen the yield considerably. A final yield of less than 3% is obtained over nine steps.

A very short synthesis of mimosamycin, which is applicable to the preparation of a number of derivatives, has been developed by McKillop [583] (Scheme 381). Hetero Diels-Alder reaction of quinone 2149 with 2-aza-l,3-bis(tert-butyldimethylsilyloxy)-1,3-butadiene affords intermediate 2150 which yields lactam 2151 upon treatment with HCl. The use of concentrated solutions of the diene is crucial to the success of the cycloaddition step. Methylation of 2151 under phase-transfer conditions provides mimosamycin in three steps and 54% overall yield.

5.6.2 Reniera lsoindole

Along with renierone (2179) and mimosamycin (2141), the bright-blue sponge Reniera sp., found near Isla Grande, Mexico, provides a wide variety of antibiotic metabolites. One of these, 2,5-dimethyl-6-methoxy-4,7-dihydroisoindole-4,7-dione (2156), the first example of a naturally occurring isoindole, has been isolated and synthesized by Faulkner [584] (Scheme 382). The

o Meo~ ~N-CH'

o

Reniera isoindole 2156

I)

MeO

MC

HO

°2N

I) S

nCI 2

aq

HC

I

2) N

aN0 2

•

UC

HO

M

eO

MeO~ NH

2

2) H

2/P

t02

3)

TsC

I /

pyr

~

HO~N

2138

°2

/Cu (

OA

ch

mor

phol

ine

50%

Zn

AC

20/H

OA

c

92%

aq H

CI

refl

ux

3) M

ezS

04

aqN

aOH

54%

(0)

N

r ~N-J

O~N

o 21

40

OA

c ro

~N~

CH30~~

Q

Ac

Sch

eme

379.

Fuk

umi

Syn

thes

is o

f M

imos

amyc

in

4) a

q H

CI

/ di

ox

refl

ux

5) c

onc

HB

r

71%

2139

I) a

q ac

id o

r ba

se

MeO

H

o ro

'l(yyN~

CH30~~

2) C

H2N

2

60%

I) M

ellD

MF

10

0°C

2) A

gO

/MeO

H

49%

o

o XXx

?'

0

CH

30

~

N, C

H3

o

mim

osam

ycin

21

41

N w

N ~ 8 g ~ ~ ~

))

K~ *

~B' *~

I I·

• ~

18-c

row

n-6

I #

97%

I

CH

3 0

TH

F 6

0%

CH

30

CN

C

H 0

#

CN

CH

30

OC

H3

' 3

OC

H3

OC

H3

CH

3I, K

2CO:

J • ac

eton

e, 8

8%

H2,

RaN

i

AcO

CH

O

2143

~

CH

30

KM

n04

:XX:~H

CH

30

I #

CN

•

BU

4NB

r C

H30

#

CN

OC

H3

OC

H3

2144

21

45

:J¢c

:H3

I C

02M

e

CH

30 #

NH

CH

O

OC

H3

BH3

x»

OC

H3

_

~

0

55%

I

CH

P

# N

CH

3

OC

H3

2147

21

48

Sche

me

380.

Par

ker

Syn

thes

is o

f M

imos

amyc

in

OH

C,"

,NM

" ~

,. I

heat

, 8

hr,

74%

#

CH

30

CN

OC

H3

CH

30

CH

,N,

:XX:co

,CH,

80%

fro

m·

CH

0

# C

N

21

44

3

Ag

O

soni

cati

on

18%

OC

H3

2146

o :J¢crr:?

0

CH

30

~

N ...

CH

3

o

mim

osa

my

cin

21

41

>:l ~ ~. ~ ~ o ~

N

W

W


0 ~OTBS

~:¢ fN OTBS ..

PhH

0

2149

o

~~o o

2151

0 WOffiDM5 I I N

CH30

.. DMF, IDA-I,

90%

0 OTBDMS

2150

Hel, -60%

mimosamycin 2141

Scheme 381. McKillop Synthesis of Mimosamyscin

synthesis involves building the quinone portion onto an N-methylated pyrrole. Addition of one equivalent of 2-lithio-2-ethyl-l,3-dithiane to 3,4-diearbomethoxy-l-methylpyrrole (2153) gives ketone 2154 in 27% yield. Hydrolysis of the dithiane, under conditions that do not preferentially attack the pyrrole, gives (l-diketone 2155. Annulation and methylation with diazomethane provides 2156, thus confirming the structure of the natural product. A yield of 3% of 2156 is obtained over four steps.

Padwa and Parker's synthesis [585] of isoindole 2156 (Scheme 383) involves annulation of the pyrrole moiety onto a preformed quinone ring. Electrochemical oxidation of 1,2,4-trimethoxy-3-methylbenzene (2157) in methanol yields quinone monoacetal 2158 which upon hydrolysis provides quinone 2159. Treatment of aminosilane 2160 with five equivalents of silver fluoride generates an unstable azomethine ylide whieh undergoes cycloaddition with quinone 2159 giving isoindole 2156 in 68% yield.

5.6.3 7 -Methoxy-l,6-Dimethyl-5,8-Dihydroisoquinoline-5,8-Dione and N-Formyl-l,2-Dihydrorenierone (2171) (2164)

Two other Reniera metabolites, 7-methoxy-l,6-dimethyl-5,8-dihydroisoquinoline-5,8-dione (2164) and (±)-N-formyl-l,2-dihydrorenierorie (2171), have been synthesized by Kubo [586] (Schemes 384 and 385). The dihydroisoquinoline 2164 was prepared via two different pathways. Tosylation of carbinol 2162 and reduction gives I-methylisoquinoline 2163. Cerie ammonium nitrate oxidative demethylation of 2163 provides the natural product in 30% yield along with 42% of the ortho-quinone. An alternative pathway begins with nitro

(1u

r~NCH'

0 M

eo2c)

: T

HF

N

CS

I Ag

N0 3

~NC~

;:,....

NC

H3

.. ...

Me0

2C

-43

°C

aq

CH

3CN

27%

M

e0 2

C

94%

M

e0 2

C

2153

21

54

2155

0 °

N

aH I

DM

F

H~

CH

zNz

M*

.. ,

::

NC

H3

... ,

::

NC

H3

80

°C

E

tzO

I C

HzC

l z

30%

°

40

%

0

Ren

iera

iso

indo

le

2156

Sche

me

382.

Fau

lkne

r Sy

nthe

sis

of R

enie

ra I

soin

dole

215

6

CN

(

::>::I

0 N

'Me

0

'" O

Me

M~3Q~

<

::<

elec

tro-

M»

(ii'

M:¢

TM

S

M*

... ox

idat

ion

H3 0

+

, ::

NC

H3

I:>

2160

~

',6-

.. ..

... aq

MeO

H

AgF

a 8,

0.

. O

Me

0 °

68

%

°

en

2157

21

58

2159

R

enei

ra a

lkal

oid

2156

IV

Sc

hem

e 38

3. P

adw

a/P

arke

r Sy

nthe

sis

of R

enie

ra I

soin

dole

215

6 <

.;.)

V

I

~OCH3 ~

I ,.

:N

~

CH

30

OC

H3

OH

1) P

hLi,

TsC

I o D

C, 7

4%

2) L

iEt3

BH

, T

HF

,69%

~

~O~N

OC

H3

2162

W~

~ I

,.

:N

CH

30

N02

O

H

2165

1) P

hLi,

TsC

I, w~

85%

I

-~ ..

-

~,.:N

2) L

iEt3

BH

, C

HP

57%

N

0 2

2166

Sche

me

384.

Kub

o Sy

nthe

sis

of R

enie

ra M

etab

olit

e 21

64

2163

H2,

Pdl

C

----;

78%

o

CA

N,C

H3C

N

(or

AgO

)

30%

plu

s 42

%

orth

oqui

none

CH'W

Y

0

CH,on

N

NH

2

2164

J F

rem

y sa

lt ox

idat

ion

83%

N

W

0\ ~ g s:::

~

I» ~ rr

Reniera Alkaloids 237

2164 2171

substituted carbinol 2165. Tosylation and reduction provides the nitro substituted 1-methylisoquinoline 2166. Catalytic reduction of 2166 and oxidation with Fremy's salt provides 2164 in 37% overall yield.

The synthesis of (±)-N-formyl-1,2-dihydrorenierone (2171), as shown in Scheme 385, also begins from isoquinoline carbinol 2162. Simultaneous reduction and formylation of 2162 provides N-formyltetrahydroisoquinoline 2167. Acylation of 2167 with acid chloride 2168 leads to compound 2169 which is converted to quinone 2170 by oxidation with eerie ammonium nitrate. Dehydrogenation with palladium on carbon gives the natural product in four steps from 2162 and 12% overall yield.

5.6.4 Renierone

There have been two syntheses of renierone (2179). The first of these, by Danishefsky [587], begins with the chloromethylation of compound 2173 (Scheme 386). Homologation of 2173 with cyanide, reduction to the amine and protection as the carbamate affords 2174. Formation ofthe tetrahydroisoquinoline 2175 and aromatization gives isoquinoline 2176. Reduction of 2176 to the alcohol and acylation with angelic acid gives 2177 which is oxidized to a mixture of the ortho-quinone 2178 and renierone (2179). Conversion of the orthoquinone to renierone increases the overall yield to approximately 1.1 % over 14 steps.

MeO:¢5~ o-r, I I N

.#

o

Renierone 2179

xaOC

H3 ~

, I,&

N

AcO

H

CH

3 0

HC

0 2E

t 77

%

OC

H3

OH

H2

/

Pt0

2

OC

H3 xa' I

N ...

CH

O

CH

30

OC

H3

OH

2162

21

67

0

CA

N

W P

dlC

40%

C

H30

0

"'C

HO

59

%

)(

2170

Sche

me

385.

Kub

o Sy

nthe

sis

of R

enie

ra M

etab

olit

e 21

71

PhL

i

lJ

0' 1 21

68

66%

o

OC

H3

~, I

N ...

CH

O

CH

30

OC

H3

0

2169

o~

WI ~"'C

HO C

H30

o oJ

y 21

71

IV

I.H

0

0 t s:: ~ i

MeO

M

eO

M~;¢

1) c

h1or

omet

hy1a

tion M~~

l)O

HC

CO

OH

:

I N

HCO

OBn

~I

.. 2)

KC

N /

DM

SO

2)

C1 2

CH

CO

OH

3)

BH

30T

HF

3) C

H2N

2 M

eO

4) B

nOC

OC

l

2173

MeO

C

0 2M

e

MeO~~HCOOBn

/yV

M

eO 21

75

37%

1) H

2 P

dlC

2) c

hlor

anil

xy

lene

1

50

°C

50-5

5%

from

217

4

MeO

2174

MeO

C

0 2M

e

MeoY0~

~

MeO

2176

1) D

iba1

50

-70

% ..

2)

1 H

ooel

55%

DM

AP

/DC

C

~eo 0

Y'l

M

eO

'<:::::

1f?

~

0 I

N

~

.#

AgO

HN~

diox

ane

Meo

»S

°Y

'l

I I

~N 0

.#

52%

»50.

1 o

1'1

I ~N

0

38%

~

.#

MeO

o

2177

Sche

me

386.

Dan

ishe

fsky

Syn

thes

is o

f R

enei

rone

2179

ren

eiro

ne 1) a

q H

2S0 4

ac

eton

e /

diox

2) A

g 20

Mel

C

HC

l3

83%

MeO

21

78

'" § ~. > ~

E- 2. ~

to..)

W

\0

~

CH30~N

N0

2

PhC

OC

I, K

CN

W

I ~ ..

N

CH

2C1 2

, H

20

CH

30 ~

"CO

C6H

6

1) P

hLi,

diox

ane,

et

her,

-20

°C ~

CH30~N

2) H

CH

O 6

1%

73%

N

02

CN

1) a

qNaO

H

EtO

H

2180

2) h

ydro

gena

tion

83%

))R~

I N

~

&

CH

30

NH

2 O

H

2183

Sche

me

387.

Kub

o Sy

nthe

sis

of R

enie

rone

2181

Frem

y sa

lt ox

idat

ion

64

% *

'0

~

I I

&N

CH

P

°

OH

21

84

1) P

hLi

ethe

r, -

20°C

2) C

lOY

2185

37%

I

N0

2 C

HZ0

2CC

6HS

2182

*'

0 ~

I &

N

CH

,O

0 oJ

( R

enie

rone

21

79

~ ~ g ~

~ f.

Zoanthoxanthins 241

Kubo's synthesis [588] of renierone is outlined in Scheme 387. Addition of benzoyl chloride and potassium cyanide to isoquinoline 2180 provides Reissert compound 2181. Lithiation of 2181 and treatment with gaseous formaldehyde yields benzoate 2182 which is saponified and hydrogenated to give amine 2183. Fremy salt oxidation of 2183 gives quinone 2184 which is acylated with 2185 to provide renierone in six steps and 8.6% overall yield.

5.7 Zoanthoxanthins

Biichi has described a biomimetic route to parazoanthoxanthin A (2189) (Scheme 388) and pseudozoanthoxanthin A, which is equally short and efficient [589]. These metabolites are fluorescent pigments produced by marine anthozoans and are dimers of a presumed CSN3 biogenetic precursor [590]. Parazoanthoxanthin A was produced in a two-step process from 2-aminobutyrolactone (2187). Treatment with cyanamide and sodium amalgam in aqueous ethanol led to the aminoimidazole 2188 in 64% yield. Treatment of this with aqueous acid at elevated temperature gave way to 2189, probably involving dimerization of an imidazolium cation. The route to pseudozoanthoxanthin A was somewhat longer (Scheme 389) beginning with the oxadiazole 2190 which

Parazoanthoxanthin A 2189 Pseudozoanthoxanthin A

NH2 rl H2NCN,

<"0>=0 2:5% NaJH; aqEtOH,64%

N f }-NH2

HO~N H

.. 90-100 °C, 50%

2187 2188

.. N¥,N H2N~' ~NH N N 2

H

parazoanthoxanthin A 2189

Scheme 388. Buehl Synthesis of Parazooanthoxanthin A

N~NH2

II i

Ph

./"'

-,. 0

' N

2190

Meo~

o ..

900C

,75%

O~

N:~J

II

\\ P

h./

"'-,

. , N

o

N

rt,

1.5

hr,

62

0/;

P

hC

ON

H-{

:y

+N

H

NaH

,DM

F,

NaB

H4,

i-P

rOH

,

refl

ux,

89%

2191

21

92

0 in

1:3

rat

ios

wit

h 21

94

NH

2 N

P

hCO

NH

-{ II

T

sOH

~-y

88%

N

PhC

ON

H -{ /1

H

2 S0

4, 90

-100

°C

,

~ .J

.V

4 hr

, 10

%

H2

N'F

N

Ny

Njj-N

O

H

2193

H, N-N

X'l ~,

COPh

"...

H

o

2194

Sche

me

389.

Buc

hi S

ynth

esis

of

Pse

udoz

oant

hoxa

nthi

n A

pseu

dozo

anth

oxan

thin

A

plus

tra

ce o

f P

araz

oant

hoxa

nthi

n A

~ I a:: ~ ~ o ~

Pyrrole-Containing Alkaloids 243

was converted to 2191 and rearranged to the imidazole 2192 with base. Conversion of the ketone to the olefin 2193 producing the desired precursor. Acid treatment at 90-100°C provided psudozoanthoxanthin A in 10% yield along with a trace of parazoanthoxanthin A.

5.8 Pyrrole-Containing Alkaloids

5.8.1 Oscarella Lobularis Pyrrole Metabolite (3-0ctadecyl Pyrrole-2-Carbaldehyde)

The 3;-Alkylpyrrole-2-carbonxaldehyde (2197) has been isolated from the sponge Oscarella lobularis [591], although it has been suggested that the structure of the natural product was misassigned [592]. Muchowski's synthesis of 2197 [593] begins with the bromination of silyl-protected pyrrole 2195 (Scheme 390). Transmetallation and alkylation of 2195 affords compound 2196. Desilylation and formylation provides 2197 four steps and 38% overall yield. The natural product is obtained as an inseparable mixture with the 5-carboxaldehyde isomer.

3-Alkylpyrrole-2-carbaldehyde 2197

5.8.2 5-N onylpyrrole-2-Carbaldehyde

A number of simple pyrroles have been isolated from various marine sources. 5-Nonylpyrrole-2-carbaldehyde was synthesized by ColI [594] to confirm the structure of a soft coral metabolite (Scheme 391). Acylation of pyrrolemagnesium iodide with nonanoyl chloride gave 2198 which was reduced to 2199. Standard formylation gave rise to a substance identical to the natural product which was thus assigned as 2200.

5-Nonylpyrrole-2-carbaldehyde 2200

Br

nC1s

H37

nC

1sH

37

0 N

BS

0 1)

t-B

uLi

0 1)

TB

AF

Q-C

HO

76%

..

• •

N

TH

F,

-78

°C

N

2) n

CIg

H37

! N

2)

PO

CI 3

I

I I

DM

F

I Si

(i-P

rh

89%

Si

(i-P

rh

88%

Si

(i-P

rh

H

2195

21

96

3-a'

lkyl

pyrr

ole-

2-ca

rbal

dehy

de

21

97

(a

s a

3 :

I m

ixtu

re

with

in

sepa

rabl

e 1,

3-is

omer

)

Sche

me

390.

M

ucho

wsk

i Sy

nthe

sis

of P

yrro

le M

etab

olit

e 21

97 f

rom

Osc

arel

la l

obul

aris

o M

eMgI

,

N I H

CH

3(C

Hv

7C

OC

l 85

%

0-(

CH

2)gC

H3

N I H

2199

0-C

O(C

H2h

CH

3 N

I H

21

98

N2l

-4,K

OH

,

refl

ux,

75%

(CH

3hN

CH

O,

POC

I 3,8

1%

O

HC

-f)-

-(CH

2lsC

H3

I H

5-no

nylp

yrro

le-2

-car

bald

ehyd

e 2

20

0

Sche

me

391.

Col

i Sy

nthe

sis

of 5

-Non

ylpy

rrol

e-2-

carb

alde

hyde

t ~ .... o g a:::

~

10 c:r ~

~

Pyrrole-Containing Alkaloids 245

5.8.3 Pentabromopseudilin

Pentabromopseudilin (2206) is a highly brominated cytotoxic phenylpyrrole that has been isolated from the marine bacterium Alteromonas luteo-violaceus. It exhibits antibiotic and enzyme-inhibitory properties. Laatsch [595] has prepared pentabromopseudilin in five steps as shown in Scheme 392. Substituted benzaldehyde 2202 is converted to ketone 2203 and then cyclized to pyrrole 2204 by treatment with ammonium acetate in refluxing acetic acid. Bromination ofthe pyrrole ring with pyidinium hydrobromide perbromide affords compound

Br

Br Br

Br

Pentabromopseudilin 2206

OMe 0 OMe

BryYCHO

y 1) ('yO

BrMg oJ 2) PDe 61%

• B'~) Br

2202

~Me r' Nl40Ac Br ,

----~.- I ~ HOAc I reflux .#

56% Br

2204

Br Br •

58%

Br

pentabromopseudilin 2206

Br

pyridinium hydrobromide

perbromide

90-99%

Scheme 392. Laatsch Synthesis of Pentabromopseudilin

2203

Br •

Br

2205

Br


2205 which is converted to pentabromopseudilin by demethylation with BBr3 •

The natural product is obtained in approximately 19% overall yield.

5.8.4 Bonellin, Methyl Ester

Bonellin is a green pigment isolated from a marine echurian worm, Bonellia viridis, native to the sea bottom of the Gulf of Pozzuoli near Naples [596]. Sexually undifferentiated larvae of B. viridis that come into contact with bonellin develop into males. Those that avoid contact develop into female worms [597]. In addition, bonellin exhibits anti-tumor activity [598]. The synthetic strategy developed by Battersby [599] for the synthesis of bonellin methyl ester (2220) is convergent. The right and left halves of the molecule are constructed separately (Scheme 393), joined via a condensation reaction of a pyrrole and an aldehyde, and then cyc1ized photochemically (Scheme 394). Preparation of the right hand fragment begins with the oxidation and subsequent reduction of highly functionalized pyrrole 2207 to obtain pyrrolone 2208. Condensation of 2208 with aldehyde 2209 provides the carbon skeleton of the right-hand fragment 2210. Decarboxylation and formylation of 2210 with benzoyl chloride and DMF, followed by methylation yields aldehyde 2211. Construction of the left-hand fragment begins with the transformation of pyrrole 2212 to nitro alkene 2213. Conjugate addition of the nitropyrrole to the known enone 2214, catalyzed by TBAF, provides compound 2215. Reduction of 2215 with TiCl3 provides the desired imine 2216. Acid-catalyzed condensation of imine 2216 and aldehyde 2211 provides the seeD system as a mixture of two isomers 2217 and 2218. Photochemical cyc1ization of the mixture occurs slowly in the presence of proton sponge to give nitrile 2219, which is converted to the methyl ester of the natural product by hydrolysis to the amide. Bonellin methyl ester (2220) is obtained in 11 steps and 8.6% overall yield.

Me

Me

Me

C02Me

Bonellin methyl ester 2220

H

OH

H

t-

BU

0 2Cr:;M

C 'N

I)

H

N

b ~~""'

OHC ~'

M,

Me

PE

A.

~02BU-t

o (J'

M,

TF

A,

Et3

SiH

22

09

oJM

' CHO

..

60%

he

at,

87%

K

OH

,CH

3OH

MC-

YH

CH

O

22

12

C0

2Me

2207

t-B

u0

2C o

Me

C0

2Me

2210

MeN

H2e

HC

I, •

KO

Ac,

MeN

02

MeO

H,8

8%

Me

C0

2Me

Me

OH

C

1) H

+, h

eat

2) B

zCl,

DM

F ..

3) a

lum

ina,

H2O

°

83%

ove

rall

C0

2Me

M'~NH

1) A

cOH

, M

eOH

, o

DC, N

aBH

4

2J X,; ~ 221

4

°2N

CN

DM

F,

TB

AF

, 22

13

57%

Sche

me

393.

Bat

ters

by S

ynth

esis

of (

± )-

Bon

ellin

Dim

ethy

l E

ster

Me

2) C

H2N

2> 9

0%

C0 2

Me 22

08

BF3

, m

ethy

lati

on ..

74%

Me M

e NC

2215

OH

C

MeO

Me 1

C0

2Me

2211

Me

-=

Me~NH

NaO

Me,

TiC

I3

" ------..

NH

40A

c,3

8%

M

e

CN

22

16

Me

~ 8 'f

(") o =

~. Jg"

~

PI" S- a: '" N

.j::..

-..

.l

N

.j::

. 0

0

Me

Me

Me

OH

C-Iu

M

e r

r 1-

~ Me~

_NH

M

e N

H

HN

#

0 T

FA

o,'i

+

H

-::s

----

71%

M

e ~

MeO

.-iZ

..r

Me

Me

CD

Me-

.J

\L

Me

S-M

e M

e a"

Me

0 M

e =:

Ii I

( (

r /

CN

C0 2

Me

CN

CN

C

0 2M

e C

0 2M

e

2216

22

11

2217

22

18

Me

Me

0 ~

Me

\.

NH

N

"....

Me

hV

,7 D

ays,

A

cOH

,70°

C

71%

M

e_

l-N

HN

"'\.

BF 3

-E

t 20

,59%

M

e M

e X

1\

J ,r

Me

n M

e M

e CN

C0 2

Me

CO

NH

2 C

0 2M

e

2219

bo

nell

in m

ethy

l es

ter

22

20

Sche

me

394.

Joi

ning

of

Bon

ellin

Dim

ethy

l E

ster

Fra

gmen

ts (

Bat

ters

by)

6 Miscellaneous Metabolites

6.1 Metabolites Related to Citric Acid

6.1.1 Delesserine

Delesserine (2226) is a secondary metabolite isolated from the alga Delesseria sanguinea (Lamouroux). Its relative configuration has been determined by X-ray crystal structure analysis [600]. Although aqueous extracts of D. sanguinea collected on the European Atlantic coast are powerful anticoagulants for human blood [601], delesserine does not exhibit 'this property. The first synthesis of 2226, by Seebach [602], is shown in Scheme 395. Condensation of ester 2222 with aldehyde 2223 (available in four steps from diethyl tartrate) gives a mixture of four diastereomers 2224. Oxidation of 2224 and treatment with TsOH in methanol provides lactone 2225 in 32% yield along with 59% of its diastereomer. Removal of the benzyl protecting groups affords ( + )-delesserine in four steps (eight steps from diethyl tartrate) and 18% overall yield.

(+)-Delesserine 2226

Poss utilizes ascorbic acid as a chiral template to provide a short synthesis [603] (Scheme 396) of ( + )-delesserine (2226) along with the structurally related brominated metabolites (+ )-rhodomelol (2230) and (+ )-methylrhodomelol (2232) (2230 and 2232 have been isolated [604] from the red alga Polysiphonia lanosa). Methylation of the dianion of ascorbic acid provides monomethyl derivative 2227 [605]. Reaction of 2227 with p-methoxybenzyl alcohol in water at 50°C gives ( + )-delesserine in 80% yield. The reaction is thought to proceed


OBn

OMe

2222

l)LDA/THF -75°C

2)OHC BnO

>-/ -\0 2223

..

OBn OBn

DMSO I (COCl)z ..

2224 62% overall

OH

p-TsOH I MeOH .. .. 32% OBn MeOH

90%

2225 (+)-delesserine 2226

along with 59% of the diastereomer

Scbeme 395. Seebach Synthesis of ( + )-Delesserine

HO

~~9 Q .. .. ¢ .. .. HO HO +0 ... H

2228

via p-quinone met hide 2228 as diagrammed followed by C-alkylation of the ascorbic acid to give 2226. No reaction is observed with either 0- or mhydroxybenzyl alcohol. In a similar manner, rhodomelol and methylrhodomelol are obtained from brominated phenols 2229 and 2231.

6.1.2 Leptosphaerin

In the course of studies of chemical constituents of higher marine fungi, leptosphaerin (2239) was isolated from laboratory cultures of the ascomycete

H~OH

O=\"VOH

o ~ , ii ~OH

ascorbic acid

Me~OH

O=\"VOH o :. ~

H e)H 2227

h OH

HO-H'Br

2229 Be

H20 75°C /12 hr

54%

..

troP:-______ H20

50 °C/3 days

80%

~ HOJj.,

Bf 0 H20 2231

70°C /12 hr 36%

Metabolites Related to Citric Acid 251

HO

Bf

o

'I'hodomelol 2230

OH

delesserine 2226

HO

Bf

methylrhodomelol 2232

<;"OH

Scheme 396. Poss Synthesis of (+ )-Delsserine, (+ )-Rhodomelol and (+ )-Methylrlrodome101

Leptosphaeria oraemaris (Linder) [606]. Spectroscopic and X-ray crystallographic analyses initially led to an incorrect assignment of the structure of leptosphaerin [607], This was corrected following the synthesis of 2232. The

H. r(NHAC

HO~O}::::.O 6H

(+)-Leptosphaerin 2239

H. r=<'0AC

HO~N~O 6H A

Erroneous Leptosphaerin Structure 2232


1) BnOH, 1) PhSH, TBAF EIO OEI KHS04, 44% OBo

XC02El 77%

OBo 2) NCS, CCl4

~C02EI PhS~ .. .. CONHMe

2) P20 5, 3) TEA, CHCl3 2234 DMF, 4) MeNH2, 2235

82% MeOH,65%

OBo 1) n-octane, OBo X LDA, THF,

.••• CONHMe reflux, 87%

~O 1) H2, Pd(OHh, HMPA 2) n-Bu3SnH 100% .. .. ,,-CHO : OH ..

AIBN,PhH

~o XO 2) MsCl, TEA, o :. 3) pyr, HBr,

,x0 79% 97%

2236 59%

2237 2238

..

NHAc

~O o :

XO

HCl,THF

NHAc

HO~O OH

..

(+ )-leptosphaerin 2239

Scheme 397. White Synthesis of (+ )-Leptosphaerin

1) EtSH,

E·~f 1) HgO,

f?-~ HCI,O°C BF300Et2,

2) acetone NHAc aqTHF

.. 0 .. HO 4AMS

\f~l( 2) t-BuOK

NHAc H+,52% THF,O°C

N-acetyl-D-glucosamine 2240 64%

2241

NHAc NHAc

~OH -tJ 0

l)PCC NaOAc, 4AMS CH2Cl2 ..

2) aq TFA, 72%

OO~O OH

2242 (+)-leptosphaerin 2239

Scheme 398. Rollin Synthesis of (+ )-Leptosphaerin

Brominated Phenolic Ethers 253

synthesis of leptosphaerin (2239) by White [608] is illustrated in Scheme 397. Transformation of the diethyl ketal of ethyl pyruvate (2234) to amide 2235 occurs in six steps and 18% yield. Addition of the lithio dianion of 2235 to aldehyde 2236 provides alcohol 2237 as a crystalline product in 59% yield. Closure to the y-Iactone and removal of the phenylthio moiety with n-Bu3SnH gives benzyl enol ether 2238. Completion of the synthesis requires five steps to replace the benzyloxy substituent with an acetamido group and give (+)leptosphaerin (2239) in a total of 15 steps and an overall yield of 4.3%.

In the following year, a second synthesis of ( + )-leptosphaerin by Rollin appeared [609] (Scheme 398). N-Acetyl-D-glucosamine (2240) is ring-opened and fully protected to give 2241. Unmasking of the aldehyde followed by (l,~elimination gives the previously known lactol 2242 as a mixture of anomers. Oxidation and hydrolysis gives leptosphaerin in six steps and 24% overall yield.

6.2 Brominated Phenolic Ethers

A variety of highly brominated diphenyl ethers that act as self-defense substances have been isolated from Dysidea herbacea and Ptychodera flava laysanica [610]. Many of these exhibit antibacterial activity against Gram-positive and -negative bacteria. The synthesis of a highly brominated P. flava metabolite by Yamamura [611] is shown in Scheme 399. Anodic oxidation of brominated phenol 2244 affords trimer 2245. Reduction of 2245 with zinc in acetic acid provides biphenyl ether 2246 in 26% yield along with 43% of byphenyl 2247. Demethylation of 2246 by treatment with BBr 3 gives 2248 in three 5teps and 26% overall yield.

OH Br BrYyBr ly0H BrVoYBr

OH Br 2248

A series of2-phenoxy substituted brominated phenols has been isolated from sponges of the Dysidea sp. [612] and one member of the Callyspongiidae family [613]. Ghisalberti has synthesized [614] five of these, which are shown in Scheme 400. Coupling of potassium phenoxide 2250 with nitro-activated phenyl bromide 2249 provides diphenyl ether 2251. Control of temperature is crucial at this point, as higher temperatures lead to the formation of dioxins. Reduction of the nitro group affords the amine 2252 which is subjected to substitutive


OMe

BrVBr

~I Br

OH

2244

MeOH-OfCl3 LiCI04, AcOH

+610 mV vs. SCE

OMe Br

..

OMe

BrVBr

1# Br

MeO 0 Br

~~ (y0~ BrYO¥Br

o Br

2245

OMe OMe

Zn,AcOH &:<:(*mkfu Br

• ~ 1 ~ 1 + 3 hr, rt Br 0 BrBr Br

OH Br OH OH

2246 (26%) 2247 (43%)

OH Br

BrYyBr ~OH

Br¥O¥Br O°C

near quantitative OH Br

2248

Scheme 399. Yamamura Synthesis of Polybrominated Diphenyl Ethers from Ptychodera ftava

Rl Rz R3 ~ Rs

h°:¢c a Br Br Br Br H

b Br Br H Br H

Br #Ri #R4 c H Br H Br H

R3 d H Br H H H

2254 e Br H Br H Br

deamination according to the procedure of Doyle [615] to give methoxy compound 2253. Demethylation yields the natural products 2254.

As part of the structure elucidation process, Sharma and Vig synthesized the antibacterial pentabromodiphenyl ether 2258 as shown in Scheme 401 [616]. The phenol 2256 was tribrominated and coupled to 2,4-dinitro-chlorobenzene

R,

OM

e

O)~"

0'<

K'O;

¢C

HM

PA

+

I

.. 0

zN I~RZ I

~ R4

°2N

~

~

70-1

00°C

R

z R4

R3

R3

2249

22

50

2251

R,

OM

e

oo~~

$,O

NO

ho*~

BB

r3

CuB

r2 -

I ~

I ~

.. I ~

I ~

OC

H2C

H20

C

H3C

N

Sr

Rz

R4

Sr

Rz

R4

R3

R3

2253

22

54

Sche

me

400.

Ghi

salb

erti

-Fra

nces

coni

Syn

thes

is o

f Pol

ybro

min

ated

Dip

heny

l E

ther

s fr

om S

pong

es

0°*"

N

aS

H..

I

I 60

-84%

H

N ~

R

~

R

Z

Z

4

R3

2252

Rl

R2

R3

~

Rs

a B

r B

r B

r B

r H

b B

r B

r H

B

r H

C

H

Br

H

Br

H

d H

B

r H

H

H

e B

r H

B

r H

B

r

~ ~. [ f if f ~

VI


H0X)~

MeO ~ 2) Brz, AcOH

2256

2258

Sf

HO~Sf )LA

MeO Sf NaOH,EtOH

Sf Sf

.. diazotization, .. nox)Sf

I ~ I ~ 50% CuBr Sf MeO Sf

2258

Scheme 401. Sharma Synthesis of Brominated Diphenyl Ether from Dysidea herbacea

via an addition-elimination process to give 2257. Reduction of the nitro groups to the amines followed by Sandmeyer reaction led to 2258 which was identical to the natural product.

6.3 Others

6.3.1 Metabolites of Delisea fimbriata

Red algae of the Bonnemaisoniaceae are sources of large amounts of a number of polyhalogenated substances. Sims has synthesized several halogenated 1-octen-3-ones as part of the structure elucidation process [617] (Scheme 402).

~x x

2262 X, Y = Br 2263 X = Br, Y = I

·~B' X Br

2264 X=Br 2267 X=Cl

OH

~

2259

OH

Y

~X

Jone

s [0

]

x

x, Y

= B

r 96

%

X =

Br,

Y =

I 83

%

0

S02C

i2

~

CC

l 4

Br

32%

22

65

aqK

OX

OH

x =

Br

100%

X

= I

10

0% 22~

2261

x

..

o Y

~X

x 22

62

X,

Y =

Br

91 %

22

63

X =

Br,

Y =

I 55

%

0

~

Cl

Br

2266

pyri

dini

um

hydr

obro

mid

e pe

rbro

mid

e

69%

Br2

/ C

Cl 4

..

K2C

03

46%

Sche

me

402.

Sim

s S

ynth

esis

of

Hal

oket

ones

fro

m D

elis

ia fi

rnbr

iata

Br2

/ C

Cl 4

o B

r

~Br

Br

Br

2264

0 B

r

~Br

CI

Br

2267

o ;.

~

en

tv

Vl

-...l


The known octynol2259 was terminally halogenated to produce the iodide 2261 and bromide 2260. The bromoalkyne was further brominated and oxidized to metabolite 2262. Controlled ex-monobromination of 2262 produced the tetrabromo metabolite 2264. The iodoalkyne 2261 was treated similarly to produce metabolite 2263. Metabolite 2267 was produced by ex-chlorination of the alkynone 2265 to give 2266 which was then brominated. It is thought that n~ural products in Asparagopsis and Bonnemaisonia arise via a bromoperoxidase mechanism. Support for this idea was found by Hager [618] who produced a number of naturally occurring simple haloketones by halogenation catalyzed by an algal-derived enzyme extract.

~Br

O~o~ Br

Fimbrolides (E and Z)

Delisea jimbriata produces a number of halogenated lactones, including the fimbrolides (Scheme 403) [619]. Sims [620] has also synthesized two members of this family, confirming their structures. The keto acid was produced using standard chemistry. Symmetrical bromination to 2269 occurred on reaction with bromine/CHCl3 to give a dibromide which was not separated, but directly cyclized with accompanying oxidation using 100% H 2S04 to a mixture of the isomeric fimbrolides shown.

~ o •

NaOEt

EtOH

45%

•

~r

BOOC o

Br

.. heat

aqNaOH

heat

98%

•

Br

2269 Z olefin (28%) E olefin (trace)

Sdleme 403. Sims Synthesis of Fimbrolides from Delisea jimbriata

Others 259

6.3.2 Kjellmanianone

Kjellmanianone is a member of the cyclopentanoid class of antibiotics. It was first isolated in 1980 from the brown alga Sargassum kjellmanianum and was shown to have moderate activity against Gram-positive bacteria. Its absolute configuration has been determined by single crystal X-ray analysis [621]. Smith's synthesis [622] of kjellmanianone (2272) is illustrated in Scheme 404. Oxidation of the enolate of 2271 with MCPBA provides 2272 in two steps and 32% yield from ketone 2270. The synthesis can be made stereoselective, if an (+ )-N-aryl-camphorsulfonyloxaziridene replaces MCPBA as the oxidizing agent. The natural enantiomer (+ )-kjellmanianone is obtained in 36.5% enantiomeric excess.

{+)-Kjellmanianone 2272

6.3.3 Pukeleimide A

Along with the known irritants debromoaplysiatoxin and lyngbyatoxin, the blue-green alga Lyngbya majuscula also produces [623] the pukeleimides. The first synthetic entry into this class of 5-ylidenepyrrole-2-ones is the preparation of pukeleimide A (2277) by Pattenden (Scheme 405) [624]. Treatment of Nmethylimide 2274 with five equivalents of carboethoxymethylenetriphenylphosphorane regio- and stereo-selectively affords ester 2275 in low yield. Reaction of

0

Q LDA •

° OCH3 MeO)l.Imid

2270 51%

0 ° _C-Q I)KH H~ • Me02C A 2) MCPBA, OCH3 n,63% OCH3

2271 (±)-kjellmanianone 2272

I) KH, THF

° 2) (+)-N-Aryl-camphorsulfonyloxaziridine -:~

-78°C, 44%, 36.5% ee

OCH3

(+ )-kjellmanianone

Scheme 404. Smith Syntheses of (±)- and ( + )-Kjellmanianone


o

OH 0

Pukeleimide A 2277

0 ° ~O

MeNH3+ -OAc

~N-M' 0

I) aq KOH / TIlF 2) SOCI2 / PhH

3) Me0ll"r Lt-Li

2276 0

11lF 25%

• HOAc 83% °

2274

o

• L{ MeO\('~~ ° I I. N-Me

o

Scheme 405. Pattenden Synthesis of Pukeleimide A

:< Et02C"-../ !Ph3

• I N- Me PhCH3

36 hr reflux

31% ° 2275

o

SeOz .. MeOlQ~ HOAc 0 I I. N - Me

60% OH 0

pukeleimide A 2277

the acid chloride of 2275 with lithiated amide 2276 followed by allylic oxidation provides pukeleimide A in six steps with an overall yield of 3.9%.

6.3.4 Latrunculin B

Latrunculin B (2288) and the related latrunculin A are novel macrocydic toxins isolated from the Red Sea sponge Latrunculia magnifica (Keller), found in the Gulf of Eilat. When disturbed, the sponge emits a reddish fluid that causes any nearby fish to leave the vicinity immediately [625]. The latrunculitls also exhibit the interesting property of inducing reversible reorganization of cytoskeletal proteins. The structure of latrunculin A was determined through spectroscopic, degradative and X-ray crystal analysis. The structure of latrunculin B was determined by spectroscopic comparison with latrunculin A. Smith's synthesis [626J of ( + )-latrunculin B, shown in Scheme 407, is convergent. The general

Others 261

strategy involves aldol coupling of ketone 2283 with aldehyde 2281 to afford compound 2284. Rearrangement of 2284, homologation and macrolactonization completes the synthesis. Fragments 2281 and 2283 are prepared as shown in Scheme 406. Baeyer-Villiger oxidation of ketone 2278 and methylation affords a 1: 1 mixture of diastereomeric lactones 2279. Conversion to the

0 0 LDA/THF 0

~ MCPBA -78 °C .. .. CH2Cl2 CH3!

NaHC03 ~ ~

2278

~" ; 'h HO OH

2280 .. CSA/PhH

6 : 1 (trans/cis) diastereomer

separation

42%

55% overall 2279 I cis/trans

",.O~O '. 0

~

- III"~Q~ CHO

"near quant."

2282

I) NaH/DMF PMB-Br

2) aq. KOH 3) CH3Li I eq;

CH3MgBr 2 eq

30%

aldehyde 2281

ketone 2283

Scheme 406. Synthesis of Latrunculin B Fragments


orthoesters with chiral diol 2280 equilibrates the diastereomers to give a 6: 1 trans to cis ratio and allows separation, to give aldehyde 2281 in 23% yield after ozonolysis. Ketone 2283 is obtained from ester 2282 [627] in three steps and 30% yield. Aldol condensation between 2281 and 2283 proceeds to give diastereomeric mixture 2284 (Scheme 407). Treatment of 2284 with catalytic acid in methanol results in hydrolysis of the orthoester and formation of the mixed methyl ketal 2285. Conversion of 2285 to aldehyde 2286 and Wittig olefination provides lactone precursor 2287. Lactonization of 2287 and deprotection yields (+ )-latrunculin B in 13 steps and 0.68% overall yield.

6.3.5 Bisucaberin

Siderophores are iron-chelators which are produced by various organisms to acquire exogenous iron(III). The naturally occurring siderophore bisucaberin has been isolated from the marine bacterium Alteromonas haloplanktis and possesses a symmetrical hydroxyamide structure [628]. Bergeron [629] has produced this substance in short order, naturally taking advantage of this symmetry (Scheme 408). O-Benzylhydroxylamine was protected and alkylated to give 2290, which was converted to both fragments 2291 and 2292. These were coupled classically to give 2293 and converted to the seeD compound 2294. Macrocyclization occurred in 43% yield and debenzylation gave the natural siderophore 2295.

Bisucaberin 2295

6.3.6 Hormothamnione

Hormothamnione (2300) was isolated [630] by Gerwick from the blue-green alga Hormothamnion enteromorphoides in 1986. It is the first example of a naturally occurring styrylchromone. Hormothamnione exhibits potent cytotoxicity vs. P388 lymphocytic leukemia and HL-60 human promyelocytic leukemia cell lines in vitro and appears to be a selective inhibitor of RNA synthesis. The first syntheses of 2300 appeared in 1988. Brossi [631] prepared 2300 in a 14-step process (Scheme 409). Conversion of 2,3,4-trimethoxybenzaldehyde (2296) occurs in seven steps to afford the key intermediate pentamethoxybenzene 2297 in 54% yield. Friedel-Crafts acylation of 2297

~B-A

rS

o ke

tone

22

83 1)

LiH

MD

S

TH

F I

-78

°C

2) a

ldeh

yde

2281

CHO

'",.~

o I"

, .. 7

22

84

S

PM

B,N

-( o

TsO

H

.. M

eOH

25%

for

la

st t

wo

step

s

OM

o 13

PM

B_

N rS

o 2

28

5

~

1) T

BS

CI/

DM

F

Et3N

ID

MA

P

2) s

epar

ate

dias

t. ~ .O

TB

S

""'~

..

Ph3t~

'ooe

~

~HOO

~~~

""'~

""OT

BS

1) H

F I

pyr I T

HF

OM

•

o OM

PM

B-

N

o I

3) D

ibal

53%

OM

PMB.:

rS

o 22

86

1) C

AN

I aq

CH

3CN

. 2)

HO

Ac

I aq

TH

F 6

0°

C

42%

OH

TH

F 10

°C

81%

o 2)

DE

AD

I Ph

3P

PhH

PM

B_

N

66%

rS

o 22

87

MY

""'~o

o {+

)-la

trun

culi

n B

2

28

8

H_

N

rS

.

o

rS

o Sc

hem

e 40

7. A

ssem

bly

of (

-)-

Lat

runc

ulin

B F

ragm

ents

(Sm

ith)

f ~

w

1) t

-BuO

C0 2

t-B

u,

TE

A, T

HF

2)

NaH

,DM

F,

NaI

1) T

FA

, 75

%

/ 2)

suc

cini

c ..

~oc

anhy

drid

e

o

Nc(CH:z}4~~OH

BnO

0

BnO

NH

2·H

Cl

Bn

O-

N(C

IiV4 C

N

pyr,

d

Cl(CH~4CN,

87%

22

90

H2,

NH

3 "'"

R

a-N

i,

MeO

H,

83

%

1) D

CC

, D

MA

P,

65%

o

NC

(CH

:z}4

NJl

.-. _~~NH .....

I -~ ~

OB

o 2)

TF

A,

83%

B

nO

0 2293

~o H

9B

n

N

N

CO

H

H2N(CH:z}5~ ~ Y

'-'

2

BoO

0

0

2294

Sche

me

408.

Ber

gero

n S

ynth

esis

of

Bis

ucab

erin

1) D

PP

A,

DM

F,

o °c,

43%

2) H

2, P

dlC

, M

eOH

, I

atm

2291

.. H2N~NHOBn

1) s

ucci

nic

anhy

drid

e,

py

r,9

6%

2)H

2' N

H3,

R

a-N

i,

MeO

H,

65%

2292

:l~lo

HN~N"'OH

bisu

cabe

rin

2295

~ ~ I ~ I

Others 265

OH

MeO OH

MeO

Hormothamnione 2300

I) MCPBA, CHO CH2Ci2, rt OMc OMe

M~~ 2) Ag. KOH,

M~~ PhN(CH3)CHO M,oqCHO MeOH ..

MeO ~ 3) KOH, MeO ~ POCI3,80% MeO ~

OMe Me2S04,

OMe OMe 90%

2296

OMc OMe I) Na, 1) MCPBA,

M~*OM' I) EtCOCI

M~~ AcOEt, rt CH2Ci20 rt AICI3, rt

- - .. 2) Aq. KOH, MeO ~ 2) NaOH MeO ~ 2) HCI,

MeOH,82% 3) HCI, 55% OMe 0 55°C 75%

3) Me2S04, OMe

acetone, 92% 2297 2298

OH I) NaOMe, MeOH,

OMe 3,5-(BnOhC6H3-CHO

Meow 90°C, 80% MeO

: I I ---------MeO 2) AcOH, HCI MeO

OMe 0 100°C 79%

OH

OH o

2299 hormothamnione 2300

Scheme 409. Brossi Synthesis of Horomothamnione.

with propionyl chloride occurs with monodemethylation of an ortho methoxy group to give 2298, Claisen condensation of ketone 2298 with ethyl acetate followed by cyclization gives chromone 2299. Condensation of 2299 with 3,5-dibenzyloxybenzaldehyde followed by debenzylation and selective demethylation of the adduct provides hormothamnione 2300 in 14% overall yield.

A second synthesis of hormothamnione by Ayyangar [632] appeared later (Scheme 410), Monomethylation of ketone 2302 produces the same intermediate


OMe

H0Yy0H

MeO~ OMe 0

2302

1) NaOEt, EtOH OBn

oHcOOBn MeO 100%

2) BCI3, CH2CI2 -15°C, 100%

MeO

1) K2C03

MezS04

C6H6,50% •

2) AC20 NaOAc 180°C, 35%

Kostanecki-Robinson Reaction

OH

OMe

Meowo CH3

~ I I MeO CH3

OMe 0

2303

OH

OH

hormothamnione 2300

Scheme 410. Ayyangar Synthesis of Hormotharnnione

as that utilized by Brossi (Scheme 409). Application ofthe Kostanecki-Robinson reaction to this tetramethoxypropiophenone yields chromone 2203. Condensation of 2203 with 3,5-dibenzyloxybenzaldehyde, via the dienolate and monodemethylation affords hormothamnione (2300) in 35% yield from the common intermediate.

6.3.7 Bissetone

Bissetone (2306) is a metabolite of the soft coral Briareum polyanthes, isolated [633] in 1987. Lichtenthaler's synthesis [634] of 2306 is outlined in Scheme 411. The key starting material for Lichtenthaler's preparation of bissetone is the dihydropyranone 2304, available form D-glucose in two one-flask conversions in 67% yield. Stereospecific addition of methylallyl titanium isopropoxide followed by saponification gives diol 2305. Use of the lithium enolate of acetone gives 2306 and its epimer in a 5: 1 ratio. Ozonolysis of 2305 provides bissetone in three steps and 59% overall yield (four steps and 47% yield from D-glucose).

Bissetone 2306

2304

1) NHzOHeHCI py, 70°C, 14 hr ..

2) CH3CHO, HCI, CH3CN, ft, 10 hr

84%

o

BzO

O~ lO~OBZ

2304

Others 267

1) (CHz=C(CH3)-CHzlTi(OiPrh CHzClz, -78°C ..

2) NaOMe, MeOH, 15 min, 25°C, 83%

~OH 0 3, AcOH,Zn

o

~OH .. 2 hr, 25°C, 84%

2305 (-)-bissetone 2306

O-u+

A THF, -78 °c, ..

o t ~ NaOMe, MeOH, J

~ l o~ OBz -12-hr-, -0-"'C-,-9-2-%----' 10 min, 60%

Scheme 411. Lichtenthaler Synthesis of (- )-Bissetone

6.3.8 (S,S)-Palythazine

Along with the very poisonous palytoxin and a number of cyclohexanoid iminium salts, Palythoa tuberculosa produces [635] two heterocycles containing the dipyranopyrazine skeleton 2310 and 2311. One of these, (S,S)-palythazine (2310), is clearly related to bissetone and has also been prepared by Lichtenthaler [636] (Scheme 412). Formation of the oxime 2308 (readily available from D-glucose) followed by saponification gives pyranone 2309. Hydrogenation to afford the amine and air oxidation gives the natural product 2310 in three steps and 49% yield from 2308. Interestingly, the physical properties of 2310 suggest that the original structural assignments of palythazine and isopalythazine may be reversed.

~pNVOH HO ~ ° N

HOUN:(:('OH

° ~ ° N

Palythazine 2310 Isopalythazine 2311

6.3.9 Dysidin

Williard's synthesis [637] of dysidin [638] appeared in 1984 (Scheme 413). The general strategy involves the independent preparation of two fragments (2314


BzO BzO 0

o~ NH2OH·HCl HON~ NaOMe HON~ .. • pyr MeOH

96% 89% OBz OBz OBz

2308 2309

o

.. .. ~Nl\ air

EtOH 57%

OBz OH

(S, S)-palythazine 2310

Scheme 412. Lichtenthaler Synthesis of (S, S)-Palythazine

and 2316) which are coupled in the last step. Because of its relative inertness, the trichloromethyl functionality was introduced early in the synthesis. Radical chain addition of bromo trichloromethane to crotonic acid affords acid 2312 as a mixture of diastereomers. Reduction of 2312, conversion to the acid chloride and formation of the adduct with Meldrum's acid allows easy preparation of ester 2313. Ester 2313 was chosen due to its ease of hydrolysis after the formation of methyl enol ether fragment 2314. Fragment 2316 is formed from the N-phthalimide substituted acid chloride 2315 which is converted to the 0-methyltetramic acid in three steps and 15% overall yield. Activation of 2314 by treatment with thionyl chloride and addition of 2316 gives a 1: 1 mixture of (± )-dysidin along with its diastereomer. Dysidin (2317) is obtained in eight steps and 3.4% overall yield.

A second and similar synthesis was reported by Gerlach [639] in that same year which indicated that the absolute configuration assigned to dysidenin and isodysidenin should be revised. The Gerlach synthesis of ( - )-dysidin (Scheme 414) involved the coupling of an optically active trichloromethyl hexenoic acid

I) Z

n,

CH

2CI 2

CC

I3B

r 2)

SO

CI 2

, O

MF

I)

KH

, O

MS

, 0

CH

3 0

3) M

eldr

um's

Aci

d C

H3

0 H

MP

A,S

oC ~OH

~OH

AIB

N

CC

I 3¥

OH

pyri

dine

CCI3

~ ..

.. 2)

Me3

0+

BF

/ C

Cl3

0

90

°C

, 86%

4)

Et

S _

_ O

H

Br

EtS

CH

2CH

202C

C

6H6;

31

% o

vera

ll

53%

23

12

2313

23

14

CH

3 0

CH

3 0

0 1)

KH

, C

H30

N

H2N

H2,

CH

3¥C

l

Et0

2Cy

C0 2

-

CH3~OEt

HM

PA

,5°

C

CH

>-J=

y

~~

.. N

-Pht

h 1

HF

53%

23

15

2314

N-P

hth

I) S

OC

I2

2) 2

316

TH

F

Et2

0

24%

Sche

me

413.

Wil

liar

d Sy

nthe

sis

of (±

)-O

ysid

in.

MeO

H

-O

Et

H-N

I

.. ..

CH

re

flux

2)

CH

30S

QzF

3

N-P

hth

0 55

%

53%

0 23

16

o O

CH

CH

3 ~

cc,I--Y

-N I

' C

H30

o

(±)-

dysi

din

2317

+ r

acem

ic d

iast

ereo

mer

f $

~o C

OO

Et

NH

~OOCH2C6H5

~H3CO

0

5 N

H

2319

rac

emic

1) H

2/P

d

2) N

aOt-

amyl

1) B

uLi

CC

I

2)C\OC~-:-

3

OC

H3

(-)-

23

20

50%

Ro

°

(MeO

hS0

2

MeO

H,7

0%

;:;

0 C

CI 3

I N

-{ ~

_5

'==

( \

H3C

O

~ O

CH

3 ;-

(-)-

2317

an?

_ (+

)-5-

epid

ysl(

lin

~CCI3

HOOC~""

1) S

OC

l 2

2) M

eldr

um's

aci

d py

r

Me0

2C\

~CC\3

~

-':-

1) H

C(O

Meh

H

2S0

4 66

%

<-

3) M

eOH

, 6

5°

C

93%

(+

)-23

22 r

esol

ved

by

crys

tall

izat

ion

of d

iast

ereo

mer

ic

N-(

I-ph

enyl

elhy

l)-a

mid

es

Sche

me

414.

Ger

lach

Syn

thes

is o

f D

ysid

in

2) K

OH

I EtO

H

o 3)

(C

OC

lh I

PhH

CIO

C,

.r--

(CC

\3

'==\

":-

OC

H3

tv

--.l o ~ ~ ~ o ~ ~ '" S- O

" o [

Others 271

>rJ~ (Ph 0 RandS 2323 2321

piece with a racemic pyrrolinone piece. The racemic carboxylic acid 2322 was resolved via crystallization of diastereomeric amides to give the R isomer. This configuration was assigned by comparison of the NMR spectra of the isomers of 2322 with the corresponding trideuterio-compounds of known absolute configuration. Therefore, this structural assignment is only as good as the spectral analogy. In any case, the (- )-acid chloride 2320 was coupled with the lithium salt of the racemic pyrrolinone 2319 giving ( - )-dysidin and its 5-epiisomer.

6.3.10 Grateloupia Filicina Metabolite and Related Compounds

The pyrogallol derivative 2327 along with 3,4,5-trihydroxybenzyl methyl ether are found in the red alga Grateloupia filicina [640]. Both compounds show moderate antibacterial activity against Bacillus subtilis. An attempted synthesis of 2327 by Nakayama [641] that confirmed its structure is shown in Scheme 415. Ester 2324 is converted to sulfide 2325 in 70% yield. Reduction and oxidation produces sulfone 2326 in 4 steps and 21 % overall yield. Attempts to demethylate the phenolic hydroxyls were unsuccessful. However, methylation of the natural product and comparison with sulfone 2327 confirmed the identity of 2327.

OMe

~~~ HO~OH

OH

Grateloupia filicina Metabolite 2327

During an investigation of the constituents of marine red algae, three brominated hydroxy dibenzyl ethers were isolated from the red alga Symphyocladia latiuscla [642]. Amiya's [643] syntheses of the methyl ethers ofthese compounds are illustrated in Scheme 416. The starting material, 3,4-diinethoxybenzyl acetate (2329), is obtained via standard methods from vanillin. Bromination of 2329 affords the tribromobenzyl bromide 2330, which can be hydrolyzed to benzyl alcohol 2334. Williamson ether coupling of 2330 with ethanol, methanol and substituted benzyl alcohol 2334 produces the methyl ethers 2332, 2333 and 2331 of the natural products. Confirmation of the structures of the


~MO OCH2SCH3 q:SM. 1) LAH, 87% q:SMO • •

MeO # OMe SnCI4,70% MeO # OMe 2) TsOH MeOH, MeO # OMe reflux, 53%

OMe

2324

MCPBA •

66%

OMe

2325

OMe

q:S~M' q:S~M' X • HO # OH MeO OMe

OMe OH

2326 2327

Demethylation step unsuccessful; the natural product (2326) was methylated to establish the identity of (2327)

Scheme 415. Nakayama Attempted Synthesis of Grateloupia filicina Metabolite 2327

Br*::oc:: 1# Br OMe

OMe

2331 2333

Br Br Br Br

~*C~~*OM' MeO Br Br OMe

2332

Halogenated SymphyocJadia Metabolites

OMe

methyl ethers was obtained by methylation of authentic samples of the natural materials.

6.3.11 Didemnenones A and B

The didemnid tunicate Trididemnum cyanophorum, collected on the seagrass beds off Shroud Cay, Bahama Islands, produces (+ )-didemnenones A (2342)

CH20Ac

~ Br2,Fe.

~oMe 19%

OMe

2329

Br:¢c::Br Br

I~ Br OMe

OMe

2330

I H20 +90%

Br:¢c::OHBr

I~ Br OMe

OMe

2334

Others 273

2334, NaH •

34%

~35~~a,

~

2333

Scheme 416. Synthesis of Brominated Phenolic Compounds of the Rhodomelaceae

Didemnenone A 2342 (a-OH) Didemnenone B 2343 (P-OH)

and B (2343). The relative stereo structures of A and B were determined by X-ray diffraction analysis followed by chemical and spectral correlations [644]. Didemnenones A and B show antibacterial activity and antifungal activity vs. the pathogenic marine fungus Lagenidium callinectes. Scheme 417 illustrates Clardy's synthesis of 2342 and 2343 [645]. Addition of hydroxymethyl anion equivalent 2336 to cyclopentenone 2335 (94% ee) affords alcohol 2337 as a 7: 1 diastereomeric mixture. Conversion of 2337 to propargyl ether 2338 sets the stage for the key step of the synthesis, i.e., the formation of the C6-C7 bond. Mercuric chloride mediated cyclization of the alkyne onto the silyl enol ether

TBS~

t-B

lIO

CH

2Li

TB

SO

I) N

aH /

TH

F

~

Q

2336

qOH

H =

CH

2Br

.. •

TH

F /

t-B

lIO

Me

2) T

BA

F /

TH

F

0 -7

8 °C

/ 5

min

3)

PC

C /

CH

2Ci 1

O

IBu

23

35

75

%

23

37

85

%

as a

7 :

1

dias

tere

omer

ic

mix

ture

1) H

gCIl

/ H

MD

S

~

CH

1CI 1

A

c10

/F

eCI 3

•

\ 0

2) N

IS /

NaI

o °

C /

1 hr

91 %

fro

m 2

33

8

OtB

u 88

%

~Ih

\ 0 O

Ac

23

39

2

34

0

v ( Sn

Bu 3

o \ qo OIB

u

23

38

SeO

z

tBuO

OH

C

ICH

1CH

1Cl

83

°C

/ 8

hr

HC

l M

eOH

/ p-

TsO

H

23

°C

/ 4

days

~Hl

h ·''

'OM

e ..

\ 0

(Ph 3

PhP

dCl z

·"

'OM

e

23

41

DM

F/2

4°

C/1

8h

r O

Ac

72%

24%

fro

m 2

34

0

Sche

me

417.

C

lard

y S

ynth

esis

of (

+ )-

Did

emne

none

s A

an

d B

OA

c

aq T

HF

70%

T"O~

\ T

BS

OT

f •

Et3

N

<:to

CH

1Ci 2

O

IBu

... ~

\{i~OIBU

OA

c

1 :

1 m

ixtu

re

OH

OH

obta

ined

as

a I

I m

ixtu

re

dide

mne

none

A

a-O

H

23

42

di

dem

neno

ne B

~-OH

23

43

tv

-l

oj:>

.

~ ~ ~ ~ a:: ft <T ~

Others 275

followed by treatment with NIS gives iodide 2339 with the correct geometry for subsequent formation of the diene system. Iodide 2339 is transformed into compound 2341 in three steps. Palladium-catalyzed coupling of 2341 with tri-nbutylvinylstannane and hydrolysis provides didemnenones A and B as a 1: 1 mixture. The didemnenones are obtained in only 12 steps and 5.1 % overall yield.

6.3.12 Tridacna Maxima Metabolite

Arsenic-containing metabolites have been isolated from a variety of marine sources. One ofthese, the naturally occurring carbohydrate (R)-2',3'-dihydroxypropyl 5-deoxy-5-dimethylarsinyl-~-D-riboside (2350) has been the subject of a total synthesis by Stick [646] (Scheme 418). Metabolite 2350 has been isolated from both the brown kelp Ecklonia radiata [647] and the kidney of the giant clam Tridacna maxima [648]. Stick's synthesis of 2350 begins with orthoester 2345, easily obtainable from commercially available 1-0-acetyl-2,3,5-tri-Obenzoyl-~-D-ribose. Transesterification of 2345 with alcohol 2346 gives orthoester 2347 which is immediately rearranged into glycoside 2348 in 76% yield. Exchange of protecting groups and chlorination by treatment with Ndichloromethylene-N,N-diethylammonium chloride yields chloride 2349. Displacement of the ehloride with dimethylarsinosodium and oxidation completes the synthesis to provide 2350 in nine steps and 22% overall yield, thus establishing the relative and absolute configuration of 2350.

Tridacna maxima Metabolite 2350

6.3.13 Nereistoxin

The 1,2-dithiolane nereistoxin (2357) [649] is a neurotoxin produced by the worm Lumbriconereis heteropoda. It and related substances have been prepared by Hagiwara [650] from 1,3-dichloro-2-propanol (Scheme 419) in one of the earliest references to marine natural products synthesis. Double chloride displacement on 2351 by sodium phenylsulfide gave 2352 as a protected form of a disulfide. Treatment with SOC1 2 gave a mixture ofthe desired 2353 as well as

"(XX)'vo~

~+OMe

PhC

OO

0

Ph

2345

o HO~O>(

2346

PP

TS

/PhC

H3

NaO

CH

3

CH

30H

H°'v0~~O

H

0+

HO

O

H

Cl'v0~~O

H

0+

o o

·

X 23

49

Mez

AsN

a

TII

F

81%

"coo

~ O~:><

PhC

OO

0

+

Ph

PhC

OO

~

~ ~

Of

2347

Me

CX

Me

CH

2CI 2

/HC

I

H°'v0~~O

H

0+

o 0

X

66%

As ~

"';/\:1

\+

X

1)H

202

/TH

F 2)

aq.

TF

A

3) a

q N

H3

64%

PhC

OO

O

OC

Ph

+ NE~ cr

C

l)l.

Cl

CH

2C1 2

85%

0- I

2348

76

%

Me .

.... NQ~

Me

0 0

\ O

H

OH

o 0

X

Trid

acna

m

axim

a m

etab

olit

e 2

35

0

Sche

me

418.

Stic

k Sy

nthe

sis

of T

ridac

na m

axim

a M

etab

olite

235

0

!j

0'1 ~ f f [

Others 277

Nereistoxin 2357

2354, probably derived by cationic rearrangement involving an episulfonium ion intermediate. Chloride displacement by dimethylamine gave 2355 and 2356. Deprotection and air oxidation of the resulting dithiol gave the naturallyoccurring disulfide 2357.

6.3.14 3-n-Hexyl-4,5-dithiacycloheptan-5-one

Another interesting disulfide is the dithiacycloheptanone 2361 isolated from the brown alga Dictyopteris plagiogramma. Although this is clearly related to the C11 brown algal pheromones reviewed earlier (Sect. 5), it is included here because of its structural similarity, albeit somewhat vague, to nereistoxin. Moore has prepared this substance as part of the structure elucidation process (Scheme 420) [651]. Bis-Michael addition ofthioacetic acid to the dienone 2359 gave rise to 2360. Methanolysis ofthe thioacetates and iodine oxidation gave the cyclic disulfide 2361 in short order, confirming the structure of this substance.

o

s-s 3-n-Hexyl-4,5-dithiacycloheptanone 2361

6.3.15 3-Methylnavenone B

When molested, the blind carnivorous sea-slug N avanax inermis releases a photosensitive mixture of trail-breaking alarm pheromones. The components of this bright yellow mixture have been identified as a series of 10-aryldeca-3,5,7,9-tetraen-2-ones along with several minor metabolites [652]. One of these minor metabolites, the yellow tetraenone 3-methylnavenone B (2364), has been prepared by Knox [653] in a single step from triene aldehyde 2362 (Scheme 421).

Ph~Me Me

3-Methy~navenone B 2364

OH

O

H

Ii P

hCH

2SN

a

Ii

• C

l C

l (S

S

]

2351

P

h P

h

2352

CH

3 'N

"CH

3

Ii

Na,

NH

3 r---r~"CH3

+

(S

S]

(S

S

]

CH

3

Ph

Ph

Ph

Ph

2355

23

56

Sche

me

419.

Hag

iwar

a S

ynth

esis

of

Ner

eist

oxin

Cl Ii

SOC

12

r---r

Cl

• +

(S

Ph

CH

3,

"C

H3

N Ii

SH

SH

S]

(S

S

]

Ph

Ph

Ph

2353

23

54

+ r---r~"CH3

SH

SH

CH

3

(CH

3hN

H

O2 - (air)

CH

3,

"C

H3

N Ii

S-S

nere

isto

xin

2357

yi

eld

of 6

% f

rom

235

5 an

d 23

56

N

-....I

0

0 s:: [ § <>

o ~ s:: <> g. o s.: <> '"

Others 279

OH

~CHO ~ • 2 hr, chromatography

o

~ AcS 0 MeOH-HCl

CH3COSH I II -------i.~ --=-----1.~ ~SAc 1.5 hr, 75°C

2359 2360

o

SH 0

~SH ~ S-S

• 66-70%

3-n-hexy 1-4,5-dithiacycloheptanone 2361

Scheme 420. Moore Synthesis of 3-n-Hexyl-4,5-dithiacycloheptanone

Ph~CHO

2362

o ~ )lp-OEl

Me' I 'OEl Me

• NaH,DME

o

Ph~Me Me

3-methylnavenone B 2364

Scheme 421. Knox Synthesis of 3-Methylnavenone B

Olefination of 2362 provides the natural product 2364. The stereochemistry of the natural product was determined unambiguously via formation of its monoand di-Fe(COh complexes, followed by regeneration of the original tetraene.

6.3.16 Malyngolide

Malyngolide is a six-membered lactone isolated from the lipid extract of the shallow-water variety of the blue-green alga Lyngbya majuscula [654]. It

Malyngolide 2370


exhibits antibiotic activity against Mycobacterium smegmatis and Streptococcus pyogenes. Due to its structural simplicity, its combination of two chiral centers (one of which is quaternary), and the large number of more complex natural products that possess the 5-substituted o-lactone moiety, malyngolide has been the target of a large number of syntheses designed to test new methodology.

The first reported synthesis of malyngolide is that of Mukaiyama [655] shown in Scheme 422. The key intermediate in this synthesis is the chiral exhydroxy aldehyde 2368, which is obtained in three steps from proline derivative 2366. Reduction of 2368 and selective silylation of the resulting diol followed by ozonolysis provides lactol 2369. Oxidation and methylation of 2369 yields malyngolide and 2-epimalyngolide with poor diastereoselectivity. Malyngolide (2370) is obtained in 15% yield over nine steps. The yield of (- )-malyngolide can be increased by epimerization of 2-epimalyngolide to a 1: 1 mixture of diastereomers followed by separation.

A racemic, though diastereospecific, synthesis of malyngolide by Babler [656] is illustrated in Scheme 423. The Michael reaction between diethyl methylmalonate and I-dodecen-3-one (2371) followed by decarboxylation and Wittig olefination affords o,&-unsaturated acid 2372. MCPBA oxidation of 2372 in a toluene/cyclohexane mixture produces epoxide 2373 which cyclizes in situ to give malyngolide as a single diastereomer. Malyngolide (2370) is obtained in six steps and an overall yield of 17%.

Cardillo [657] has developed two syntheses ofmalyngolide based upon the addition of the dianion of tiglic acid to either an aldehyde or ketone (Scheme 424). Addition of decanal to the tiglic acid dianion proceeds initially at the exposition. Allowing the resulting ~-hydroxy carboxylate to warm gives the thermodynamically more stable o-addition product 2375. Hydroxy acid 2375 is converted in five steps to the o,&-unsaturated acid 2376. Iodolactonization of 2376 followed by mercuric ion assisted hydrolysis of the resulting iodide gives malyngolide 2370 with almost no stereo selectivity. Malyngolide is obtained in 21 % overall yield over eight steps. An alternative procedure for the preparation of 2370 involves the addition of tiglate dianion to THP protected ex-hydroxy ketone 2377. Hydrogenation of 2378 and treatment with 6N HCI provides malyngolide as a 1 : 1 mixture of diastereomers. After separation malyngolide is obtained in six steps and 45% yield from decanoyl chloride.

A synthesis of malyngolide (2370) by Torii [658] also proceeds with an absence of diastereoselectivity (Scheme 425). Electrooxidative cleavage of exhydroxycyclopentanone 2379 affords the cleavage product 2380 in 93% yield. Wittig olefination and hydrolysis followed by iodolactonization gives iodolactone 2381. Due to difficulties in the hydrolysis of the iodide, the iodolactone was converted to the epoxy ester 2382 and reclosed with BBr3 to give'a 1: 1 mixture of the malyngolide diastereomers. After separation, a 27% yield of malyngolide was obtained in six steps from substituted cyclopentanone 2379.

Matsuo has developed two approaches towards the synthesis of malyngolide (2370). The first of these [659] involves alkylation of ~-ketoester 2384 to give 2385 (Scheme 426). Protection of the ketone as its enolate and reduction of the

~

H

NH

Ph

23

66

NaB

H4

, rt

,

52%

ove

rall

from

236

7

PD

C,D

MF

,

rt,

100%

o MeO~OMe

OH

~

}-NP

h

~MgBr

MgC

lz, -

100°

C" ~

1) n

-C9H

\9M

gBr

-100

°C

N

..

)-~Ph

2) 2

% H

Cl

OH

~'''CHO

C9H

Wn

oA

OM

e

2367

OH

~",,/OH

TB

SCI

Et3

N,D

MA

P

98%

C

9HW

n

o 60T

BS

.. ,..

1 L

DA

, -7

8 °C

,

HM

PA,

Mel

, 74%

• C

9H

19-n

O~

. .

,H ~",,/OTBS

~Hwn

o U O

TBS

o I

..1

\\

TB

AF

C9H

Wn

2368

1) 0

3, -

78 °

C

2) M

ezS,

69%

~O OH

~.)

OH

6 .. .1'

C9H

Wn

23

69

C9H

Wn

(-)-

mal

yngo

lide

23

70

58%

plu

s 29

%

of 2

-epi

mal

yngo

lide

Sche

me

422.

Muk

aiya

ma

Synt

hesi

s of

(-

)-M

alyn

golid

e

o S- CI> ::;l

N

00

-


MCPBA ..

2373 (±)-malyngolide 2370

Scheme 423. Babler Synthesis of (±)-Malyngolide

ester affords ~-hydroxy ketone 2386, which is subjected to Baeyer-Villiger oxidation giving lactone 2387. Protection of the hydroxyl as its THP ether and methylation results in a 5: 4 mixture of malyngolide (2370) and its C2 epimer. Malyngolide is obtained in six steps and an overall yield of 11 %.

The second approach by Matsuo [660] diastereoselectively provides malyngolide (2370) in four steps (Scheme 427). Sequential alkylation of ~-ketoester 2384 produces a mixture of diastereomers. Protection of the ketone as its enolate and LAH reduction of the ester results in formation of the alcohol and epimerization at C2 to provide 2386 as one diastereomer. Baeyer-Villiger oxidation of 2386 provides malyngolide in 62% overall yield.

The key step in the synthesis ofmalyngolide by Kozikowski [661] involves the reductive coupling of an organomercurial with an electron deficient olefin (Scheme 428). Alkylation of dianion 2388 with l-iodooctane and protection of the hydroxyl as its THP ether affords alkene 2389. Oxymercuration affords organomercurial 2390 which undergoes radical addition to methylacrylonitrile when reduced with NaBH (OMeh. Treatment of the resulting o-hydroxy nitrile 2391 with TsOH produces a 1: 1 mixture of malyngolide diastereomers. Malyngolide (2370) is obtained in five steps and < 11 % yield after separation.

A synthesis of malyngolide that is somewhat similar to the Matsuo synthesis (Scheme 426) is that of Kim [662] (Scheme 429). Baeyer-Villiger oxidation of ~ketoester 2393 followed by methylation and ester hydrolysis gives lactone 2394. Reduction of the acid via its mixed anhydride yields a 70: 30 mixture of malyngolide 2370 along with its C2 epimer. Malyngolide is obtained in 42% yield over five steps. The yield is increased by epimerization of the C2 epimer.

An enantiospecific, though non-diastereoselective, synthesis of malyngolide was developed by Sinay [663] (Scheme 430). The overall strategy involves the use of methyl 4,6-0-benzylidene-2-deoxY-\l.-o-erythro-hexopyranosid-3-ulose (2395) as a chiral template. DIose 2395 is available in five steps from the commercially available methyl \I.-o-glucopyranoside. Stereospecific addition of nonylmagnesium bromide to 2395 followed by hydrolysis and olefination gives

fOH

1) J

ones

[0

] 85

%

2) C

H2(

Mg

lh,

80%

3)

KO

H,

100%

NaH

/LD

A

n-y

HI9

CH

O,

70%

OH

~ OH

o U

C9

HI9

-n

23

75

~

12,C

H3C

N;

o 90

%

C9H

Wn

23

76

Alt

erna

te S

ynth

esis

:

o

1) C

H2N

2 • 2)

H2,

Pdl

C

100%

o '6J C

~19-n

o

~OH

o U

C9

Hw

n

Hg(

C10

4h I

aqD

ME

83%

~OOH

~ .. \.1

C

9H19

-n

mal

yngo

lide

2

37

0

(60%

) ep

i-m

alyn

goli

de

(40%

)

)l

n-~HI9

CH

N2

1) 2

N H

2S0

4, 8

3%

2) D

HP

, am

berl

yst

H15

92

%

n-C

9H19

~OTI

fP

[ 0]

2" fO

~i'+

68%

o

HO~T&

C9H

19-n

23

78

Sch

eme

424.

Car

dill

o S

ynth

esis

of

Mal

yngo

lide

1) H

2> P

dlC

2) 6

NH

Cl

87%

23

77

~OOH

~ .• \\I

C

9H19

-n

mal

yngo

lide

2

37

0

f tv

co

w


° ~C9HI9-n -2e, MeOH, ¢C'HW" •

OH LiCI04,93% C02Me

° 2379 2380

2381

Scheme 425. Torii Synthesis of{±)-Malyngolide

1)ph3P=CH2 89%

2) aq KOH 910/;

2382

¢C'H"" .. C02H

(±)-malyngolide 2370 1 : I mixture

tetraol 2396. Hydrogenation and hydrolysis of 2396 affords a 1: 1 mixture of diastereomers that was separated after lactonization to give lactone 2397. Oxidative cleavage of 2397 and reduction with diphenyltin hydride produces (- )-malyngolide in eight steps and 16% overall yield.

The strategy of Eliel [664J for the enantio- and diastereospecific synthesis of malyngolide involves the coupling of optically pure Grignard reagent 2399 with optically pure ketone 2401 (Scheme 432). Grignard reagent 2399 is prepared in five steps and approximately 55% yield from N -crotyl-( - )-ephedrine (Scheme 431). Oxathiane 2400 is converted to ketone 2401 by addition of its lithio anion to decanal followed by oxidation. Addition of Grignard reagent 2399 to 2401 proceeds with 98% stereo selectivity, giving 2402 in 96% yield. Alcohol 2402 is converted to (i-hydroxy acid 2404 which cyclizes to (- )-malyngolide upon standing. A yield of 20% is achieved over 12 steps. In a similar manner, the other three isomers of ( - )-malyngolide can be obtained.

Another enantiospecific synthesis of malyngolide (2370) that does not exhibit diastereoselectivity is that of Ho [665J (Scheme 433). The synthesis begins with mannofuranose 2406 available from D-mannose. Conversion of 2406 to epoxide 2407 occurs in two steps and 80% overall yield. Copper-catalyzed opening of epoxide 2407 with n-nonylmagnesium bromide gives diol 2408. Removal of the secondary hydroxyl requires five steps to yield lactol 2409, after hydrolysis. Wittig olefination, hydrogenation and saponification produces diol 2410 as a 1: 1 mixture of diastereomers at C3. Lactonization gives 2370 ami epimalyngolide as a separable mixture of diastereomers. Malyngolide is obtained in approximately 12% yield over 12 steps.

Hagiwara's [666J synthesis (Scheme 434) of malyngolide (2370) is one of the few to solve the problem of diastereoselectivity. Condensation of ~-ketoester 2411 with THP protected cx.-hydroxy ketone 2412 provides lactone 2413. Reduction of the ketone and elimination give cx.,~-unsaturated lactone 2414.

°

°

OH

1)

LD

A

° I

C

OO

Et

.. ~

.. &

"-

c,H

"Ik,

N

aH,

DM

F,

82%

ij;O

OE

t

.' C

9HW

n 2

)LA

H (j l C 9

HW

n 3)

2 N

HC

1

2384

DH

P,p

TsO

H

CH

2C12

,79%

[&

:] 23

85

LD

A,H

MP

A

Mel

Sche

me

426.

Mat

suo

Syn

thes

is o

f (±

)-M

a1yn

go1i

de

64%

23

86

°

UO

TH

P

° I ." '~9H19"n

as m

ixtu

re o

f IX

and

~

met

hyl

(not

sep

arat

ed)

MC

PB

A,

NaH

C0:

3,

82%

aq.A

cOH

58%

.. °

C(

~.) ~H19

-n

2387

° °

I '6

0H

-,,

\. C9H

Wn

(±)-

ma1

yngo

lide

23

70

as a

5:4

mix

ture

w

ith

its

C-2

epi

mer

o ;.

~ N

00

V

'o


a

&COOEt [ a 1 COOEt

~~Rwn LDA. Mel.

NaH.DMF HMPA

2384 2385

LDA.LAH

a

MCPBA 'OaR ----i .. ~ ~.)

THF. NaHC0:3 74% from 2385 84% ~Hwn

2386 (±)-malyngolide 2370

Scheme 427. Matsuo Improved Synthesis of (±)-Malyngolide

1) CH3(CH2hl jaTHP _ .. 2) DHP. POCl3

C~wn

2388 2389

2390 2391 as 4: I mixture with

1) Hg(OAch. H20

2) NaBr. 45% overall

TsOH

17 hr

b

~J" C9RWn

(f)-malyngolide 2370 product of simple reduction

Scheme 428. Kozikowski Synthesis of (±)-Malyngolide

a ~ .."COOMe _K_O_H_._n_-<4l __ 19_B_r ........ ~ U DMSO

1) MCPBA

2) LDA. Mel. HMPA.91%

3) Lil. py. 98% 2393

a

'Ct=H C~wn

2394

Zn(B14h. 80%

Scheme 429. Kim Synthesis of Racemic Malyngolide

.. ~IH C9R19-n

(±)-malyngolide 2370 as 70:30 with

epi-malyngolide

O~

<

n-C

-l-l

J9M

gBr

Ph

""

0 ~.

0""

""

OM

e

0 DC

, 3

hr,

85%

o 2395

H

°D

Ph

<

1) H

CI,

acet

one

'".

0 0

""

''''O

Me

2)

(Ph

hP =

CC

H3 C

OO

Et

n-C

9H19

~

70%

O

H

H

UC0

2E

t<?

'·C

I

HO

O

H

.••• \

OH

C9H

Wn

2396

o

1) H

2, P

d/C

·~~

·~t~:9

<?"C

OH

~ •• ,

OH

[Osl

~~""

COH

~)(

OH

1) P

b(O

Ac)

4 o

I D

OH

.. 2)

NaO

H

99%

Ph 3

P 90

%

C9H

Wn

)

2) P

h ZS

nH2

60%

.' "'

C9H

19-n

C

9HW

n

1 :

1 m

ixtu

re

of

C2

epim

ers

2397

(-

)-m

alyn

goli

de

23

70

Sche

me

430.

Sin

ay S

ynth

esis

of (-

)-M

alyn

goli

de

I H

~Nr;:

°H

O ~

Ph

H

N-c

roto

nyl

(-)-

ephe

drin

e

I H

C6H sM

gBr ~ Nr;

: ------.;

--

r~' .. ·,.

Y>"

II E

t20

C6H

5'<:

H

0 H

O ~

Ph

H

87%

de

(pur

ifie

d to

97

% d

e, 7

0% y

ield

6N

HzS

0 4

AcO

H 9

70/, ~ ~OH

, 0

C6Ht

~H

II o

LA

H, E

tzO

99%

~OH

C6H5

~'~H

-

Ph3P

Br2

.. D

MF

,89

%

59%

ove

rall

~Br

C6H5

~"~H

-

Mg,

Et2

0

soni

cati

on

~MgBr

C6H/"~H

-

(R)-

2399

Sche

me

431.

Syn

thes

is o

f G

rign

ard

Rea

gent

239

9 (E

liel)

o [ N

00

-..

.l


2403

2402

on standing 25°C .. CHCl}, 24 hr

2404

Scheme 432. Eliel Synthesis of (+)- and ( - )-Malyngolide

2401

o

.. CDCI3, 7-11 hr

high yield

I) NaHC03 .. THF, H20

2) HCl, ether

o I '6 CH20H

..,,\\.

C9HW n

(-)-malyngolide 2370 43% from 2403

Reduction and hydrolysis of 2414 (the lower pathway) affords malyngolide and 2-epi-malyngolide in approximately a 1: 1 ratio. However, if the sequence is reversed and the THP group is removed prior to hydrogenation, participation of the free hydroxyl in the hydrogenation process gives malyngolide in a 15: 1 ratio with 2-epi-malyngolide. Choice of solvent is crucial; the highest diastereoselectivity is obtained using hexane. Racemic malyngolide is obtained in five steps and 34% overall yield.

Another enantiospecific, but not diastereospecific synthesis of malyngolide is that of Nagano [667J shown in Scheme 435. Alkylation of the acetonide of dimethyl tartrate gives a 1: 4 mixture of the r:t. and ~ diastereomers 2417a and 2417b, along with 20-30% of the dialkylated product. Reduction of the major isomer gives triol 2418 which is converted to 2420 by transformation to the iodide 2419 and alkylation with diethyl methylmalonate. Deprotection, decarboxylation and cyclization of 2420 gives (+ )-malyngolide (2370) along with 30% of 2-epi-malyngolide. Malyngolide is obtained in 4.3 % yield over 11 steps.

HO

oryf

:;l

-To H

do-

-/-1)

ref

. 6

2) T

sCl,

py

r 10

0%

2406

n-C

gH17

MgB

r

CuI

, T

HF

, 10

0%

_1~"c9Hwn

MeO

r l

.... OH

OH

2408

aq.H

Cl

OT

s

l~ .. ,1

HO~)(i

HO

I

-

1) A

C20

, py

2) A

C20

DM

SO

3)

K2C

03,

aq.

MeO

H

89%

?\ .

.. ,C9H

19-n

Meo

A/'-

OC

H2S

Me

acet

one,

75%

?\ .

.. ,C9H

19-n

HO

A/'

-O

H

2409

TsO

H M

eOH

l~"

'''1

Meo~y '0

re

flux

, 80

%

_,l~

"C9H

19-n

M

eOJ'"

y '

OC

H2S

Me

OH

OH

2407

1)

S N~N)lN~N

'I=

l \=

I

TH

F,

refl

ux,

87%

2)

n-B

u3S

nH

AIB

N

82%

PP

h 3

Et0

2CJl

....

CH

3CN

,72

% ~o

OH

OH

I E

tO

I .....•

C9H

19-n

1) H

2, 1

0% P

d/C

3

hr,

EtO

H ~o

OH

OH

I H

O

.,~\\\

[n 1

N

S

t

o

~OH

o

I

2) K

OH

, aq

. M

eOH

10

0%

Sche

me

433.

Ho

Syn

thes

is o

f (-

)-M

alyn

goli

de

C9H

19-n

2410

Ph3P

, 90

%

,., "~9H19-n

(-

)-m

alyn

goli

de

23

70

pl

us 3

-epi

mal

yngo

lide

o go

(II Ol tv

0

0

'Cl

0 0

0 0

Na

H/n

-Bu

Li

TII

F

t-B

uNH

2·B

H3,

SO

CI 2

,py,

..

• ..

0 oX

xm<W

~OEt

&

MeO

H, c

itri

c ac

id

74%

fro

m 2

413

C H

.J

l-O

TH

P

HO

C

9H19

-n

83%

C

9HW

n

2411

9

19 24

12

74%

Jo ?THP

~

C~19-n

2414

2413

TsO

H

aq.

EtO

H

;:Y

5%~

~

o '{v"

I 0 ~H19

"n

&

o ~H19

"n

Sche

me

434.

Hag

iwar

a S

ynth

esis

of (±

)-M

alyn

goli

de

5% P

dlC

, __

____

_ H

2

hex~

76%

~

aq.E

tOH

99

%

from

241

4

o

~OOH

0) C

~19-n

(±)-

mal

yngo

lide

23

70

as 1

5: 1

ratio

with

2-

epi-

mal

yngo

lide

via

hydr

ogen

atio

n of

alc

ohol

; on

ly 5

5 : 4

5 vi

a hy

drog

enat

ion

of T

HP

ethe

r

N

\0

o ~ [ r ~ '" g. ~

<t '"

39% 2416

Li(EthBH ..... OH

.. n-C9H\9~OH THF,98%

OH

2418

..... 01( ~"~

CH3CH(C~Eth

• NaH,89%

2419

1) H2, 10% Pd/C, .. AcOH,70%

2) MsCl, py, 89%

2417a) R= ~-CH2CH=CHCt;H13 2417b) R= a-CH~H=CHCt;H13 plus 20-30% of dialkylated product

(~.1:4)

..... 01( pTsOH, acetone

,-c,H"~ .. n,3 hr,76%

OH

..... 01( 1) AcOH, 4 hr

,-c,H" 5 reflux .. 2) NaOH, ether 3) toluene, reflux

Me COzEt COzEt

2420

Scheme 435. Nagano Synthesis of (+ )-Malyngolide

Others 291

1) MsCl, py, 90% ..

2) NaI/MEK 93%

° '_(y}H '. 3 °

" ". n-C9H\9

(+)-malyngolide 2370 40% plus 30%

of 2-epimalyngolide

The synthesis of malyngolide (2370) by Wuts [668] is outlined in Scheme 436. The key step involves carbon-carbon bond fragmentation of acid 2422 via oxidative electrolysis. Acid 2422 is obtained through standard transformations, begining with Birch reduction of 3-methoxybenzoic acid (2421), in six steps. Electrolysis of 2422 gives unsaturated ester 2423 which is alkylated to give compound 2424. Oxidation and cyclization provides malyngolide as a 1.8: 1 mixture with 2-epi-malyngolide, in a total of 11 steps.

Giese's synthesis [669] of malyngolide provides all four stereoisomers in approximately 10% overall yield for each (Scheme 437). Sharpless epoxidation of ally lie alcohol 2426 provides epoxide 2427 in41 % yield and >96% ee. Lightinitiated radical coupling of iodide 2428 with methyl methacrylate in the presence of sodium borohydride and catalytic amounts of tri-n-butyltin chloride gives ester 2429 as a mixture of all four diastereomers. Hydrogenation and solvolysis of 2429 gives an approximately 1: 1 mixture of ( - )-malyngolide and 2-epi-malyngolide (2370) in a total of 6 steps. Use of the enantiomer Of epoxide 2427 gives ( + )-malyngolide in a similar manner.

One of the few syntheses of malyngolide (2370) that is both enantio- and diastereospecific is that of Fujisawa [670] shown in Scheme 438. Incubation of ~-keto thiolester 2431 with baker's yeast in aqueous sucrose solution produces ~-hydroxy ester 2432 in 88% yield (100% de and > 96% ee). Transesterification


I) Hz, Pd

I 1, 3 QC02H L' NH distillation 2) TsOH, MeOH •

2421

KOH,EtOH

heat, 99%

2422

2424

144-146°C 83% overall

3) (CH20Hlz, TsOH reflux, 98%

electrolysis

I) OS04, NMO t-BuOH, H20

• 2) KOH,EtOH 3) HCI, CHCI3

2423

° '(xl C9HWn

(±)-malyngolide 2370 63% plus 35% epimalyngolide

Scheme 436. Wuts Synthesis of (±)-Malyngolide

2426

Ti(Oi-Pr)4, S,S-DET, •

TBHP,41%

0 Ph

2427

1) LiI, ether

2) PhCH(OMelz amberlyst, 71 %

0

yOCH3 Moo,C~ A I) H2, Pd/C

'6 2) KOH,EtOH OH

• 3 0 0 .. ~.\) BU3SnCI, NaB~ .\--1 3) amberlyst, hv, EtOH, 70% ",

CH3CN

o

'. ° I ""60H .. ,,,,\

C9HW n

3-epimalyngolide 2430

C9HWn

2429

o

"" ~O 9H "l)( ':.~Hwn

C9HWn

(-)-malyngolide 2370 37% plus 40%

2-epimalyngolide

o

'OJ" 'C9HI9-n

37% and 33% if enantiomer of 2427 is used

Scheme 437. Giese Synthesis of (- )-Malyngolide And Its Three Stereoisomers

2428

•

o 0

OH

0

OH

0

bake

rs y

east

N

aOC

H3

LD

A, C

H3(

CH

:z)g

I ..

.. ~SCzH5

88%

O

,,·)

l'S

CZH

5 M

eOH

,94%

O"

"'~O

CH3

chro

mat

ogra

phy

2431

OH

0

~ Il

0,'

,.'

OC

H

C9H

wn

3

2433

82

% p

lus

2%

of a

dia

ster

eom

er

Cr0

3 - 90% o

°

A , .. ,

JlO

CH

3

LPc~

wn 24

32

1) a

-met

hyla

tion

2) L

DA

; th

en

LA

H

53%

Sche

me

438.

Fuj

isaw

a Sy

nthe

sis

of (

-)-

Mal

yngo

lide

o O

H

'&1

.,\

" C

9HW

n

°

MC

PBA

'6

0H

------~ .. -

° 1

66%

, ••

,\ C9H

Wn

(-)-

mal

yngo

lide

23

70

o f ~

w


and alkylation provides 2433 in 82% yield, along with 2% of its diastereomer. The synthesis is completed by following the procedure of Matsuo (Scheme 427) to give ( - )-malyngolide in seven steps and 21 % overall yield.

6.3.17 Okadaic Acid

The potent antitumor agent okadaic acid (Scheme 439) was first isolated from sponges of the genus H alichondria and was shown to possess structure 2435 by X-ray crystallography [671]. The structurally similar metabolites acanthafolicin [672] and dinophysistoxins 1-3 [673] as well as 2435 have been isolated from other organisms including dinoflagellates, suggesting that these metabolites may be synthesized by symbiotic microorganisms. Metabolites 2435-2437 are unique in that they possess 3 spiro ketal arrangements within their complex skeleta. In the solid state, each of the three spiroketals appear to be anomerically maximized (axial spiro C-O bonds), suggesting that the relative stereochemistry of the spiro carbons might be established in acid-promoted thermodynamic spirocyclizations.

Isobe and coworkers took a classical approach to the problem [674], culminating in the only synthesis of okadaic acid. The molecule was divided into three segments (2447, 2461 and 2472) which were synthesized in optically pure form using chiral pool elements and then coupled using sulfone -anion additions to aldehydes.

Segment 2447 was assembled in 15 steps from the sugar derivative 2438 (Scheme 440). Although 2438 contains 3 stereogenic centers, only the one at C4 was incorporated into 2447. The exocyclic stereocenter at C2 was established via diastereoselective oxymercuration of the E-alkene 2442 giving 2443. This was converted to lactone 2444 which was combined with the optically pure acetylide anion 2445 giving ketone 2446. Conjugate addition of methyl cuprate to the alkyne results in a (Z)- Il.,~-unsaturated ketone which is spirocyclized to the key segment 2447.

Segment 2461 is characterized by the presence of 5 contiguous stereocenters bearing C-O bonds (C22-C26). Carbon Ferrier rearrangement of the glucal 2449 (Scheme 441) followed by ester saponification and acetalization led to 2450 in which 3 of these C-O stereocenters were established. The C23-C24 olefin was eventually epoxidized and opened with sodium pheylmethanolate to establish the stereocenters at these two carbons resulting in 2454 after protection. Again, an optically active sulfone was added to an aldehyde 2455 leading to the cyclization precursor 2458. Closure was achieved by hydrogertolysis of the benzyl ether in the presence of catalytic HOAc. Functional group manipulation led from 2459 to aldehyde segment 2461.

Segment 2472 was also assembled from a carbohydrate (Scheme 442). D

Glucose led in three steps to tetraacetate 2462. Ferrier rearrangement led to 2463 which, when treated with a methyl cuprate reagent led to 2465. This isomer

Me

2447

Me

2435

oka

daic

aci

d R

= H

24

36 d

inop

hysi

stox

in-3

(R

= CH

3)

2437

aca

ntha

foli

cin

(R =

H, 9

,1O

-a-e

pisu

lfid

e)

S02P

h

OM

OM

H

=

MX

x=

: .0

Bn

15

-

~

0""

TBD

PS

O

0 e

HO

27

2461

Sche

me

439.

Oka

daic

Aci

d Sy

nthe

sis

Str

ateg

y (I

so be

)

28

0 y:

r .. , .... P

h02S

0 0

2472

o :;. ~ tv

1.0

VI

~

I)

LiA

IH4

~

I)T

BSC

I ~

:0:0

O

HC

U··

··O

A

cO

.' l)

"0

.. H

O

.'

.. A

cO···

· #

OA

c 2)

H

2 \P

d-C

""

OH

2)

PhC

H2B

r ""

OB

n 3)

TB

AF

24

38

96%

4)

[0]

24

39

81%

24

40

~

Ph 3

P

C0 2

Et

83%

Et0

2C

~

yU

.... O 11"O

Bn

I) n

HO

C

l

H+

HO~OCH2CH2Cl

'OB

n

Hg(

OA

c)z,

NaB~

81%

2) D

ibal

24

42

2441

6.

4 :

1 m

ixtu

re

HO

hO

yO

CH

2C

H2

Cl

HO

..-1

V""O

Bn

2443

EE

O

2446

I)

Me2

C(O

Me)

z \H

+ _

_ X

0y

YO

yO

2)

Ph

S0 2

Na,

KI

0..

-1

V""O

Bn

3) B

r2 /

NaO

Ac

(70%

) 24

44

SO

zPh

I) M

e2C

uLi

2) P

PTS

Me2

C(O

Meh

/ H

+

30%

Sc

hem

e 44

0. S

ynth

esis

of

Oka

daic

Aci

d Se

gmen

t 24

47 (

Iso b

e)

. ~S02Ph

Ll~ E

E~

2445

Me

S02P

h

Me

2447

IV

\0

0'1 s:: in· [ [ o c:: '" s:: (I

) g. ~

~

Others 297

OAc 1) CH:z=CHCH2SiM"3 24 1) B2H60H202

BF3"Et20 2) B2C1 ~H 6::AC ~yPh .. ..

o OH o OAc 2) Et~. aq MeOH , 0 0 3) H30+

3) PhCH(OMen, CSA BzO 2449 2450 2451

75% 70%

I) MCPBA

r1Xy~ 1) (COClh

~Y~ 2) PhCH(OMe)20 CSA DMSO I)PhCH~Na .. .. 3) NaOMe o 0

2) HC(OMe) MeO 0 0 2)CH3OCHP

70% HO 2452 H+ MeO 2453 48%

OMOM OMOM gEE 2456 ;:xxBnO : 0 Ph .' Y

MeO 0 0 ~ BnOy\ •• OyPh 1) IBuP~SiO~ SO Ph

2 ..

98% OHC~O""O 24SS

2) (COClh I DMSO

MeO 2454

BnO OMOM

TBDPSO_ ~O h.·O y Ph

...... OEEV.O~O 2457

H?MOM

~: •• OH

0" OH TBDPSO 0

2459

3) Al/Hg

BnO OMOM

~ TBDPSO_ ~O h .. OH

...... ()HV.O~OH

1) TrCl ..

40%

2458

H 9 MOM .1l--0~ .. OBn

TBDPS6 -O··V.o~OTr 2460

H9MOM ~O~ •• OBn

TBDPs6 -o"~O~CHO 2461

Scheme 441. Synthesis of Okadaic Acid Fragment 2461 (Isobe)

-PdIC HOAc MeOH

2) (COClh DMSO

arises via elimination to enone 2464 which then underwent axial addition of the cuprate reagent giving 2465. Five steps led to lactone 2467 which was combined with sulfone 2468 leading to 2469. Further manipulation led to 2471. Addition of MeLi to the <X,~-unsaturated sulfone led eventually to 2472. The stereocontrol in this reaction is thought to be due to chelation of the alkyllithium with a tetrahydropyran oxygen delivering the reagent to one face of the olefin (2473 -. 2474). Segment 2472 was thus available in 16 steps from 2462.

..

OA

e

Aeo

D:

I O

Ae

AeO

....

.. ,

,,\

0 2462

iPrO

H,

BF

3·E

t20

63

%

OA

e A

eO

n

AeO

, ••••

• °

y

AeO

"""a

o ....

...... ,,

, .... '

°

°

2465

Y

2463

1)

N2l

it,

EtO

H

2) N

aCH

2SO

CH

3

3)

PhC

H2B

r, N

aH

74%

Me(

CN

)CuL

i

80

%

Bno~"'

::O

""

0 2466

1) A

lIH

g

""',

(')

Bn

O,

•• ~~A

TH

PO

Ph0

2S.:

J 2

468

.. B

nO """

S}:r

,.....

° O

TH

P

OH

2) P

PT

S,

EtO

H

3) H

2 P

dlC

" .. "

0

0

2467

1) (

CO

Clh

, D

MS

O,

TE

A

2) I

."hS

(TM

ShC

Li

3) M

CP

BA

56%

86

%

Ph0

2S 24

69

PhSO

""',

(')

2

~jr-0

TM

SA

... ·· °

0

2471

Sche

me

442.

Syn

thes

is o

f O

kada

ic A

cid

Fra

gmen

t 24

72 (

Iso b

e)

1)

MeL

i

2)

KF,

MeO

H

89%

81%

AeO

........ ,

'," ce

o

°

°

2464

Y

1)

H30

+

2)

Br2

, N

aOA

c

52%

oo~:

:::00

2470

,"so

, 1::::

00

2472

N

1.0

00

~ ~ ~ o '" '" s:: S 8" =::

~

Others 299

.. PhS~ \9_ TMS~~

2473 2474

The segments were combined in a B + C -+ BC -+ ABC sequence (Scheme 443). The anion of sulfone segment 2472 was joined with the aldehyde of segment 2461 generating 2476. The resulting diastereomeric mixture was oxidized to the ketone and the sulfone was reductively removed to give an intermediate ketone which was reduced to give the correct configuration of the alcohol at C27 (2477). The reduction proceeded stereospecifically with NaBH4 or LiAlH4:Zn(BH4h (85:15, desired:undesired) and DIBAL (70:30) reduced with less selectivity. These results were rationalized via the two transition state models shown in Scheme 444. It was stated that the NaBH4 .and LiAIH4 reductions proceeded via 2483 while the "low or opposite-dominant selectivities" were caused by "chelative interaction .... at the transition state." Experimental support for these hypotheses other than the product structures and ratios was not given. Attention was next turned to adding the C41 methylene carbon which was easily accomplished in three steps from 2478 with the parent Wittig reagent Ph3P=CH2 performing the methylenation. From here, three steps were required to convert C15 to aldehyde 2480, ready for coupling to segment 2447. The reaction sequence used to form the CI4-C15 olefin entailed sulfone anion addition to the aldehyde, acetylation of the resulting alcohol and reductive elimination with sodium amalgam, resulting in a trans olefin (2481) in 32% yield for the 3 steps. At this juncture, the entire carbon skeleton was complete leaving only the Cl carboxylic acid terminus to be established. This was accomplished by deprotection of the CI-C2 diol and oxidation in 2 stages to the carboxylic acid via the aldehyde 2482. Final removal of 3 benzyl groups with LifNH3 provided 1.7 mg of crystalline okadaic acid (2435).

An analysis of the course of the synthesis is shown in Scheme 445. The three starting materials were simple sugar derivatives and led in nearly linear fashion to each of the three main segments 2447, 2461 and 2472. The assembly of the segments took an additional 19 steps, resulting in an overall 54 step process in the longest linear sequence. A total of 106 separate operations (minimum) were required to assemble okadaic acid.

6.3.18 Debromoaplysiatoxin

A series of complex hemi-spiroketals were isolated from the marine aplysiid Stylocheilus longicauda by Scheuer in the early 1970s [675]. The aplysiatoxinoscillatoxin metabolites were eventually traced to the blue-green alga Lyngbya majuscala and other sources [676]. A partial listing of the metabolites is shown in Scheme 446. The relative and absolute confil!urations of this metabolite series


H <?MOM .1Jr.0~ ... OBn

.... 00 2472 PhS02~'" 00

I) Cr03'2Pyr 2)AI/Hg

TBDPs6 -O¥VO.J..CHO

2461

92%

57% 2476

I)~~S ~~ ~M~~H ••••• ______ ~.~ 0 0

2)H2 TBDPSO 0 Ii • 0 0

OHC 15

OHC

HO

2477 Pd(OHh I C OTHP 78% 2478

OH I) (COClh.DMSO ~~ 5 .... 2) Ph3P=CH2. TH!, 15 0 _ "_ 0

3) MC3SiBr TBDPSO 0 Ii 5 0 -0 OH

50% 2479

• 2) AC20. pyr 3) Na/Hg 32%

I) PhCH2Br INaH •

2) n-BIl.jNF 3) (COClh I DMSO

48%

I) H30+

• 2) S03/pyr

52%

I) NaC102 .. 2) Li \NH3

80%

Scheme 443. Assembly of Okadaic Acid Segments (Isobe)

•

~ OMOM

1-t::G' ....,.OBn O~If 0' R

2483

Stereoelectronically-controlled anti-periplanar addition

(LiAll4 • NaB14)

Others 301

~ OMOM

I~o" ....,.OBn

/O~ "0 .... R

M/ ) If

2484

Chelation -controlled addition (Dibal. Zn(B14h. B2Hc;)

Scheme 444. Transition State Hypotheses Concerning the Reduction of the C27 Ketone

were eventually confirmed by Moore and coworkers using extensive spectroscopic and chemical degradation techniques, in addition to X-ray crystallography [677]. Compounds in this family exhibit a variety of physiological activities, ranging from tumor promotion to a peculiar form of contact dermatitis [678]. The compounds possess potentially mobile hemi-spiroketal arrangements due to a hydroxyl at C3, although open forms of the spiroketal ring system have not been observed. In addition, the spiroketal configurations are not anomerically maximized (see 2490).

The approach of Kishi is the only successful synthesis of a metabolite in this series to-date [679]. The fragments used to assemble debromoaplysiatoxin 2487 are shown in Scheme 447. The synthesis offragments 2492, 2494, 2496 and 2498 was straightforward and proceeded from optically active starting materials. Fragment 2497 is a common reagent. The combining of the fragments is an instructive exercise in manipulation of functionality utilizing protecting group technology (Schemes 449 and 450). The anion of sulfone 2492 was alkylated with the epoxide 2496 and the sulfone was removed by reduction providing 2500. Diol deprotection and conversion to the epoxide 2501 was straightforward. Epoxide opening with the dithiane 2494 led to 2502 in "almost quantitative" yield. Esterification with 2498 followed by protecting group manipulation led to 2503. Note that the last two steps in the 2502 --. 2503 sequence exchanged the TBDPS group for BOM. Apparently a BOM group already installed on 2498 in place ofTBDPS was not satisfactory in the esterification. Elaboration of 2504 to the carboxylic acid 2507 proceeded via a two stage oxidation. Coupling with the magnesium salt 2497 and removal of the MPM groups gave the cyclization substrate 2509 in reasonable overall yield. It is noteworthy that 2509 does not exist in a cyclic form. Conversion of 2509 --. 2510 with silver tritluoroacetate suggests that macrocyclization facilitates formation of the hemispiroketal and further suggests that the natural products exist as the most thermodynamically stable isomer at C3 and C7. Removal of the protecting groups from 2510 produces debromoaplysiatoxin 2487. Aplysiatoxin has already been produced from 2487 by bromination. The synthesis of 2487 proceeds in 18 steps from the fragments pictured in Scheme 447 in 2-3% overall yield.

AeO~

y 'I

....

24

38

OA

e ex:

I O

Ae

0

24

49

OA

e

Aeo

D' O

Ae

AeO

...

~.~ I

.......

,'11

0

·24

62

Me

H ~

36

-/\ -

1·'

Me V~O'

y st

eps

0 ~'I

~

SOzP

h

24

47

OM

OM

H

;;

(otl)

:0B

. 35

•

• ....

_ 0

step

s TB

DPS

O

0 C

HO

24

61

16

~" (",

Ph"SI;~O{)

- steps 2

47

2

Sche

me

445.

Sum

mar

y of

Oka

daic

Aci

d Sy

nthe

sis

(Iso

be)

7 ok

adai

c ac

id 2

435

step

s

# st

eps

(lon

gest

line

ar s

eque

nce)

54

tota

l # o

f ope

ratio

ns 1

06

over

all

yiel

d ca

. 0.

01%

w S :::: t !il :::: ~ i

2486 Aplysiatoxin 0i.J Br H H 2487 Debromoaplysiatoxin Cll.J H H H 2488 Oscillatoxin A CH3 Br Br Br 2489 19,21-dibromaplysiatoxin H H Br Br

Scheme 446. Some Metabolites of Lyngbya majuscala

Others 303

2490 solid state spiroketal conformation

Although not culminating in a completed metabolite synthesis, the work of Ireland in this area is worthy of note [680]. Utilizing extensive studies on the hetero Diels-Alder reaction performed by this group, the C3 nor-hydroxy compound 2532 was assembled (Scheme 452). The key step involved the [4 + 2] cycloaddition of optically active partners 2517 and 2521. The vinyl ether 2517 was prepared from the lactone 2516 by reaction with the Tebbe reagent (Scheme 450). The lactone, in tum, was derived via standard manipulations from the alcohol 2511, using the Sharpless epoxidation of 2512 to enter the desired enantiomeric series. Enone 2521 was produced from (S)-2519 and was used as a mixture of epimers at C15 (Scheme 451). It was shown, however, that the absolute stereochemistry at C15 could be induced by reduction of the corresponding ketone using the Noyori chiral binaphthol reagent producing 2522.

The cycloaddition between 2517 and 2521 proceeded to give 2523 which was manipulated to 2524 (Scheme 452). Spiroepimerization of 2524 was induced by HCI in CHCl3 leading to 2525 possessing the maximum number of equatorial substituents. Apparently, steric considerations outweighed the stereoelectronic preference of the anomeric effect. After a series of standard transformations to give 2528, the diastereomers were separated providing 2529. Unfortunately, the key remote oxidation of 2529 ~ 2532 could not be realized under a variety of conditions (Scheme 453). Anticipating eventual success, compound 2529 was converted to 2533 featuring a DCCjDMAP mediated macrocyclization.

HO

+:I

H+

OH

C0 2

EI

2490

"'rCO

OH

HO

2493

2487

6 st

eps

know

n ch

emis

try

9 st

eps

43%

(')

~N~OH

~ O

H

2495

'" ... ~ 2

494

Mg+

+ 2

(-0

0C

THPO

~ S ~~

_M

PM

O

24

97

}

V

11

13

o S

I-Bu

0

MP

MO

0

0

S02

Ph

OH

(OB

n

BnO~

OH

2491

", •.. ~

TH

PO

) -~

-S

S

V

2494

31~ 2

7fl

0

~ .9

~

2492

O

TBD

PS

0

2498

14 s

teps

MPMO~

0+

~02

Ph

00

2492

4 st

eps

(')

~OBOM

o 24

96

Sche

me

447.

Fra

gmen

ts u

sed

in t

he K

ishi

Deb

rom

oapl

ysia

toxi

n Sy

nthe

sis

OB

OM

2496

w ~

~ en ~ ~ o 13l s:: " g. o i

MPMO

~

8'~ I)

2 e

q n-

BuL

i he

xane

s 1 T

IIF

2) !

>,A

r

o

~Ar

I)N

a/H

g

H

MPM

O

NaH

2P04

/MeO

..

OH

S<

¥h

2) C

Hy

1 KO

H

o D

MS

O

Ao

24

99

~Ar

OC

H3

00 0

2492

U

Ar=~O-OBn

2496

l)aq

HO

Ac

40

°C

MPMO~Ar

2)K

H/T

sCl

TI%

~

&u3

o

MP

MO

C

I

I)~

2498

lr

mD

PS

0

DM

AP

1 py

r 125

°C

2) T

BA

F 1

TII

F 1

25°C

3)

BO

M-C

lI i-

Pr2E

tN

. CH

2Cl2

/25

°C

2501

THPO

MPM

O

0'

~

OB

OM

', •.. ~

THPO

) ft~

!-i

S S

2494

V

T

IIF

1 -2

0 °C

124

hr

"a1m

ost q

uant

itativ

e"

Ar

2503

aqH

OA

c

TIl

F/5

5°C

5.

5 h

r

Sch

eme

448.

Ini

tial

Ass

emby

of

Deb

rom

oapl

ysia

toxi

n F

ragm

ents

HO

'

HO

2502

MP

MO

~O

OB

OM

0

2500

54

% f

rom

249

3

Ar

2504

ca

. 40%

Ar

f w

o VI

HO

MP

MO

~O

OB

OM

0

25

04

~O

OB

OM

0

2508

55

% f

rom

250

4

o ~O

OB

OM

0

25

10

Ar

1) D

MS

OID

CC

T

FA

12

5°

C

2) N

CS

aq a

ceto

ne

3) N

aCI0

2 1

NaH

2P04

aq

. t-

BuO

H

Ar O

BO

M 4e

quiv

DD

Q

CH

2Cl 2

/H20

2

5°

C 1

40 m

in

70%

H21

10%

Pd-

C

Et3

N I

EtO

H

25

°C

61%

Sche

me

449.

Fin

al A

ssem

bly

of D

ebro

moa

plys

itox

in (

Kis

hi)

..

HO

MP

MO

~O

OB

OM

0

2507

Ar

I) C

O(i

mid

h T

HF

12

5°

C

2)

Mg+

+ 2(

-OO

Cl o

St-

Bu

TH

F 1

40

°C

24

97

Ar

o ~O

OB

OM

0

2509

o _

0

~

OH

0 de

brom

oapl

ysia

toxi

n (2

487)

X

=H

OH

AgO

TF

A

NaH

2P0 4

1 C6

H6

25

°C

60%

know

n

chem

istr

y ap

l ysi

atox

in

X =

Br

w ~

s::: [ ~ o ~ s::: ~ ~ '"

H

HOJ--

--°Bn

2511

1) R

ed-A

I P

hCH

3

2) Me~Me

p-T

sOH

/ ac

eton

e

70%

1) (

CO

Clh

/DM

SO

E

t3N

/ C

H2C

I 2

2) (

i-P

r0hP

OC

H2C

02E

t t-

Bu

OK

/TH

F

H

Et02C

4-°

Bn 1)

Dib

al

hexa

ne /

Et2

0

2) S

harp

less

ep

oxid

atio

n

..

88%

H

r¢::

0B

n

1) L

i/ N

H3

/TH

F

2) M

sCI

/ E

t3N

C

H2C

I 2

°XO

2514

3) N

aI /

ace

tone

1) T

BS

CI

!im

idaz

ole

DM

F

2) C

P2 T

iCH

2(C

I)A

IMe2

P

hCH

3/T

HF

58%

2512

97

%

~+--,

D{-

[''j(

.'H

TH

F

XO

ac

idif

icat

ion

25

15

nso~

25

17

Sche

me

450.

Syn

thes

is o

f V

inyl

Eth

er 2

517

(Ire

land

)

H

HO

~oBn

~

..

H

25

13

90

: 1

0 m

ixtu

re

of

dias

tere

omer

s

HO~ °

2516

35

% f

rom

251

4

o So ~ w

o -.J

rl

2519

1) m

CP

BA

/Na

HC

0 3

CH

2C1 2

2) H

I04

1 H

20 I

Et2

0

3) ~MgBr

~

OC

H3

TIi

F

Sche

me

451 •

. Syn

thes

is o

f E

none

252

1

cf7

H

, 15

I

,I

OM

e 25

20

67%

1) (

CO

Clh

I DM

SO

E

t3N

I C

H2C

I2

I) K

H/M

eIlT

HF

2)~/MeOH;

DM

S

3) v

inyl

MgB

r I T

IiF

4)

(C

OC

lh I

DM

SO

E

t3N

I C

H2C

I 2

28%

2) (

S)-

2,2'

-hin

apht

hol

LiAI~ I

EtO

H I

TIi

F

~

Y li

I

OM

e 25

22

o

OM

e

w o 00

~ t I o i

TBSO~ 2517 HMe OJ

PI ~

2521 OMe

anhydrous HCI CHa3 ..

48% along with recovered SM

TilSO

1) KHMDS 1 THF

110·C 148 hr .. free radical

inhibitor 56%

BzO

2) TFzNPh TBSO .. 3) MezCuLi 1 EtzO

50%

TBSO

hv >350mn HOOC ..

74%

OMe

2529

2531

1) BH3• TIIF; H2(h1 NaOH ..

Others 309

P - 0

2) BzCll DMAP 54%

~SO 0

I ., OBz MeO ~

2525

OMe

1) LiAl141 TIIF .. 2) (COCIh 1 DMSO

Et3N 1 CH2Cl2 92%

OMe 1) BH3 • THF Et~ ITHF; H2(h/NaOH ..

2) (COClh 1 DMSO Et~/CHzCI2

TBSO

TBSO

2527 3) K(s-Bu)~H 1 THF

69%

I)BnO ~OH

PNBO 0

DCC 1 DMAP 1 CH2a2 .. 2) HOAc 1 TIIF 1 HzO 3) Jones oxidation

66%

OMe

0 DCC ..

DMAP 1 DMAP· Ha CHa3 74%

MeO 2524

OMe

2526

OMe

diastereomers separated at this stage

OMe

2530 PNB = p-nilrobenzyl

OMe

Scheme 452. Cycloaddition of 2517 with 2521 and Subsequent Transformations (Ireland)


OMe

TBSO Remote

X .. C3 oxidation

2529

OMe

TBSO

2532

Scheme 453. Attempted Remote Oxidation of 2529 -+2532 (Ireland)

7 Summary

Clearly the activity in marine natural products synthesis is deeper and broader than one might have expected and in every way mirrors not only synthesis of terrestrial metabolites, but organic synthesis as a whole. As long as the marine environment continues to be a source of biologically active substances and molecules of unprecedented architecture and complexity, it is anticipated that synthesis activity in this area will continue its remarkable growth.

8 References

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Watase H (1958) Bull Chern Soc Japan 31:932 316. Irnpe11izzeri G, Mangiafico S, Oriente G, Piaatelli M, Sciuto S, Fattorusso E, Magno S,

Santacroce C, Sica D (1975) Phytochemistry 14:1549 317. (a) Murukami S, Takernoto T, Shimizu Z (1953) J Pharm Soc Japan 73:1026, (b) Nilta I,

Watase H, Tomiie Y (1958) Nature 181:761, (c) Maeda M, Kodama T, Tanaka T, Yoshizurni H, Takemoto T, Nornoto K, Fujita T (1987) Tetrahedron Lett 28:633

318. (a) McGeer EG, Olney JW, McGeer PL (eds) (1978) Kainic Acid as a Tool in Neurobiology. Raven Press, New York and references therein, (b) Goldberg 0, Luini A, Teichberg VI (1983) J Med Chern 26:39

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K (1959) J Pharm Soc Japan 79:350 329. Ohfune Y, Tomita M (1982) J Arn Chern Soc 104:3511 330. Andersen RJ (1978) Tetrahedron Lett 2541 331. (a) Schmidt U, Lieberknecht A, Griesser H, Bokens H (1982) Tetrahedron Lett 23:4911,

(b) Schmidt U, Lieberknecht A, Griesser H, Bokens H (1985) Liebigs Ann Chem 785 332. (a) Hofheinz W, Oberhansli WE (1977) Helv Chim Acta 60:660, (b) Erickson KL,Wells RJ

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S (1985) Bull Chern Soc Japan 58:3453 346. (a) Kazlauskas R, Lidgard RO, Murphy PT, Wells RJ (1980) Tetrahedron Lett 21:2277,

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Miyata T, Iwanaga S, Yajima H (1989) Chern Pharm Bull 37:2661 352. Rinehart KL Jr, Kishore V, Nagarajan S, Lake RJ, Gloer JB, Bozich FA, Li K-M, Maleczka

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Subject Index

aaptamine 199-206 acarnidines 139 aerophobin-1 20 aerothionin 20 algal pheromones 107-138 amphimedine 206-210 aplysinadiene 19 aplysinopsin 169-172 arsenioriboside 275 ascidiacyc1amide 54-59 ascididemin 195-199 aucantene 128-131

bastadins 20-24 bisucaberin 262 bissetone 266-267 bonellin 246-248 bromobenzyl ethers 272 (E)-3-( 6-bromoindole-3-yl)prop-2-

enoate 173-175 bromophenol ethers 253-256

carbazoles 175-192 carnosadine 1 6-chlorohyellazole 175-179 chlorovulone II 92 clavulone I 87 c1avulone II 87 c1avulone III 87-91 c1avulones 84-96 c1avularin A 135-138 clavularin B 135-138 4-n-butyl-2,6-cycloheptadienone

120-121

deacetylclavulone II 91-92 debromoaplysiatoxin 299-310 debromoeudistomin L 184, 188 de1esserine 249-250 demethyldysidenin 14-16 demethylisodysidenin 14-16 demethyloxyaaptamine 199-206 dendrodoine 172-173

desmarestene 125-128 diacetylenes 156-157 dibromophakellin 223 dictyoprolene 107 dictyopterene A 110-115,117 dictyopterene B 115-117, 133 dictyopterene C 117-119 dictyopterene C' 111,117-119 dictyopterene D' 115, 119-120, 131, 133 dictyopterenes 107-138 didemnenone A 272-275 didemnenone B 272-275 didemnins 26-30 dithiacycloheptanone 277 dolastatin-3 54-59 dolastatin-1O 59-63 domoic acid 9-13 doridosine, see 1-methylisoguanosine dysidin 267-277

ectocarpene, see dictyopterene D' D-erythro-1-deoxydihydroceramide-1-

sulfonic acid 142-143 eudistomin A 179-180 eudistomin D 181 eudistomin H 180-181 eudistomin I 180-181, 184 eudistomin L 184, 188 eudistomin M 181 eudistomin N 181 eudistomin 0 181 eudistomin P 180-181 eudistomin S 184 eudistomin T 181, 184 eudistomins 179-192

fimbrolides 258 flustramine B 158 N-formyl-1,2-dihydrorenierone 234-237 fucoserratene 131-132

geodiamolides 39-43 giffordene 133-135

322 Subject Index

girolline 223-225 guanidine derivatives 210-225

halogenated l-octen-3-ones 256-258 hexaacetylce1enamide 59-63 hexacosadienoic acids 156 homoaerothionin 20 hormosirene, see dictyopterene B hormothamnione 262-266 hybridalactone 106-107 hyellazole 175-179

indoles 158-175 isoindole 231-234

jaspamide 30-39 jasplakinolide, see jaspamide

allo-kainic acid 3-9 alpha-kainic acid 3-9 kjellmanianone 259

lamoxirene 129 latrunculin B 260-262 laurediols 71-74 laurencenyne 69-71 Laurencia haloethers 69-84 laurencin 74-78 laurenyne 78 leptosphaerin 250-253 lyngbyatoxin A, see teleocidins

malyngolide 279-294 cis-maneonenes 79 trans-maneonene B 79 manzamine C 188-192 7 -methoxy-1,6-dimethyl-5,8-dihydro-

isoquinoline-5,8-dione 234-237 1-methylisoguanosine 229-230 3-methylnavanone B 277-279 ( + )-methylrhodomelol .249 mimosamycin 230-231 multifidene 121-125 mycalisine A 226-227

navanone A 192-193 nereistoxin 275-277 5-nonylpyrrole-2-carbaldehyde 243-244 Notheia anomala metabolite 146-147 nuc1eosides 226-230

octacosadienoic acids 147-156

okadaic acid 294-299 oroidin 220-223 ovothiol A 1-2 ovothiol C 1-2 6-imino-1,9-dimethyl-8-

oxopurine 228-229

pahutoxin 139-142 palythazine 257-261 panacene 84 patellamides 43-51 pentabromopseudilin 245-246 peptides 24-68 phidolopin 227-228 phosphonosphingoglycolipid 145 Plexaura metabolites 144-146 prec1avulone A 92-96 prostanoids 84-107 ptilocaulin 217-220 pukeleimide A 259-260 pulo'upone 193-195 punaglandin-3 102-106 punaglandin 4 96--102 (7E)punaglandin 4 102-106 punaglandins 96-106 pyridines 192-310 pyrogallol derivative 271-272 pyrrole derivatives 243-247

quinols 17-19

Reniera alkaloids 230-241 renierone 237-241 ( + )-rhodomelol 249

saxitoxin 211-216 serenin, see dictyopterene D' surugatoxins 158-165

teleocidin A-I 63-68 te1eocidin A-2 63-68 tetraacetylc1ionamide 13-14 tetrahalogenoindoles 173 tetrodotoxin 210-211 trikentrins 165-169

ulicyc1amide 51-54 ulithiacyc1amide 51-54

viridiene 125-128

3-octadecyl pyrrole-2-carbaldehyde 243 zoanthoxanthins 241-243

P.J.Scbeuer, University of Hawaii at Manoa (Ed.)

Bioorganic Marine Chemistry

K. F. Albizati, V. A. Martin, M. R. Agharahimi, D. A. Stolze, Wayne State University, Detroit, MI

Volume 5

Synthesis of Marine Natural Products 1 Terpenoids 1991. Approx. 220 pp. Hardcover ISBN 3-540-54375-9

Volume 6

Synthesis of Marine Natural Products 2 Nonterpenoids 1991. Approx. 270 pp. Hardcover ISBN 3-540-54376-7

These reviews are devoted to a compilation of the domain of natural product synthesis that involves metabolites from marine organisms. The vast amount of material has been roughly organized along structural-biogenetic lines into two volumes: the first covers all terpenoid derived structures, the second nonterpenoid (amino acid, heterocyclic, fatty acid and other miscellaneous derived) metabolites. For each metabolite the source is discussed and some of the properties are described that make the compound attractive to synthesis chemists. These are mainly the substances' biological activities.

Documents

Synthesis of Marine Natural Products 2: Nonterpenoids