Drugs of the Future 2002, 27(2) 143-158

8/6/2019 Drugs of the Future 2002, 27(2) 143-158

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6). On the other hand, construction of a versatile chiralbuilding block for biologically active natural compoundswould provide us with powerful tools for the synthesis oftarget natural products. In addition, it is very important forthe evaluation of the biological activities of synthetic com-pounds that both enantiomers of the chiral building blocksbe available in a similar manner. Accordingly, wedesigned two chiral building blocks ( 1 , 2) for the synthe-sis of biologically interesting alkaloids. This reviewdescribes the synthesis of the chiral building blocks ( 1 , 2)and its application to the stereodivergent synthesis of3-piperidinol alkaloids, the flexible route to the dart-poison frog alkaloids and the synthesis of cytotoxicmarine alkaloids.

Design and synthesis of chiral building blocks

First, we designed the piperidinol ( 1) as the chiralbuilding block for the synthesis of 3-piperidinol alkaloids.

As mentioned above, it is very important that both enan-tiomers of the chiral building block be synthesised in asimilar manner. To this end, we examined thechemo-enzymatic differentiation of azabicyclic meso gly-col ( 3) and its acetate ( 4) as shown in Figure 1.

CONTENTS

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143Design and synthesis of chiral building blocks . . . . . . . . . 143Synthesis of 3-piperidinol alkaloids . . . . . . . . . . . . . . . . . . 147Synthesis of dart-poison frog alkaloids . . . . . . . . . . . . . . . 149Synthesis of marine alkaloids . . . . . . . . . . . . . . . . . . . . . . 150Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Introduction

A number of piperidines and indolizidines bearing car-bonaceous substituents at both and positions havebeen isolated from natural sources (1, 2), and many ofthem have received much attention due to a variety ofbiological activities. 3-Piperidinol alkaloids havingappendages at both and positions also have beenisolated from plants (3). These 3-piperidinol alkaloids alsoexhibit a variety of pharmacological properties such asanesthetic, analgesic and antibiotic activities. Recently,the alkaloids containing this ring system were isolatedfrom marine species and all of them showed substantialcytotoxic activity against human solid tumor cell lines (4-

Drugs of the Future 2002, 27(2): 143-158Copyright 2002 PROUS SCIENCECCC: 0377-8282/2002

Review Article

Application of chiral building blocksto the synthesis of drugs

Naoki Toyooka* and Hideo Nemoto Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194,Japan. *Correspondence

N OH

AcO

CO 2Me

MeO 2C

(+)-1

(-)-1

N R

OAc

AcO

4: R = CO 2Me

OH

N R

OH

3: R = CO 2Me

N OH

AcO

CO 2Me

MeO 2C

lipase-mediated

transesterification

hydrolysis

N R

OAc

OH

N R

AcO

OH

lipase-mediated

Fig. 1.


2/16

cases, and recrystallization of the enantiomeric ketone ( 7)derived from oxidation of the enantiomeric monoacetate(6) with PCC furnished an enantiomerically pure ketone(+)-(7) or ()-( 7) in 74% or 65% yield, respectively, from 3or 4.

The ketone (+)-( 7) was converted to the desired build-ing block (+)-( 1) by the oxidative cleavage of the piperi-

The substrates ( 3 , 4) for the lipase-mediated differen-tiation reaction were prepared from a known bicyclicamine ( 5) (7) as depicted in Scheme 1.

With the requisite 3 and 4 in hand, we focused ourattention on the lipase-mediated enantioselective trans-esterification of 3 and hydrolysis of 4 . As shown in TablesI and II, the use of lipase CE gave the best results in both

144 Chiral building blocks for the synthesis of drugs

N CH 3

OAc

OH

N R

OAc

R = CO 2Me

N R

OAc

5

ClCO 2Me

CHCl 3, reflux

(95%)R = CO 2Me

N R

OAc

AcO

4: R = CO 2Me

OH

N R

OH

3: R = CO 2Me

N RO

OAc

N RO

OAc

R = CO 2MeR = CO 2Me

1) NaBH 42) 10% Na 2CO 3 (aq)

1) NaBH 42) Ac 2O, pyridine(74% in 2 steps)

PCC(90%)

H2, 5% Pd / C

(98%)

SeO 2

dioxane - H 2O, reflux

( 77 %)

(77 % in 2 steps)

Scheme 1

Table I: a

Lipase b Solvent t/h Yield (%) c (% ee) d

CE C 6H6 98 38 (99) 32

CE i -Pr 2O 109 85 (99) 90 (>99)

AY i -Pr 2O 87 33 (99) 56

CCL i -Pr 2O 91 15 (94) 54aAll runs were conducted with substrate (0.23 mmol), lipase (100mg) and vinyl acetate (2 equiv.) in the organic solvent (10 ml).bLipase CE (from Humicola lanuginosa ) and AY (from Candidarugosa ) were supplied by the Amano Pharmaceutical Co., Ltd.cYields for the isolated monoacetates; yields in parentheses arethose based on the conversion rate. dOptical yields were deter-mined by HPLC analyses by using a column packed withChiralpak AD (EtOH-hexane, 9:1) after oxidation of the monoac-etate with PCC. Optical yield in parentheses is based on a sam-ple after single recrystallization from i -Pr 2O.

OH

OH

N R

OHN R

OAc

O

N R

OAc

vinyl acetate lipase

32 ~ 35 oC

PCC

3: R = CO 2Me 6: R = CO 2Me (+)-7: R = CO 2Me

Table II: a

Lipase b t/h Yield (%) c (% ee) d

CE 23 84 (99) 80 (>99)

AY 35 42 (76) 78

CCL 66 23 (70) 58

PPL 84 14 (45) 48

PLE 48 39 (76) 75aAll runs were conducted with substrate (0.17 mmol), lipase (100mg) and phosphate buffer in the solvent (6 ml). bPLE (pig liveresterase) was supplied by the Amano Pharmaceutical Co., Ltd.and PPL (porcine pancreas lipase) was purchased from theSigma Chemical Co., Ltd. cYields for the isolated monoacetates;yields in parentheses are those based on the conversion rate.dDetermined for () -6 as in the transesterification of 3 . Opticalyield in parentheses is based on a sample after recrystallizationtwice from i -Pr 2O.

N R

OAc

AcO

N R

OH

AcO

N R

O

AcOlipase

32 ~ 35 oC

PCC

4: R = CO 2Me 6: R = CO 2Me (-)-7: R = CO 2Me(pH = 7)

0.25 Mphosphate buffer


3/16

four stereoisomers of , -disubstituted 3-piperidinolbuilding blocks from 2 is presented in Figure 2.

Thus, we examined the preparation of both enan-tiomers of 2 , and prepared them from the known -ketoester ( 8) (10) using bakers yeast reduction of 8 or

done ring in 7 . Similarly, ()- 7 was transformed into ()- 1as shown in Scheme 2 (8, 9).

Next, we designed the 2-piperidone ( 2) as the moreflexible chiral building block for the synthesis of 3-piperidi-nol alkaloids. The basic strategy we used to prepare all

Drugs Fut 2002, 27(2) 145

N RO

OAc

N R

OCH3

OAc

N RO

OAc

N OH

CO 2Me

MeO 2C

AcO

N R

OCH3

OAc

N OH

CO 2Me

MeO 2C

AcOHC(OMe) 3cat. H 2SO 4

(86%)

O3, then NaBH 4

CH2Cl2-MeOH(10:1)(98%)

O3, then NaBH 4

CH2Cl2-MeOH(10:1)(98%)

HC(OMe) 3cat. H 2SO 4

(86%)

(+)-7: R = CO 2Me

(-)-7: R = CO 2Me

R = CO 2Me

R = CO 2Me

(+)-1

(-)-1

N O

OR

EtO 2C

CH2Ph

N O

O

EtO 2C

CH2Ph

N O

OH

EtO 2C

CH2Ph

+(-)-2

8

1) NaBH 4, EtOH (92%)

2) vinyl acetate, lipase AK

i-Pr2O

Bakers' yeast, tap water

(88%, > 99% ee)

(-)-2

(52%, 91% ee)

(47%, >99% ee)

R = Ac

(+)-2: R = HK2CO 3, EtOH (90%)

Scheme 2

Scheme 3

N O

OH

EtO 2C

CH2Ph

N R2R1

OH

R

N R2R1

OH

R

N R2R1

OH

R

N R2R1

OH

R

stereoselective introductionof various alkyl side-chains

epimerization todesired configuration

reduction to methyl or

hydroxymethyl

2

(R = H or Me, R 1 = H or OH, R 2 = various alkyls)

I II III IV

Fig. 2


4/16


NH

CH3

OH

CH3

O

NCH3CH2(CH2)7

CO 2Me

MOMO

NCH3 OH

CO 2Me

MOMO

NCH3 OTBDPS

CO 2Me

MOMO

S

S

N OTBDPSCO 2Me

MOMO

N OTBDPSOH

CO 2Me

MOMO

N OHCO 2Me

MeO 2C

AcO

4 steps 1) PCC, AcONa

2) ethanedithiolBF3 .Et 2O(68% 2 steps)

Raney Ni(W-4)

(95%)

TBAFTHF (85%)

1) Swern ox.2) CH 2=CH(CH 2)8P +Ph 3Br-

1) O 2, PdCl 2, CuCl, DMF-H 2O (70%)

2) H2, 5% Pd / C

3) TMSI, CHCl 3, reflux (65% 2 steps)

(-)-1

(+)-1

(-)-cassine

NCH3 OH

MOMO

CO 2MeNCH3

CH2(CH2)9

MOMO

CO 2Me

NH

CH3

OH

CH3

O

1) Swern ox.

2) CH 2=CH(CH 2)10P +Ph 3Br-

n-BuLi (86% 2 steps)

n-BuLi (77% 2 steps)

1) O 2, PdCl 2, CuCl, DMF-H 2O (70%)

2) H2, 5% Pd / C

3) TMSI, CHCl 3, reflux (65% 2 steps)

(+)-spectaline

NH

CH3

OH

OH

O

NCH3 O

O

(CH2)11

AcO

Ac

CH3(-)-1

spicigerine

Scheme 4


5/16

shown in Scheme 4. The absolute configuration of natur-al cassine, spectaline and spicigerine was unambiguous-ly determined by the above chiral synthesis.

More efficiently, we synthesized the chiral buildingblocks (I, II, III and IV as shown in Figure 3) starting from()-2 and achieved the stereodivergent synthesis of the3-piperidinol alkaloids prosafrinine, iso-6-cassine, proso-phylline and prosopinine, respectively (14) (Schemes5-8).

lipase-mediated kinetic resolution of the correspondingracemic 2 (11) (Scheme 3).

Synthesis of 3-piperidinol alkaloids

The synthetic utility of (+)- and ( )- 1 has been demon-strated by the first total synthesis of ()-cassine, (+)-spec-taline, (12) and methyl N ,O -diacetylspicigerinate (13) as

Drugs Fut 2002, 27(2) 147

N

CO 2Me

ORMeO 2C

Introduction of various alkyl,

alkenyl or alkynyl groups

Chain extension and cyclization toan indolizidine or quinolizidine system

Chain extension and functionalization

5,8-disubstituted indolizidines

1,4-disubstituted quinolizidines

Fig. 3

N O

OH

EtO 2CCH2Ph

(-)-2

N O

OH

CH2Ph

MOMO

N OCH3CH2Ph

MOMO

N SCH3CH2Ph

PhCH 2O

NCH3 O

O

CH3

CH2Ph

PhCH 2O

NCH3 O

O

CH3

CO 2CH2Ph

PhCH 2O

OO

NCH3CH3

(CH2)6CO 2CH2Ph

PhCH 2O

NH

CH3

OHO

CH3

1) MOMCl, Hnig baseCHCl 3, reflux (98%)

2) super-hydrideTHF (96%)

1) PhSSPh, n-Bu 3Ppyridine (95%)

2) Raney Ni (W-4)EtOH (95%)

1) c. HCl, MeOH

2) NaH, BnBr(84% 2 steps)

3) Lawesson's reagent(96%)

BrCH 2CO 2Me

then Ph 3P, Et 3NMeCN (83%)

1) H 2, Ph(OH) 2

2) CBzCl, K 2CO 3(96% 2 steps)

1) super-hydride THF (90%)2) Swern ox.3) Wittig reagent A, n-BuLi

THF (60% 2 steps)

1) H 2, Ph(OH) 22) Na, liq. NH 3

3) p-TsOH, acetone(50% 3 steps) prosafrinine

OOCH3Ph 3P+

Br

Wittig reagent A:

type I of chiralbuilding block

Scheme 5


6/16


NCH3 OCH3

OPhCH 2O

CH2Ph

NH

CH3

OH

CH3

O

NCH3 CH3

O

(CH2)7

PhCH 2O

CO 2Me

NCH3 OCH3

OPhCH 2O

CH2PhNCH3 OH

PhCH 2O

CO 2Me

NaBH 3CN, TFA

CH2Cl2, 0 oC(99%)

trans: cis = 14:1

1) H2, Pd(OH) 2

2) ClCO 2Me, K 2CO 3(68% 2 steps)

3) super-hydride

(92%)

1) H2, Pd(OH) 22) TMSI

CHCl 3, reflux(58% 2 steps)iso-6-cassine

type II of chiralbuilding block

1) Swern ox.2) CH 2=CH(CH 2)8P +Ph 3Br-

n-BuLi (80% 2 steps)3) O 2, CuCl, PdCl 2

DMF-H2O (64%)

NH

OH

OH

O

CH3

OOCH3Ph 3P+

Br

Wittig reagent A:

CH3

CH3 OO

NCH3

(CH2)6

O

O

CH2Ph

CH3

CH3

N

O

OOH

CH2Ph

CH3

CH3

N

O

OO

CH3

O

CH2Ph

CH3

CH3

N

O

O O CH3

O

CH2Ph

CH3

CH3

N O

O

O

CH2Ph

N O

OH

OH

CH2Ph

N O

O

CH2Ph

PhCH 2ON O

OH

MOMO

CH2Ph

1) NaH, PhCH 2BrDMF-benzene(2:1) (96%)

2) c. HCl, MeOH3) PCC, AcONa

(83% 2 steps)

1) H 2, Pd(OH) 2

2) NaB(OAc) 3H(97% 2 steps)

2,2-dimethoxypropanep-TsOH, MS 5A

CH2Cl (91%)

Lawesson's reagentTHF, reflux (57%)

BrCH 2CO 2Me then

Ph 3P, Et 3NMeCN, reflux (72%)

NaBH 3CN, TFACH2Cl2, 0 oC(59%)

CH3

CH3

N S

O

O

CH2Ph

LiAlH4(99%)

1) Swern ox.2) Wittig reagent A, n-BuLi

THF (59% 2 steps)

1) H 2, Pd(OH) 2

2) 10% HCl, EtOH(75% 2 steps)prosophylline

type III of chiralbuilding block

Scheme 7

Scheme 6


7/16

The above synthetic strategy involved the highlystereoselective Michael reaction of the cyclic enam-inoester to give rise to 2,3,6-trisubstituted piperidine ringsystems, which were suitable intermediates for the synth-sis of the above Dendrobates alkaloids. The results aresummarized in Table III.

Synthesis of dart-poison frog alkaloids

Another application of building block ()- 1 to the syn-thesis of natural alkaloids was accomplished by the flexi-ble synthesis of 5,8-disubstituted indolizidine and 1,4-disubstituted quinolizidine types of Dendrobates alkaloidsas shown in Figure 3.

Drugs Fut 2002, 27(2) 149

OOCH3Ph 3P+

Br

Witting reagent A:

CH3

CH3 OO

NCH3

(CH2)6

O

O

CH2Ph

N OAcO

AcO

CH2Ph

N O

OH

OH

CH2Ph

CH3

CH3

N

O

OOH

CH2Ph

NH

OH

OH

O

CH3

N O

O

CH3AcO

AcO

CH2Ph

N O

O

CH3

CH2Ph

AcO

AcO

Ac2O, pyridine

(88%)

1) Lawesson's reagentTHF, reflux (99%)

2) BrCH 2CO 2Me thenPh 3P, Et 3NMeCN, reflux (92%)

NaBH 3CN, TFACH2Cl2, 0 oC(84%)

trans: cis = 11:1

1) LiAlH4, THF, reflux

2) 2,2-dimethoxypropane, p-TsOH, MS 5ACH2Cl2, rt (75% 2 steps)

1) Swern ox.2) Wittig reagent A, n-BuLi

THF (59% 2 steps)

type IV of chiralbuilding block

1) H 2, Pd(OH) 22) 10% HCl, EtOH

3) p-TsOH, acetone

(73% 3 steps) prosopinine

Scheme 8

Table III:

R1 X R Solvent Yield (%)

Et MgBr TBS THF 96

Vinyl Li MOM Et2O 91

Allyl MgBr MOM THF 80

n -Bu Li TBS Et 2O 94

N OR

CO 2Me

MeO 2C N OR

R1

CO 2Me

MeO 2C

(R 1)2CuX

solvent


8/16

Synthesis of marine alkaloids

Cardellinas group reported the isolation of the quino-lizidine alkaloids clavepictines A and B from the tunicateClavelina picta , which are the first quinolizidine alkaloidsfrom a tunicate. In the same year, Faulkner et al. isolatedpictamine from the same marine species and its grossstructure was determined to be a bis-nor analog ofclavepictine A. Furthermore, lepadins A, B and C wereisolated from the tunicate Clavelina lepadiformis bySteffan and Andesen et al. These marine alkaloidsinvolved the 3-piperidinol nuclei and showed significantcytotoxic activity against a variety of murine and humancancer cell lines. Although their relative stereochemistryhad been determined by extensive NMR studies of anX-ray diffraction analysis, the absolute stereochemistry

Analysis of the coupling patterns of the methine pro-ton at C-2 and the methyleme protons at C-7 in the NMRspectrum of the oxazolizinone ( 9) suggested that thestereochemistry of 9 could be assigned as depicted inScheme 9, by assuming that all the ring appendages liein equatorial orientation.

The stereoselectivity of this key Michael reactionresults from the preferred -axial attack, leading not toboatlike transition state B but to chairlike transition stateA where the C-6 side chain occupies the quasiaxial ori-entation owing to A (1,3) strain (Fig. 4).

As a result, we achieved the enantioselective formalsynthesis of indolizidines 207A and 209B from the aminoalcohol ( 10 ) (15, 16), and total synthesis of indolizidines235B and 223J and C1-epimer of quinolizidine 2071 (17)(Schemes 10, 11).


N

O

CO 2MeCH3

TBSO

OMe

NCO 2MeCH3

TBSO

CO 2Me

NCO 2Me

TBSO

CO 2Me

[Me-]

[Me-]

H3O+

X

N

O

CO 2Me

CH3 OTBS

OMe

NCO 2Me

OTBS

CO 2Me

Fig. 4

NOR

OAc

CO 2Me

CO 2Me

NTBSO

CO 2Me

CO 2Me N2

3

TBSO

CH3

CO 2Me

CO 2Me

NOH

TBSO

CH3

CO 2Me

TBSO

CH3

N

O

H

O

NaH

50 oC(92%)

TBSON

O

O

Hb

CH3

Ha

TBSCl, Et 3NDMAP, CH 2Cl2(95%)

(-)-1: R = H

R = TBS

Me2CuLi

-60 oC ~ rt(92%)

Super-hydride(94%)

NaH

50 oC(93%)

J Ha-Hb = 10.5 Hz 9

Scheme 9


9/16

Drugs Fut 2002, 27(2) 151

NOCH3O

OTBS

CH3

CO 2Me

N

CH3

CH2

H

N

CH3

CH2CO 2Me

MOMO

N

CH3

I

CO 2Me

MOMO N

CH3

OR' CH2

R

N

CH3

OH

CO 2Me

MOMO

N OTBS

CH3

O

OCH3CO 2Me

N OTBS

CH3

OH

CO 2Me

1) Super-hydride (94%)

2) Swern ox.3) (EtO) 2P(O)CH 2CO 2Me

NaH (90%) 2 steps)

1) H 2, 5% Pd / C2) Super hydride

(91% 2 steps)

1) MOMClHnig base (93%)

2) TBAF (95%)

1) MsCl, Et 3N, 0 oC2) Nal, acetone

(85% 2 steps)

CH2=CHCH 2MgCl, Cul

-30 oC, THF (74%)

indolizidine 207Aindolizidine 209B

CH2=CH(CH 2)3MgCl, Cul

-30 oC, THF (82%)

(-)-indolizidine 235B'

R = CO 2Me, R' = MOM10: R = H, R' =H

1) n-PrSLi, HMPA2) c. HCl, MeOH reflux

3) Ph 3P, CBr 4, Et 3N

(63 % 3 steps)

1) n-PrSLi, HMPA

2) c. HCl, MeOH

(65 % 2 steps)

Scheme 10


10/16


NO

CH3O

OTBS

R

CO 2Me

N

O

OCH3

CH3

CO 2Me

OTBS

N OH

CH3

CO 2Me

MOMO

N CH2

CH3

CO 2Me

MOMO

N CH3

CH3 HN

CH3

CH2

H

1) super-hydride (95%)2) Swern ox.

3) W ittig-Horner(81% 2 steps)

(R = n-Bu)

R = n-BuR =Et

1) super-hydride (92%)2) Swern ox.3) MOMO(CH 2)3P +Ph 3Br-

n-BuLi (89% 2 steps)4) H 2, 5% Pd / C5) TBAF (89% 2 steps)

(R =Et)

1) H 2, 5% Rh / C2) Super-hydride (86% 2 steps)3) MOMCl Hnig base4) TBAF (77% 2 steps)

1) Swern ox.

2) MeP +Ph 3Br- n-BuLi

1) Swern ox.

2) MeP +Ph 3Br- n-BuLi

1) H2, Pd(OH) 21) n-PrSLi, HMPA2) c. HCl, MeOH, reflux3) Ph 3P, CBr 4, Et 3N (63% 3 steps)

2) n-PrSLi, HMPA3) c. HCl, MeOH, reflux4) Ph 3P, CBr 4, Et 3N

indolizidine 223IC1-epimer of quinolizidine 207I

MOMO N

CH3

OH

CO 2Me

MOMO N CH2

CH3

CO 2Me

(81% 2 steps)(64% 2 steps)

(43% 4 steps)

Scheme 11

OS

O

CH3

CH3

N

O

O

Troc S

O

O

CH3

CH3

O

ON

H

10% Cd-Pb

THF-1N NH 4OAc (92%)

11

12

Scheme 12


11/16

Drugs Fut 2002, 27(2) 153

OS

O

CH3

CH3

N

O

O

Troc

CH3

CH3

N

O

O

Troc

OH

CH3

CH3

N

O

OO

O

CH3

CH2Ph

CH3

CH3

N

O

OOH

CH2Ph

1) Swern ox.

2) (EtO) 2P(O)CH 2CO 2Et

NaH(80 % in 2 steps)

1) Swern ox.

2) (EtO) 2P(O)CH 2sO 2Et

NaH

(80 % in 2 steps)11

(65 % in 3 steps)

1) H 2, Pd(OH) 22) LiAlH43) TrocCl, K 2CO 3

Scheme 13

CH3

CH3O

O

N

PhSO 2

H NOO

CH3

CH3

SO 2PhHaHb

Hc

NOE12

d 2.65 dm, J = 12.2 Hz

CH3

CH3O

O

N

PhSO 2

H

6

NOO

CH3

CH3SO 2Ph

H

6

NOO

CH3

CH3

SO 2Ph

H

HaHb

12

CH3

CH3O

O

N

PhSO 2

H

C-6 epimer of 12

A B

2+

Fig. 5

Fig. 6


12/16

Treatment of ( 11 ) with Cd-Pb gave the quinolizidine(12 ) as the only cyclized product in excellent yield. Thestereochemistry of ( 12 ) was initially assigned on the basisof the following NOE and coupling constant, and thisassignment was confirmed by X-ray analysis (Fig. 5).

This high-kinetic stereoselectivity can be rationalizedas shown in Figure 6. Comparison of two kinds of foldedchairlike transition states ( A and B) leading to ( 12 ) andC-6 epimer, respectively, reveals a potential steric repul-

was unknown. We achieved the first enantioselective totalsynthesis of clavepictines A and B, pictamine and lepadinB starting from chiral building block ( 2). The syntheticstrategy for clavepictines and pictamine involved thehighly stereoselective quinolizidine ring closure as thekey step (Scheme 12).

The key intermediate ( 11 ) for the above Michael typeof quinolizidine ring closure reaction was synthesised asshown in Scheme 13.


NCH3

CH3

H

AcO

11

CH3

CH3

N

O

OH

PhSO 2

NOHH

PhSO 2

MOMO

NCH3

H

PhSO 2

MOMO

MOMO

NCH3

CH3

HNCH3

CH3

H

OH

NCH3

H

PhSO 2

MOMO MOMO

NCH3CH3

H

NCH3CH3

H

OH

NCH3CH3

H

AcO

1) 10 % HCl, EtOH, reflux2) TBDPSCl, imidazole

(85 % 2 steps)

3) MOMCl, Hnig base (93 %)

4) 40 % HF, pyridine (95 %)

1) I2, Ph 3P, imidazole

(89 %)

2) n-Bu 3SnH, AIBN

(94 %)

1) n-BuLi, thentrans -2-nonenal

2) 5 % Na-Hg, Na 2HPO 4(53 % 2 steps)

(+)-clavepictine B

c. HCl, MeOH

reflux (82 %)

Ac2O, pyridine(92 %)

(-)-clavepictine A

1) n-BuLi, thentrans -2-heptenal

2) 5 % Na-Hg, Na 2HPO 4(48 % 2 steps)

c. HCl, MeOHreflux (82 %)

Ac2O, pyridine(92 %)

(-)-pictamine

Scheme 14


13/16

sion involving the Ha and Hb protons for B. Therefore, thecyclization occurs via the transition state A to give rise tothe desired product ( 12 ).

Completion of the total synthesis of clavepictines A, Band pictamine is depicted in Scheme 14. Thus, weachieved the first enantioselective total synthesis ofclavepictines A, B and pictamine, and the absolute stere-ochemistry of these interesting alkaloids was determinedby the present synthesis (18, 19).

Furthermore, we adopted the intramolecular aldoltype of cyclization reaction of 13 to construct the hexahy-droquinolinone ring system ( 14 ) for the synthesis oflepadin B as the key step as shown in Scheme 15.

Drugs Fut 2002, 27(2) 155

N

CH3

O

O

CH3

H

OMOM

CO 2Me

N CH3O

OMOM

CO 2Me

H

H

4 eq. DBU

benzene, reflux (crude NMR, cis : trans = 14:1)

(60% isolated yield)

1413

N

OH

O

CH2Ph

CO 2Et N CH 3O

OMOM

CO 2Me

N CH 3TfO

OMOM

CO 2Me

N

Cl

N(Tf)2

N CH 3

OMOM

CO 2Me

MeO 2CN CH 3

CH2OMOM

CO 2Me

MeO 2CN CH 3

CH2

O

OCH3

OMOM

CO 2Me

N CH 3

CH2

O

CH3

OMOM

CO 2Me

N CH 3

CH2

O

N

CH3

OCH3

OMOM

CO 2Me

N CH 3

O

O

CH3

H

OMOM

CO 2Me

several steps LiHMDS, THF, -78 oC to -50 oC (80%)

Pd(PPh 3)4, PPh 3,Et3N, MeOHDMF, CO ballon, r.t (74%)

(vinyl)2CuLi1) LiOH .H 2O, H 2O-MeOH (1:3)2) ClCO 2Et, Et 3N

3) CH 2N2, Et 2O4) PhCO 2Ag, Et 3N, MeOH

(71% in 4 steps)

(89%)

1) LiOH .H 2O, H 2O-MeOH (1:3)

2) 1,1'-carbonyldiimidazoleO,N-dimethylhydroxylamine .HClEt3N, CH 2Cl2, (83% in 2 steps)

MeMgBr, THF (97%) OSO 4-NalO 4 (84%)

13

(-)-2

Scheme 15

N CH3

OMOM

CO 2Me

O

Ha

Hb

Hc

14

NOE

NOE

Fig. 7

Scheme 16


14/16

The conformation of 13 is restricted to conformer Abecause of the A (1,3) strain and because the appendageson C-2 and C-3 in A lie in a noncyclizable trans diaxialrelationship.

Consequently, epimerization at the C-3 position willfirst give A , which will cyclize easily to afford the desired4a,8a- cis -hexahydroquinolinone 14 (Fig. 8).

Completion of the total synthesis of lepadin B isdepicted in Scheme 17. Thus, we achieved the first enan-

The key intermediate ( 13 ) for the above cyclizationwas synthesized as shown in Scheme 16.

Treatment of ( 13 ) with 4 equiv. of DBU in refluxingbenzene afforded the cyclized product in a ratio of 14:1,and the major product was isolated in 60% yield. Thestereochemistry of the major product was determined tobe that of the desired cis hexahydroquinolinone ( 14 ) onthe basis of the observation of NOEs between Ha and Hb,Ha and Hc on the NOESY experiment (Fig. 7).


R

N

CH3

3

2

CH3

O

OMOM

CHO

13

RN

CH 3

CH3

O

OMOM

OHC

(R = CO 2Me)

epimerizationcyclization

14

R

N

CH3CH3

O

OMOMOHC

R

N

CH 3O

OMOM

H

H A(1,3) strain

NH

OH

CH3

CH3

H

H

N CH3

CH3

H

H

OMOM

CO 2t-Bu

N

CO 2t-Bu

CH3

H

H

OMOM

SO 2Ph

N CH3

H

H

OMOM

SO 2Ph

CO 2Me

N CH3

H

H

OMOM

SO 2Ph

CO 2Me

ON CH3

H

H

OMOM

SO 2Ph

CO 2Me

O

PhS

N CH3

H

H

OMOM

CO 2Me

O

14

n-BuLiPhSCH 2SO 2Ph

THF (78 %)

n-Bu 3SnH, AIBNbenzene, reflux

(85 %)

1) NaBH 4, CH 2Cl2-MeOH (10 : 1)

2) 1,1'-thiocarbonylimidazole

ClCH 2CH2Cl, reflux (75 % in 2 steps)

3) n-Bu 3SnH, toluene, reflux (84 %)

1) n-PrSLi, HMPA-THF2) (t-BuOCO) 2O

(59 % in 2 steps)

1) n-BuLi, THF, -78 oC to -70 oC

then trans -2-heptanal

2) Na-Hg, MeOH, r.t.

(49 % in 2 steps)

benzene, reflux

lepadin B

c. HCl, MeOH, reflux

(85 %)

Fig. 8

Scheme 17


15/16

lar aldol type of cyclization reaction as the key steps,respectively. These results are summarized in Figure 9.

References

1. Wang, C.-L., Wuonola, M.A. Recent progress in the synthesis and reactions of substituted piperidines. A review. Org Prep ProcInt 1992, 24: 585-621.

2. Takahata, H., Momose, T. Simple indolizidine alkaloids. In:The Alkaloids, Vol. 44. G.A. Cordell (Ed.). Academic Press: SanDiego 1993, 189-256.

3. Strunz, G.M., Findlay, J.A. Pyridine and piperidine alkaloids.In: The Alkaloids, Vol. 26. A. Brossi (Ed.). Academic Press: NewYork 1985, 89-183.

4. Raub, M.F., Cardellina, J.H. II, Choudhary, M.I., Ni, C.-Z.,Clardy, J., Alley, M.C. Clavepictines A and B: Cytotoxic quinolizidines from the tunicate Clavelina picta. J Am Chem Soc 1991,113: 3178-80.

5. Steffan, B., Lepadin, A. A decahydroquinoline alkaloid from the tunicate Clavelina lepadiformis. Tetrahedron 1991, 47:8729-32.

tioselective total synthesis of lepadin B, and the absolutestereochemistry of these interesting alkaloids was deter-mined by the present synthesis (20, 21).

Conclusions

We have demonstrated the efficient synthesis of thetwo enantiomers of versatile chiral building blocks ( 1 , 2)and its application to the synthesis of biologically activenatural products. As a result, we accomplished the firstchiral synthesis of the 3-piperidinol alkaloids cassine andspectaline starting from the chiral building block 1 , stere-odivergent process for all four stereoisomers of 3-piperidi-nol chiral building block and its application to the stereo-divergent synthesis of the 3-piperidinol alkaloidsprosafrinine, iso-6-cassine, prosophylline and prosopi-nine. Furthermore, we achieved the first enantioselectivetotal synthesis of the marine alkaloids clavepictines A andB, pictamine and lepadin B starting from the chiral build-ing block 2 using the highly stereocontrolled Michael typeof quinolizidine ring closure reaction and the intramolecu-

Drugs Fut 2002, 27(2) 157

N OH

CO 2Me

MeO 2C

AcO

1

N O

OH

EtO 2C

CH2Ph2

NHCH3

OHO

CH3

(CH2)9

NH

CH3

OH

CH3

O

(CH2)10

NH

OH

OH

O

CH3(CH2)9

NH

OH

OH

O

CH3(CH2)9

N

H

R1

R2

N

CH3

CH2

H

NCH3

H

RO

H3C(CH 2)n NH

OH

CH3

CH3

H

H

cassine

spectaline

prosafrinine

both enantiomers of

iso-6-cassine

prosophylline

prosopinine

C1-epimer of 207I

207A: R 1 = (CH 2)3CH=CH 2, R 2 = CH 3209A: R 1 = (CH 2)4CH3, R 2 = CH 3235B': R 1 = (CH 2)5CH=CH 2, R 2 = CH 3223J: R 1 = (CH 2)3CH3, R 2 = (CH 2)2CH3

lepadin B

clavepictine A: R = Ac, n = 5clavepictine B: R = H, n = 5pictamine: R = Ac, n = 3

O

NH

CH3

OH

(CH2)10 CH3

O

CH3NH

CH3

OH

(CH2)12

Fig. 9.


16/16

15. Shishido, Y., Kibayashi, C. Enantiogenic total synthesis of ( )-indolizidines (bicyclic gephyrotoxins) 205A, 207A, 209B, and 235B via the intramolecular Diels-Alder reaction of a chiral N-acylnitroso compound. J Org Chem 1992, 57: 2876-82.

16. Momose, T., Toyooka, N. Asymmetric synthesis of the indolizidine alkaloids 207A, 209B, and 235B : 6-Substituted 2,3-didehydropiperidine-2-carboxylate as a versatile chiral building block. J Org Chem 1994, 59: 943-5.

17. Toyooka, N., Tanaka, K., Momose, T., Daly, J.W., Garraffo,H.M. Highly stereoselective construction of trans(2,3)-cis- (2,6)-trisubstituted piperidines: An application to the chiral synthesis of dendrobates alkaloids. Tetrahedron 1997, 53: 9553-74.

18. Toyooka, N., Yotsui, Y., Yoshida, Y., Momose, T. Enantio- selective total synthesis of the marine alkaloid clavepictines Aand B. J Org Chem 1996, 61: 4882-3.

19. Toyooka, N., Yotsui, Y., Yoshida, Y., Momose, T., Nemoto, H.Highly stereoselective construction of 4,6-cis-substituted quinolizidine ring core: An application to enantioselective total synthe-

sis of the marine alkaloid clavepictines A, B and pictamine.Tetrahedron 1999, 55: 15209-24.

20. Toyooka, N., Okumura, M., Takahata, H. Enantioselective total synthesis of the marine alkaloid lepadin B. J Org Chem1999, 64: 2182-3.

21. Toyooka, N., Okumura, M., Takahata, H., Nemoto, H.Construction of 4a,8a-cis-octahydroquinolin-7-one core using an intramolecular aldol type of cyclization: An application to enantioselective total synthesis of lepadin B. J Org Chem 1999, 55:10673-84.

6. Kubanek, J., Williams, D.E., de Silva, E.D., Allen, T., Ander-sen, R.J. Cytotoxic alkaloids from the flatworm Prostheceraeus villatus and its tunicate prey Clavelina lepadiformis. TetrahedronLett 1995, 36: 6189-92.

7. Portmann, R.E., Ganter, C. Heterotricyclodecane XVI.2-Oxa-7-aza-isotwistane and 2-oxa-7-aza-twistane. Helv ChimActa 1973, 56: 1991.

8. Momose, T., Toyooka, N., Jin, M. Asymmetric twin-ring differentiation by lipase-catalyzed enantiotoposelective reaction of the ring-crossed meso glycol: Asymmetric synthesis of a highly func- tionalized piperidine from the conjoined twin piperidine system.Tetrahedron Lett 1992, 33: 5389-90.

9. Momose, T., Toyooka, N., Jin, M. Bicyclo[3.3.1]nonanes as synthetic intermediates. Part 21. Enantiodivergent synthesis of the cis,cis 2,6-disubstituted piperidin-3-ol chiral building block for alkaloid synthesis. J Chem Soc Perkin Trans 1 1997, 2005-13.

10. Bonjoch, J., Seffet, I., Bosch, J. Synthesis of 2,5-piperidi- nones. Regioselectivity in the Dieckmann cyclization. Tetra-hedron 1984, 40: 2505-11.

11. Toyooka, N., Yoshida, Y., Momose, T. Enantio- and diastere- odivergent synthesis of all four diastereomers of the 2,6-disubstituted 3-piperidinol chiral building block. Tetrahedron Lett 1995,36: 3715-8.

12. Momose, T., Toyooka, N. Asymmetric synthesis of the alkaloid 2,6-disubstituted piperidin-3-ols, ( )-cassine and (+)-spectaline. Tetrahedron Lett 1993, 34: 5785-6.

13. Momose, T., Toyooka, N. Asymmetric synthesis of methyl N,Odiacetylspicigerinate. Heterocycles 1995, 40: 137-8.

14. Toyooka, N., Yoshida, Y., Yotsui, Y., Momose, T. 2-Piperidone type of chiral building block for 3-piperidinol alkaloid synthesis. JOrg Chem 1999, 64: 4914-9.


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Drugs of the Future 2002, 27(2) 143-158