[Strategies and Tactics in Organic Synthesis] Volume 7 || Chapter 3 Total syntheses of zoapatanol

STRATEGIES AND TACTICS IN ORGANIC SYNTHESIS, VOL. 7 �9 2008 Elsevier Ltd. All rights reserved.

Chapter 3

TOTAL SYNTHESES OF ZOAPATANOL

Janine Cossy, Vdronique Bellosta, and Catherine Taillier Laboratoire de Chimie Organique, ESPCI, CNRS 10 rue Vauquelin, 75231 Paris Cedex 05, France

I. Introduction II. Nicolaou's Synthesis III. Chen's Synthesis IV. Cookson's Synthesis V. Kocienski's Synthesis VI. Kane's Synthesis VII. Trost's Synthesis VIII. Our Approaches for the Total Synthesis of (+)-Zoapatanol

A. Ring-Closing Metathesis Approach B. Homer-Wadsworth-Emmons Approach

IX. Conclusion References and Footnotes

59 60 64 67 69 73 78 83 83 90 95 95

I. Introduct ion

(+)-Zoapatanol 1, montanol 2, tomentanol 3 and tomentol 4 are diter- penoid oxepanes isolated from the leaves of the Mexican zoapatle plant Montanoa tomentosa, which Mexican women have been using for cen- turies to prepare "tea" to induce menses, labor and to terminate early pregnancy. 1 Recent studies support the belief that zoapatanol and its metabolites might be responsible for the observed antifertility activity. 2 In 1979, the isolation and the structure of zoapatanol were described. 3

Due to its biological profile and its challenging structure, several synthetic approaches have been described 4 and seven total syntheses of zoapatanol have been reported 5-11 but only two of them were enantioselective, l~

Key issues for a successful synthesis of zoapatanol 1 are the stereo- controlled construction of the oxepane ring containing the two stereogenic centers, the introduction of the (E)-exocyclic double bond and the instal- lation of the nonenyl side chain. Since (+)-zoapatanol was isolated as

60 JANINE COSSY, VI~RONIQUE BELLOSTA, AND CATHERINE TAILLIER

4 p 5 p

HO,,.

O

OR'

1 R = (CH3)2C=CHCH 2- R'= H Zoapatanol 2 R = (CH3)2CHC(CH3)=CH- R'= H Montanol 3 R = H2C=C(CH3)CH(CH3)CH 2- R'= H Tomentanol 4 R = (CH3)2C(OH)CH=CH- R'= Ac Tomentol

FIGURE 1. Oxepane derivatives isolated from M. tomentosa.

a 1/1 mixture of epimers at C6, control of this stereocenter is not required (Figure 1).12

In 1980, the first two syntheses of (_+)-zoapatanol were disclosed, one by Nicolaou 6 and the other by Chen and Rowand, 5 and six other syntheses have been disclosed since then. 4,7-11 For all of them, the construction of the oxepane ring was achieved through the formation of the O1'-C7' or O1 '-C2' bonds except for one ~ in which the C4'-C5' bond was formed.

II. Nicolaou's Synthesis

A convergent synthesis of (+)-zoapatanol was achieved. 6 In the retrosynthetic analysis, the oxepane ring would be obtained by nucleophilic attack of the tertiary alcohol on the epoxide present in compound I via a 7-exo-tet process that would allow the formation of the O 1 '-C7' bond. The syn-1,2-diol present in compound I would come from a chelation-controlled addition of a methyl Grignard reagent to the ~-benzyloxymethoxy ketone II according to the Cram-chelate model A (Figure 2). ~3 Ketone II would be synthesized from glycidol 5 as the starting material and bromide 10 as the precursor of the long side chain of zoapatanol (Scheme 1).

Bromide 10, which would allow the introduction of the side chain of zoapatanol, was synthesized from 5-hydroxy-2-pentanone. By reaction with an excess of (methoxymethyl)triphenylphosphorane, ketone 6 was transformed in 75% yield to methoxy enol ether 7, which was directly and quantitatively converted to dithiane 8 [HS(CHz)3SH, HC1 gas, CHC13, 0-25 ~ Alkylation of the dianion derived from 8 (2.2 equiv, of n-BuLi, THF, - 7 8 ~ ---> - 1 5 ~ with 1-bromo-3-methyl-2-butene (1.1 equiv., - 7 8 ~ ---> -15 ~ led to 9 (85% yield), which was converted to 10 in five steps, with a 60% overall yield, by using classical transformations: acetylation (Ac20, Pyr, DMAP, CHzC12, 0 ~ followed by removal of the

3 TOTAL SYNTHESES OF ZOAPATANOL 61

N u ~ % Ph ~.O,,,, O.si...t_gu O---M Ph CH2Ph

A

FIGURE 2. Cram-chelate model.

CH2OH

0 (+_)-Zoapatanol 1

O/-Ph OH k_O,,, O

I

k~oH 5

~ 0 ~ ~ ~ 0 Br

10

/--Ph OSi(Ph)2t-Bu

II

SCHEME 1. The Nicolaou strategy.

dithiane by using HgC12 (CaCO 3, MeCN/H20, reflux), formation of the dioxolane (HOCHzCHzOH , TsOH, benzene, reflux) then reduction of the acetate using LiA1H 4 (ether, 0 ~ Finally, transformation of the resulting alcohol by using CBr 4 in the presence of PPh 3 ( -40 ~ ~ 0 ~ produced the desired bromide 10 (Scheme 2).

The construction of the oxepanic fragment began with the preparation of the protected aldehyde 11 from glycidol 5 employing classical chemistry (Scheme 3). Incorporation of the side chain of zoapatanol was accomplished by the coupling of the Grignard reagent derived from bromide 10 (Mg, THF, 25 ~ with aldehyde 11 at - 78 ~ providing a secondary alcohol (80% yield), which was oxidized to ketone 12 (Collins' reagent, 0 ~ CH2C12). This ketone was then treated with MeMgC1 (THE -105 ~ to afford the Cram-chelate-derived syn-1,2-diol 13, as the only detectable product (Scheme 3 and Figure 2).

62 JANINE COSSY, Vt~RONIQUE BELLOSTA, AND CATHERINE TAILLIER

~ 6

MeO PPh 3

75%

1. n-BuLi

85%

M e O ~ O H

7

quant. I .s/ sH HCI (g)

r% S ~ O H

1. Ac20, Pyr, 4-DMAP 2. HgCI 2, CaCO 3, MeCN/H20 3. HOCH2CH2OH, TsOH

4. LiAIH 4, Et20 5. CBr 4, PPh 3

60%

@ V ~ B r

10

SCHEME 2. Synthesis of the side-chain precursor.

After deprotection of the silyl ether (n-Bu4NF), a chemoselective epoxidation of the allylic alcohol in the presence of the unactivated olefin was performed with tert-butyl hydroperoxide in the presence of vanadyl bis- acetoacetate [VO(acac) 2] to produce the epoxy alcohol 14 (80%). ~4 This selectivity is due to the complexation of the vanadium derivative [VO(acac)2] by the free hydroxyl group of the allylic alcohol and by the oxidative reagent t-BuOOH, according to a six-membered ring pseudo- chair transition state of type B (Scheme 3). The construction of the oxepane ring by an internal epoxide ring-opening was realized with a high degree of regioselectivity by subjecting epoxide 14 to KCH2SOCH 3 in MezSO, leading to the desired oxepane 15 (75%). This latter compound was then transformed to the key ketone 16 by oxidative cleavage of the 1,2-diol using NaIO 4 via intermediate C (95%) (Scheme 3). The oxepanone 16 then underwent a condensation with the lithium salt of


1. DHP, H +

~ ~-~o., n-~u,i H 3. TBDPSCl

4. PhCH2OCH2Cl, iPr2NEt 5 5. AcOH, THF/H20

6. Pyr.SO 3 56%

.OBn r / MeMgBr

| l O " ] " " ~ ' ~ OTBDPS EHF,-100~

~ OH " 95%

L__/ 13

r . . .ov Ph

~ ~ OTBDPS

I 1.10, Ug, THF 2. CrO 3, Pyr

OBn r"

i . l ~ ~176 0 ~ 0 "

~ 12

1. n-Bu4NF 2. t-BuOOH

VO(acac) 2 80%

L H I

o~Vi ' ',L R ~ . ~ O - O - t - B u

BnO OH

~ J 14

KCH2SOCH 3 DMSO

75%

BnO OH k---O,,,

15

OH l'-/4-~- 11o- l" "~

C

NalO 4 95% EtOH/H20

B n O __ CO2M e BnO | ~ k - - O ' " ~ k / - ~ "1 (MeO,2P(O)CH2CO2Me | ~ ~ - - O ' " ~ ~ :~O

~ O --'J n-BuLi, THE - " ~ ~ 0 ''J

L__/ 17 k_J 16 E / Z = 2.5/1

1. DIBAL-H 1 70% /

2. Separation

BnO CH2OH ~--O . . . . 1. Li/NH3(liq)

= (+)-Zoapatanol 1 2. AcOH/THF/H20

k ~ / 18 80%

SCHEME 3. Completion of the Nicolaou synthesis.


trimethylphosphonoacetate (LDA, - 2 0 ~ to afford selectively the unsaturated methyl ester 17 as a 2.5/1 mixture of geometric isomers. After reduction of this mixture of isomers by DIBAL-H, the corresponding allylic alcohols were obtained as a mixture of E/Z-isomers (2.5/1) that were separated by chromatography to provide the desired stereoisomer 18 of E-configuration.

Finally, deprotection of the secondary alcohol of the obtained oxepane 18 under Birch conditions [Li~H3(liq), - 7 8 ~ according to the mechanism presented in Scheme 4, followed by acidic treatment (AcOH, THF/H20) to release the carbonyl function, furnished ( +)-zoapatanol.

RCH2 O_ C H 2 ~ f--"~e-

RCH2OH =H20

,. RCH2 O~- CH2~--- ~ ,

1 RCH2 O@ + H2C==~"

e-

H20 H3C

SCHEME 4. Birch reduction of a benzyl group.

The Nicolaou total synthesis of racemic zoapatanol required 16 steps, and was accomplished in an overall yield of 12%.

I I I . Chen's Synthesis

Instead of using basic conditions to build the oxepane ring from an co-hydroxy epoxide, Chen and Rowand 5 chose to utilize acidic conditions to transform an e,~-epoxy alcohol to an oxepane by creating the O1'-C2' bond of (_)-zoapatanol.

The synthesis of (_)-zoapatanol was envisioned starting from the ~,~-epoxy alcohol III. This compound would be prepared by selective epoxidation of 2-methyl-6-methylene-(E)-2,7-octadien-l-ol 19, which could be synthesized from myrcene (Scheme 5).


(_+)-Zoapatanol 1

Myrcene

~ OH

RO;"~CH3 LOH III

H O ~ '

19

SCHEME 5. The Chen strategy.

The regioselective oxidation of myrcene by SeO 2 (Scheme 6) produced the allylic alcohol 19, ~5 which after treatment with m-CPBA was transformed to the epoxy alcohol 20. Reaction of 20 with bromine gave an allylic dibromide (Scheme 7, via intermediate D), which was subjected to potassium acetate to give a diacetate intermediate. This latter was then tosylated to afford, after treatment under basic conditions (KzCO 3, CH3OH/H20 ), the pure diol 21. Reaction of 21 with the Grignard reagent 22 (3.3 equiv.) in the presence of a catalytic amount of LizCuC14 ( -20 ~ ----> 0 ~ gave a complex mixture that was directly treated with acetic anhy- dride. After purification by chromatography followed by a basic hydrolysis, the key intermediate 23 was isolated in 32% yield. Next, treatment of 23 with trifluoroacetic acid (0.1 equiv.) in methylene chloride afforded

)••,•e=o H~._.,/O

OH

ene reaction = ~ ~ e -OH

I [2,3]-sigmatropic rearrangement

,, H20 ~ / R

O-Se-OH

SCHEME 6. Allylic oxidation by selenium dioxide.

Myrcene

1. i) SeO 2 ii) NaBH 4

2. m-CPBA 16%

He

20

/ / i Br 2 / ~ ~ B r - Br 14%

1. Br2, CH2012, 0~ 2. AcOK, Acetone

reflux

3. TsCI, Et3N 4. K2003, MeOH/H20

OH

0:: i : . THPO ~

~k .... 23 22

( ' ' " 2. ,,~:~O 014 OTHP

3. K2CO 3, MeOH/H20

1. CF3CO2H CH2CI 2, 0 ~

2. Ac20, Pyr

path b

17%

OH

TsO ~ O H

O MgBr 21

32% iOAc

,~ THPO

25

/ i O A c

THPO_ 30% ~ / ~ "-,,s-.---O

24

24%

1. Jones reagent (CrO 3, H2SO4)

2. ~ L i

(+)-Zoapatanol 1

SCHEME 7. Chen's synthesis of (+__)-zoapatanol.


the oxepane 24 as the major product (30% yield), resulting from nucleophilic attack of one of the primary hydroxy groups on the more substituted carbon of the epoxide (Scheme 7, path a). Under these conditions, tetrahydropyrane 25 was also formed in 17% yield, resulting from the nucleophilic attack of the hydroxy group on the less substituted carbon of the epoxide, according to a 6-exo-trig process (Scheme 7, path b). The final transformation of 24 to (_+)-zoapatanol was accomplished in two steps. After a deprotection-oxidation process of the primary alcohol using Jones reagent, the corresponding carboxylic acid was formed and its treatment with an excess of 3-methyl-2-butenyllithium led to (+_)-zoapatanol (24% yield, two steps). This synthesis of racemic zoapatanol spanned 13 steps from myrcene and gave an overall yield of 0.15%.

A similar approach to Chen's strategy was used by Cookson et al. and Kocienski et al. to build up the oxepane ring of ( +)-zoapatanol as the O 1'-C2' bond of the oxepane was formed by treatment of an e,~-epoxy alcohol under acidic conditions.

IV. Cookson's Synthesis

Cookson et al. have envisaged the synthesis of the key intermediate e,~- epoxy alcohol IV from the homoallylic alcohol V, which would come from a methylalumination of the acetylenic compound VII, followed by functionalization of intermediate VI. The acetylenic compound VII would be obtained by alkylation of the enolate resulting from deprotonation of tert-butyl propionate (Scheme 8).

/ / - - - x ~ oH

(+_)-Zoapatanol 1 ", R O ~ c H 3 ~ j O H

IV

VI

VII

OH 3 )

t-BuO2C

SCHEME 8. The Cookson strategy.


The synthesis of (_+)-zoapatanol started with the alkylation of the enolate of tert-butyl propionate with 5-iodopent-1-yne. The straightforward reduction of the obtained acetylenic ester with LiA1H 4 and subsequent benzylation of the resulting alcohol gave the terminal acetylenic compound 27 (68%). The transformation of the acetylenic compound 27 to the homoallylic alcohol 28 was achieved by methylalumination with trimethylaluminium in the presence of bis(cyclopentadienyl)zirconium dichloride (CpzZrCI2) (Scheme 9). 16 The conversion of the alane intermediate of type VI into the more reactive aluminate with n-BuLi, followed by quenching with ethylene oxide allowed the formation of the desired homoallylic alcohol 28 with an overall yield of 62%. ~7 One proposed mechanism for the zirconium-catalyzed carboalumination involves the methylenation of CpzZrC12 with Me3A1 producing MeZrCpzCI and MezA1C1, followed by methylzirconation of the alkyne. After transmetalation of the resulting alkenylzirconium derivative with MezA1C1, the alkenyldimethylalane is formed and CpzZrC12 is regenerated. 18

,,CI. Me3AI + Cp2ZrCI 2 _ - Me2A I - ~ ZrCP2Me

CI

R R'

Me/~-~Z,rCP2 Cl ,Cl

~,[Me 2

1 R R'

AIMe 2

I R R ~ - ~ - R' =

i

'+8 -5 Me--ZrCP2--CI- -AIMe2CI

+ CP2ZrCI 2

m R '

SCHEME 9. Proposed mechanism for the Zr-catalyzed carboalumination.

Compound 28 was then transformed to the e,~-epoxy alcohol 31 in seven steps using classical chemistry. After mesylation of 28 (MsC1, Et3N ), nucleophilic displacement of the mesylate using NaI in acetone, the corresponding iodide derivative was produced. Alkylation of the lithium anion of diethyl 2-triphenylphosphoranylidene butadienoate 29 by the previously synthesized iodide under basic conditions (LDA) afforded, after benzoic acid-catalyzed elimination of triphenylphosphine, the E-diester 30 in 63% yield. Reduction of 30 with DIBAL-H resulted in the formation of the corresponding unsaturated diol (97% yield). After acetylation of this diol


(Ac20, Et3N), epoxidation of the more electron-rich olefin with m-CPBA 19 and saponification with K2CO 3 in MeOH, the desired e,~-epoxy alcohol 31 was isolated in 88% yield over four steps. This latter compound cyclized when treated with SnC14 in THF leading to the oxepane derivative 32 in 79% yield and to the corresponding tetrahydropyran derivative 33 in 7% yield. The epoxide ring-opening had presumably occurred stereospecifi- cally with inversion of configuration.

We have to point out that the use of SnC14 is crucial for the success of this cyclization and appears to be much better than CF3COzH, previously used by Chen et al., in terms of regioselectivity, as the oxepane derivative is formed preferentially to the pyrane derivative. The end of the synthesis of (_+)-zoapatanol from 32 was straightforward. After protection of the hydroxy groups as tert-butyldimethylsilyl ethers (TBSOTf, 2,6-1utidine), selective cleavage of the benzyl ether using Birch conditions [Li/NH3(liq), -78 ~ followed by oxidation of the resulting primary alcohol with PCC on alumina, and subsequent treatment of the corresponding aldehyde with silver(I) oxide, carboxylic acid 34 was isolated with an overall yield of 61%. Addition of prenyllithium to acid 34 then allowed the introduction of the desired [~,y-unsaturated ketone moiety. Finally, treatment with 25% HF in acetonitrile led to the cleavage of the silyl ethers, producing (+_)-zoapatanol (Scheme 10). Cookson's approach to (_+)-zoapatanol took 19 steps from tert-butyl propionate, and was achieved with an overall yield of 4.9%.

V. Kocienski's Synthesis

Kocienski et al. envisaged the synthesis of zoapatanol by forming the O1'-C2' bond according to the same procedure developed by Cookson et al., i.e., the formation of the oxepane ring by SnC14-induced intramolecular cyclization of an ~,~-epoxy alcohol. The synthesis of the ~,~-epoxy ether VIII precursor of (_+)-zoapatanol was envisioned from diene IX, which would be obtained by the ring-opening of dihydrofuran 35. The stereochemistry of the exocyclic double bond would be controlled during the formation of the oxepane ring as the hydroxyl group at C 1' would be the only one to be able to open the oxirane ring (Scheme 11).

Construction of the C3-C4 double bond of the key homoallylic ether IX was performed via a Ni(0)-catalyzed coupling between MeMgBr and 2-alkyl dihydrofuran 352o (Scheme 12). At first, the 5-1ithio-2,3- dihydrofuran was alkylated with the appropriate alkyl iodide affording 35, which reacted with MeMgBr in the presence of (PPh3)zNiC12 to produce

CO2t-Bu .)

26

1. LDA, THF,-78~ then

~ " " ' - ' " ~ I, HMPA

-78~ to rt

2. LiAIH 4, Et20 3. Nail, DMF then PhCH2Br

68% 62%

Bn

27

1. Me3AI, CP2ZrCI 2 CICH2CH2CI, rt

2. n-BuLi then O

/___&

I/OBn / CO2Et

30 CO2Et

88%

1. DIBAL-H, PhMe -78~ to -30~

2. AcCI, NEt 3 3. m-CPBA 4. K2003, MeOH

,--OH

o:;'

BnO - - / 31

1. MsCI, Et3N 2. Nal, Acetone

3.C. O2Et , ~ P P h 3 , LDA

29 CO2E t

then PhCO2H Phil, reflux

63%

.OBn

28

SnCI 4

THF

.OH

0 ~ , OH

33 (7%)

,. H O , , , ~ OH

BnO oJ 32 (79%)

~)-Zoapatanol 1

1. ~ L i

2. 25% HF, MeCN

44%

1. TBSOTf, 2,6-1utidine

60% 2. Li, NH3(liq) THF, -78~

3. PCC, AI203, rt 4. AgNO 3, NaOH,

MeOH

OTBS

34

SCHEME 10. Cookson's synthesis of (_+)-zoapatanol.

3 TOTAL SYNTHESES OF ZOAPATANOL

(+)-Zoapatanol 1 >

35

1/--R OR , "~2 O',' 1

VIII

2

IX

SCHEME 11. The Kocienski strategy.

71

alcohol 36. The C2-C3 double bond of the key intermediate of type VIII was then introduced by using carbomagnesiation of butyn-l,4- dio121 with Grignard reagent 37, which was obtained by standard methods from alcohol 36 (mesylation, transformation to the corresponding bromide by displacement of the mesylate by LiBr, and treatment with magnesium). The high trans-stereoselectivity (>95%) is probably due to an internal coordination of the alkenylmagnesium bromide 38. Protection of the hydroxy groups as acetates (Ac20, Et3N), and treatment of 39 with 1 equiv, of m-CPBA afforded epoxide 40. It is worth mentioning that the reaction was not totally chemoselective, as compet- itive epoxidation of the disubstituted terminal alkene also took place. After methanolysis of the acetate, opening of epoxy alcohol 41 occurred when this compound was subjected to SnC14 in THF at - 20 ~ affording the required oxepane 42. Conversion of the oxepane 42 to (_+)-zoapatanol started with the protection of the hydroxy groups as t-butyldimethylsilyl ethers (TBSOTf, 2,6-1utidine), followed by selective hydroboration of the terminal double bond, and Swern oxidation. Reaction of the aldehyde thus formed with dimethylsulfonium methylide 22 gave epoxide 43 via intermediate E. Nucleophilic cleavage of the resulting epoxide 43 was achieved with the homocuprate derived from 2,2-dimethylvinyllithium and CuI to afford the alcohol 44. Finally, Swern oxidation of the secondary alcohol and removal of the protecting groups with HF produced (+)-zoapatanol. The synthesis of (_+)-zoapatanol developed by Kocienski's group proceeded over 16 steps from dihydrofuran in 6.6% overall yield (Scheme 12).

1. n-BuLi

89% 35 MeMgBr

92% (PPh3)2NiCI 2 Et20/PhH i rl sc"Et3 MgB ~ OH

2. LiBr 3. Mg, Et20 36

/ \ 92% OMgBr OMgBr

Et20

OMgBr

~ ~ / # M g B E /

38 OMgBr J

Ac20

Et3N 50%

~ OH SnCI4

64%

42

78%

1. TBSOTf, 2,6-1utidine

2.9-BBN-H, H202, NaOH

3. Swern 4. Me2S=CH 2

OTBS

.--~ ~ ~ . . ~ / O A c

~OAc 39

I m-CPBA @ @ . . O R

"ON K2CO 3 ~ 40 R = Ac MeOH L_..

41 R=H quant.

[ R'~fH| (~S(Me)2 |174 . ]

~ J'~S(Me)2 R vk_A

/ ~ 2 CuLi , Et20

-10oC

64%

43 ..OTBS 1. Swern TBSO,,,/----~~ 2. HF/MeCN ~ J \ //- ~)-Zoapatanol 1

73% O OH 44

SCHEME 12. Kocienski's synthesis of (_+)-zoapatanol.


VI. K a n e ' s Synthesis

In their retrosynthetic analysis, Kane and coworkers envisaged access to (+_)-zoapatanol from the seven-membered ring lactone X, which would come from a regioselective oxidation of the cx,cx-disubstituted cyclohexa- none XI under Baeyer-Villiger conditions. The synthesis of XI was envisaged from the Wieland-Miescher ketone 45 (Scheme 13).

(+)-Zoapatanol 1 ) o

x

OR'

45 XI

SCHEME 13. The Kane strategy.

The synthesis of (_+)-zoapatanol was achieved from the Wieland-Miescher ketone (45), which was transformed to ketal 46 in five steps using classical transformations (Scheme 14). After acidic hydrolysis, the obtained cx,[3-unsaturated ketone 47 was treated with H202/NaOH to produce a mixture of diastereomeric epoxides 48 that were transformed to the monocyclic co-acetylenic ketone 50 via tosyl- hydrazone 49, by using an Eschenmoser fragmentation under acidic conditions via intermediate F (Scheme 14). 23 Ten steps were then nec- essary to transform ketone 50 to the key seven-membered ring lactone of type X (Scheme 13). After protection of the carbonyl group of 50 [HO-(CH2)2-OH, TsOH] followed by oxidative hydroboration of the acetylenic moiety using an excess of 9-BBN-H, alcohol 51 was produced as the major product. 24 This latter compound was then oxidized with Collins' reagent (CrO 3, Pyr) and the resulting aldehyde was treated with CH3Li to give a secondary alcohol. After a second oxidation with Collins' reagent, the resulting methyl ketone led to olefin 52 upon treatment with methyltriphenylphosphonium iodide/Nail in DMSO.

O

45

1. NaBH 4 2. Ac20, Pyr

3. HOCH2CH2OH, Ph, H + 4. LiAIH 4 5. BnBr, PhH/DMSO

< 60%

I ; ?c.2Phl j

90% 1

_OCH2Ph

I H

5O

H +

H202, NaOH CH3OH

74%

+s

OCH2Ph

83%

_OCH2Ph

46

I AcOH MeOH

_OCH2Ph

H H

_OCH2Ph

48

p-TsNHNH 2 CH3COOH CH2CI 2

_OCH2Ph

Ts 49

80%

V--] 1. HO OH, H +

2.9-BBN-H NaOH, H202

_OCH2Ph HO ~ :

51

1. CrO 3, Pyr 2. CH3Li 3. CrO 3, Pyr

4. Ph3PCH31

68%

O_ CH2Ph

52

SCHEME 14. Preparation of the Kane intermediate.


The alkene 52 was converted to a primary alcohol upon oxidative hydroboration (9-BBN-H/NaOH, H202), hydrolysis of the ketal function (H2SO4), and protection of the alcohol as its THP derivative to afford the ketone 53 in 81% yield (Scheme 15). This ~,~-disubstituted ketone was oxidized under Baeyer-Villiger conditions with m-CPBA, to produce the

1.9-BBN-H NaOH/H202 BnO t t t ~

2. H2SO 4, 0.002N

3. DHP, TsOH/EteO " O O OTHP O L._/ 81%

52 53

m-CPBA NaOAc

BnO ,,,/ \

T H P O ~ o ~ O

54

85% LDA, (EtO)2POCI

TMEDA, HMPA, THF

70%

m

OTHP Ar ,(~.O O)

o

~ B n O , , , / ~ ~ Na/NH3(liq) HO,, ~ O r

THPO II

O O'~-OEt %" OEt

55

1. NaH, BnBr ~ O 2. BH3 then HO,,, --~

. j THPO - 3. CrO 3, Pyr

OTHP 66%

..• ~174 ~"R Et :

H

57% 1 H+

57 56

SCHEME 15. Kane's approach to the key oxepanone intermediate.


desired lactone 54. This reaction is highly regioselective as the more electron-rich bond preferentially migrates via a concerted mechanism (intermediate G, Scheme 15). 25 In order to transform lactone 54 to the oxepanone 57, an 1,2-transposition of a carbonyl group was needed. This transposition was achieved in five steps. After formation of the lithiated anion of 54 using LDA and trapping of the enolate intermediate by diethyl chlorophosphate, the obtained enol phosphate 55 was reduced, via intermediate H, to an oxepene using an electron transfer process induced by Na in NH3(liq). Under these conditions, a Birch reduction took place and at the same time the benzyl ether was cleaved. The hydroxy group of 56 was then reprotected (Nail, BnBr) and the enol ether was regioselectively hydroborated to produce a secondary alcohol that was then oxidized using CrO 3 in pyridine. The desired oxepanone 57 was thus obtained in 66% yield (Scheme 15).

The next stage of the synthesis focused on the elaboration of the side chain. Ketalization of 57 and concomitant deprotection of the primary hydroxy group followed by oxidation with Collins' reagent, produced an aldehyde intermediate. Next, addition of the Grignard reagent generated from 4-bromo-2-methyl-l-butene provided an alcohol that was acety- lated to give acetate 59 (Scheme 16). Isomerization of the double bond of 59 under acidic conditions (TsOH, Phil), basic hydrolysis of the acetate (K2CO3, MeOH/H20), THP ether formation and reductive cleavage of the benzyl ether under Birch conditions [Na/NH3(liq), t-BuOH/THF] afforded alcohol 60. Acetylation of the secondary alcohol and non- selective hydrolysis of the ketal moiety (0.002N H2SO4) followed by reprotection of the secondary alcohol afforded the tetrahydropyran ether 61.

Completion of the synthesis of ( +)-zoapatanol required the transformation of the ketone at C6' to the exocyclic (E)-2-hydroxyethylidene group and a functional group transformation on the side chain at C5. Thus, compound 61 was condensed onto triethylphosphonoacetate under basic conditions to provide the unsaturated ester 62 as an inseparable mixture of (E)- and (Z)-isomers (Scheme 16). Reduction of 62 with LiA1H 4 gave diastereomeric diols (E/Z = 2/3 ratio) that were separated by chromatography to give the desired diol 63 (28% yield). Diol 63 was diacetylated, the tetrahydropyranyl protecting group removed (CH3CO2H/H20/THF) and the alcohol function oxidized (Collins' reagent) to give the corresponding ketone. Finally, treatment with an excess of tetrabutylammonium hydroxide was used to remove the acetate groups thus leading to (+_)-zoapatanol.

HO HO, TsOH " ~ " - - 7 ~ ", O P h H L B~ nO

OTHP 87% OH 57 58

77%

1. CrO 3, Pyr

2 / ~ , - , MgBr

3. Ac20, Pyr

HO, , , / / -~O ~] . BnO ,,,~----~O ~

THPO % ~ ~ ~ . - O'~O. ZsOH, ph H A c O ~ ~ ~ z o > O

~ 6 0 / . -2 . Kf;flou31MeOH ~ 59

3. DHP/TsOH 4. Na/NH3(liq)

t-BuOH 66% 1. Ac20, Pyr

2. H2SO4(0.002N ) 3. DHP, TsOH

63%

98%

CO2Et . AcO,,, ~~~ - - - -O ',,

k " (EtO)2F~C;H2CO2Et k 61 Nail = 62

28% 1. LiAIH 4 2. Separation

(+)-Zoapatanol 1

1. Ac20, Pyr , 1 O H 2. CH3CO2H HO,,, "-~\ ~. / 3. CrO 3, Pyr / - 4. n-Bu4NOH THPO /

71% 63

SCHEME 16. Completion of the Kane synthesis.


Kane's racemic synthesis of zoapatanol required 40 steps from Wieland-Miescher ketone and proceeded in 0.1% overall yield.

VII. Trost's Synthesis

The first enantioselective synthesis of zoapatanol was reported by Trost et al. in 1994. l~ The key step was an intramolecular Williamson reaction to build up the oxepane ring. The control of the contiguous stereogenic centers at C2' and C3' was achieved via a Sharpless asymmetric epoxidation of an allylic alcohol using t-BuOOH, chiral diethyl tartrate (DET) and Ti(OiPr)4 .26 The configuration of the epoxide formed is dependent upon the enantiomer of DET used and can be predicted according to Scheme 17. The configuration of the (E)-exocyclic double bond was controlled by using a palladium-catalyzed 1,4-addition of triphenylsilanol to a vinyl epoxide. 27

(-)-DET

OH

(+I-BET

,,,-OH

R 0

.0. ,-OH

R

SCHEME 17. Sharpless asymmetric epoxidation of allylic alcohols.

The synthesis of (+)-zoapatanol was envisioned from alcohol XII by using an intramolecular Williamson cyclization. Compound XII would be obtained from a nucleophilic attack of an alcohol on a ~-allylic palladium complex generated from the vinyl epoxide XIII. This compound would be synthesized from epoxide XIV, which would come from a Sharpless epoxidation applied to the allylic alcohol XV, which in turn would be obtained from methallyl alcohol 64 (Scheme 18).

Methallyl alcohol 64 was transformed to allylic alcohol 66 in two steps (Scheme 19). After treatment of 64 with 2.2 equiv, of n-BuLi in the presence of tetramethylethylenediamine (TMEDA), the resulting dianion was quenched at first with 1-bromo-3-methylbut-2-ene and then with methoxymethyl chloride, allowing the isolation of dienic compound 65 (92%). The regioselective oxidation of one of the methyl groups in 65,

3 TOTAL SYNTHESES OF ZOAPATANOL

(+)-Zoapatanol 1

R ' O / ~ / ~ O M O M

XlV

H O ~ "

XV

)

" / ~ ~ -~ "OH L G H3C

X I I

11

" / ~ ~ -~ "OH H3C

X I I I

"•OH 64

SCHEME 18. The Trost strategy.

79

achieved by using 4 mol% SeO 2 in the presence of t-BuOOH and 10% salicylic acid led to alcohol 66 in 53% yield.

Use of L-(+)-diethyl tartrate [(+)-DET] as the chiral ligand gave epoxide 67 in 90% yield and with an ee greater than 95%. 2s The transformation of this latter epoxide 67 to the terminal epoxide 68 was accomplished sequentially, first by a titanium-promoted regioselective opening of the epoxide 29 with acetic acid as the nucleophile. A tosylation of the primary alcohol of the resulting 1,2-diol followed by treatment under basic conditions were used to build up epoxide 68. This sequence of reactions set the two contiguous stereogenic centers present on the oxepane ring of zoapatanol. In order to introduce the side chain present at C2', epoxide 68 was opened by using a cuprate derived from 3-butenylmagnesium bromide and the resulting product was transformed to diol 69 after acidic hydrolysis. The straightforward conversion of allylic alcohol 69 to the vinyl epoxide 70 was achieved in two steps. The first one was an oxidation with Dess-Martin periodinane 3~ (DMP) (Scheme 20), and the second one was Corey's epoxidation using the dimethylsulfonium methylide. 22

The key step, which is the vinyl epoxide ring-opening to stereoselec- tively produce the monoprotected diol 71, was achieved by treatment of

" ~ O H

64

1. n-BuLi (2 eq) TMEDA

2. ~~-Br

then MOMCI

92%

t-BuOOH L-(+)-DET

~ O M O M Ti(O/-Pr4)

90%

67 (ee > 95%)

66% 1. AcOH, Ti(O/-Pr4) 2). TsCI 3. OH resin

~ ~ A ' O M O M

65

I SeO , t-BuOOH 53% salicylic acid

HO I v ~ ~OMOM

66

A C O ~ o M O M

~'0 "ell

68

1. ~ M g B r Cul, THF

2. HCI 6N, MeOH

,. OH =

72

-/ k-)3 I:- OH / ~ O H

69

71% / 1. DMP 2. (CH3)2S=CH 2

"/ ~,-}3 I: "OH 70

67%

[Pd2( dba)3]. CHCI3

P(O/-Pr) 3 Ph3SiOH, THF

H

73

1. Ac20

2. KF

79% 71

SCHEME 19. Preparation of the Trost intermediate.


OH

R I - ~ R 2

AcC~ OAc

0 0

RI~" -R 2

.,. OAc AcO~) I .OAc

O y R 2

O R 1

OAc /

0

AcO, 0 ~ H

0

O + J ] + AcOH

R 1 / \ R 2

SCHEME 20. Dess-Martin periodinane oxidation.

70 with [Pd2(dba)3].CHC13 in the presence of triphenylsilanol in THF at room temperature. 27 Under these conditions only the product resulting from cleavage of the distal bond of the epoxide was obtained, and exclu- sively with the required E-configuration. It is noteworthy that the formation of oxepane 72, which could arise from an intramolecular attack of the tertiary alcohol of 70 on the vinyl epoxide, was not observed. Acetylation of the primary allylic alcohol of 70, followed by the cleavage of the silyl ether using KF, led to the diol 73.

The primary alcohol of 73 was then transformed to the corresponding primary triflate [(CF3SO2)20), 2,6-1utidine], and this latter spontaneously cyclized in situ under the reaction conditions, affording oxepane 74 (Scheme 21). At this stage the elaboration of the side chain was required to complete the synthesis. After oxidation of the terminal double bond under Wacker's conditions 31 (LiC1, PdC12, CuC1, DMF, H20, 0 2, rt) gen- erating a methyl ketone (Scheme 22), the acetyl protecting groups were exchanged with tert-butyldimethylsilyl (TBS) groups in order to mini- mize problems of chemoselectivity at the end of the synthesis. The resulting ketone 75 was transformed to vinylstannane 76, via a vinyl triflate

82 JANINE COSSY, V]~RONIQUE BELLOSTA, AND CATHERINE TAILLIER

~ OAc

-/ \-)31 ~ un [ 73

(0F3SO2)20 ~ A~cO'"~/--~ -~~OAc 2'6"17~i~ ~ / / ~ v ~ - " O

74

71%

TBSO 1. KHMDS, T ~ O , : ~ -= | ' ) ; ~ O T B S ,,. TBSO ',. CI ~ N(SO2CF3)2

Me3Sn" ~3 "~-0 2. [(CHs)sSn]2, 0 ~ ~ ~'0 76 Pd(PPh3) 4, LiCI 75

~ C I 34 atm CO Pd2(dba)3.CHCI3 PPh 3, Phil, 60 ~

67%

76%

1. LiCI, PdCI 2, DMF, H20, 02, rt

2. K2CO3, MeOH 3. TBSCI,

imidazole

/OTBS TBSO,,, ~

~ ~ ~ ~ J l ~ ~ _ S 11 [Ph3PCuH]6, H20, Phil O 2 HF, H20, CH3CN, rt

O 85% 77

.~ (+)-Zoapatanol 1

SCHEME 21. Completion of the Trost synthesis.

intermediate, in order to produce the 0~,[3-unsaturated ketone 77 by a carbonylative alkylation under 34 atm of CO in the presence of Pdz(dba) 3. CHC13 and prenyl chloride. The obtained 0~,[3-unsaturated ketone 77 was then reduced chemoselectively by conjugate addition of hydride by using the Strycker reagent [Ph3PCuH]632 and, after cleavage of the protecting groups using HF, (+)-zoapatanol was obtained. The Trost sequence led to the first enantioselective total synthesis of (+)-zoapatanol in 20 steps from methallyl alcohol in 1.6% overall yield.


R ~ cat PdCI 2, H20 _ O CuCI 2, 02 -- R,,~,"

a ' ~ ~176 "f~ PdCl2 ~ ( olefin Regeneration of Pd(ll)

"~ complexation Pd(0) Pd(0) + 2CuCI 2 ~ PdCI 2 + 2CuCI

Hc, .'-m / c,,p reductive ~ Regeneration of Cu(ll)

elimination \ CI" ..~.-R H-Pd-CI H..O..H 2CuCI + 1/202 + 2HCI-~,'- 2CuCI 2 + H20

fl-hydride ~ elimination f ~ OH nucleophilic O OH ~ I[,- _PdCI attack

SCHEME 22. Wacker oxidation.

VIII. Our Approaches for the Total Synthesis of (+)-Zoapatanol

Two synthetic strategies have been examined to construct the oxepane ring of (+)-zoapatanol, one utilizing a ring-closing metathesis (RCM) and the other one an intramolecular Horner-Wadsworth-Emmons (HWE) reaction.

A. R I N G - C L O S I N G M E T A T H E S I S A P P R O A C H

The first strategy envisioned to synthesize (+)-zoapatanol relies on a RCM reaction to produce the seven-membered ring. When a diene is treated with a transition metal alkylidene complex, a metallacyclobutane intermediate is formed and a succession of [2+2]-cycloadditions and cycloreversions takes place (Scheme 23). Each step is reversible and the driving force is the elimination of a molecule of ethylene and the formation of a cyclic adduct.

The retrosynthetic analysis revealed that an oxidation of oxepene XVII should lead to ketone XVI (Scheme 24), which is a precursor of zoapatanol according to Kane's synthesis. 70xepene XVII could be obtained by using a RCM applied to the unsaturated enol ether XVIII in which the two stereogenic centers could be controlled through application of a Sharpless asymmetric dihydroxylation 33 of the trisubstituted (Z)-olefin XX. The result of the enantioselective cis-dihydroxylation of olefins using an osmium catalyst [K2OsOz(OH)4 ] in the presence of K2CO 3, K3Fe(CN)6


[M]--CH 2

"~[M] ~[[M]

SCHEME 23

. f / - - O H HO,,,..//---',~ { R'01,.~O

0 1 XVI

�9 R ' O , , , . ~

RO ~ O ~ " . < - - - RO XVIII XVII

HOI,.~OR" H O ~ ' ~ O R

XIX

XXII

OR"

XX

XXI

SCHEME 24. Our first retrosynthetic approach toward zoapatanol.


AD-mix-13

K2OsO2(OH)4

K3Fe(CN)6, K2CO3 tBuOH/H20

(DHQD)2-PHAL

'D" (DHQ)2.PHA L AD-mix-o~

HO OH

R s " ~ " R M RE H

Rs RM R L ~ H

HO OH

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine used in AD-mix-I[]

jo . o,; .

(DHQ)2-PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine used in AD-mix-o~

N-N

SCHEME 25. Sharpless asymmetric dihydroxylation.

and cinchona alkaloids, (DHQD)2-PHAL or (DHQ)2-PHAL, can be predicted according to the model represented in Scheme 25.

The olefin XX would be synthesized by using a Suzuki-Miyaura cross-coupling 34 between an organoborane derived from olefin XXI and (Z)-vinyl iodide XXII. This reaction follows the general mechanistic cycle represented in Scheme 26. After an oxidative addition of RX, the catalytic complex LzPd(0 ) is transformed to intermediate J. Complex J reacts with the organoborane partner by transmetalation and, after isomerization, complex K is formed. The final step, a reductive elimination, then produces the coupling product and regenerates the catalytic species, allowing propagation of the catalytic cycle.


Pd(0)L2 R-R' ~ R X

Oxidative addition

eliminationReduc \ R ~Pd j L \ L_ ~ \ X

L /L J

\Pd ~ ~ T r a R / \ R'M R' ~.. nsmetalation

K I$omerization MX

SCHEME 26. Catalytic cycle of the Pd cross-coupling.

It was desirable to adopt an orthogonal protecting group strategy to permit a selective deprotection of the hydroxy groups. The use of two silylated ethers that can be deprotected selectively, a tert-butyldiphenylsilyl (TBDPS) group for R and a TBS group for R", plus a benzyl group (Bn) for R' was thus envisaged (Scheme 24). To test our strategy an approach toward racemic zoapatanol was first performed.

The synthesis of zoapatanol started with the preparation of the (Z)- olefin 86 from vinyl iodide 80 (Scheme 27) and olefin 84 (Scheme 29). Vinyl iodide 80 was prepared in three steps from 1,4-butanediol 78 (Scheme 27). After monoprotection of 78 (TBSC1, Et3N, CH2C12), the resulting monosilylated ether was oxidized to aldehyde 79 by using a Swern oxidation [(COC1) 2, DMSO, Et3N, CH2C12] with an overall yield of 94%. Aldehyde 79 was then transformed to the (Z)-vinyl iodide 80 in

+ _ n-BuLi 12 + Ph3PCH2CH31 > Ph3P=CHCH 3 = Ph3PCHICH31

NaHMDS CH 3 Ph3P =~

I 81

1. TBSCI, Et3N,

CH2CI2 H ~ O T B S H O ~ o H 2. (0001)2, O

78 DMSO, Et3N 79 94%

81 ,, ~ O T B S

-20~ rt / "1 80

47%

SCHEME 27. Preparation of vinyl iodide 80.


47% yield using a Wittig-type reaction with a-iodophosphonium ylide 81. 35 This latter was prepared from ethyltriphenylphosphonium iodide by deprotonation with n-BuLi followed by the addition of iodine and subsequent deprotonation of the resulting phosphonium salt using NaHMDS to form the ~-iodo ylide 81, which was added to aldehyde 79.

The trisubstituted olefin (Z)-80 was obtained as a single isomer in accord with the literature data. 36 The modest yield can be explained by the formation of by-products. Under these conditions, the olefination can compete with a Darzens type reaction, which can produce a cis-epoxide XXIV or a methyl ketone of type XXV (Scheme 28). 35,36 This secondary reaction is likely responsible for the high (Z)-stereoselectivity of the olefination. Among the four adducts coming from the condensation between an aldehyde and the ~-iodo ylide 81, only two betaine intermediates can produce the (Z)-vinyl iodide XXIII via an oxaphosphetane. The two other betaines, which could potentially produce the (E)-vinyl iodide, are probably transformed preferentially to an ~,13-epoxy phosphonium salt, a precursor of the methyl ketone XXV or the cis-epoxide XXIV (Scheme 28).

In order to prepare the (Z)-olefin 86 from iodide 80 using a Suzuki-Miyaura coupling, an organoborane derived from alkene 84 was prepared (Scheme 29). The alkene 84 was prepared in three steps from pro- pionic acid 82. Thus, the dianion of 82 was alkylated with allyl bromide (Nail, then LDA, allyl bromide) leading to 2-methylpent-4-enoic acid 83 in 96% yield. 37 The reduction of 83 by LiA1H 4 (THF, rt) followed by protection of the resulting alcohol (TBDPSC1, Imidazole, DMF, rt) led to the desired olefin 84 (86% yield, two steps). Olefin 84 was then transformed into the organoborane 85 (9-BBN-H, THF), which was not isolated but directly engaged in the Suzuki-Miyaura coupling with (Z)-vinyl iodide 80 in the presence of a catalytic amount of Pd(PPh3) 4 and K2CO 3 in dioxane at 85 ~ to afford the (Z)-olefin 86 in 82% yield. 34 It is worth noting that the (Z)-configuration was confirmed by differential ~H NMR-NOE exper- iments. To introduce the two contiguous hydroxyl groups at C2' and C3', olefin 86 was dihydroxylated [OsO 4, NMO, acetone/H20 (1/6), rt] to produce diol 87 in 61% yield, followed by transformation to benzyl ether 88. The best conditions for obtaining 88 in good yield were found to be the treatment of 87 with Nail (2.2 equiv.) in the presence of n-tetrabutylammonium iodide (40 mol%) and HMPA (3 equiv.) followed by the addition of benzyl bromide (1.1 equiv.). After 12 h at room temperature, compound 88 was isolated in 87% yield. To complete the construction of the oxepene ring precursor, compound 88 had to be transformed to diene 93. After selective cleavage of the tert-butyldimethylsilyl ether (TBAF, THF, rt, 1 h)


+ Ph3P R'

81

1 Ph3P\ ~ ..Me

R' I k._

+ O- O- + Ph3P Me ~ ~ _ PPh3

R' R' J \

Y Y

O~ R , , . , ~ ~ / p p h 3

I ] ...... R' I

R' I

XXIII

R,

O- + Me ~ PPh 3

R' I J

l O- Li +

R L,,~ ,,,,'+ '7 ..... ~'PPh3 R'

R' PPh 3 O

i_

0

or R, ~ 0

XXIV XXV

SCHEME 28. Intermediates involved in the Wittig-type olefination.


1. Nail (1 eq) 2 LDA (1 eq)

~CO2H ~, CO2H 3. ~--.v Br 83 82 96%

"'/'~'OTBS //"~/~'~OTBS / ~I 80

. . ~ ~ ~ . / O T B D P S Pd(PPh3)4, K3PO4,

86 dioxane, 85 ~ 82%

O/ol Os04, NMO 61 Acetone/H20

HO,,,[//"~~OTBS H O " ~ ' v ~ OTBDPS

87

1. LiAIH4 ,. /~-~~OTBDPS 2. TBDPSCI, imidazole, DMF 84

I 9-BBN-H THF

( ~ B ~ O T B D P S

85

Nail, n-Bu4NI, BnO,,,I//...~OTBS HMPAFFHF, BnBr, rt= , ~ . ~ / ~

87% HO' OTBDPS

88 1. TBAF

84o/o 2. PDC, DMF

BnO,, ,~ =-1 B.nO,~~_ _ DIBAL-H '"

OTBDPS OTBDPS OTBDPS 91 90 89

68% MeP(Ph)3Br n-BuLi, THF

I(C F3COKO)H ~-~~:t ]

BnO, , , [ / ' ~~ ~OEt BnO,,,[../'V~

H O " ~ ~/~OTBDPS Hg(OCOCF3)2 ~ e t s N , 50 ~ ~ O " ~ OTBDPS

92 47% 93 I CI2(PCY3)2Ru=CHPh

70% Phil, 50 ~

Conditions ~ see text

~ . , x /

TBDPSO 95 TBDPSO 94

SCHEME 29. Oxepene synthesis via RCM reaction.


and oxidation of the resulting primary alcohol by PDC (DMF, rt), lactone 89 was obtained in 84% yield (two steps). The transformation of lactone 89 to olefin 92 could be achieved via lactol 90 by treatment with a Wittig reagent as the lactol is in equilibrium with the corresponding hydroxy aldehyde 91. The reduction of 89 by DIBAL-H (THE -78 ~ produced the corresponding lactol 90, which was treated directly with methyltriphenylphosphonium ylide [MeP(Ph)3Br, n-BuLi, THF] to afford olefin 92 (44% yield, two steps). 38 The tertiary alcohol of 92 was then etherified by treatment with Hg(OCOCF3) 2 and ethyl vinyl ether (Et3N, 50 ~ 39 to afford the desired diene 93 in 47% yield via the mercuric intermediate K.

Compound 93 was then converted to oxepene 94 in 70% yield by treatment with the "first generation" Grubbs catalyst [C12(PCy3)zRu=CHPh (30 mol%), Phil, 50 ~ 4~ The resulting oxepene 94, by analogy to Kane's intermediate 56, was expected to lead to 95 via oxidative hydroboration (BH3-THF; H202, NaOH) followed by oxidation (CrO 3, Pyr, CH2C12). 7 Unfortunately, when 94 was subjected to BH3.THF and then H202, NaOH, no reaction occurred. Moreover, when 94 was treated with various oxidizing agents (dimethyldioxirane or m-CPBA in MeOH) to produce a precursor of ketone 95, only degradation or recovery of 94 was observed.

Due to this failure, a second route using a HWE reaction was envisioned to construct the oxepane ring of zoapatanol.

B. HORNER-WADSWORTH-EMMONS APPROACH

The retrosynthetic analysis of oxepinone XXVI revealed that the oxepene ring with the required stereochemistry could potentially be con- structed through application of an intramolecular HWE reaction applied to the phosphono-aldehyde XXVII derived from anti-diol XXVIII. Control of the two contiguous stereogenic centers of XXVIII could be achieved by applying a Sharpless asymmetric dihydroxylation to the (Z)-trisubstituted olefin XXIX, using AD-mix-13. Olefin XXIX could be derived from a Suzuki-Miyaura coupling between vinyl iodide 96 and organoborane XXX. In this approach, an orthogonal protecting group strategy for R and R' was also required. Therefore, the protection of the secondary alcohol in XXVII by a benzyl group and the primary alcohol by a TBDPS group was planned (Scheme 30).

The preparation of (+)-zoapatanol started with the synthesis of phosphono-aldehyde 101 from the silylated 2-methylpent-4-en-l-ol 84 and (Z)-vinyl iodide 96. This latter species was obtained by treatment of ethyl but-2-ynoic ester with NaI in acetic acid (70 ~ 95% yield). 4~ The high stereoselectivity of this reaction ruled out the possibility of direct HI


HOt,,.~

0 1

~: HO I~" [""~OR"

R O ' v ' " ~ , - ~ ~ : 0 H

OH

Ro.r ~ XXVI

o~ P(OI(OMe)2

. R'O,,,./~ ~-i~0

_

, . . . .

XXVlll

0

XXlX

XXVII

0

EtO 1 ~ 96

XXX

SCHEME 30. Retrosynthetic pathway involving a HWE reaction.

addition to the propynoate in AcOH, which has been reported to proceed with low stereoselectivity. 41a The observed high level of stereocontrol may be explained by assuming that a trimolecular transition state of type L (Scheme 31), in which the halide and acetic acid lie on opposite sides of the carbon-carbon triple bond would be favored on steric grounds. Another explanation would be to consider that a vinyl anion intermediate is generated by nucleophilic addition of iodide to the electron-deficient alkyne. In this case, repulsion of the electron pairs on the halogen atom and the carbanion should destabilize intermediate M,, leading to the (E)-isomer, while the electron pairs are away from each other in intermediate M b, leading to the observed (Z)-isomer (Scheme 31).

Alkene 84 was treated with 9-BBN-H (9-BBN dimer, THE rt) and the resulting organoborane product was then subjected to a Suzuki-Miyaura cross-coupling with (Z)-vinyl iodide 96 (Scheme 32) in the presence of Pd(PPh3) 4 and K3PO 4 (dioxane, 85 ~ to afford the (Z)-~,~-unsaturated ester 97 in 74% y ie ld . 34,42 To transform 97 to diol 98, the enantioselective

92 JANINE COSSY. VI~RONIQUE BELLOSTA, AND CATHERINE TAILLIER

I - - ' I R

H---~ - -7--R ,, = ~ X ~

H --OAc H H

L Z-isomer

R = electron withdrawing group

% H R

Ma

H + I H )=( H R

E-isomer

"I" R

Mb

H + I R

H H

Z-isomer

SCHEME 31. Proposed explanations for the mechanism of formation of 96.

Sharpless dihydroxylation was achieved with AD-mix-[3 (65% yield, 92% ee). 43 The phosphono-aldehyde 101 was then prepared from diol 98. After selective protection of the secondary alcohol of compound 98 using benzyl bromide in the presence of silver oxide and n-tetrabutylammonium iodide, 44 reduction of the carboxylic ester with LiA1H 4 and protection of the resulting primary hydroxy group as a methoxymethyl ether, compound 99 was obtained in 66% yield. A rhodium-catalyzed insertion of ethyl dia- zoacetate (N2CHCOzEt, [Rh(OAc)2]2, toluene, 110 ~ followed by the condensation of an excess of the lithium salt of methyldimethylphosphonate with the resulting ester led to the [~-keto-phosphonate 100 (60% yield). 46

As an intramolecular HWE reaction was envisioned to construct the oxepane ring of zoapatanol, the methoxymethyl ether group had to be transformed into an aldehyde. Thus, after removal of the methoxymethyl ether protecting group with TMSBr, the corresponding hydroxy- phophonate was obtained (84%) 47 and the oxidation of the primary alcohol was conveniently accomplished with PDC. The resulting crude aldehyde 101, which turned out to be unstable, was then directly subjected to Nail in THF to afford oxepinone 102 in 53% overall yield via an intramolecular HWE cyclization (Scheme 32). 48


CO2Et Nal, CH3CO2H, 70~ 95%

O

E t O ~

96

TBDPSO

84

9-BBN dimer THF, rt

O HO,,.r~OEt AD-mix-fl H2NSO2Me

T B D P S O ~ ~ ' @ : O H ~ t-BuOH/H20

" 65% 98 ee = 92%

] ' B D P S O ~ B ~

85

74% / 96, Pd(PPh3) 4 /

K3PO4

O

/ EtO~ T B D P S O . . . ~ . . ~ o ~

97

66%

OMOM

BnO,, /

r" v TBDPSO 99

1. BnBr, Ag20, n-Bu4NI 2. LiAIH 4 3. MOMCI, Nail, THF

1 [Rh(OAc)2]2 O �9 I I

N2CHCO2Et, PhMe MOMO p(OMe)2 2. MeP(O)(OMe)2 , .~ ~~:O

n-BuLi, THF 60% O"

TBDPSO 100

~ 0

TBDPSO 102

NaH

45%

1. TMSBr 2. PDC

- - O - - I I

(~ P(OMe)2

OTBDPS 101

SCHEME 32. Preparation of the oxepinone intermediate.


To complete the synthesis of (+)-zoapatanol, the unsaturated side chain as well as the [3,y-unsaturated ketone had to be introduced on oxepinone 102, but first this compound has to be reduced selectively in order to obtain the corresponding oxepanone. The chemoselective hydro- genation of 102 was performed in the presence of Pd/C (10%) in ethanol for 5 min. The benzyl protecting group was not affected and oxepanone 103 was isolated in 98% yield (Scheme 33). 49 The resulting oxepanone 103 was then treated with the lithium salt of triethylphosphonoacetate [EtO2CCHzP(O)(OEt)2, LiHMDS, THF, rt] to generate the corresponding 0t,[3-unsaturated esters (97%) as an inseparable mixture of E/Z-isomers (E/Z = 70/30 ratio by 1H NMR spectroscopy). 48",5~ After reduction with LiA1H 4, the corresponding stereoisomeric allylic alcohols were separated by SiO 2 flash chromatography, and the desired (E)-allylic alcohol 5~ was obtained in 63% overall yield. This latter compound was then protected as a benzyl ether 104 (BnBr, Ag20, n-Bu4NI, CH2C12) in 98% yield. As a stable tetrahedral intermediate resulting from the addition of an organo- lithium to a Weinreb amide can serve as a carbonyl protecting group

~ O

OTBDPS 102

MeO B n O , , . ~

Me ; N ~ / ~ _ _ : 0 J

0 105

OBn

Et20/THF

[- F-OBn-] tl. /

L Me "" 106 __J

Ii. Pd/C, EtOH,98% 5 min~ ~ 0

OTBDPS 103

60%

1. EtO2CCH2P(O)(OEt)2 LiHMDS, THF

2. LiAIH 4 3. BnBr, Ag20, n-Bu4NI

~ 1" n-Bu4NF 1 B n O , , . ~

2. CrO3/H2SO 4 r'" V "-.~-"O ~ 3 HN(OMe)Me HCl �9 " OTBDPS EDCI, iPr2NEt, DMAP 104

60%

OBn

Li/NH3(liq) t-BuOH, THF

66% = (+)-Zoapatanol 1

SCHEME 33. Completion of the synthesis of (+)-zoapatanol.


during the debenzylation of hydroxy groups under the Birch reduction conditions, 52 104 was transformed to the Weinreb amide 105 in order to elaborate the nonenyl side chain present in (+)-zoapatanol.

Thus, after removal of the silyl protecting group in 104, the resulting primary hydroxy group was oxidized to the carboxylic acid (Jones' reagent) and this latter compound was directly converted to the Weinreb amide 105 [HN(OMe)Me, HC1, EDCI, iPrzNEt, DMAP, CHzCI2] with an overall yield of 60%. 53 Treatment of amide 105 with prenyllithium 54 (THF/Et20, - 7 8 ~ led to the stable intermediate 106, which was directly subjected to Birch reduction conditions 55 [Li/NH3(liq), t-BuOH/THE -78 ~ to afford the desired (+)-zoapatanol in 66% yield. ~

In conclusion, this second approach involving four key steps, a Suzuki-Miyaura cross-coupling, a Sharpless asymmetric dihydroxylation, an intermolecular HWE cyclization and a chemoselective nucleophilic addition/Birch reduction process, allowed the total synthesis of (+)-zoapatanol in 19 steps from alkene 84 and 3% overall yield.

IX. Conclusion

Up to now, seven total syntheses of zoapatanol have been reported and only two of them are enantioselective. Among the racemic ones, Nicolaou's synthesis is the shortest and the most efficient (16 steps, 12% overall yield). For the enantioselective syntheses, the synthesis using a Sharpless dihydroxylation to control the stereogenic centers at C2' and C3' and an intramolecular HWE cyclization, as the key steps, is the most efficient one.

References and Footnotes

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[Strategies and Tactics in Organic Synthesis] Volume 7 || Chapter 3 Total syntheses of zoapatanol

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