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

Copyright 2002 PROUS SCIENCE CCC: 0377-8282/2002

Review Article

Application of chiral building blocks to the synthesis of drugs

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

Naoki Toyooka* and Hideo Nemoto

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

Introduction A number of piperidines and indolizidines bearing carbonaceous substituents at both and positions have been isolated from natural sources (1, 2), and many of them have received much attention due to a variety of biological activities. 3-Piperidinol alkaloids having appendages at both and positions also have been isolated from plants (3). These 3-piperidinol alkaloids also exhibit a variety of pharmacological properties such as anesthetic, analgesic and antibiotic activities. Recently, the alkaloids containing this ring system were isolated from marine species and all of them showed substantial cytotoxic activity against human solid tumor cell lines (4-

6). On the other hand, construction of a versatile chiral building block for biologically active natural compounds would provide us with powerful tools for the synthesis of target natural products. In addition, it is very important for the evaluation of the biological activities of synthetic compounds that both enantiomers of the chiral building blocks be available in a similar manner. Accordingly, we designed two chiral building blocks (1, 2) for the synthesis of biologically interesting alkaloids. This review describes the synthesis of the chiral building blocks (1, 2) and its application to the stereodivergent synthesis of 3-piperidinol alkaloids, the flexible route to the dartpoison frog alkaloids and the synthesis of cytotoxic marine alkaloids. Design and synthesis of chiral building blocks First, we designed the piperidinol (1) as the chiral building block for the synthesis of 3-piperidinol alkaloids. As mentioned above, it is very important that both enantiomers of the chiral building block be synthesised in a similar manner. To this end, we examined the chemo-enzymatic differentiation of azabicyclic meso glycol (3) and its acetate (4) as shown in Figure 1.

OH HO N R transesterification 3: R = CO2Me lipase-mediated HO

OAc

AcO

MeO2C

N CO2Me (+)-1

OH

OAc AcO N R lipase-mediated hydrolysis 4: R = CO2Me AcO

OH AcO N R MeO2C N CO2Me (-)-1 OH

Fig. 1.

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Chiral building blocks for the synthesis of drugs

Scheme 1
OAc ClCO2Me N CH3 CHCl3, reflux (95%) 5 OH HO N R 1) NaBH4 2) 10% Na2CO3 (aq) (77 % in 2 steps) 3: R = CO2Me OAc AcO N R 1) NaBH4 2) Ac2O, pyridine (74% in 2 steps) 4: R = CO2Me R = CO2Me R = CO2Me O N R OAc H2, 5% Pd / C (98%) O N R OAc PCC (90%) R = CO2Me N R OAc SeO2 dioxane - H2O, reflux ( 77 %) R = CO2Me HO N R OAc

The substrates (3, 4) for the lipase-mediated differentiation reaction were prepared from a known bicyclic amine (5) (7) as depicted in Scheme 1. With the requisite 3 and 4 in hand, we focused our attention on the lipase-mediated enantioselective transesterification of 3 and hydrolysis of 4. As shown in Tables I and II, the use of lipase CE gave the best results in both

Table II:a
OAc AcO N R 0.25 M phosphate buffer (pH = 7) 32 ~ 35 oC lipase AcO N R PCC OH AcO N R O

4: R = CO2Me

6: R = CO2Me

(-)-7: R = CO2Me

Lipaseb CE AY

t/h 23 35 66 84 48

Yield (%)c 84 (99) 42 (76) 23 (70) 14 (45) 39 (76)

(% ee)d 80 (>99) 78 58 48 75

Table I:a
OH HO N R vinyl acetate lipase 32 ~ 35 oC HO N R OAc PCC O N R OAc

CCL PPL PLE

aAll

3: R = CO2Me

6: R = CO2Me

(+)-7: R = CO2Me

Lipaseb CE CE AY CCL
aAll

Solvent C 6H 6 i-Pr2O i-Pr2O i-Pr2O

t/h 98 109 87 91

Yield (%)c 38 (99) 85 (99) 33 (99) 15 (94)

(% ee)d 32 90 (>99) 56 54

runs were conducted with substrate (0.17 mmol), lipase (100 mg) and phosphate buffer in the solvent (6 ml). bPLE (pig liver esterase) was supplied by the Amano Pharmaceutical Co., Ltd. and PPL (porcine pancreas lipase) was purchased from the Sigma 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. Optical yield in parentheses is based on a sample after recrystallization twice from i-Pr2O.

runs were conducted with substrate (0.23 mmol), lipase (100 mg) and vinyl acetate (2 equiv.) in the organic solvent (10 ml). bLipase CE (from Humicola lanuginosa) and AY (from Candida rugosa) were supplied by the Amano Pharmaceutical Co., Ltd. cYields for the isolated monoacetates; yields in parentheses are those based on the conversion rate. dOptical yields were determined by HPLC analyses by using a column packed with Chiralpak AD (EtOH-hexane, 9:1) after oxidation of the monoacetate with PCC. Optical yield in parentheses is based on a sample after single recrystallization from i-Pr2O.

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 3 or 4. The ketone (+)-(7) was converted to the desired building block (+)-(1) by the oxidative cleavage of the piperi-

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145

Scheme 2
OAc O N R OAc H3C O N R O3, then NaBH4 CH2Cl2-MeOH (10:1) (98%) MeO2C N CO2Me (+)-1 OH

HC(OMe)3 cat. H2SO4 (86%)

AcO

(+)-7: R = CO2Me

R = CO2Me

OAc O N R HC(OMe)3 cat. H2SO4 (86%) (-)-7: R = CO2Me H3C O

OAc O3, then NaBH4 CH2Cl2-MeOH (10:1) (98%)

AcO

MeO2C

N CO2Me (-)-1

OH

R = CO2Me

epimerization to desired configuration

HO stereoselective introduction of various alkyl side-chains

EtO2C

N CH2Ph 2

reduction to methyl or hydroxymethyl

HO R1 R1

HO R1

HO R1

HO

N R

R2

N R

R2

N R

R2

N R

R2

II

III

IV

(R = H or Me, R1 = H or OH, R2 = various alkyls)

Fig. 2 Scheme 3
O 1) NaBH4, EtOH (92%) N CH2Ph (47%, >99% ee) R = Ac (+)-2: R = H K2CO3, EtOH (90%) O 2) vinyl acetate, lipase AK i-Pr2O EtO2C N CH2Ph 8 O O Bakers' yeast, tap water (88%, > 99% ee) EtO2C N CH2Ph (-)-2 O HO

R (-)-2

+
EtO2C

(52%, 91% ee)

done ring in 7. Similarly, ()-7 was transformed into ()-1 as shown in Scheme 2 (8, 9). Next, we designed the 2-piperidone (2) as the more flexible chiral building block for the synthesis of 3-piperidinol alkaloids. The basic strategy we used to prepare all

four stereoisomers of ,-disubstituted 3-piperidinol building blocks from 2 is presented in Figure 2. Thus, we examined the preparation of both enantiomers of 2, and prepared them from the known -keto ester (8) (10) using bakers yeast reduction of 8 or

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Chiral building blocks for the synthesis of drugs

Scheme 4

AcO 4 steps MeO2C N CO2Me (+)-1 OH

MOMO HO 1) PCC, AcONa N CO2Me OTBDPS 2) ethanedithiol BF3 .Et2O (68% 2 steps)

MOMO S N S CO2Me Raney Ni (W-4) (95%) OTBDPS

MOMO (CH2)7 MOMO CH2 H3C 1) Swern ox. 2) CH2=CH(CH2)8P+Ph3Brn-BuLi (86% 2 steps) N CO2Me OH MOMO TBAF THF (85%) H3C

H3C

N CO2Me

N CO2Me

OTBDPS

1) O2, PdCl2, CuCl, DMF-H2O (70%) 2) H2, 5% Pd / C 3) TMSI, CHCl3, reflux (65% 2 steps) HO CH3 (-)-cassine O

H3C

N H

MOMO (-)-1 H3C N CO2Me OH

1) Swern ox. 2) CH2=CH(CH2)10P+Ph3Brn-BuLi (77% 2 steps)

MOMO (CH2)9 CH2

H3C

N CO2Me

1) O2, PdCl2, CuCl, DMF-H2O (70%) 2) H2, 5% Pd / C 3) TMSI, CHCl3, reflux (65% 2 steps) HO CH3 O (+)-spectaline

H3C

N H

AcO (-)-1 H3C N Ac

O (CH2)11 O CH3

HO

O N H spicigerine OH

H3C

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Introduction of various alkyl, alkenyl or alkynyl groups Chain extension and functionalization MeO2C Chain extension and cyclization to an indolizidine or quinolizidine system N CO2Me OR

5,8-disubstituted indolizidines 1,4-disubstituted quinolizidines

Fig. 3

Scheme 5
HO 1) MOMCl, Hnig base CHCl3, reflux (98%) N CH2Ph (-)-2 O 2) super-hydride THF (96%) MOMO HO 1) PhSSPh, n-Bu3P pyridine (95%) N CH2Ph O 2) Raney Ni (W-4) EtOH (95%) 1) c. HCl, MeOH 2) NaH, BnBr (84% 2 steps) 3) Lawesson's reagent (96%) PhCH2O O N CO2CH2Ph O CH3 PhCH2O 1) H2, Ph(OH)2 2) CBzCl, K2CO3 (96% 2 steps) H3C N CH2Ph O O CH3 PhCH2O BrCH2CO2Me then Ph3P, Et3N H3C MeCN (83%) N CH2Ph S MOMO

EtO2C

H3C

N CH2Ph

H3C type I of chiral building block

1) super-hydride THF (90%) 2) Swern ox. 3) Wittig reagent A, n-BuLi THF (60% 2 steps)

PhCH2O O H3C N CO2CH2Ph (CH2)6 O CH3

1) H2, Ph(OH)2 2) Na, liq. NH3 3) p-TsOH, acetone (50% 3 steps)

HO

O N H prosafrinine CH3

H3C

O Wittig reagent A: Ph3P+ Br

O CH3

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

Synthesis of 3-piperidinol alkaloids The synthetic utility of (+)- and ()-1 has been demonstrated by the first total synthesis of ()-cassine, (+)-spectaline, (12) and methyl N,O-diacetylspicigerinate (13) as

shown in Scheme 4. The absolute configuration of natural cassine, spectaline and spicigerine was unambiguously determined by the above chiral synthesis. More efficiently, we synthesized the chiral building blocks (I, II, III and IV as shown in Figure 3) starting from ()-2 and achieved the stereodivergent synthesis of the 3-piperidinol alkaloids prosafrinine, iso-6-cassine, prosophylline and prosopinine, respectively (14) (Schemes 5-8).

148

Chiral building blocks for the synthesis of drugs

Scheme 6
PhCH2O H3C O N CH2Ph O CH3 PhCH2O NaBH3CN, TFA CH2Cl2, 0oC (99%) H3C N CH2Ph O O CH3 PhCH2O H3C OH

1) H2, Pd(OH)2 2) ClCO2Me, K2CO3 (68% 2 steps) 3) super-hydride (92%)

N CO2Me

trans: cis = 14:1

type II of chiral building block 1) Swern ox. 2) CH2=CH(CH2)8P+Ph3Brn-BuLi (80% 2 steps) 3) O2, CuCl, PdCl2 DMF-H2O (64%)

HO CH3 iso-6-cassine O

1) H2, Pd(OH)2 2) TMSI N H

PhCH2O H3C N CO2Me

O (CH2)7 CH3

H3C

CHCl3, reflux (58% 2 steps)

Scheme 7
MOMO HO N CH2Ph O

1) NaH, PhCH2Br DMF-benzene (2:1) (96%) 2) c. HCl, MeOH 3) PCC, AcONa (83% 2 steps) PhCH2O

O 1) H2, Pd(OH)2 N CH2Ph O 2) NaB(OAc)3H (97% 2 steps) HO

HO

N CH2Ph

2,2-dimethoxypropane p-TsOH, MS 5A CH2Cl (91%) H3C H3C O N CH2Ph NaBH3CN, TFA CH2Cl2, 0 oC (59%) H3C H3C O N CH2Ph O H3C O O CH3 LiAlH4 (99%) H3C O N CH2Ph type III of chiral building block H3C O N H CH3 prosophylline 1) H2, Pd(OH)2 2) 10% HCl, EtOH (75% 2 steps) H3C O O O H3C O O CH3 BrCH2CO2Me then Ph3P, Et3N MeCN, reflux (72%) H3C O N CH2Ph S O H3C H3C Lawesson's reagent THF, reflux (57%) O N CH2Ph O O

OH 1) Swern ox. 2) Wittig reagent A, n-BuLi THF (59% 2 steps)

HO HO

O O N CH2Ph (CH2)6 O CH3

O Wittig reagent A: Ph3P+ Br

O CH3

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149

Scheme 8
HO HO N CH2Ph O Ac2O, pyridine (88%) AcO AcO N CH2Ph O 2) BrCH2CO2Me then Ph3P, Et3N MeCN, reflux (92%) 1) Lawesson's reagent THF, reflux (99%) AcO O AcO N CH2Ph NaBH3CN, TFA CH2Cl2, 0 oC (84%) H3C H3C O N CH2Ph type IV of chiral building block 1) Swern ox. 2) Wittig reagent A, n-BuLi THF (59% 2 steps) HO HO O CH3

O 1) LiAlH4, THF, reflux OH 2) 2,2-dimethoxypropane, p-TsOH, MS 5A CH2Cl2, rt (75% 2 steps)

AcO O AcO N CH2Ph O CH3

trans: cis = 11:1

H3C H3C O

O O N CH2Ph (CH2)6 O CH3

1) H2, Pd(OH)2 2) 10% HCl, EtOH 3) p-TsOH, acetone (73% 3 steps)

O N H prosopinine CH3

O Witting reagent A: Ph3P+ Br

O CH3

Table III:
R1 R (R1)2CuX solvent MeO2C N CO2Me O R

MeO2C

N CO2Me

R1 Et Vinyl Allyl n-Bu

X MgBr Li MgBr Li

R TBS MOM MOM TBS

Solvent THF Et2O THF Et2O

Yield (%) 96 91 80 94

Synthesis of dart-poison frog alkaloids Another application of building block ()-1 to the synthesis of natural alkaloids was accomplished by the flexible synthesis of 5,8-disubstituted indolizidine and 1,4disubstituted quinolizidine types of Dendrobates alkaloids as shown in Figure 3.

The above synthetic strategy involved the highly stereoselective Michael reaction of the cyclic enaminoester to give rise to 2,3,6-trisubstituted piperidine ring systems, which were suitable intermediates for the synthsis of the above Dendrobates alkaloids. The results are summarized in Table III.

150

Chiral building blocks for the synthesis of drugs

Scheme 9
OAc R NaH O N CO2Me 50 oC (92%) TBSO N CO2Me Me2CuLi -60 oC ~ rt (92%) TBSO N
2 3

CH3 CO2Me

CO2Me TBSCl, Et3N DMAP, CH2Cl2 (95%) (-)-1: R = H R = TBS

CO2Me

CO2Me Super-hydride (94%)

Ha TBSO O N O Hb O 9 CH3 TBSO N O

CH3 H NaH 50 oC (93%) TBSO N CO2Me CH3 OH

JHa-Hb = 10.5 Hz

[Me-] CH3 CO2Me N OMe TBSO O CO2Me OTBS N CO2Me CO2Me

[Me-] TBSO

CO2Me

X
H3O+ O CH3 N CO2Me N CO2Me TBSO CH3 CO2Me OTBS OMe

Fig. 4

Analysis of the coupling patterns of the methine proton at C-2 and the methyleme protons at C-7 in the NMR spectrum of the oxazolizinone (9) suggested that the stereochemistry of 9 could be assigned as depicted in Scheme 9, by assuming that all the ring appendages lie in equatorial orientation. The stereoselectivity of this key Michael reaction results from the preferred -axial attack, leading not to boatlike transition state B but to chairlike transition state A where the C-6 side chain occupies the quasiaxial orientation owing to A(1,3) strain (Fig. 4). As a result, we achieved the enantioselective formal synthesis of indolizidines 207A and 209B from the amino alcohol (10) (15, 16), and total synthesis of indolizidines 235B and 223J and C1-epimer of quinolizidine 2071 (17) (Schemes 10, 11).

Synthesis of marine alkaloids Cardellinas group reported the isolation of the quinolizidine alkaloids clavepictines A and B from the tunicate Clavelina picta, which are the first quinolizidine alkaloids from a tunicate. In the same year, Faulkner et al. isolated pictamine from the same marine species and its gross structure was determined to be a bis-nor analog of clavepictine A. Furthermore, lepadins A, B and C were isolated from the tunicate Clavelina lepadiformis by Steffan and Andesen et al. These marine alkaloids involved the 3-piperidinol nuclei and showed significant cytotoxic activity against a variety of murine and human cancer cell lines. Although their relative stereochemistry had been determined by extensive NMR studies of an X-ray diffraction analysis, the absolute stereochemistry

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151

Scheme 10

H3C H3C O O 1) Super-hydride (94%) 2) Swern ox. N CO2Me OTBS 3) (EtO)2P(O)CH2CO2Me NaH (90%) 2 steps) H3C O O

H3C N CO2Me OTBS

1) H2, 5% Pd / C 2) Super hydride (91% 2 steps)

H3C MOMO N CO2Me OH

1) MOMCl Hnig base (93%) 2) TBAF (95%) HO

H3C N CO2Me OTBS

1) MsCl, Et3N, 0 oC 2) Nal, acetone (85% 2 steps)

H3C MOMO N CO2Me I CH2=CHCH2MgCl, Cul -30 oC, THF (74%) R' O

H3C N R R = CO2Me, R' = MOM 10: R = H, R' =H CH2 indolizidine 207A indolizidine 209B

CH2=CH(CH2)3MgCl, Cul -30 oC, THF (82%)

1) n-PrSLi, HMPA 2) c. HCl, MeOH (65 % 2 steps)

H3C MOMO N CO2Me CH2

1) n-PrSLi, HMPA 2) c. HCl, MeOH reflux 3) Ph3P, CBr4, Et3N (63 % 3 steps)

H3C H N (-)-indolizidine 235B' CH2

152

Chiral building blocks for the synthesis of drugs

Scheme 11

R O O

1) super-hydride (95%) 2) Swern ox. N CO2Me R =Et R = n-Bu 1) super-hydride (92%) 2) Swern ox. 3) MOMO(CH2)3P+Ph3Brn-BuLi (89% 2 steps) 4) H2, 5% Pd / C 5) TBAF (89% 2 steps) OTBS 3) Wittig-Horner (81% 2 steps) (R = n-Bu) H3C

H3C O O N CO2Me OTBS

H3C

(R =Et)

1) H2, 5% Rh / C 2) Super-hydride (86% 2 steps) 3) MOMCl Hnig base 4) TBAF (77% 2 steps)

H3C H3C MOMO N CO2Me 1) Swern ox. 2) MeP+Ph3Br- n-BuLi (64% 2 steps) H3C MOMO N CO2Me 1) n-PrSLi, HMPA 2) c. HCl, MeOH, reflux 3) Ph3P, CBr4, Et3N (63% 3 steps) 1) H2, Pd(OH)2 2) n-PrSLi, HMPA 3) c. HCl, MeOH, reflux 4) Ph3P, CBr4, Et3N (43% 4 steps) CH2 1) Swern ox. 2) MeP+Ph3Br- n-BuLi (81% 2 steps) H3C MOMO N CO2Me CH2 OH MOMO N CO2Me OH

H3C

H N CH2

H3C

H N indolizidine 223I CH3

C1-epimer of quinolizidine 207I

Scheme 12
H3C H3C H3C O N Troc 11 12 H3C O O S O 10% Cd-Pb THF-1N NH4OAc (92%) S O O O N O H

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153

Scheme 13
H3C H3C O

O 1) Swern ox. N CH2Ph OH 2) (EtO)2P(O)CH2CO2Et NaH (80 % in 2 steps)

H3C H3C O

O N CH2Ph 1) H2, Pd(OH)2 2) LiAlH4 3) TrocCl, K2CO3 (65 % in 3 steps) O CH3

H3C H3C O

O O N Troc 11 S O 1) Swern ox. 2) (EtO)2P(O)CH2sO2Et NaH (80 % in 2 steps)

H3C H3C O

N Troc

OH

d 2.65 dm, J = 12.2 Hz H3C H3C O PhSO2 12 NOE O H N H3C O Ha CH3 O Hb N Hc SO2Ph

Fig. 5

2+ CH3 H3C O O A N
6

CH3 SO2Ph H3C H B O O Ha

SO2Ph N Hb
6

H3C H3C O

O H N

H3C H3C O

O H N

PhSO2 12

PhSO2 C-6 epimer of 12

Fig. 6

154

Chiral building blocks for the synthesis of drugs

Scheme 14

H3C H3C O

O H N

1) 10 % HCl, EtOH, reflux 2) TBDPSCl, imidazole (85 % 2 steps) 3) MOMCl, Hnig base (93 %) 4) 40 % HF, pyridine (95 %)

MOMO HO PhSO2 H N 1) I2, Ph3P, imidazole (89 %) 2) n-Bu3SnH, AIBN (94 %)

MOMO H H3C PhSO2 1) n-BuLi, then trans-2-nonenal 2) 5 % Na-Hg, Na2HPO4 (53 % 2 steps) N

PhSO2 11

HO H H3C H3C (+)-clavepictine B N c. HCl, MeOH reflux (82 %) H3C H3C N MOMO H

Ac2O, pyridine (92 %)

AcO H H3C H3C (-)-clavepictine A N

MOMO H H3C PhSO2 N

1) n-BuLi, then trans-2-heptenal 2) 5 % Na-Hg, Na2HPO4 (48 % 2 steps) H3C

MOMO H H3C N

AcO H H3C H3C (-)-pictamine N Ac2O, pyridine (92 %)

c. HCl, MeOH reflux (82 %)

HO H H3C N

H3C

was unknown. We achieved the first enantioselective total synthesis of clavepictines A and B, pictamine and lepadin B starting from chiral building block (2). The synthetic strategy for clavepictines and pictamine involved the highly stereoselective quinolizidine ring closure as the key step (Scheme 12). The key intermediate (11) for the above Michael type of quinolizidine ring closure reaction was synthesised as shown in Scheme 13.

Treatment of (11) with Cd-Pb gave the quinolizidine (12) as the only cyclized product in excellent yield. The stereochemistry of (12) was initially assigned on the basis of the following NOE and coupling constant, and this assignment was confirmed by X-ray analysis (Fig. 5). This high-kinetic stereoselectivity can be rationalized as shown in Figure 6. Comparison of two kinds of folded chairlike transition states (A and B) leading to (12) and C-6 epimer, respectively, reveals a potential steric repul-

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155

Scheme 15
H O CH3 O N OMOM 4 eq. DBU benzene, reflux (crude NMR, cis : trans = 14:1) (60% isolated yield) O N H 14 CH3 H

OMOM

CH3

CO2Me 13

CO2Me

Scheme 16
OH several steps O N CH2Ph (-)-2 N N(Tf)2 Pd(PPh3)4, PPh3, Et3N, MeOH DMF, CO ballon, r.t (74%) CO2Et O N CH3 Cl OMOM LiHMDS, THF, -78 oC to -50 oC (80%) TfO N CH3 OMOM

CO2Me

CO2Me

CH2 OMOM O H3C O N CH3 1) LiOH .H2O, H2O-MeOH (1:3) 2) ClCO2Et, Et3N 3) CH2N2, Et2O 4) PhCO2Ag, Et3N, MeOH (71% in 4 steps)

CH2 OMOM (vinyl)2CuLi MeO2C N CH3 (89%) MeO2C N CH3 OMOM

CO2Me

CO2Me

CO2Me

1) LiOH .H2O, H2O-MeOH (1:3) 2) 1,1'-carbonyldiimidazole O,N-dimethylhydroxylamine .HCl Et3N, CH2Cl2, (83% in 2 steps) CH2 OMOM O H3C O N CH3 N CH3 CO2Me MeMgBr, THF (97%) H3C O N CH3 OSO4-NalO4 (84%) O CH2 OMOM H O CH3 N OMOM

CH3

CO2Me 13

CO2Me

NOE

NOE

Ha

Hc

OMOM

N Hb 14

CH3

CO2Me

Fig. 7

sion involving the Ha and Hb protons for B. Therefore, the cyclization occurs via the transition state A to give rise to the desired product (12). Completion of the total synthesis of clavepictines A, B and pictamine is depicted in Scheme 14. Thus, we achieved the first enantioselective total synthesis of clavepictines A, B and pictamine, and the absolute stereochemistry of these interesting alkaloids was determined by the present synthesis (18, 19). Furthermore, we adopted the intramolecular aldol type of cyclization reaction of 13 to construct the hexahydroquinolinone ring system (14) for the synthesis of lepadin B as the key step as shown in Scheme 15.

156

Chiral building blocks for the synthesis of drugs

H H N R CH 3 O 14 O (R = CO2Me) OHC OMOM cyclization H3C N R CH 3 OMOM epimerization H3C O

2

CHO
3

O OMOM A(1,3) strain H3C

OHC N R CH3 OMOM

N R CH 3 13

Fig. 8

Scheme 17

PhS OMOM n-BuLi PhSCH2SO2Ph THF (78 %) O

SO2Ph H OMOM n-Bu3SnH, AIBN benzene, reflux (85 %) N H CH3 O

SO2Ph H OMOM

N H 14

CH3

CO2Me

N H

CH3

CO2Me

CO2Me

1) NaBH4, CH2Cl2-MeOH (10 : 1) CH3 2) 1,1'-thiocarbonylimidazole ClCH2CH2Cl, reflux (75 % in 2 steps) 3) n-Bu3SnH, toluene, reflux (84 %) 1) n-BuLi, THF, -78 oC to -70 oC H then trans-2-heptanal OMOM 2) Na-Hg, MeOH, r.t. (49 % in 2 steps) H N SO2Ph H OMOM 1) n-PrSLi, HMPA-THF 2) (t-BuOCO)2O benzene, reflux CH3 (59 % in 2 steps) H N CH3 SO2Ph H OMOM

N H

CH3

CO2t-Bu

CO2t-Bu

CO2Me

c. HCl, MeOH, reflux (85 %)

CH3

OH

N H H lepadin B

CH3

The key intermediate (13) for the above cyclization was synthesized as shown in Scheme 16. Treatment of (13) with 4 equiv. of DBU in refluxing benzene afforded the cyclized product in a ratio of 14:1, and the major product was isolated in 60% yield. The stereochemistry of the major product was determined to be that of the desired cishexahydroquinolinone (14) on the basis of the observation of NOEs between Ha and Hb, Ha and Hc on the NOESY experiment (Fig. 7).

The conformation of 13 is restricted to conformer A because of the A(1,3) strain and because the appendages on C-2 and C-3 in A lie in a noncyclizable trans diaxial relationship. Consequently, epimerization at the C-3 position will first give A, which will cyclize easily to afford the desired 4a,8a-cis-hexahydroquinolinone 14 (Fig. 8). Completion of the total synthesis of lepadin B is depicted in Scheme 17. Thus, we achieved the first enan-

Drugs Fut 2002, 27(2)

157

207A: R1 = (CH2)3CH=CH2, R2 = CH3 209A: R1 = (CH2)4CH3, R2 = CH3 235B': R1 = (CH2)5CH=CH2, R2 = CH3 223J: R1 = (CH2)3CH3, R2 = (CH2)2CH3 HO

R2 H N R1

H3C

H N CH2

C1-epimer of 207I

O N H (CH2)10 CH3 both enantiomers of AcO

HO

O N (CH2)10 H iso-6-cassine CH3

H3C

H3C

cassine HO O N H (CH2)12 CH3

MeO2C

N CO2Me 1

OH HO HO O N H (CH2)9 prosophylline CH3

H3C

spectaline HO HO O N (CH2)9 H prosafrinine CH3 EtO2C N CH2Ph 2 CH3 O HO HO

O N H (CH2)9 prosopinine CH3

H3C

RO clavepictine A: R = Ac, n = 5 clavepictine B: R = H, n = 5 pictamine: R = Ac, n = 3 H3C(CH2)n H H3C N HO H

H3C

N H H

lepadin B

Fig. 9.

tioselective total synthesis of lepadin B, and the absolute stereochemistry of these interesting alkaloids was determined by the present synthesis (20, 21). Conclusions We have demonstrated the efficient synthesis of the two enantiomers of versatile chiral building blocks (1, 2) and its application to the synthesis of biologically active natural products. As a result, we accomplished the first chiral synthesis of the 3-piperidinol alkaloids cassine and spectaline starting from the chiral building block 1, stereodivergent process for all four stereoisomers of 3-piperidinol chiral building block and its application to the stereodivergent synthesis of the 3-piperidinol alkaloids prosafrinine, iso-6-cassine, prosophylline and prosopinine. Furthermore, we achieved the first enantioselective total synthesis of the marine alkaloids clavepictines A and B, pictamine and lepadin B starting from the chiral building block 2 using the highly stereocontrolled Michael type of quinolizidine ring closure reaction and the intramolecu-

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 Proc Int 1992, 24: 585-621. 2. Takahata, H., Momose, T. Simple indolizidine alkaloids. In: The Alkaloids, Vol. 44. G.A. Cordell (Ed.). Academic Press: San Diego 1993, 189-256. 3. Strunz, G.M., Findlay, J.A. Pyridine and piperidine alkaloids. In: The Alkaloids, Vol. 26. A. Brossi (Ed.). Academic Press: New York 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.

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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. Enantioselective total synthesis of the marine alkaloid clavepictines A and 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 synthesis 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 Chem 1999, 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.