Enantioselective total synthesis of a trans-hydrindane rings/side-chain building-block of vitamin D - Asymmetric induction in an acid-catalyzed conjugate-addition reaction

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Enantioselective Total Synthesis of a trans-Hydrindane Rings/Side-Chain

Building-Block of Vitamin D ؊ Asymmetric Induction in an Acid-Catalyzed

Conjugate-Addition Reaction

Evgueni Gorobets,^[a]Viatcheslav Stepanenko,^[a]and Jerzy Wicha*^[a]

Keywords: Total synthesis / Vitamin D / Diastereoselectivity / Induced diastereoselectivity / Asymmetric synthesis

For the enantioselective total synthesis of 1α,25-dihydroxyvi- homochiral (S)-ketene acetals 28, 40, 44 and 58 with 10 was

tamin D₃(3), we have developed an enantioselective ap-

proach to the ‘‘northern’’ portion building-block 8, starting

from the optically active hexanoic acid derivative 44, 2-

examined. We found that in the cases of 28, 44 and 40, the

reactions occur with high simple and induced (facial) diaster-

eoselectivities.

methylcyclopent-2-en-1-one (10) and 1-(phenylthio)but-3- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

en-2-one (9). The steric course of the addition reaction of

Germany, 2004)

Introduction

chain and A-ring prior to or after the photochemical re-

arrangement. The rapid expansion of medicinal appli-

cations of vitamin D-metabolites and their analogues for

the treatment of human diseases related to bone-metab-

olism, immune effects, cell differentiation and hormone se-

cretion^[3,4]has been paralleled by progress in the develop-

ment of convergent synthetic methodologies.^[5Ϫ8]In the

most efficient syntheses of compound 3, the requisite pre-

cursors to the ring A and/or the CD-rings/side chain build-

ing blocks could be conveniently acquired from commer-

cially available vitamin D₂(2), by regioselective oxidative

cleavage of the appropriate double bond(s),^[9]as outlined in

Scheme 1. Total synthesis provides a complementary and

more versatile approach to vitamin metabolites and their

analogues. Several methods for the total synthesis of vit-

amin D are presently available. However, the development

of an efficient and enantioselective total synthesis of the

CD-rings/side-chain building-block (i.e. the ‘‘northern’’

portion) presents an ongoing challenge to organic

chemists.^[10Ϫ15]

Various strategies have been developed for the synthesis

of vitamin D₃and its congeners (Figure 1, 1Ϫ3) in decades

of studies on the chemistry and therapeutic applications of

these compounds. In the pioneering approaches, 7-dehydro-

cholesterol 4 or ergosterol 5 were subjected to a UV-induced

rearrangement, followed by thermal rearrangement, to af-

ford vitamin D₃(1) or vitamin D₂(2), respectively.^[1,2]

Figure 1. The most important representatives of the vitamin D

group, and their respective biosynthetic and synthetic precursors

The discovery of 1α,25-dihydroxyvitamin D₃(3), and

other biologically active metabolites of vitamin D₃, focused

chemical research onto transformations of the sterol side

[a]

Institute of Organic Chemistry, Polish Academy of Sciences,

ul. Kasprzaka 44, 01-224 Warsaw, Poland

Fax: (internat.) ϩ48-22-6328117

E-mail: jwicha@icho.edu.pl

Scheme 1. Convergent synthetic approaches to 1α,25-dihydroxyvit-

amin D₃and its derivatives

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Recently, we reported^[16]a concise diastereoselective syn- The choice of compounds ii as optically active precursors to

thesis of the northern building-block of 25-hydroxyvitamin the vitamin D building-block 8 was particularly appealing

D₃8 (Scheme 2), in which we utilized two tandem because, firstly, the required optically active dihydroxy de-

MukaiyamaϪMichael reactions. Herein, we present the re- rivatives of fatty acids are readily accessible and inexpen-

sults from our efforts to combine diastereoselectivity and sive, and secondly, C-24 and C-25 hydroxylated metabolites

efficiency in carbonϪcarbon bond-forming reactions with and analogues of vitamin D could be synthesized directly

the demands of enantioselectivity in the generation of four from these starting materials. We expected that the acid-

contiguous stereogenic centers, at C-13, C-14, C-17 and C- catalyzed reaction of ii and enone 10 would occur with sim-

20 (steroid numbering), in 8. The configuration of the fifth ple diastereoselectivity, to afford the respective like (l) ad-

stereogenic center at C-8 is of no consequence for the duct.^[30]Induced diastereoselectivity favoring one of the

further synthesis, since the phenylsulfonyl group will serve diastereomeric pairs (17R,20R or 17S,20S) of the silyl enol

as a handle for the coupling of 8 to an appropriate A-ring ether iii was anticipated. However, there was no literature

building-block, using the Julia olefination reaction.^[17Ϫ19]

precedent to allow us to estimate the magnitude of induc-

tion or predict the facial selectivity. Further reaction of silyl

enol ether iii with 9 would afford intermediate i. It is well

documented that the formation of the stereogenic center (at

C-13) in this process is controlled by the stereogenic center

already present in the five-membered ring^[31](C-17). Stereo-

selective transformation of i into 8 has already been re-

ported.^[16,32]

Results and Discussion

Synthesis of Optically Active Side-Chain Precursors

Several optically active dihydroxy esters and their deriva-

tives were needed for the present studies. 2,2-Dimethylcy-

clohexan-1,3-dione (11) (Scheme 3) was subjected to baker’s

yeast reduction^[33,34]to give the hydroxy ketone 12.

Scheme 2. General plan for the synthesis of 8 from ketene acetals

ii and Michael acceptors 10 and 9

Reports of enantioselective reactions of cyclic α,β-un-

saturated ketones and silyl enol ethers are scarce. The reac-

tion of cyclopent-2-en-1-one with ketene acetals derived

from acetic acid, promoted by chiral titanium/BINOL com-

plexes, has been reported to afford the respective adducts

(with one stereogenic center) with significant enantioselec-

tivities.^[20]Relevant studies using propionic acid-derived ke-

tene acetals have suggested that additional activation of the

electrophile by an α-alkoxycarbonyl group is required.^[21,22]

Due to the generation of two new asymmetric centers, stere-

ochemical control of the reaction becomes more

complex.^[23Ϫ26]More promising approaches involve op-

tically active reagents. Thus, reaction of a propionamide ke-

tene acetal with an ephedrine-derived chiral auxiliary and

Scheme 3. Synthesis of optically active building-blocks by microbi-

ological reduction of 2,2-dimethylcyclohexan-1,3-dione (11). Re-

agents and conditions: (a) Baker’s yeast; (b) TBSCl/imidazol/DMF;

(c) mCPBA/NaHCO₃/CH₂Cl₂, 87% yield in two steps; (d) mCPBA/

CH₂Cl₂, 82%

The seven-membered ring lactone 15 was then obtained

various alkyl vinyl ketones in the presence of TiCl₄afforded in an excellent yield via protection of the hydroxy group in

the respective adducts with significant simple and induced 12 followed by oxidation with mCPBA. In contrast, direct

(facial) diastereoselectivities.^[27,28]A high degree of induced oxidation of 12 with the same reagent yielded the product

diastereoselectivity has also been reported in the case of that showed spectral properties suggestive of a six-mem-

the TrSbCl₆(Tr ϭ trityl) catalyzed addition of an achiral bered ring derivative. A diagnostic piece of evidence was

propionate-derived ketene acetal to optically active 4-meth- provided by a lower field shift of the C-6 signal (δ ϭ

oxy-2-methylcyclopent-2-en-1-one.^[29]

88.6 ppm) in the ¹³C NMR spectrum, compared to that re-

Analysis of various enantioselective approaches to com- corded in 15 (δ ϭ 75.3 ppm). We surmised that the

pound 8 and some preliminary experiments focused our at- BaeyerϪVilliger oxidation of 12 was accompanied by a

tention on optically active ketene acetals bearing a pro- ring-contraction, affording 14. Indeed, all our attempts to

tected diol functionality, of general structure ii (Scheme 2). transform the alcohol 14 into its TBS derivative failed, thus

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Synthesis of Vitamin D trans-Hydrindane Rings

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confirming the hydroxyl group bound to a tertiary carbon into the thioester 24 in an analogous manner to that

atom.

described above for its homologue.

Lactone 14 was treated with a reagent prepared from tri-

methylaluminum and tert-butylmercaptan to afford the re-

spective dihydroxy thioester.^[35]This compound was trans-

formed, without isolation, into the isopropylidene deriva-

tive 16 (Scheme 4). The product 16, purified by consecutive

column chromatography and distillation, was obtained in

56% yield, 96% ee (as determined by HPLC, Chiralcel OD

column). The enantiomeric excess determined for 16 is in-

dicative of the enantioselectivity achieved in the microbiol-

ogical reduction of 11, and of the ee’s of all the chiral de-

rivatives shown in Scheme 3.

Scheme 5. The synthesis of optically active side-chain precursors;

C20ϪC23 unit. Reagents and conditions: (a) AD-mix-α, 70%, 96%

ee; (b), 1. AlMe₃/tBuSH, 2. 2,2-dimethoxypropane, TsOH, 60% in

2 steps

Finally, the thioester 27 (Scheme 6), lacking geminal

methyl groups at the chain terminus, was obtained from the

methyl ester 26, itself synthesized from the -glutamic acid

(25), essentially following literature procedures.^[42,43]

Scheme 6. The synthesis of optically active precursors of the side

chain lacking gem-dimethyl groups. Reagents and conditions: (a)

as reported^[42,43](b) AlMe₃/tBuSH, 47%

Synthesis of CD-Rings/Side-Chain Building-Blocks Starting

from Optically Active Side-Chain Precursors

Scheme 4. The synthesis of optically active side-chain precursors;

C20ϪC27 unit. Reagents and conditions: (a) 1. AlMe₃/tBuSH; 2.

2,2-dimethoxypropane, TsOH, 56%, 96% ee; (b) as reported;^[36](c)

Sharpless asymmetric dihydroxylation, 18 into 20: AD-mix-α, 76%

yield (after distillation), Ͼ 95% ee; 19 into 21: DHQ-PHAL,

K₃Fe(CN)₆, K₂CO₃, OsO₄, 54%, 96% ee and 14, 8%; (d) 2,2-di-

methoxypropane, TsOH, 16, 89%, 17, 96%; (e) AlMe₃/tBuSH, 76%

With all the required optically active precursors to vit-

amin D in hand, the stage was set for studies on asymmetric

induction in the conjugate-addition reaction. We started

with the ketene acetals that contained all the carbon atoms

of the ultimative vitamin D side chain.

The thioester 16 was transformed into the ketene acetal

28 (Scheme 7) in the usual way,^[44]and the product was

purified by a short-path distillation. A mixture of (E)- and

In an alternative approach to 16, we used 6-methylhept- (Z)-isomers in a ratio of 89:11 was obtained.^[45]Reaction

5-enoic acid as starting material.^[36]The methyl ester 18 was of 28 with the enone 10 in the presence of TrSbCl₆(7

subjected to the Sharpless asymmetric dihydroxylation mol %) in dichloromethane at Ϫ78 °C afforded the adduct,

(AD), using either commercially available AD-mix-α^[37,38]which was treated in situ with the enone^[32]9. The product

or an oxidant prepared in situ,^[39]to afford the dihydroxy of tandem conjugate-addition was obtained in 55% yield.

derivative 20. When AD-mix-α was used, the dihydroxy es- HPLC analysis and spectroscopic data indicated that two

ter 20 was formed along with the hydroxy lactone 14, in a diastereomers had been obtained in a ratio of 76:24. All our

ratio of 89:11 (as determined by GC). The dihydroxylation attempts to separate the diastereomers by column chroma-

product was allowed to react with 2,2-dimethoxypropane in tography failed. Fortunately, the major diastereomer crys-

the presence of TsOH, affording 17. Then, thioester 16 was tallized (m.p. 103 °C, methanol), and was isolated from the

obtained from 17 using the trimethylaluminum sulfide re- mixture by crystallization (ca. 27% yield from 28). A single-

agent. The order of the transformations on the route from crystal X-ray analysis revealed it to be the

18 to 16 could be reversed since thioester 19 was smoothly (13R,17R,20R,24S) diastereomer^[46]29. It is noteworthy

dihydroxylated to give 21. When the commercially available that the absolute configuration of 29 is consistent with our

reagent was used, the dihydroxy derivative 21 was ac- plans for the synthesis of natural vitamin D₃derivatives.

companied by a small amount of a side product, presum- After some time, a further quantity of crystals was obtained

ably lactone 14. On all routes involving AD, ester 16 was from the mother liquors (m.p. 69Ϫ70 °C). This material

obtained uniformly with over 95% ee.

proved to be a 1:1 mixture of 29 and its minor diastereomer,

In order to prepare the subsequent side-chain precursor, to which the structure 30 (13S,17S,20S,24S) was assigned

the unsaturated ester^[40]22 (Scheme 5) was subjected to the later (vide infra). Exposure of the 1,5-diketone 29 to meth-

dihydroxylation procedure to give the five-membered lac- anolic potassium hydroxide afforded the bicyclic derivative

tone^[41]23 (70% yield, 96% ee). Lactone 23 was transformed 31.

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Scheme 7. Synthesis of the CD-rings /side-chain building-block 35. Reagents and conditions: (a) TrSbCl₆, cat., 55% yield, then crystalliza-

tion of 29; (b) KOH/MeOH, 84%; (c) DIBALH/CH₂Cl₂, Ϫ78 °C; (d) TsCl/Et₃N; (e) mCPBA; (f) LiAlH₄, 35, 36% and 36, 16% from31;

(g) 1. CsCl₃·H₂O/NaBH₄, 2. LiAlH₄, 32, 87% and 33, 5%; (h) as (f), 32, 73% and 33, 15%; (i) 1. TsCl, Et₃N, 2. mCPBA, 3. LiAlH₄, 70%

from 31; (j) as (d), 89%; (k) mCPBA and then LiAlH₄, 72%

Various synthetic pathways from 31 to the trans-hydrind- transformed into 35 (72% yield) using the aforementioned

ane derivative 35 were then explored. First, DIBALH was sequence of steps. Finally, 31 was reduced in one step with

used to simultaneously reduce the tert-butylthioester and LiAlH₄to afford a mixture of diols 32 and 33 (88% yield),

the keto groups. The crude product (a mixture of dia- and the mixture was transformed further, without isolation,

stereomers) was treated with TsCl, which resulted in the to give 35 in 54% overall yield from 31.

selective esterification of the primary hydroxy groups. Then,

Both of the routes where DIBALH was not used pro-

the intermediates were oxidized with mCBPA to form the vided the saturated sulfone 35 in high yields. The diastereo-

corresponding sulfones. Finally, the tosyloxy/sulfone deriva- selectivities in the reduction of 31 are noteworthy; 9β- and

tives were reduced with LiAlH₄.^[47]A mixture of two com- 9α-hydroxy derivatives were formed in ratios as follows: DI-

pounds was obtained. The major product, separated by col- BALH Ϫ ca. 70:30; LiAlH₄Ϫ 83:17; the Luche reagent

umn chromatography (36% yield from 31), was identified as Ϫ 95:5.

the required acetonide 35. Structure 36 was assigned to the

Deprotection of acetal 35 using Amberlyst-15H in meth-

minor product (16% yield) on the grounds of analytical and anol gave the diol 38 (Scheme 8). This compound was

spectral properties. We concluded that the multi-step trans- treated with mesyl chloride and triethylamine, and the

formation of 31 into 35, without purification of the inter- crude mesylate was reduced with LiAlH₄. The target prod-

mediates, could be handled smoothly. However, the first uct 8 was obtained (66% yield in 2 steps) and was found to

step of the sequence, DIBALH reduction of 31, afforded be identical to an authentic sample.

the expected diols 32 and 33 along with a side product 34

All that remained to be done for the completion of the

(presumably as a mixture of isomers). Mechanistically, re- study on the synthesis of 8 from the ketene acetal 28 was

ductive opening of the dioxolane ring is likely to involve the clarification of the structure of the minor diastereomer

a Lewis acid-catalyzed formation of the oxonium ion (ii, generated along with 29 in the conjugate-addition reaction.

Scheme 7). All our attempts to minimize the amount of the Since the minor diastereomer could not be separated, we

side product 36 formed, by diminishing the excess of DI- thought it would be reasonable to subject the mixture to a

BALH or by altering the reaction conditions, failed.

sequence of operations that would eventually transform 29

In a subsequent approach, 31 (Scheme 7) was reduced into 8. We anticipated that the diastereomer of then un-

with the Luche reagent^[48]and then the intermediate allylic known structure would, under these conditions, afford the

alcohols, with their unaffected thioester groups, were respective isomer of 8, and that this would be easier to

treated with LiAlH₄. After chromatography, the 9β,21-diol identify. The mixture (a sample enriched in the minor dia-

32 was obtained (87% yield) along with a small amount of stereomer by crystallization, dr 1:1) was subjected to the

its C-9 epimer 33 (5% yield). Diol 32 was tosylated to give annulation procedure (Scheme 8), and the crude product

the 21-mono-tosylate 37 (not shown), and the tosylate was was acidified with HCl in order to remove the acetal protec-

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Synthesis of Vitamin D trans-Hydrindane Rings

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adduct was formed as expected, however, it failed to react

with the ‘‘second’’ acceptor 9. After the usual work-up, a

mixture of three isomers was obtained in a ratio of 80:12:8

(as shown from integration of the methyl group signals in

1

the H NMR spectrum). Further experiments showed that

reaction-quenching and work-up procedures affect the ratio

of the two major diastereomers, indicating that these prod-

ucts differ by a stereogenic center labile to epimerization.

The major component of the mixture was obtained in a

crystalline form (51% yield from 40). Its structure was de-

termined to be 42 by X-ray analysis.^[53]Consequently, struc-

ture 41 was assigned to the immediate adduct and 43 to the

major side product.

At this stage, it was also established that the conjugate-

addition reaction of 40 and 10 occurred with relatively high

diastereoselectivity, dr ca. 90:10. However, the relative con-

figuration of the newly formed stereogenic centers was un-

like (u), which was at odds with the synthetic plan (for some

comments on the stereochemistry of the reaction, vide in-

fra). This line of research was subsequently abandoned. It

should be mentioned that we attributed the failure of the

attempted reactions of 41 with 9 to steric hindrance.

Next, we turned our attention to the ketene acetal 44

(Scheme 10) derived from the thioester 24.

Scheme 8. Transformation of 35 into 8; correlation of the structures

of diastereomers 29 and 30. Reagents and conditions, (a) Am-

berlyst-15H/MeOH, 81%; (b) 1. MsCl/Et₃N, 2. LiAlH₄, 87%; (c) 1.

KOH/MeOH, 2. HCl, 70%; (d) 1. DIBALH, 2. MsCl/Et₃N, 3.

mCPBA, 4. LiAlH₄, 26% in 4 steps

tive group. Intermediates 39 were treated with an excess of

DIBALH to produce the respective tetrols, which were used

without purification. The tetrols were treated with two mo-

lar equivalents of mesyl chloride in the presence of triethyl-

amine, and then consecutively with mCPBA and LiAlH₄. A

single product identical in all respects with racemic 8 was

obtained. It was evident that the diastereomer ac-

companying 29 contributed to the racemate with its

(13S,17S,20S) enantiomer; structure 30 was assigned to

this compound.

These results demonstrate that readily accessible chiral

ketene acetals can be conveniently used as precursors to the

optically active vitamin D building block 8. However, the

diastereoselectivity observed in the generation of 29 and 30

(76:24) left room for improvement. To this end, we became

interested in examining the use of the ketene acetal 40 de-

rived from lactone 15. The ketene acetal function in 40

(Scheme 9) is clearly more sterically hindered than that in

28. It has been found that a stereogenic center in the α-

position to the reaction-site in cyclic ketene acetals directs

the addition.^[49Ϫ51]Longer-range effects remain unclear.^[52]

A shorter distance between the stereogenic center and the

reaction site (i.e. in a 1,3-relationship) was expected to be

advantageous for asymmetric induction.^[54]It should be

noted that 24 does not include all the carbon atoms of the

vitamin D side chain, and that a routine extension of the

side chain would be required in the course of the synthesis

of 8. The reaction of the ketene acetal 44 consecutively with

the enones 10 and 9 afforded a mixture of products, in a

ratio of 85:11:4 (as determined by HPLC), in 75% yield.

The major constituent of the mixture 45 was isolated in a

pure form by preparative TLC, and its gross structure was

confirmed by spectroscopic methods. However, its NMR

spectra were too complex for us to attempt stereochemical

assignments. In contrast to the earlier discussed synthesis,

no crystalline material could be obtained.^[55]The crude

mixture was subjected to the annulation procedure to afford

the enones, 49 and its respective diastereomer. The major

product 49 was isolated, but no crystals suitable for X-ray

analysis could be gained. In an attempt to obtain a deriva-

tive of 45 that would be helpful in structural elucidation,

the five-membered lactones 47 and 48 (Scheme 10) were

prepared. The isomeric products were separated by column

chromatography, but the high-field signals corresponding to

1

the lactone ring-protons in the H NMR spectra of both

isomers were poorly resolved.

In a search for evidence that would allow us to assign the

stereochemistry, CD spectra of adduct 45 and its homol-

ogue 29 were taken. The spectra were similar in shape, but

the Cotton effect was of the opposite sign, suggesting that

45 and 29 differed in configuration at C-13. Assuming a

(13S) configuration for 45, it could be deduced that the

Scheme 9. Attempted use of ketene acetal 40 for the synthesis of

8. Reagents and conditions: (a) LDA and then TMSCl, 92%; (b)

TrSbCl₆, 69%; (c) Amberlyst-15H, crystallization

Lactone 15 was transformed into the silyl enol ether 40 center at C17 has the (S) configuration (see the discussion

(Scheme 9), and the latter was allowed to react with the of the synthetic plan). For the third newly generated stere-

enone 10 in the presence of the trityl catalyst. The initial ogenic center, the (20S) configuration would be expected on

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Scheme 10. Synthesis of ent-8 from ketene acetal 44. Reagents and conditions: (a) TrSbCl₆, 7 mol %; 75%, isomer ratio 85:11 4; (b) KOH/

MeOH, 79%; (c) Amberlyst-15H/MeOH; (d) CeCl₃·7H₂O/NaBH₄/MeOH and crystallization, 66%; (e) LiAlH₄; (f) TsCl/DMAP/Et₃N; (g)

mCPBA; (h) LiAlH₄, 63% in 4 steps; (i) as in (c) 80%; (j) Pb(OAc)₄; (k) (Ph)₃PCHCO₂Me, 80%; (l) H₂/Pd; (m) MeMgI, 88% in 2 steps

the grounds of the preference of l products in the latter was allowed to react with methyl (triphenylphos-

MukaiyamaϪMichael reaction. For these reasons, the phoranylidene)acetate, without isolation, to afford the un-

(13S,17S,20S,23S) configuration appeared to be the most saturated ester 56. Finally, 56 was hydrogenated, and the

likely for 45.

isolated dihydro derivative 57 was treated with an excess

The synthesis was continued with the premise that the of the Grignard reagent to afford the enantiomer of the

structure of 45 and its derivatives would be confirmed at previously prepared building-block: ent-8. The specific ro-

later stages. Reduction of the enone 49 and its ac- tation of the enantiomers is inconclusively low; the enanti-

companying isomers (the crude product of an annulation omeric nature of the synthesized compounds was confirmed

reaction) with the Luche reagent afforded the respective al- by their CD spectra.

lylic alcohols in an almost quantitative yield. The major

The synthesis we accomplished involved seven isolated

component of the mixture crystallized, and was isolated in

intermediates, and afforded ent-8 in 14% overall yield from

66% yield by crystallization. Single crystal X-ray analysis^[53]

44. Obviously, for the synthesis of natural enantiomers of

of the isolated allylic alcohol revealed its structure as 50.

vitamin D derivatives by this route, the (R)-enantiomer of

Consequently, structures were established as 45 for the

the protected dihydroxy ester 24 must be used.

major product of the conjugate-addition reaction, 47 for

the major isomer of the lactonization, and 49 for the major

Not all of the carbon atoms of the dihydroxy ester deriva-

diastereomer of the annulation product.

tive 24 were incorporated into the target compound ent-8

For the second major product of the conjugate-addition in the above approach. The terminal isopropyl group was

step, structure 46 appeared to be most likely (as the alterna- cleaved off after all of the stereogenic centers had been in-

tive l diastereomer). Accordingly, structure 48 was tenta- stalled. Therefore, it was tempting to examine the dihydroxy

tively assigned to the isomeric lactone. The minor product ester derivative 27, which is devoid of the geminal methyl

(4%) presumably represents one of the u diastereomers.

groups. Replacement of 44 by 58 (Scheme 11) would con-

Isomerically pure 50 was transformed into 54 (47% over- tribute to ‘‘atom economy’’. Additionally, we believed that

all yield), as indicated in Scheme 10. Next, the protective a comparison of 44 and 58 would contribute to our under-

group was removed, and the resulting diol 55 was cleaved standing of the steric effects in the conjugate-addition reac-

with lead tetraacetate to afford the respective aldehyde. The tion.

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Synthesis of Vitamin D trans-Hydrindane Rings

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tion of the ketene acetal double bond has no effect on the

reaction course, since two sterically bulky groups tBuS and

Me₃SiO are involved; secondly, the ethylenic bonds partici-

pating in the reaction are in the relative anti-periplanar

orientation; thirdly, the ketene acetal vinylic proton is di-

rected towards the enone methyl group.

Scheme 11. Attempted synthesis of 8 using ketene acetal 58. Re-

agents: (a) TrSbCl₆, 39%.

Thioester 27 was treated consecutively with LDA and tri-

methylsilyl chloride to give ketene acetal 58 as a mixture of

(E) and (Z) isomers, in a ratio of 82:18. The reaction of 58

with enones 10 and then 9 turned out to be less effective

than expected. After some experimentation, the tandem

addition product 59 was obtained in 39% yield. It is note-

worthy that the pyran derivative 60 was isolated from one

of the experiments in which 58 reacted with cyclopent-2-en-

1-one, thus demonstrating that 58 is susceptible to cycliza-

tion.

Scheme 12. Stereochemistry of the conjugate-addition reactions

The highest induced diastereoselectivity was recorded for

the ketene acetal 44 in which the stereogenic center and the

reaction site have a 1,3-relationship. The diastereomers of

(17R,20R) and (17S,20S) configuration were formed in a

ratio of 12:88. The one-carbon-longer ketene acetal 28 af-

forded diastereomers (17R,20R) and (17S,20S) in a ratio of

76:24. Formally, reversal of facial selectivity occurred.

An inspection of molecular models suggests that the

Re,Re approach (l) of 44 to 10, in which the dioxolane ring

is essentially perpendicular to the cyclopentenone ring, and

the dioxolane proton is orientated towards the enone

methyl group, is favored (Scheme 12, iii). In this arrange-

ment, the interaction of the dioxolane methyl groups with

the enone is minimal. With the extension of the ketene ace-

tal chain, the difference in stereofacial approaches of 28 and

10 diminishes. The Si,Si approach, presumably with the di-

oxolane proton located in the vicinity of enone carbonyl,

accounts for the observed selectivity.

The cyclic ketene acetal 40 afforded a (17R,20S) product

41 and its minor diastereomer in a ratio of ca. 87:13. Analy-

sis of the model indicates that a half-boat conformation of

the seven-membered ring, with the tert-butyldimethylsily-

loxy group in a pseudo-equatorial orientation, is favored

(Scheme 12, iv). The Re-side (exo) of the ketene acetal is

exposed to the attack of the reagent. As regards the enone,

addition occurs on its Si-side. This favors the approach of

the carbonyl group orientated towards the silyloxy group,

and with the enone methyl group eclipsed by the ketene

acetal vinylic proton. This reaction may be viewed as sub-

strate-controlled,^[56]in the sense that the specific require-

ments of one the reactants imposes simple and induced dia-

stereoselectivity.

¹H and ¹³C NMR spectral analysis of 59 showed the

presence of two diastereomers in a ratio of ca. 1:1. Hence,

it is clear that the geminal methyl groups at the terminus of

the ketene acetal chain are crucial for the diastereoselec-

tivity of the conjugate-addition reaction.

Comments on the Stereochemistry of Conjugate-Addition

Reactions

In our studies aimed at the enantioselective synthesis of

the hydrindane derivative 8, we examined the reactions of

four homochiral ketene acetals of (S) configuration with 2-

methylcyclopent-2-en-1-one and, where applicable, with the

subsequent Michael acceptor 9. In reviewing the stereo-

chemical outcome of these reactions, we assume that the

ratio of diastereomers isolated from a tandem conjugate-

addition reaction reflects well the stereoselectivity in the

initial step.

Reaction of the acyclic ketene acetals 28 and 44 with the

enone 10 occurred with a high simple diastereoselectivity,

affording respective adducts of like (l) configuration

[(17S,20S) or (17R,20R)], as virtually the only products.

The cyclic ketene acetal 40 reacted with 10, again to give

predominantly a single diastereomer of the adduct (dr ca.

90:10), but in this case, the main product was of unlike (u)

configuration (17R,20S). Initial experiments in which ke-

tene acetal 58 reacted with 10 indicated a lack of diastereo-

selectivity in this reaction.

We conclude that ketene acetals 28 and 44 react in ac-

cordance with the general stereochemical model of the

MukaiyamaϪMichael conjugate-addition involving 2-

methylcyclopent-2-en-1-one (Scheme 12, i). The major fea-

Conclusion

In conclusion, enantioselective synthetic approaches to

tures of this model are as follows:^[30]firstly, the configura- the vitamin D building-block 8, starting from optically ac-

Eur. J. Org. Chem. 2004, 783Ϫ799

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

789

E. Gorobets, V. Stepanenko, J. Wicha

FULL PAPER

(m, 2 H, C3-H), 3.72Ϫ3.63 (m, 1 H, C6-H) ppm. ¹³C NMR: δ ϭ

Ϫ4.9 (SiMe), Ϫ4.2 (SiMe), 17.9 (SiCMe₃), 18.5 (C4), 24.3 (C7-Me),

25.7 (SiCMe₃), 27.6 (C7-Me), 32.5 (C5), 36.6 (C3), 75.3 (C6), 83.7

(C7), 174.3 (C2) ppm. C₁₄H₂₈O₃Si (272.45): calcd. C 61.72, H

10.36; found C 61.49, H 10.43.

tive derivatives of fatty acids, were developed. Simple and

induced diastereoselectivity in the MukaiyamaϪMichael re-

action of selected optically active ketene acetals with 2-

methylcyclopent-2-en-1-one were examined.^[63]

(6S)-6-O-(tert-Butyldimethylsilyl)-7,7-dimethyl-2-O-(trimethylsilyl)-

4,5,6,7-tetrahydrooxepine-2,6-diol (40): A solution of LDA was pre-

pared from diisopropylamine (0.410 mL, 3.13 mmol) and BuLi

(1.35  in hexanes, 1.315 mL, 3.13 mmol) in THF (6 mL) at 0 °C,

and cooled toϪ78 °C. A solution of the lactone 15 (695 mg,

2.56 mmol) in THF (3 mL) was added, followed, after 45 min, by

TMSCl (0.570 mL, 4.51 mmol). The mixture was set aside at room

temperature for 12 h, and then the solvent was evaporated. The

residue was diluted with hexanes (15 mL) and filtered through a

pad of Celite. The solvent was evaporated, and the residue was

distilled in a kugelrohr apparatus (220°/1.0 Torr) to give 40

Experimental Section

Melting points were determined with a hot-stage apparatus and are

uncorrected. Optical rotations were measured with a Perkin-Elmer

model 141 polarimeter using a 1-mL capacity cell (5-cm path

length) in CHCl₃. NMR spectra were recorded in CDCl₃solutions,

¹H at 200 MHz and ¹³C at 50 MHz unless otherwise indicated, with

a Varian Gemini instrument. ¹H spectra at 500 MHz and ¹³C spec-

tra at 125 MHz were recorded with a Bruker AMX spectrometer.

Chemical shifts are quoted on the δ scale with the solvent signal

1

as an internal standard (CDCl₃, H NMR: δ ϭ 7.26 ppm. CDCl₃;

(875 mg, 92%): [α]²_D²ϭ Ϫ34.7 (c ϭ 2.0). H NMR: δ ϭ 0.05 (s, 6

1

¹³C NMR: δ ϭ 77.00 ppm). In ¹³C NMR spectra, the multiplicities

of the signals were assigned using the DEPT technique. IR spectra

were recorded with a PerkinϪElmer 1670 FT spectrophotometer.

MS (electron impact, 70 eV) were recorded with an AMD 604

(AMD Intectra GmbH) mass spectrometer. HPLC analyses were

performed using a Shimadzu LC-8A system provided with a SPD-

6A variable UV detector; flow rate 0.5 to 1 mL/min. Column chro-

matography was performed with gradient elution on Merck silica

gel 60, 230Ϫ400 mesh. TLC was performed on aluminum sheets,

Merck 60F 254 and preparative TLC on glass plates, 20 ϫ 20,

covered with Merck silica gel FG 254. Anhydrous solvents were

obtained by distillation from benzophenone ketyl (THF) or cal-

cium hydride (CH₂Cl₂, benzene). Air-sensitive reactions were per-

formed in oven- or flame-dried glassware under argon. Organic ex-

tracts were dried with anhydrous Na₂SO₄or MgSO₄, and solvents

were evaporated using a rotary evaporator. Microanalyses were per-

formed at our analytical laboratory. DHQ: dihydroquinine;

PHAL: phthalazine.

H, tBuMe₂Si), 0.19 (s, 9 H, SiMe₃), 0.88 (s, 9 H, SiCMe₃), 1.24 (s,

3 H), 1.33 (s, 3 H), 1.41Ϫ1.77 (m, 2 H, C4-H), 1.81Ϫ2.02 (m, 2 H,

C5-H), 3.47 (dd, J ϭ 9.8, 3.9 Hz, 1 H, C3-H), 4.21Ϫ4.31 (m, 1 H,

C6-H) ppm. ¹³C NMR: δ ϭ Ϫ4.8 (tBuMe₂Si), Ϫ3.9 (tBuMe₂Si),

0.3 (SiMe₃), 17.9 (SiCMe₃), 18.1 (C7-Me), 19.8 (C5), 25.8

(SiCMe₃), 27.9 (C7-Me), 31.4 (C4), 79.0 (C6), 80.5 (C7), 86.7 (C3),

154.5 (C2) ppm. C₁₇H₃₆O₃Si₂(344.64): calcd. C 59.25, H 10.53;

found C 59.17, H 10.31.

(6S)-6-(1-Hydroxy-1-methylethyl)tetrahydro-2H-pyran-2-one (14):

Powdered NaHCO₃(8 g) and mCPBA (70%, 2.132 g, 8.67 mmol)

were added to a solution of 12 (985 mg, 6.94 mmol) in dichloro-

methane (25 mL). The mixture was stirred for 6 h, and then poured

into saturated aqueous Na₂S₂O₃. The product was extracted with

dichloromethane. The solvent was evaporated. The residue was fil-

tered through silica gel (30 g, hexanes/acetone, 5:1) and then dis-

tilled in a kugelrohr apparatus (150 °C/1.5 Torr) to give 14 (900 mg,

82%): [α]²_D²ϭ ϩ17.1 (c ϭ 2.0). IR (film): ν˜ ϭ 3445, 1769, 1185

cm^Ϫ1. ¹H NMR: δ ϭ 1.19 (s, 3 H, Me), 1.24 (s, 3 H, Me), 1.42Ϫ2.06

(3S)-3-Hydroxy-2,2-dimethylcyclohexan-1-one (12): This compound

was prepared following the reported procedure.^[33]In a typical run,

2,2-dimethylcyclohexa-1,3-dione (11) (4.00 g, 28.17 mmol), com-

mercially available baker’s yeast (150 g), sucrose (80 g), water (1 L),

ethanol (96%, 10 mL) and Triton X-100 (0.2%, 40 mL) were used.

The mixture was stirred at 30 °C for 48 h. The crude product was

purified by chromatography on silica gel to give the unchanged

dione 11 (1.28 g, 32%) and the ketol 12 (1.23 g, 31%): [α]²_D²ϭ ϩ23.7

(c ϭ 2.0). Reported:^[33][α]²_D²ϭ ϩ23.0 (c ϭ 2.0).

(m, 4 H), 2.68Ϫ2.26 (m, 3 H), 4.03Ϫ4.13 (m, 1 H, C6-H) ppm. ¹³

C

NMR: δ ϭ 18.4, 22.4, 24.3, 25.6, 29.4, 71.4 (C1Ј), 88.6 (C6), 171.5

(C2) ppm. C₈H₁₄O₃: calcd. C 60.74, H 8.92; found C 60.49, H 9.17.

S-tert-Butyl 4-[(3S)-2,2,5,5-Tetramethyl-1,3-dioxolan-4-yl]butane-

thioate(16). a. From Lactone 14: tBuSH (2.25 mL, 19.87 mmol) was

added dropwise to a solution of trimethylaluminium (2.0  in hep-

tane, 9.94 mL, 19.88 mmol) in dichloromethane (25 mL) at 0 °C.

The solution was warmed to room temperature, and, after 30 min,

a solution of lactone 14 (1.39 g, 8.80 mmol) in dichloromethane

(8 mL) was added. The mixture was stirred for 14 h and then

poured into 10% aqueous tartaric acid. The product was extracted

(6S)-O-(tert-Butyldimethylsilyl)-6-hydroxy-7,7-dimethyloxepan-2-

one (15): Imidazole (3.63 g, 53.38 mmol) and TBSCl (3.81 g,

25.28 mmol) were added to a solution of 12 (1.365 g, 9.61 mmol)

in DMF (18 mL). The mixture was stirred at room temperature for with dichloromethane. The solvent was evaporated. The residue

16 h, then at 50 °C for 9 h, and then poured into water. The product

was extracted with dichloromethane. The organic extract was

washed consecutively with ice-cold 1% HCl, 5% NaHCO₃and

water. The so-obtained solution of the TBS derivative of 12 was

concentrated to ca. 25 mL, and powdered NaHCO₃(10 g), and

was dissolved in 2,2-dimethoxypropane (7 mL), and TsOH (5 mg)

was added. The mixture was set aside for 12 h and then filtered

through silica gel (2 g), and the solvent was evaporated. The residue

was purified by chromatography on silica gel (50 g, hexanes/EtOAc,

15:1) and the main fraction was distilled in a kugelrohr apparatus

mCPBA (70%, 4.00 g, 16.23 mmol) were added. The mixture was (165 °C/1.5 Torr). Thioester 16 (1.42 g, 56%) was obtained, 95.9%

stirred for 6 h, and then the reaction was quenched with saturated

aqueous Na₂S₂O₃. The product was extracted with dichlorometh-

ane. The solvent was evaporated. The residue was purified by chro-

matography on silica gel (80 g, hexanes/EtOAc, 25:1, 5:1) and then

distilled in a kugelrohr apparatus (200°/1.0 Torr) to give 15 (2.26 g,

ee by HPLC (Chiralcel OD, 10% tBuOH in hexanes, t_Rϭ 6.14 min,

for the minor (R) enantiomer, t_Rϭ 6.82 min): [α]²_D²ϭ ϩ1.6 (c ϭ

2.0). ¹H NMR: δ ϭ 0.99 (s, 3 H, Me), 1.05Ϫ1.89 (m, 4 H) overlap-

ping 1.15 (s, 3 H, Me), 1.23 (s, 3 H, Me), 1.31 (s, 3 H, Me), 1.37

(s, 9 H, CMe₃), 2.30Ϫ2.56 (m, 2 H, C2-H), 3.53Ϫ3.63 (m, 1 H,

87%) as a crystalline solid: m.p. 41 °C. [α]²_D²ϭ ϩ29.9 (c ϭ 2.0). ¹H CHOϪ) ppm. ¹³C NMR: δ ϭ 22.7, 22.9, 25.9, 26.7, 28.3 28.4, 29.7

NMR: δ ϭ 0.06 (s, 6 H, SiMe₂), 0.88 (s, 9 H, SiCMe₃), 1.40 (s, 3

(CMe₃), 44.1, 47.6, 79.9, 82.8, 106.4 (OϪCϪO), 199.7 (CO) ppm.

H), 1.43 (s, 3 H), 1.45Ϫ2.05 (m, 4 H, C5-H and C4-H), 2.54Ϫ2.73 C₁₅H₂₂O₃S: calcd. C 62.46, H 9.78; found C 62.19, H 10.01.

790

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Eur. J. Org. Chem. 2004, 783Ϫ799

Synthesis of Vitamin D trans-Hydrindane Rings

FULL PAPER

b. From Ester 17: tBuSH (3.37 mL, 29.99 mmol) was added drop-

wise to a solution of trimethylaluminium (2.0  in heptane, 2.0 

Methyl 4-[(3S)-2,2,5,5-Tetramethyl-1,3-dioxolan-4-yl]butyrate (17):

TsOH (10 mg) was added to a solution of the diol 20 (950 mg,

15.00 mL, 30.00 mmol) in dichloromethane (20 mL) at 0 °C. The 5.00 mmol) in 2,2-dimethoxypropane (10 mL). After 5 h, the reac-

solution was warmed to room temperature, and, after 30 min, a

solution of ester 17 (3.40 g, 14.78 mmol) in dichloromethane

(10 mL) was added. The mixture was stirred for 14 h and then

poured into 10% aqueous tartaric acid. The product was isolated

as described above, purified by chromatography on silica gel (100 g,

hexanes/ EtOAc, 25:1 and 10:1) and then distilled in kugelrohr ap-

paratus to give 16 (3.235 g, 76%).

tion was quenched with triethylamine (0.5 mL), and the mixture

was filtered through silica gel (2 g). The solvent was evaporated.

The residue was purified by chromatography on silica gel (25 g,

hexanes/EtOAc, 15:1), and the main fraction was distilled in a kug-

elrohr apparatus (165°/1.5 Torr) to give 17 (1.104 g, 96%): [α]²_D²

ϭ

ϩ3.9 (c ϭ 1.65). ¹H NMR: δ ϭ 1.05 (s, 3 H, Me), 1.21 (s, 3 H,

Me), 1.27 (s, 3 H, Me), 1.20Ϫ1.96 (m, 4 H, C3-H and C4-H) over-

lapping 1.37 (d, J ϭ 0.6 Hz, 3 H, Me), 2.24Ϫ2.49 (m, 2 H, C2-H),

3.64 (dd, J ϭ 4.0, 8.6 Hz, 1 H, CHOϪ), overlapping 3.64 (s, 3 H,

OMe) ppm. ¹³C NMR: δ ϭ 22.4 (2), 22.8 (3), 26.0 (3), 26.8 (3),

28.4 (3), 28.6 (2), 33.8 (2), 51.4 (OMe), 80.0 (C5Ј), 83.0 (C4Ј), 106.5

(OϪCϪO), 173.7 (CO) ppm. C₁₂H₂₂O₄(230.30): calcd. C 62.58, H

9.63; found C 62.56, H 9.40.

c. From diol 21: TsOH (15 mg) was added to a solution of diol 21

(1.19 g, 4.80 mmol) in 2,2-dimethoxypropane (15 mL). After 5 h,

the reaction was quenched with triethylamine (1.0 mL), and the

mixture was filtered through silica gel (2 g). The solvent was evapo-

rated and the residue was purified by chromatography on silica gel

(20 g, hexanes/ EtOAc, 20:1) to give 16 (1.23 g, 89%).

S-tert-Butyl

(5S)-5,6-Dihydroxy-6-methylheptanethioate

(21).

Asymmetric Dihydroxylation of the Unsaturated Thioester 10 with

the Use of (DHQ)₂-PHAL and OsO₄: The reaction was carried in

an analogous way to the asymmetric dihydroxylation of ester 18,

as described above. The reagents were used as follows: (DHQ)₂-

PHAL (400 mg, 5%mol), K₃Fe(CN)₆(9.90 g, 30 mmol), K₂CO₃

(4.2 g, 30 mmol), OsO₄(25 mg, 1%mol), tBuOH/H₂O (1:1) 100 mL,

thioester^[36]19 (2.14 g, 10.00 mmol), Na₂SO₃(15 g). Reaction time

6 h. The product was extracted with dichloromethane (5 ϫ 30 mL)

and purified by chromatography on silica gel (100 g, hexanes/

EtOAc, 5:1 and then 3:1) to give diol (Ϫ)-21 as the main fraction

(TLC, EtOAc/hexanes, 1:1, R_fϭ 0.29) and a side product (R_fϭ

0.10, same as the lactone 14). The crude diol was distilled using a

Methyl 6-Methylhept-5-enoate (18): A mixture of 6-methylhept-5-

enoic acid^[36](10.50 g, 73.94 mmol), dry methanol (150 mL) and

sulfuric acid (98%, 0.5 mL) was heated at reflux temperature for

4 h. After cooling, triethylamine (3 mL) was added, and the mix-

ture was filtered through silica gel (25 g). The filtrate was evapo-

rated. The residue was distilled. The fraction at 82Ϫ85 °C/30 Torr

1

was collected to give ester 18 (9.46 g, 82%). H NMR: δ ϭ 1.55 (s,

3 H, CϭC-Me-trans), 1.57Ϫ1.70 (m, 5 H, C3-H and CϭC-Me-cis),

1.88Ϫ2.04 (m, 2 H, C4-H), 2.26 (m, 2 H, C2-H), 3.62 (s, 3 H,

OMe), 4.98Ϫ5.11 (m, 1 H, C5-H) ppm. ¹³C NMR: δ ϭ 17.6 (3),

25.0 (C3), 25.6 (3), 27.3 (C4), 33.4 (C2), 51.3 (OMe), 123.3 (C5),

132.3 (C6), 174.0 (CO) ppm. C₉H₁₆O₂(156.22): calcd. C 69.19; H-

10.32; found C 69.28, H 10.37. Reported:^{[57] 1}H NMR: δ ϭ

(60 MHz, CDCl₃): δ ϭ 5.07 (m, 1 H), 3.63 (s, 3 H), 1.68 (br. s, 3

H), 1.58 (br. s, 3 H) ppm.

kugelrohr apparatus (210 °C/1.0 Torr) to give the diol (Ϫ)-21

22

(1.34 g, 54%): [α] ϭ Ϫ19.5 (c ϭ 2.5). HPLC analysis, Chiralcel

D

OD, 10% tBuOH in hexanes, (R)-21 (t_R, 15.64 min): (S)-21 (t_R,

1

16.52 min), 2.26:97.74. H NMR: δ ϭ 1.08 (s, 3 H, Me), 1.14 (s, 3

H, Me), 1.15Ϫ2.22 (m, 4 H, C3-H and C4-H) overlapping 1.40 (s,

9 H, CMe₃), 2.40Ϫ2.51 (m, 2 H, C2-H), 2.60Ϫ3.15 (br. s, 2 H,

C5ϪOH and C6-OH), 3.29 (dd, J ϭ 2.4, 10.1 Hz, 1 H, C5-H) ppm.

¹³C NMR: δ ϭ 22.6 (2), 23.1 (3), 26.3 (3), 29.7 (CMe₃), 30.5 (2),

44.0 (2), 47.8 (CMe₃), 73.0 (C6), 77.8 (C5), 200.8 (CO) ppm.

C₁₂H₂₄O₃S (248.38): calcd. C 58.03, H 9.74; found C 58.04, H 9.84.

Methyl (5S)-5,6-Dihydroxy-6-methylheptanoate (20). Asymmetric

Dihydroxylation of the Unsaturated Ester 18 with (DHQ)₂-PHAL

and OsO₄: The reaction was carried out according to the procedure

of Crispino and Sharpless.^[39]Ester 18 (1.56 g, 10.00 mmol) was

added to a well stirred solution of (DHQ)₂-PHAL (400 mg, 5.0

mol %), K₃Fe(CN)₆(9.90 g, 30 mmol), K₂CO₃(4.2 g, 30 mmol),

and OsO₄(25 mg, 1.0 mol %) in tBuOH/water (l:1, 100 mL) at 0

°C. The mixture was stirred for 8 h, then Na₂SO₃(15 g) was slowly

added, and the suspension was warmed to room temperature. The

product was extracted with dichloromethane (5 ϫ 30 mL). The ex-

tract was dried with and the solvent was evaporated. The residue

was purified by chromatography on silica gel (70 g). Elution of the

column with hexanes/EtOAc, 5:1 and then 1:1 gave the fraction

containing the diol 20 (TLC, EtOAc/hexanes, 1:1, R_fϭ 0.19).

Further elution with hexanes/EtOAc, 1:2 afforded a side product

with the same R_f(0.10) as lactone 14 (TLC, EtOAc/hexanes, 1:1).

The main fraction was distilled in a kugelrohr apparatus (175 °C/

1.5 Torr) to give the diol (Ϫ)-20 (1.06 g, 56%): [α]²_D²ϭ Ϫ22.4 (c ϭ

1.65). ¹H NMR: δ ϭ 1.07 (s, 3 H, Me), 1.12 (s, 3 H, Me), 1.20Ϫ1.98

(m, 4 H, C3-H and C4-H), 2.25Ϫ2.38 (m, 2 H, C2-H), 2.75 (br. s,

1 H, C6-OH), 3.12 (br.d, 1 H, J ϭ 4.1 Hz, C5-OH), 3.22Ϫ3.35 (m,

1 H, C5-H), 3.61 (s, 3 H, OMe) ppm. ¹³C NMR: δ ϭ 21.9 (2), 23.1

(3), 26.2 (3), 30.8 (2), 33.6 (2), 51.4 (OMe), 72.9 (C6), 77.8 (C5),

174.2 (CO) ppm. C₉H₁₈O₄(190.24): calcd. C 56.82, H 9.54; found

C 56.78, H 9.51.

Asymmetric dihydroxylation of the thioester 19 using commercially

available AD-mix-β^[37,38]gave the diol (ϩ)-21 in 73% yield, at least

95% ee by HPLC: [α]²_D²ϭ ϩ21.0 (c ϭ 1.03).

(1E)- and (1Z)-1-(tert-Butylthio)-4-[(4S)-2,2,5,5-tetramethyl-1,3-di-

oxolan-4-yl]-1-trimethylsilyloxy-but-1-ene (28): A solution of LDA

was prepared from diisopropylamine (0.475 mL, 3.63 mmol), and

BuLi (1.35  in hexanes, 2.68 mL, 3.62 mmol) in THF (5 mL) and

cooled to Ϫ78 °C, and a solution of 16 (745 mg, 2.59 mmol) in

THF (2 mL) was added. After 45 min, TMSCl was added

(0.59 mL, 4.68 mmol). The mixture was set aside at room tempera-

ture for 12 h, and then the solvent was evaporated. The residue was

diluted with hexanes (15 mL), and filtered through a pad of Celite.

The solvent was evaporated, and the residue was distilled in a kug-

elrohr apparatus (180 °C/1.0 Torr) to give 28 (867 mg, 93%) as a

mixture of E:Z isomers in a ratio of 89:11 (as determined by inte-

1

gration of the SCMe₃signals in the H NMR spectrum). Major

Isomer: ¹H NMR: δ ϭ 0.21 (s, 9 H, SiMe₃), 1.08 (s, 3 H, Me), 1.23

(s, 3 H, Me), 1.32 (s, 3 H, Me), 1.37 (s, 9 H, CMe₃), 1.41 (s, 3 H,

Me), 1.28Ϫ1.80 (m, 2 H), 2.24Ϫ2.42 (m, 2 H, C3-H), 3.64Ϫ3.75

(m, 1 H, CHOϪ), 5.23 (tr, 1 H, J ϭ 7.4 Hz, C2-H) ppm. ¹³C NMR:

δ ϭ 0.3 (SiMe₃), 22.8, 26.0, 26.5, 26.7, 28.5, 29.7, 31.7 (CMe₃), 46.3

(CMe₃), 80.1 (C5Ј), 82.6 (C4Ј), 106.4 (OϪCϪO), 119.5 (C2), 145.9

(C1) ppm. Minor isomer: ¹H NMR: δ ϭ 0.22 (s, SiMe₃), 1.33 (s,

The diol (5S)-(Ϫ)-20, over 95% ee, was also obtained from the un-

saturated ester 18 in 76% yield using commercially available AD-

mix α and the reported procedure.^[37,38]The crude product con-

sisted of the diol 18 and the lactone 14 in a ratio of 89:11.

Eur. J. Org. Chem. 2004, 783Ϫ799

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

791

E. Gorobets, V. Stepanenko, J. Wicha

CMe₃) ppm. ¹³C NMR: δ ϭ 31.4 (CMe₃) ppm. C₁₈H₃₆O₃SiS: calcd. 44 was obtained as described above for its homologue using: diiso-

FULL PAPER

C 59.95, H 10.06; found C 59.71, H 10.21.

propylamine (0.84 mL, 6.42 mmol), BuLi (2.23  in hexanes,

2.85 mL, 6.36 mmol) in THF (10 mL), then the thioester 24

(1.551 g, 5.66 mmol) in THF (4 mL) and then TMSCl (1.10 mL,

8.71 mmol). The crude product was distilled in a kugelrohr appar-

atus (210 °C/1.5 Torr) to give 44 (1.86 g, 95%) as a mixture of E:Z

isomers in a ratio of 85:15 (as determined by integration of the

SCMe₃signals in the H NMR spectrum). (E) Isomer: H NMR:

δ ϭ 0.20 (s, 9 H, SiMe₃), 1.10 (s, 3 H, Me), 1.23 (s, 3 H, Me), 1.29

(s, 3 H, Me) 1.35 (s, 9 H, CMe₃), 1.38 (s, 3 H, Me), 2.21Ϫ2.62 (m,

2 H, C3-H), 3.62 (dd, J ϭ 7.9, 5.6 Hz, 1 H, C4Ј-H), 5.25 (dd, J ϭ

8.3, 6.4 Hz, 1 H, C2-H) ppm. ¹³C NMR: δ ϭ 0.3 (SiMe₃) 23.0,

26.2, 26.8, 28.5, 29.5 (C3), 31.7 (CMe₃), 46.3 (CMe₃), 79.4 (C2Ј),

82.9 (C4Ј), 116.4 (C5Ј), 115.9 (C2), 146.9 (C1) ppm. (Z) Isomer: ¹H

NMR: δ ϭ 0.22 (s, SiMe₃), 1.32 (s, CMe₃) ppm. C₁₇H₃₄O₃SSi

(346.60): calcd. C 58.91, H 9.89; found C 58.87, H 10.08.

Ethyl 5-Methylhex-4-enoate (22): A solution of tBuOK (6.72 g,

60.0 mmol) in THF (50 mL) was added dropwise to a stirred sus-

pension of (3-ethoxycarbonylpropyl)triphenylphosphonium bro-

mide^[58](25.0 g, 54.7 mmol) in dry THF (70 mL) at 0 °C. After

30 min, dry acetone (4.77 mL, 65.0 mmol) was added, and the mix-

ture was warmed to room temperature. Stirring was continued for

4 h, and then the solvent was evaporated. Water (100 mL) and hex-

anes (100 mL) were added to the residue. The solid was filtered off

and washed with hexanes (3 ϫ 20 mL). The layers were separated.

The aqueous layer was washed with hexanes (3 ϫ 20 mL). The

combined organic extracts were dried, and the solvent was evapo-

rated. The residue was distilled and fractions boiling at 83Ϫ87 °C/

16 Torr were collected. Ester 22 was obtained (5.92 g, 69%). ¹H

NMR: δ ϭ 1.22 (tr, 3 H, J ϭ 7.1 Hz, OCH₂CH₃), 1.59 (s, 3 H, Cϭ

C-Me-trans), 1.65 (s, 3 H, CϭC-Me-cis), 2.25Ϫ2.31 (m, 4 H, C2-

H and C3-H), 4.10 (q, J ϭ 7.1 Hz, 2 H, OCH₂CH₃), 4.98Ϫ5.12

(m, 1 H, C4-H) ppm, in agreement with those reported.^{[40] 13}C

NMR: δ ϭ 14.2 (OCH₂CH₃), 17.6 (3), 23.6 (C3), 25.6 (3), 27.3

(C3), 34.4 (C2), 60.1 (OCH₂CH₃), 122.4 (C4), 132.8 (C5), 173.3

(CϭO) ppm.

1

S-tert-Butyl 3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]propanethioate

(27):

Methyl

3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]propano-

ate^[42,43](26), [α]²_D⁸ϭ Ϫ2.6 (c ϭ 5.34) (97% ee) was transformed

into 27 as described above for its homologues. The reagents were

used as follows: 26 (6.5 g, 35 mmol) in dichloromethane (15 mL),

trimethylaluminium (2  solution in hexanes, 35 mL 70 mmol),

tBuSH (7.9 mL, 70 mmol) and dichloromethane (50 mL). Thioester

27 was obtained (4.0 g, 47%): [α]²_D⁸ϭ Ϫ1.15 (c ϭ 4.84) (at least

97% ee by HPLC, Chiralcel OD-H column, hexanes/iPrOH, 320:1,

t_R27 and its enantiomer 8.55 and 9.30 min, respectively). ¹H

NMR: δ ϭ 1.36 and 1.30 (2s, 6 H, Me₂C), 1.42 (s, 9 H, Me₃C),

1.85 (m, 2 H, C3-H), 2.54 (m, 2 H, C2-H), 3.49 (dt, J ϭ 7.8, 1.1

Hz, 1 H, CHOϪ), 3.94Ϫ4.12 (m, 2 H, CH₂OϪ) ppm. ¹³C NMR:

δ ϭ 25.62 and 26.91 (Me₂C). 29.11 (C3), 29.79 (Me₃C), 40.52 (C2),

47.91 CMe₃), 69.0 (C5Ј), 74.82 (C4Ј), 108.85 (OϪCϪO), 199.40

(CϭO) ppm. C₁₂H₂₂O₃S (246.37): calcd. C 58.50, H 9.00; found C

58.31, H 9.02.

(5S)-5-(1-Hydroxy-1-methylethyl)dihydrofuran-2(3H)-one (23): This

compound was obtained from unsaturated ester 22 (1.56 g,

10.00 mmol) following the general procedure^[38]using AD-mix-α

(14 g) in tBuOH/H₂O (1:1) 100 mL, and then Na₂SO₃(15 g). The

reaction was carried out at room temperature for 6 h. The product

was extracted with dichloromethane (5 ϫ 30 mL). The crude mate-

rial was purified by chromatography on silica gel (50 g, hexanes/

iPrOH, 10:1, 3:1) and then distilled in a kugelrohr apparatus (150

°C/2.5 Torr) to give the lactone 23 (1.01 g, 70%): [α]²_D²ϭ ϩ41.4

1

(c ϭ 2.0). H and ¹³C NMR spectra were in agreement with those

recorded for racemic material.^[41]

(1E)- and (1Z)-1-(tert-Butylthio)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-

4-yl]-1-(trimethylsilyloxy)prop-1-ene (58): A solution of LDA in

THF was prepared from BuLi (2.2  in hexanes, 2.47 mL,

5.44 mmol) and (iPr)₂NH (0.77 mL, 5.5 mmol) in THF (6 mL) and

cooled to Ϫ78 °C. A solution of the thioester 27 (1.0 g, 4.07 mmol)

in THF (2 mL) was added, followed, after 45 min, by Me₃SiCl

(0.86 mL, 6.8 mmol). The mixture was left at room temperature for

12 h. The solvent was evaporated, and the residue was dissolved in

hexanes (30 mL) and filtered through a pad of Celite (2 g). The

filtrate was concentrated and the residue was distilled in a kugel-

rohr apparatus (150 °C/0.1 Torr) to give the ketene acetal 58

(1.09 g, 84% yield) as a mixture of (E) and (Z) isomers in a ratio

of 82:18 (as determined by integration of the SCMe₃signals in the

S-tert-Butyl 3-[(4S)-2,2,5,5-Tetramethyl-1,3-dioxolan-4-yl]propane-

thioate (24): tBuSH (2.93 mL, 26.00 mmol) was added dropwise

to a solution of trimethylaluminium (2.0  in heptane, 12.94 mL,

25.88 mmol) in dichloromethane (30 mL) at 0 °C. The mixture was

stirred at room temperature for 30 min, and then a solution of the

lactone 23 (1.49 g, 10.35 mmol) in dichloromethane (8 mL) was ad-

ded. After 18 h, the mixture was poured into 10% aqueous tartaric

acid, and the product was extracted with dichloromethane (6 ϫ

15 mL). The extract was dried and the solvents evaporated. The

residue was dissolved in 2,2-dimethoxypropane (10 mL), and TsOH

(10 mg) was added. The mixture was stirred for 15 h, and then tri-

ethylamine (0.5 mL) was added, and the solution was filtered

through a pad of silica gel (2 g). The silica gel was washed with

Et₂O and the filtrates were evaporated. The residue was purified by

chromatography on a silica gel column (50 g, hexanes/EtOAc,

15:1). The main fraction was distilled in a kugelrohr apparatus (160

°C/1.5 Torr) to give the thioester 24 (1.70 g, 60%): [α]²_D²ϭ Ϫ9.6

(c ϭ 2.2). HPLC analysis (Chiralcel OD column, 10% tBuOH in

hexanes, showed enantiomeric ratio of 2.17:97.83 (t_R, 7.01 and

1

¹H NMR spectrum). H NMR: δ ϭ 0.20 (s, 9 H, SiMe₃), 1.33 (s,

3 H, C2Ј-Me), 1.34 (s, 9 H, CMe₃), 1.40 (s, 3 H, C2Ј-Me), 2.50 (m,

2 H, C3-H), 3.56 (m, 1 H, CHOϪ), 4.0 (m, 2 H, CH₂OϪ), 5.17 (t,

J ϭ 7.5 Hz, 1 H, C2-H) ppm. ¹³C NMR: δ ϭ 0.32 (SiMe₃) 25.67

and 26.87 (O₂CMe₂), 31.74 (CMe₃), 33.13 (C3), 46.72 (CMe₃),

68.65 (C5), 75.68 (C4), 108.69 (OϪCϪO), 114.27 (C2), 147.64 (C1)

1

ppm. (Z)-Isomer: H NMR: δ ϭ 0.19 (s, 9 H, SiMe₃), 1.32 (s, 9 H,

1

CMe₃) ppm. ¹³C NMR: δ ϭ 0.83 (SiMe₃), 31.11 (CMe₃), 31.40

(CMe₃), 46.0, 69.03 (C5Ј), 75.18 (C4Ј), 118.9 (C2), 145.50 (C1)

ppm.

7.83 min) which corresponds to 95.7% ee. H NMR: δ ϭ 1.03 (s, 3

H, Me), 1.18 (s, 3 H, Me), 1.25 (s, 3 H, Me), 1.34 (s, 3 H, Me),1.40

(s, 9 H, CMe₃), 1.59Ϫ1.80 (m, 2 H, C3-H), 2.39Ϫ2.76 (m, 2 H, C2-

H), 3.50Ϫ3.67 (m, 1 H, CHOϪ) ppm. ¹³C NMR: δ ϭ 22.8, 22.9

(C3), 25.8, 26.7, 28.4, 29.7 (CMe₃), 41.7 (C2), 47.8 (CMe₃), 80.0

(C4Ј), 82.(C5Ј), 106.7 (C2Ј), 199.6 (C1) ppm. C₁₄H₂₆O₃S (274.42):

calcd. C 61.27, H 9.55; found C 61.18, H 9.81.

S-tert-Butyl (2R)-[(1R,2R)-3-Oxo-2-(3-oxo-4-phenylthiobutyl)cyclo-

pentyl]-4-[(4S)-2,2,5,5-tetramethyl-1,3-dioxolan-4-yl]butanethioate

(29) and S-tert-Butyl (2S)-[(1S,2S)-3-Oxo-2-(3-oxo-4-phenylthiobu-

tyl)cyclopentyl]-4-[(4S)-2,2,5,5-tetramethyl-1,3-dioxolan-4-yl]but-

anethioate(30): A solution of 28 (984 mg, 2.73 mmol) in dichloro-

(1E)- and (1Z)-1-(tert-Butylthio)-3-[(4S)-2,2,5,5-tetramethyl-1,3-di-

oxolan-4-yl]-1-(trimethylsilyloxy)prop-1-ene (44): The ketene acetal methane (3 mL) was added to a solution of 2-methyl-2-cyclopent-

792  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org

Eur. J. Org. Chem. 2004, 783Ϫ799

Synthesis of Vitamin D trans-Hydrindane Rings

1-one (10) (0.29 mL, 2.96 mmol) and TrSbCl₆(107 mg, 0.19 mmol, 106.5 (OϪCϪO), 125.1 (C4Ј), 125.3 (C-p), 127.0 (2C-m), 128.5 (2C-

FULL PAPER

7%) in dichloromethane (10 mL) at Ϫ78 °C. The mixture was

stirred at Ϫ78 °C for 1 h, and then a solution of 1-(phenylthio)but-

o ), 135.9 (C-ipso), 184.8 (C3Јa), 193.3 (C5Ј), 203.1 (C1) ppm.

HRMS calcd. for C₂₈H₄₀O₄S₂[M^ϩ]: 544.269562; found

3-en-2-one (9) (534 mg, 3.00 mmol) in dichloromethane (2 mL) was 544.268098. Calcd. for C₂₈H₃₈O₃S₂[M Ϫ Me]^ϩ: 486.22623; found

added. Stirring at Ϫ78 °C was continued for 3 h, then the mixture

was warmed to room temperature, and, after 30 min, the reaction

was quenched with water (0.5 mL). Na₂SO₄(5 g) was added, and

the mixture was filtered through a pad of Celite. The solvent was

evaporated, and the residue was purified by chromatography on

silica gel (140 g, hexanes/EtOAc, 30:1, 3:1) to give a mixture of 29

and 30 (850 mg, 55%) as an oil. The ratio of isomers 30 (t_R,

23.38 min) and 29 (t_R, 24.11 min) was determined to be 24:76 by

HPLC (Nucleosil 50:5µm, hexanes/EtOAc, 83:17). After a few

days, the mixture partly crystallized. Cold methanol was then ad-

ded, and crystals were collected. Recrystallization of this material

from methanol gave 29 (410 mg); m.p. 103 °C. [α]²_D²ϭ ϩ8.4 (c ϭ

529.244623.

(3R)-3-[(1R,3aR,4R,7aR)-7a-Methyl-4-(phenylsulfonyl)octahydro-

1H-inden-1-yl]-1-[(4S)-2,2,5,5-tetramethyl-1,3-dioxolan-4-yl]butane

(35): a. DIBALH (1  in hexanes, 4.5 mL) was added to a solution

of 31 (410 mg, 0.75 mmol) in dichloromethane (15 mL) at Ϫ78 °C.

The mixture was stirred at room temperature for 5 h, and poured

into 10% tartaric acid. The product was extracted with dichloro-

methane. The solvent was evaporated. The residue was dissolved in

dichloromethane (10 mL), and triethylamine (2 mL) and DMAP

(20 mg) were added. The solution was cooled to Ϫ25 °C, and TsCl

(432 mg, 2.26 mmol) in dichloromethane (2 mL) was added drop-

wise. The mixture was stirred at room temperature for 9 h, and the

solvent was evaporated. The residue was purified by chromatogra-

phy on silica gel (30 g, hexanes/EtOAc, 10:1, 4:1). Fractions with

R_fϭ 0.25Ϫ0.5 (TLC, hexanes/EtOAc, 1:1) were collected. This

product was dissolved in dichloromethane (12 mL), and the solu-

tion was cooled to 0 °C. mCPBA (70%, 450 mg, 1.83 mmol) was

added, and the mixture was stirred at room temperature for 1 h,

and then poured into 10% Na₂S₂O₃. The product was extracted

with dichloromethane. The extract was washed with water and the

solvent was evaporated. The residue was dissolved in THF (5 mL),

and LiAlH₄(1  in THF, 7 mL, 7.00 mmol) was added. The solu-

tion was heated at the reflux temperature for 25 min. After cooling,

methanol (2 mL) was added, and the mixture was poured into 10%

tartaric acid. The product was extracted with dichloromethane. The

extract was washed with water and dried. The solvent was evapo-

rated and the residue was purified by chromatography on silica gel

(6 g). Elution with hexanes/EtOAc, 20:1, 5:1 gave compound 35

(125 mg, 36%). Further elution with hexanes/EtOAc, 3:1 afforded

36 (56 mg, 16%). 35: M.p. 57Ϫ58 °C (pentane). [α]²_D⁷ϭ ϩ3.4 (c ϭ

1

2.0). IR (film): ν˜ ϭ 1741, 1703, 1676 cm^Ϫ1. H NMR: δ ϭ 0.99 (s,

3 H, Me), 1.07 (s, 3 H, Me), 1.22 (s, 3 H, Me), 1.32 (s, 3 H, Me),

1.40 (s, 9 H, CMe₃), 1.41 (s, 3 H, Me), 3.64 (s, 2 H, CH₂ϪS),

3.51Ϫ3.68 (m, 1 H, CHOϪ), 7.12Ϫ7.39 (m, 5 H, SPh) ppm. ¹³C

NMR: δ ϭ 18.6, 22.8, 22.9, 26.0, 26.8, 28.4, 29.1, 29.4 (CMe₃),

35.7, 36.5, 43.5, 43.9, 48.8, 51.1, 54.4, 80.0, 83.3, 106.6 (OϪCϪO),

126.6, 128.9 (2 C-m), 129.7 (2 C-o), 134.8, 203.3, 204.3, 221.0 ppm.

C₃₁H₄₆O₅S₂: calcd. C 66.16, H 8.24; found C 66.15, H 8.33.

X-ray Analysis: A sample was crystallized from methanol, initially

at 20 °C and then at 0 °C. A colorless crystal measuring 0.035 ϫ

0.28 ϫ 0.7 mm was used. Crystal data: monoclinic, space group

˚

P2₁, a ϭ 11.1535, b ϭ 6.353(1), c ϭ 22.036(4) A, β ϭ 96.79(1)°,

3

V ϭ 1603.5(5) A , Z ϭ 2, d_calcd.ϭ 1.17 g/cm³. Diffraction data

˚

were collected using an MCH3 diffractometer, Cu-K_αradiation, ω/

2θ scan mode to θ_max.ϭ 64.5°. The structure was solved using

direct method program SHELXs.^[59]The program SELXL-93^[60]

was used for refinement of the structure, which converged to R₁ϭ

0.0419, wR₂ϭ 0.1054 for reflection with [I Ն σ(I)], and R₁

ϭ

1

1.0). H NMR: δ ϭ 0.68 (s, 3 H, C7Јa-Me), 0.92 (d, J ϭ 6.4 Hz, 3

0.0445, wR₂ϭ 0.1149, and GoodF ϭ 1.05 for all 2134 data and

H, C4-H), 1.06 (s, 3 H, Me), 1.22 (s, 3 H, Me), 1.30 (s, 3 H, Me),

1.38 (s, 3 H, Me), 3.01 (br. td, 1 H, J ϭ 11.3, 3.1 Hz, CHϪSO₂),

3.54Ϫ3.63 (m, 1 H, CHOϪ), 7.46Ϫ7.68 (m, 3 H, H-o and -p Ph),

7.78Ϫ7.91 (m, 2 H, H-m Ph) ppm. ¹³C NMR: δ ϭ 11.8 (C7Јa-Me),

18.6, 21.1, 22.8, 25.3, 25.8, 26.2, 26.8, 27.3, 27.8, 28.5, 32.8, 35.5,

38.7, 44.6 (C3Јa), 48.1, 54.8, 63.7, 80.0 (C4ЈЈ), 83.9 (C5ЈЈ), 106.2

(OϪCϪO), 128.6 (C-o), 128.9 (C-m), 133.3 (C-p), 138.3 (C-ipso)

ppm. MS EI (70): m/z (%) ϭ 447 (85) [M Ϫ Me]^ϩ, 405 (6), 263

(61), 245 (100), 135 (45), 109 (42), 95 (50). C₂₇H₄₂O₄S (462.70):

calcd. C 70.09, H 9.15; found C 70.10, H 9.40.

343 variables.

Crystallographic data for 29 has been deposited with the Cam-

bridge Crystallographic Data Centre, the deposition No. CCDC-

219369. Copies of these data can be obtained, free of charge, on

application to CCDC, 12 Union Road, Cambridge CB2 1EZ UK.

Fax: (internat.) ϩ44(0)-1223-336033 or E-mail: deposit@ccdc.cam-

.ac.uk. CD measurements, vide infra.

After crystallization of 29, the mother liquors were evaporated. A

crystalline material was collected and identified as a 1:1 mixture of

29 and 30, m.p. 69Ϫ70 °C.

(3S,6R)-3-Isopropoxy-2-methyl-6-[(1R,3aR,4R,7aR)-7a-methyl-4-

(phenylsulfonyl)octahydro-1H-inden-1-yl)heptan-2-ol (36): M.p. 119

°C (benzene/pentane, 1:5). [α]²_D⁵ϭ ϩ10.3 (c ϭ 1.0). IR (film): ν˜ ϭ

1

30: H NMR: δ ϭ (resolved signals) 1.26 (s, 3 H, Me), 1.34 (s, 3

H, Me), 3.61Ϫ3.71 (m, 1 H, CHOϪ) ppm. ¹³C NMR: δ ϭ 42.8,

53.4 (CMe₃), 82.2, 202.4 ppm.

1

3580, 1149 cm^Ϫ1. H NMR: δ ϭ 0.66 (s, 3 H, C7Јa-Me), 0.88 (d,

J ϭ 6.4 Hz, 3 H, C7-H), 1.13 (d, J ϭ 6.1 Hz, 6 H, O-CHMe₂),

1.14 (s, 6 H, CMe₂OH), 2.15Ϫ2.45 (br. s, 1 H, OH), 2.85Ϫ3.18 (m,

2 H, CHOϪ and CHSO₂), 3.67 (sept., 1 H, J ϭ 6.1 Hz,

OϪCHMe₂), 7.45Ϫ7.66 (m, 3 H, H-o and -p Ph), 7.74Ϫ7.92- (m,

2 H, H-m Ph) ppm. ¹³C NMR: δ ϭ 11.8 (C7Јa-Me), 18.7, 21.0,

22.4, 23.2, 24.6, 25.3, 26.7, 27.2, 27.8, 28.0, 33.3, 35.9, 38.6, 44.5

(C3Јa), 48.0, 54.8, 63.6, 71.8, 72.9 (OϪCHMe₂), 84.4 (C2), 128.6

(C-o ), 128.8 (C-m), 133.3 (C-p), 138.2 (C-ipso) ppm. C₂₇H₄₄O₄S

(464.71): calcd. C 69.79, H 9.54; found C 69.86, H, 9.65.

S-tert-Butyl

(2R)-2-[(1R,7aR)-7a-Methyl-5-oxo-4-phenylthio-

2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-4-[(4S)-2,2,5,5-tetramethyl-

1,3-dioxolan-4-yl]butanethioate (31): KOH in methanol (30%,

0.5 mL) was added to a solution of 29 (610 mg, 1.09 mmol) in

methanol (20 mL). The mixture was set aside at room temperature

for 1 h, and the solvent was evaporated. The residue was purified

by chromatography on silica gel (100 g, hexanes/EtOAc, 30:1, 10:1,

1

4:1) to give 31 (500 mg, 84%): [α]²_D²ϭ ϩ40.5 (c ϭ 2.0). H NMR:

δ ϭ 1.03 (s, 3 H, Me), 1.17 (s, 3 H, Me), 1.19 (s, 3 H, Me), 1.27 (s,

3 H, Me), 1.36 (s, 3 H, Me), 1.44 (s, 9 H, CMe₃), 2.38Ϫ2.85 (m, 5 b. mCPBA (70%, 953 mg, 3.870 mmol) was added to a solution of

H), 3.50Ϫ3.60 (m, 1 H, CHOϪ), 6.98Ϫ7.21 (m, 5 H, SPh) ppm. tosylate 37 (792 mg, 1.290 mmol) in dichloromethane (20 mL) at 0

¹³C NMR: δ ϭ 16.5, 22.8, 25.9, 26.0, 26.6, 26.7, 28.4, 29.4 (CMe₃), °C. The mixture was stirred at room temperature for 2 h, and then

30.0, 30.3, 33.9, 34.4, 47.1, 48.6, 52.4, 54.3, 79.9 (C5ЈЈ), 83.2 (C4ЈЈ), poured into saturated aqueous NaHCO₃. The product was ex-

Eur. J. Org. Chem. 2004, 783Ϫ799

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

793

E. Gorobets, V. Stepanenko, J. Wicha

FULL PAPER

tracted with dichloromethane (3 ϫ 15 mL). The organic extract

33: M.p. 112 °C (benzene/hexanes, 1:1). [α]²_D⁷ϭ ϩ203.7 (c ϭ 1.0).

was washed with saturated aqueous Na₂SO₃and water, and the ¹H NMR: δ ϭ 1.03 (s, 3 H, C7Јa-Me), 1.10 (s, 3 H, Me), 1.25 (s,

solvent was evaporated. The residue was dissolved in THF (25 mL),

3 H, Me), 1.33 (s, 3 H, Me), 1.41 (s, 3 H, Me), 2.24 (br. s, 1 H,

and LiAlH₄(343 mg, 9.030 mmol) was added. The mixture was OH), 2.35Ϫ2.76 (m, 4 H), 3.57Ϫ3.83 (m, 3 H, C4ЈЈ- and C4-H),

heated under reflux for 20 min. After cooling, methanol (4.5 mL)

was added, and then the mixture was poured into 10% aqueous

tartaric acid. The product was extracted with dichloromethane (3

ϫ 15 mL). The organic extract was evaporated and the residue was

3.93Ϫ4.04 (br. s, 1 H, C5Ј-H), 7.09Ϫ7.37 (m, 5 H, SPh) ppm. ¹³C

NMR: δ ϭ 17.2 (C7Јa-Me), 22.9 (3), 25.2 (2),. 25.6 (2), 26.0 (3),

26.0 (2), 26.8 (3), 27.8 (2), 27.9 (2), 28.5 (3), 30.9 (2), 35.1 (2), 41.0

(3), 46.0 (C7Ј), 50.6 (C3), 62.4 (C4), 66.1 (C5Ј), 80.2 (C3), 83.9

purified by chromatography on silica gel (100 g, hexanes/EtOAc, (C1), 106.4 (OϪCϪO), 122.3 (C4Ј), 125.5 (C-p), 127.6 (C-m), 128.9

20:1, 3:1). Sulfone 35 was obtained (429 mg, 72%), which was

identical to the sample described above.

(C-o), 135.8 (C-ipso), 162.5 (C3Јa) ppm. MS EI (70): m/z (%) ϭ

460 (100) [M^ϩ], 445 (43) [M Ϫ CH₃]^ϩ, 427 (4) [M Ϫ CH₃Ϫ H₂O]^ϩ,

383 (49), 351 (16), 257 (24), 171 (32), 85 (3). C₂₇H₄₀O₄S (460.68):

calcd. C 70.40, H 8.74; found C 70.27, H 8.75.

c. LiAlH₄(97 mg, 2.663 mmol) was added to a solution of enone

31 (279 mg, 0.513 mmol) in THF (10 mL). The mixture was heated

under reflux for 40 min, then cooled, and the reaction was

quenched with methanol (1 mL). Workup with 10% tartaric acid

solution and extraction with dichloromethane (3 ϫ 15 mL) gave

the crude product, which was purified by chromatography on silica

gel (100 g, hexanes/EtOAc, 20:1, 2:1) to give the diol 32 (172 mg,

73%) and the diol 33 (35 mg, 15%), identical to the respective

samples prepared by other methods (vide infra). The crude product

from an analogous reduction (340 mg, 0.783 mmol) was added to

a dichloromethane (4 mL) solution of triethylamine (1.5 mL) and

DMAP (10 mg). The solution was cooled to Ϫ20 °C, and TsCl

(187 mg, 0.981 mmol) in dichloromethane (1 mL) was added. The

mixture was stirred at room temperature for 12 h, and then poured

into water. The product was isolated by extraction with dichloro-

methane and purified by chromatography on silica gel (30 g, hex-

anes/EtOAc, 10:1, 4:1) to give tosylates 37 and its epimer (418 mg,

87%) in a ratio of 5:1 (determined by ¹H NMR spectroscopy). This

product was dissolved in dichloromethane (10 mL). The solution

was cooled to 0 °C and mCPBA (70%, 503 mg, 2.043 mmol) was

added. The mixture was stirred at room temperature for 1 h, and

then poured into aqueous NaHCO₃. The product was isolated by

extraction with dichloromethane, dissolved in THF (12 mL) and

treated with LiAlH₄(152 mg, 4.00 mmol). The mixture was heated

under reflux for 25 min, then cooled, and the reaction was

quenched with methanol (2 mL). Work-up as described above gave

the crude product which was purified by chromatography on silica

gel (6 g, hexanes/EtOAc, 20:1, 5:1) to give sulfone 35 (219 mg,

70%), identical to the sample described above.

32: [α]²_D⁶ϭ Ϫ85.3 (c ϭ 2.7). ¹H NMR: δ ϭ 1.06 (s, 3 H, C7Јa-Me),

1.08 (s, 3 H, Me), 1.23 (s, 3 H, Me), 1.31 (s, 3 H, Me), 1.39 (s, 3

H, Me), 2.73 (br. s, 1 H, OH), 3.56Ϫ3.77 (m, 3 H, C4- and C4ЈЈ-

H), 4.00Ϫ4.15- (m, 1 H, C5Ј-H), 7.06Ϫ7.30 (m, 5 H, SPh) ppm.

¹³C NMR: δ ϭ 17.9 (C7Јa-Me). 22.8 (3), 25.6 (2), 26.0 (3), 26.1

(2), 26.2 (2), 26.8 (3), 28.3 (2), 28.3 (2), 28.5 (3), 35.1 (2), 41.0 (3),

46.0 (C7Јa), 50.8 (C6), 62.5 (C7Ј), 67.8 (C5Ј), 80.1 (C2), 83.8 (C1),

106.4 (OϪCϪO), 124.1 (C4Ј), 125.6 (C-p), 127.5 (C-m), 128.9 (C-

o), 134.9 (C-ipso), 162.2 (C3Јa) ppm. MS EI (70): m/z (%) ϭ 460

(100) [M^ϩ], 445 (39) [M Ϫ CH₃]^ϩ, 427 (3) [M Ϫ CH₃Ϫ H₂O]^ϩ,

383 (46), 257 (17), 171 (21), 85 (53). HRMS calcd. for C₂₇H₄₀O₄S

[M^ϩ]: 460.26473; found 640.26543.

(3R)-3-[(1R,5S,7aR)-5-Hydroxy-7a-methyl-4-(phenylsulfonyl)-

2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-1-[(4S)-2,2,5,5-tetramethyl-

1,3-dioxolan-4-yl]-4-tosyloxybutane (37): Diol 32 (830 mg,

1.804 mmol) and DMAP (15 mg) were dissolved in a mixture of

dichloromethane (7.5 mL) and triethylamine (2.5 mL), and cooled

to Ϫ20 °C. A solution of TsCl (477 mg, 2.435 mmol) in dichloro-

methane (5 mL) was added. The mixture was stirred at 0 °C for

12 h, and then at room temperature for 6 h, and then poured into

water. The product was extracted with dichloromethane (3 ϫ

15 mL). The extract was washed consecutively with 3.5% aqueous

HCl, saturated aqueous NaHCO₃and water, and then dried. The

solvent was evaporated, and the residue was purified by chromatog-

raphy on silica gel (100 g, hexanes/EtOAc, 10:1, 2:1). Tosylate 37

1

was obtained (986 mg, 89%): [α]²_D⁴ϭ Ϫ58.6 (c ϭ 2.18). H NMR:

δ ϭ 0.96 (s, 3 H, Me), 0.97 (s, 3 H, Me), 1.16 (s, 3 H, Me), 1.28 (s,

3 H, Me), 1.36 (s, 3 H, Me), 2.42 (s, 3 H, Ph-Me), 2.65 (s, 1 H,

OH), 3.44Ϫ3.55 (m, 1 H, C4ЈЈ-H), 3.94Ϫ4.18 (m, 3 H, C4- and

C5Ј-H), 7.09Ϫ7.32 (m, 5 H, SPh), 7.33 (d, J ϭ 8.2 Hz, 2 H, H-m

Ts), 7.79 (d, J ϭ 8.2 Hz, 2 H, H-o Ts) ppm. ¹³C NMR: δ ϭ 17.8

(C7Јa-Me), 21.6 (3), 22.6 (3), 25.9 (3), 26.0 (2), 26.1 (2), 26.7 (2),

26.8 (3), 28.1 (2), 28.2 (2), 28.5 (3), 34.8 (2), 38.5 (1), 45.9 (C7Јa),

50.3 (1), 67.4 (C4), 70.0 (C5Ј), 79.9 (C5ЈЈ), 83.5 (C4ЈЈ), 106.4

(OϪCϪO), 124.7 (C4), 125.7 (C-p, Ph), 127.6 (C-m, Ph or Ts),

127.9 (C-m, Ts or Ph), 129.0 (C-o , Ph), 129.7 (C-o , Ts), 132.6 (C-

p, Ts), 134.7 (C-ipso, Ph), 144.8 (C-ipso, Ts), 161.1 (C3Јa) ppm. MS

EI (70): m/z (%) ϭ 614 (19) [M^ϩ], 599 (9) [M Ϫ CH₃]^ϩ, 581 (2) [M

Ϫ CH₃Ϫ H₂O]^ϩ, 307 (8), 257 (17), 43 (100). HRMS calcd. for

C₃₄H₄₆O₆S₂[M^ϩ]: 614.27358; found 614.27378.

(3R)-4-Hydroxy-3-[(1R,5S,7aR)-5-hydroxy-7a-methyl-4-(phenyl-

sulfonyl)-2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-1-[(4S)-2,2,5,5-

tetramethyl-1,3-dioxolan-4-yl]butane (32) and (3R)-4-Hydroxy-3-

[(1R,5R,7aR)-5-hydroxy-7a-methyl-4-(phenylsulfonyl)-2,3,5,6,7,7a-

hexahydro-1H-inden-1-yl]-1-[(4S)-2,2,5,5-tetramethyl-1,3-dioxolan-

4-yl]butane (33): Powdered NaBH₄(114 mg, 3.000 mmol) was ad-

ded to a stirred solution of the enone 31 (1.386 g, 2.548 mmol) and

CeCl₃·7H₂O (559 mg, 1.500 mmol) in methanol (20 mL) and THF

(10 mL) at Ϫ78 °C. After 1 h, the mixture was warmed to room

temperature, stirred for an additional 1 h and then poured into 10%

aqueous tartaric acid. The product was extracted with dichloro-

methane (3 ϫ 25 mL). The extract was washed with water, dried,

and the solvent was evaporated. The residue was dissolved in THF

(12 mL), and a solution of LiAlH₄(494 mg, 13.00 mmol) in THF

(15 mL) was added. The mixture was heated under reflux for

30 min. After cooling, methanol (2.5 mL) was added, and the mix-

(3S,6R)-2-Methyl-6-[(1R,3aR,4R,7aR)-7a-methyl-4-(phenyl-

sulfonyl)octahydro-1H-inden-1-yl)heptane-2,3-diol (38): Amberlyst-

15H^(500 mg) was added to a solution of 35 (120 mg, 0.26 mmol)

ture was poured into 10% aqueous tartaric acid. The product was in methanol (5 mL), and the mixture was stirred at room tempera-

extracted with dichloromethane (3 ϫ 20 mL). The extract was

washed with water and dried, and the solvent was evaporated. The

residue was purified by chromatography on silica gel (350 g, hex-

anes/EtOAc, 20:1, 2:1) to give the diol 33 (61 mg, 5%) and diol 32

(1.022 mg, 87%).

ture for 48 h. After this time, the solid was filtered off. The filtrate

was concentrated, and the residue was purified by chromatography

on silica gel (5 g, hexanes/acetone, 10:1, 3:1) to give 38 (89 mg,

81%): m.p. 141 °C (benzene/hexane, 1:2). [α]²_D⁶ϭ Ϫ13.9 (c ϭ 0.6).

¹H NMR: δ ϭ 0.65 (s, 3 H, C7Јa-Me), 0.88 (d, J ϭ 6.5 Hz, 3 H,

794

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 783Ϫ799

Synthesis of Vitamin D trans-Hydrindane Rings

FULL PAPER

C7-H), 1.10 (s, 3 H, Me), 1.16 (s, 3 H, Me), 2.42 (br. s, 1 H, ϪOH), was extracted with dichloromethane. The extract was washed with

2.61 (br. s, 1 H, ϪOH), 3.00 (br. td, J ϭ 11.4, 3.2 Hz, CHϪSO₂), water and the solvent was evaporated. The residue was dissolved

3.22 (br. d, J ϭ 8.3 Hz, 1 H, CHOϪ), 7.46Ϫ7.66 (m, 3 H, H-o in THF (5 mL), and LiAlH₄(1  in THF, 7 mL) was added. The

and -p Ph), 7.76Ϫ7.92 (m, 2 H, H-m Ph) ppm. ¹³C NMR: δ ϭ

solution was heated under reflux for 25 min. After cooling, meth-

11.8, 18.8, 21.0, 23.1, 25.2, 26.4, 27.2, 27.8, 28.0, 33.1, 35.6, 38.7 anol (1.5 mL) was added, and the mixture was poured into 10%

(C7Јa) 44.5, 48.0, 54.8, 63.6, 73.0 (C2), 79.2 (C3), 128.5 (C-m), tartaric acid. The product was extracted with dichloromethane. The

128.8 (C-o ), 133.3 (C-p), 138.1 (C-ipso) ppm. C₂₄H₃₈O₄S (422.63): extract was washed with water and dried. The solvent was evapo-

calcd. C 68.21, H, 9.06; found C 68.37, H, 8.94.

rated and the residue was purified by chromatography on silica gel

(6 g, hexanes/EtOAc, 20:1, 5:1) to give rac-8 (24 mg, 26% from 39).

This product was identical with a sample prepared before (¹H and

¹³C NMR spectra) but showed no measurable optical rotation.

(6R)-2-Methyl-6-[(1R,3aR,4R,7aR)-7a-methyl-4-(phenylsulf-

onyl)octahydro-1H-inden-1-yl)heptan-2-ol (8): MsCl (0.042 mL,

0.540 mmol) was added to a stirred solution of the diol 38 (180 mg,

0.427 mmol) and triethylamine (1.5 mL) in dichloromethane

(10 mL) at Ϫ20 °C. After 1 h, the mixture was poured into water,

and the product was extracted with dichloromethane. The extract

was washed consecutively with water, 3% HCl and water. The sol-

vent was evaporated. The residue was dissolved in THF (10 mL),

and LiAlH₄(228 mg, 6.00 mmol) was added. The mixture was

heated under reflux for 30 min. After cooling, the reaction was

quenched with methanol (4 mL), and the mixture was poured into

10% tartaric acid. The product was extracted with dichlorometh-

ane. The extract was washed with water and the solvent was evapo-

rated. The residue was purified by chromatography on silica gel

(20 g, hexanes/EtOAc, 20:1, 5:1) to give 8 (151 mg, 87%), identical

with the authentic sample ([α], m.p., NMR).

(3S,6S)-6-tert-Butyldimethylsilyloxy-7,7-dimethyl-3-[(1S,2R)-2-

methyl-3-oxocyclopentyl]oxepan-2-one (42) and (3S,6S)-6-tert-Butyl-

dimethylsilyloxy-7,7-dimethyl-3-[(1S,2S)-2-methyl-3-oxocyclopen-

tyl]oxepan-2-one (43): Ketene acetal 40 (670 mg, 1.79 mmol) was

added to a stirred solution of 10 (0.210 mL, 2.14 mmol) and

TrSbCl₆(87 mg, 0.15 mmol) in dichloromethane (6 mL) at Ϫ78 °C.

After 1 h, the reaction was quenched with pyridinemethanol

(0.250 mL). The mixture was warmed to room temperature, and

water (0.5 mL) and Amberlyst-15H (500 mg) were added. After

48 h, the mixture was filtered through a pad of Celite and Na₂SO₄.

The solvent was evaporated and the residue was purified by chro-

matography on silica gel (80 g, hexanes/EtOAc, 25:1, 4:1). A mix-

ture of isomers 42, 43 and an undefined diastereomer was obtained

as a colourless oil (476 mg, 69%): MS EI (70): m/z (%) ϭ 368 (0.8),

353 (2), 311 (58), 253 (100), 215 (48), 173 (46), 117 (64), 97 (72),

75 (99). HRMS calcd. for C₂₀H₃₆O₄Si [M^ϩ]: 368.23829; found

368.23871. Calcd. for C₁₆H₂₇O₄Si [M^ϩϪ tBu]: 311.16786; found

311.16778. ¹H NMR (500 MHz): δ ϭ 0.90 (d, J ϭ 7.4 Hz), 0.98 (d,

J ϭ 6.5 Hz), 0.99 (d, J ϭ 6.9 Hz) ppm, of relative integration

80:12:8.

S-tert-Butyl (2R,5S)-5,6-Dihydroxy-6-methyl-2-[(1R,7aR)-7a-

methyl-4-(phenylthio)-5-oxo-2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-

heptanethioate and S-tert-Butyl (2S,5S)-5,6-Dihydroxy-6-methyl-2-

[(1S,7aS)-7a-methyl-4-(phenylthio)-5-oxo-2,3,5,6,7,7a-hexahydro-

1H-inden-1-yl]heptanethioate (39): A mixture of 29 and 30 (1:1,

mother liquors after crystallization of 29, see above)(181 mg,

0.322 mmol) was dissolved in methanol (10 mL), and KOH (30%

in methanol, 0.3 mL) was added. After 1 h, 36% HCl (0.5 mL) was

added, and the mixture was set aside for 15 h. After this time, the

bulk of the solvent was evaporated. The residue was filtered

through silica gel (10 g, hexanes/EtOAc, 1:1) to give a mixture of

enones 39 (114 mg, 70%). ¹H NMR: δ ϭ 1.11 (s, 3 H, Me), 1.19

(s, 1.5 H, Me), 1.14 (s, 1.5 H, Me), 1.45 (s, 9 H, CMe₃), 1.21 (s, 3

H, Me), 2.40Ϫ2.88 (m, 5 H), 3.18Ϫ3.47 (m,1 H, C5-H), 6.96Ϫ7.24

(m, 5 H, SPh) ppm. ¹³C NMR: δ ϭ 16.5 (split), 23.0 and 23.1 25.9,

26.0, 26.5, 27.7, 28.7, 29.1, 29.5 (CMe₃), 30.1, 30.5, 34.0, 34.5, 47.2,

48.7 and 48.8, 52.2 and 52.5, 53.4 and 54.6, 73.0 and 73.1 (C6),

77.2 and 78.6 (C5), 125.1 (C4Ј), 125.4 (C-p), 127.1 (2C-m), 128.8

(2C-o ), 135.9 (C-ipso), 185.4 (C3Јa), 193.8 (C5Ј), 203.1 and 203.6

(C1) ppm. HRMS calcd. for C₂₈H₄₀O₄S₂[M^ϩ]: 504.23679; found

504.23746. Calcd. for C₂₈H₃₈O₃S₂[M Ϫ H₂O]^ϩ: 486.22623; found

486.22617.

After standing for a few weeks in a refrigerator, the product solidi-

fied. Pentane was added, crystals were collected and recrystallized

from pentane. Product 42 was obtained: m.p. 104Ϫ105 °C. [α]²_D⁷

ϭ

1

Ϫ29.9 (c ϭ 0.6). H NMR: δ ϭ Ϫ0.01 (s, 3 H, SiMe₂), 0.00 (s, 3

H, SiMe₂), 0.83 (s, 9 H, SiCMe₃), 0.99 (d, J ϭ 6.9 Hz, 3 H, C2Ј-

Me), 1.34 (s, 3 H, Me), 1.43 (s, 3 H, Me), 3.66Ϫ3.75 (m, 1 H, C6-

H) ppm. ¹³C NMR: δ ϭ Ϫ5.2 (SiMe), Ϫ4.4 (SiMe), 13.7 (3), 17.9

(SiCMe₃), 21.4 (2), 23.2 (2), 24.4 (3), 25.6 (SiCMe₃), 28.9 (3), 30.8

(2), 36.8 (2), 46.1 (1), 46.7 (1), 47.6 (1), 73.6 (C6), 82.9 (C7), 173.7

(C2), 220.3 (C3Ј) ppm. C₂₀H₃₆O₄Si (368.59): calcd. C 65.17, H 9.84;

found C 65.16, H 9.88. X-ray analysis has been reported^[53]

1

Isomer 43: H NMR: δ ϭ 0.99 (d, J ϭ 6.9 Hz, C2Ј-Me) ppm. ¹³C

NMR: δ ϭ 73.9 (C6), 174.6 (C2). Minor Isomer: ¹H NMR: δ ϭ

Ϫ0.02 (s), 0.00 (s), 0.90 (d, J ϭ 7.4 Hz, C2Ј-Me), 1.47 (s). ¹³C

NMR: δ ϭ 73.6, 82.6, 174.2 (C2) ppm.

Transformation of 39 into rac-8: The product described above (39)

(114 mg, 0.23 mmol) was dissolved in dichloromethane (8 mL) and

cooled to Ϫ78 °C, and DIBALH (1  in hexanes, 3 mL, 3 mmol)

was added. The mixture was stirred at room temperature for 12 h,

and then poured into 10% tartaric acid. The product was extracted

with dichloromethane (5 ϫ 10 mL). The extract was washed with

brine and the solvent was evaporated. The so-obtained crude tetrol

was dissolved in a mixture of dichloromethane (3.5 mL) and tri-

S-tert-Butyl (2S)-[(1S,2S)--3-Oxo-2-(3-oxo-4-phenylthiobutyl)cyclo-

pentyl]-3-[(4S)-2,2,5,5-tetramethyl-1,3-dioxolan-4-yl]propanethioate

(45): A solution of the ketene acetal 44 (4.58 g, 13.2 mmol) in di-

chloromethane (6 mL) was added dropwise to a stirred solution of

10 (1.47 g, 15.3 mmol) and TrSbCl₆(415 mg, 0.72 mmol) in di-

chloromethane (30 mL) at Ϫ78 °C. After 1 h, 9 (2.2 g, 12.3 mmol)

was added. The mixture was stirred at Ϫ78 °C for 1 h, and then

ethylamine (0.1 mL, 0.712 mmol). The solution was cooled to Ϫ20 warmed to room temperature (over ca. 1 h). The reaction was

°C, and MsCl (0.04 mL, 0.515 mmol) was added. Stirring was con- quenched with 10% aqueous NaHCO₃(2 mL). The mixture was

tinued for 30 min and then the mixture was poured into water. The

product was extracted with dichloromethane. The extract was

washed with 1%HCl and water, and concentrated to ca. 5 mL. This

diluted with hexanes (30 mL) and filtered through a pad of Celite.

The Celite was washed with dichloromethane, and the combined

filtrates were evaporated. The residue was purified by chromatogra-

phy on silica gel (250 g, hexanes/EtOAc, 4:1, 3:1) to give dione 45,

along with two of its diastereomers (5.45 g, 75% yield, isomer ratio:

solution was cooled to

0 °C, and mCPBA (70%, 223 mg,

0.905 mmol) was added. The mixture was stirred at room tempera-

ture for 45 min, and then poured into 10% Na₂S₂O₃. The product 85:11:4 by HPLC, Nucleosil 50:5 µm, hexanes/EtOAc, 3.4:1, t_R

Eur. J. Org. Chem. 2004, 783Ϫ799

www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 795

E. Gorobets, V. Stepanenko, J. Wicha

FULL PAPER

11.3, 10.2, and 9.7 min). A sample of 45 was isolated by preparative

TLC (hexanes:EtOAc, 30:1, 5 developments): [α]²_D²ϭ Ϫ8.2 (c ϭ

1.5). H NMR: δ ϭ 1.05 (s, 3 H, Me) 1.07 (s, 3 H, Me), 1.19 (s, 3

1H-inden-1-yl]dihydrofuran-2(3H)-one (48): A mixture of 49 and its

isomers, prepared as described above (860 mg, 1.62 mmol), was dis-

solved in methanol (25 mL) and Amberlyst-15H^(4.0 g) was ad-

ded. The mixture was stirred at room temperature for 72 h, after

1

H, Me), 1.36 (s, 3 H, Me), 1.43 (s, 9 H, CMe₃), 1.44 (s, 3 H, Me),

3.65 (s, 2 H, CHϪSPh), 3.71Ϫ3.86 (m, 1 H, CHOϪ), 7.12Ϫ7.41 which time, the solid was filtered off and washed with methanol.

(m, 5 H, Ph) ppm. ¹³C NMR: δ ϭ 18.4, 22.2, 22.6, 25.0, 26.3, 28.2, The combined filtrates were evaporated. The residue was purified

28.8, 29.1 (CMe₃), 31.3, 35.5, 36.0, 43.3, 43.5, 48.5 (CMe₃), 51.0, by chromatography on silica gel (45 g, hexane/EtOAc, 1:1) to give:

51.2, 78.7 (CCMe₂OϪ), 79.6 (CHOϪ), 106.5 (OϪCϪO), 126.3 (C-

unchanged 49 (32 mg), 47 (334 mg) and a fraction containing 47

p), 128.7 (C-m), 129.3 (C-o), 134.6 (C-ipso), 203.2, 203.9, 220.7 and 48 (148 mg, in a ratio of 52:48 by HPLC, Nucleosil 50:5µ,

ppm. HRMS calcd. for C₃₀H₄₄O₅S₂[M^ϩ]: 548.26302; found hexane/EtOAc, 1:1, t_Rϭ 21.2 and 22.8 min, respectively). The

548.26535.

mixed fraction was re-purified by chromatography on silica gel

(20 g, hexane/EtOAc, 1:1) to give 47 (58 mg, 63% combined yield),

a mixture 47 and 48 (22 mg, 1:2), and 48 (38 mg, 6% yield, 97%

pure by HPLC).

To 46 (tentative structure, t_Rϭ 10.2 min) the following signal were

assigned. ¹H NMR: δ ϭ 1.34, 1.27, 1.39 ppm. ¹³C NMR: δ ϭ 48.3

(CMe₃), 53.2, 79.8, 80.6, 106.0 (OϪCϪO), 201.2 ppm.

47: [α]²_D⁵ϭ ϩ6.73 (c ϭ 3.25). ¹H NMR: δ ϭ 1.21 (s, 3 H, Me), 1.25

(s, 3 H, Me), 1.35 (s, 3 H, Me),1.70Ϫ1.80 (m, 2 H), 1.85Ϫ1.97 (m,

2 H), 2.09Ϫ2.23 (m, 2 H), 2.34Ϫ2.45 (m, 2 H), 2.56Ϫ2.63 (m, 1

H), 2.67Ϫ2.90 (m, 4 H), 4.28 (dd, J ϭ 6.8, 6.2 Hz, 1 H, CHOϪ),

7.08Ϫ7.13 and 7.18Ϫ7.23 (m, 5 H, Ph) ppm. ¹³C NMR: δ ϭ 17.41

(C7ЈЈa-Me), 24.65 (3), 24.75 (2), 26.28 (3), 26.53 (C2), 30.36 (C2),

33.69 (2), 33.80 (2), 39.53, 46.82 (C7ЈЈa), 50.86, 71.16 (C1Ј), 84.06

(C5), 125.42 (C2), 125.52 (C-p), 127.14 (C-o ), 128.77 (C-m), 135.69

(C-ipso), 178.58 (C2), 184.23 (C3ЈЈa), 193.71 (C5ЈЈ). HRMS: Calcd.

for C₂₃H₂₈O₄S [M^ϩ]: 400.17083; found 400.17203.

48: [α]²_D⁰ϭ ϩ10.8 (c ϭ 1.45). H NMR: δ ϭ (500 MHz) 1.17 (s, 3

1

H, Me), 1.19 (s, 3 H, Me), 1.36 (s, 3 H, Me), 1.74Ϫ1.86 (m, 3 H),

1.98 (dt, J ϭ 13.7, 5.5 Hz, 1 H), 2.16Ϫ2.23 (m, 2 H), 2.30Ϫ2.40

(m, 2 H), 2.56Ϫ2.63 (m, 1 H), 2.57Ϫ2.86 (m, 5 H), 4.23 (dd, J ϭ

7.2, 7.3 Hz, 1 H, C5-H), 7.08Ϫ7.13 and 7.18Ϫ7.23 (m, 5 H, Ph)

ppm. ¹³C NMR: δ ϭ 18.14 (C7ЈЈa-Me); 23.62, 23.87, 26.81, 26.86,

30.66, 33.81, 34.18, 40.07, 46.69 (C7ЈЈa), 50.02, 70.19 (C1Ј), 83.92

(C5), 125.55 (C4ЈЈ), 125.74 (C-p), 127.30 (C-o ), 128.87 (C-m),

135.72 (C-ipso), 177.57 (C2), 183.90 (C3ЈЈa), 193.64 (C5ЈЈ) ppm.

Figure 2. CD spectra of 45 (solid line) and 29 (dashed line)

An analogous reaction in which racemic ketene acetal 44 was used

(prepared from 2,2-dimethylcyclopentan-1,3-dione^[61]) afforded a HRMS Calcd. for C₂₃H₂₈O₄S [M^ϩ]: 400.17083; found 400.17022.

mixture of racemic diketones 45 and 46 in a ratio of 8:1. rac-45:

m.p. 92 °C (methanol). C₃₀H₄₄O₅S₂(548.79): calcd. C 65.66, H

8.08; found C 65.67, H 8.10.

S-tert-Butyl

(2S)-2-[(1S,5R,7aS)-5-Hydroxy-7a-methyl-4-phen-

ylthio-2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-3-[(4S)-2,2,5,5-tetra-

methyl-1,3-dioxolan-4-yl]propanethioate (50): A mixture of enone 49

S-tert-Butyl

2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-4-[(4S)-2,2,5,5-tetramethyl- was dissolved in methanol (15 mL) and THF (10 mL). CeCl₃·7H₂O

1,3-dioxolan-4-yl]propanethioate (49): A mixture of 45 and its dia- (189 mg, 0.51 mmol) was added, and the mixture cooled to Ϫ78

stereomers, prepared as described above (1.64 g, 2.99 mmol), was °C. NaBH₄(75 mg, 1.99 mmol) was added. After 2 h, the mixture

(2R)-2-[(1R,7aR)-7a-Methyl-5-oxo-4-phenylthio- and its isomers, obtained as described above (482 mg, 0.91 mmol),

dissolved in methanol (20 mL), and a solution of KOH (0.15 g)

in methanol (1 mL) was added. The mixture was stirred at room

temperature for 1 h, and then the solvent was evaporated. The resi-

due was purified by chromatography on silica gel (90 g, hexanes/

EtOAc, 4:1) to give a mixture of 49 and two other isomers (1.25 g,

79% overall yield) in a ratio of 86:10:4 by HPLC (‘‘Nucleosil 50:5’’,

hexanes/EtOAc, 12:1, t_Rϭ 43.2, 37.8 and 36.4 min, respectively).

was warmed to room temperature. The reaction was quenched with

10% aqueous tartaric acid (5 mL), and diluted with water. The

product was extracted with dichloromethane (3 ϫ 30 mL). The

combined organic extracts were washed with water and dried, and

the solvent was evaporated. The residue was crystallized from ben-

zene to give 50 (318 mg, Ͼ 99% pure by HPLC, 66% yield). A

sample was recrystallized from benzene: m.p. 186 °C (dec.). [α]²_D⁰

ϭ

1

49: H NMR: δ ϭ 1.03 (s, 3 H, Me), 1.16 (s, 3 H, Me), 1.27 (s, 3

ϩ49.3 (c ϭ 1.45). H NMR: δ ϭ 1.06 (s, 3 H, Me), 1.18 (s, 3 H,

H, Me), 1.34 (s, 3 H, Me), 1.42 (s, 3 H, Me), 1.48 (s, 9 H, CMe₃), Me), 1.37 (s, 3 H, Me), 1.49 (s, 3 H, Me), 1.51 (s, 9 H, CMe₃), 3.79

3.73Ϫ3.79 (m, 1 H, CHOϪ), 7.02Ϫ7.25 (m, 5 H, PhS) ppm. ¹³C

(dd, J ϭ 9.3, 2.5 Hz, 1 H, C4Ј-H), 4.05 (t, J ϭ 7.1 Hz, 1 H, C5ЈЈ-

NMR: δ ϭ 16.63 (C7Јa-Me), 22.45 (3), 25.28 (3), 25.88 (2), 26.58 H), 7.10Ϫ7.35- (m, 5 H, PhS) ppm. ¹³C NMR: δ ϭ 17.76 (C7ЈЈa-

(3), 28.40 (3), 29.45 (CMe₃), 30.35 (2), 32.50 (2), 33.96 (2), 34.51 Me), 22.44, 25.28, 26.59, 27.72, 28.34, 28.41, 29.47 (CMe₃), 32.46,

(2) 47.24 (0), 48.79 (CMe₃), 51.41 (1), 52.69 (1), 79.03 (CHOϪ), 34.18, 46.08, 48.56 (CMe₃), 51.84, 52.96, 67.55, 79.13, 79.92, 106.79

79.85 (CMe₂OϪ), 106.80 (OϪCϪO), 125.11 (C4Ј), 125.31 (C-p), (OϪCϪO), 124.52 (C4ЈЈ), 125.67 (C-p), 127.48 (C-m), 129.0 (C-o

127.01 (C-o), 128.74 (C-m), 135.86 (C-ipso), 184.70 (C3Јa), 193.38

(C5Ј), 203.31 (C1) ppm. HRMS calcd. for C₃₀H₄₂O₄S₂[M^ϩ]:

530.2525; found 530.2534.

), 134.71 (C-ipso), 161.33 (C3ЈЈa), 203.91 (C1) ppm. C₃₀H₄₄O₄S₂

(532.81): calcd. C 67.63, H 8.32; found C 67.58, H 8.41. X-ray

analysis of this compound has been reported.^[53]

(3S,5S)-5-(1-Hydroxy-1-methylethyl)-3-[(1S,7aS)-7a-methyl-5-oxo-

4-phenylthio-2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]dihydrofuran-

2(3H)-one (47) and (3R,5S)-5-(1-Hydroxy-1-methylethyl)-3-

[(1R,7aR)-7a-methyl-5-oxo-4-phenylthio-2,3,5,6,7,7a-hexahydro-

(1S,5R,7aS)-1-{(1S)-1-(Hydroxymethyl)ethyl-2-[(4S)-2,2,5,5-tetra-

methyl-1,3-dioxolan-4-yl]}-7a-methyl-4-phenylthio-2,3,5,6,7,7a-

hexahydro-1H-inden-5-ol (51):

A

solution of 50 (152 mg,

0.286 mmol) in THF (3 mL) was added to a clear solution of Li-

796

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 783Ϫ799

Synthesis of Vitamin D trans-Hydrindane Rings

FULL PAPER

AlH₄(15.2 mg, 0.40 mmol) in THF (3 mL). The mixture was

heated under reflux for 3 h. After cooling, the reaction was

quenched with methanol (0.5 mL), and the mixture was poured

into a 10% aqueous tartaric acid (6 mL). The product was extracted

dichloromethane (4 ϫ 20 mL). The combined organic extract was

dried and the solvent was evaporated. The residue was purified by

chromatography on silica gel (35 g, hexanes/EtOAc, 3:1) to give

sulfone 54 (0.27 g, 63% yield): m.p. 139 °C (hexanes). [α]²_D⁰ϭ Ϫ6.5

1

with dichloromethane (4 ϫ 15 mL). The extract was dried and the (c ϭ 1.4). H NMR: δ ϭ 0.73 (s, 3 H, C7ЈЈa-Me), 0.96 (d, J ϭ 6.4

solvent was evaporated. Diol 51 was obtained (128 mg, 100%

yield). H NMR: δ ϭ 1.07 (s, 3 H, Me), 1.08 (s, 3 H, Me), 1.23 (s,

Hz, 3 H, C3Ј-H), 1.04 (s, 3 H, Me), 1.19 (s, 3 H, Me), 1.31 (s, 3 H,

Me), 1.39 (s, 3 H, Me), 3.03 (dt, J ϭ 3.1, 11.2 Hz, 1 H, CHSO₂Ϫ),

3.75 (dd, J ϭ 1.5, 10.6 Hz, 1 H, C4-H), 7.5Ϫ7.7 and 7.8Ϫ7.9 (m,

1

3 H, Me), 1.35 (s, 3 H, Me), 1.42 (s, 3 H, Me), 1.4Ϫ2.75 (m, 12

H), 3.60Ϫ3.85 (m, 4 H, CH₂OH, C4ЈЈ-H, OH), 4.10 (t, J ϭ 7.2 Hz, 5 H, Ph) ppm. ¹³C NMR: δ ϭ 12.04 (C3Ј), 18.52 (C7ЈЈa-Me), 21.12

1 H, C5-H), 7.05Ϫ7.30 (m, 5 H, PhS). ¹³C NMR: δ ϭ 17.75 (C7a-

(C6ЈЈ), 22.94 (3), 25.36 (C5ЈЈ), 25.64 (3), 26.91 (3), 27.35 and 27.95

(C2ЈЈ and C3ЈЈ), 28.64 (3), 33.12 (C2Ј), 35.16 (2), 38.82 (2), 44.80

Me), 22.48, 25.54, 26.50, 26.99, 28.22, 28.40, 28.44, 29.49, 35.12,

39.20, 46.01 (C7a), 48.91, 63.50, 67.82, 78.85, 80.72, 106.82 (C7ЈЈa), 48.15 and 55.84 (C1ЈЈand C3ЈЈa), 63.70 (C4ЈЈ), 79.88 (C4),

(OϪCϪO), 124.48 (C4), 125.61 (C-p), 127.55 (C-o ), 128.95 (C-m), 80.09 (C5), 106.43 (Me₂CO₂), 128.67 and 128.90 (C-o and C-p),

135.11 (C-ipso), 161.83 (C3a) ppm. HRMS calcd. for C₂₆H₃₈O₄S 133.31 (C-m), 138.35 (C-ipso) ppm. C₂₆H₄₀O₄S (448.26): calcd. C

[M^ϩ]: 446.24908. Found: 446.24790. This material was used for the

next step without purification.

69.60, H 8.99; found C 69.67, H 9.15.

(3S,5S)-2-Methyl-5-[(1S,3aS,4S,7aS)-7a-methyl-4-phenylsulfonyl-

octahydro-1H-inden-1-yl]hexane-2,3-diol (55): A mixture of aceton-

ide 54 (272 mg, 0.61 mmol), Amberlyst-15H^(1.5 g) and methanol

(9 mL) was stirred at room temperature for 72 h. The solid was

filtered off and washed with methanol (3 ϫ 6 mL). The combined

filtrates were evaporated and the residue was purified by chroma-

tography on silica gel (30 g, hexanes/EtOAc, 2:1, 1:1) to give diol

55 (203 mg, 80% yield) and unchanged 54 (20 mg). 55: m.p. 133 °C

(benzene). [α]²_D⁰ϭ Ϫ16.2 (c ϭ 1.6). ¹H NMR: δ ϭ 0.71 (s, 3 H,

C7Јa-Me), 0.93 (d, J ϭ 6.4 Hz, 3 H, C6-H), 1.11 (s, 3 H, Me), 1.16

(s, 3 H, Me), 3.03 (dt, J ϭ 3.1, 11.2 Hz, 1 H, CHϪSO₂), 3.43 (dd,

(1S,5R,7aS)-7a-Methyl-4-phenylthio-1-{(1S)-2-[(4S)-2,2,5,5-tetra-

methyl-1,3-dioxolan-4-yl]-1-(tosyloxymethyl)ethyl}-2,3,5,6,7,7a-

hexahydro-1H-inden-5-ol (52): TsCl (224 mg, 1.17 mmol) was added

to a solution of diol 51 (128 mg, 0.286 mmol), triethylamine

(1.2 mL) and DMPA (15 mg, 0.12 mmol) in dichloromethane

(8 mL) at 0 °C. The solution was left overnight, and then the sol-

vent was evaporated at room temperature. The residue was purified

by chromatography on silica gel (15 g, hexanes/EtOAc, 2:1) to give

1

tosylate 52 (134 mg, 78% yield). H NMR: δ ϭ 1.03 (s, 3 H, Me),

1.11 (s, 3 H, Me), 1.33 (s, 3 H, Me), 2.44 (s, 3 H, PhMe), 3.43 (dd,

J ϭ 11.3, 2.1 Hz, 1 H, C4ЈЈ-H), 4.0Ϫ4.2 (m, 4 H, C5-H, CH₂OTs, J ϭ 3.3, 7.2 Hz, 1 H, C3-H), 7.5Ϫ7.7 and 7.8Ϫ7.9 (m, 5 H, Ph)

OH), 7.10Ϫ7.30 (m, 5 H, PhS), 7.35 and 7.80 (d, J ϭ 8.0 Hz, 4 H,

ppm. ¹³C NMR: δ ϭ 11.94 (C6), 18.50 (C7Јa-Me), 21.07 (3), 23.11

Ph-Me) ppm. ¹³C NMR: δ ϭ 17.93 (C7a-Me), 21.60 (Ph-Me), (2), 25.32 (2), 26.52 (3), 27.33 (3) 28.11 (3), 32.51 (C5), 37.73 (2),

22.96, 25.63, 26.32, 26.52, 28.14, 28.22, 28.47, 34.85, 35.69, 46.08 38.74 (2), 44.78 (C7Јa), 48.12 (1), 55.68 (1) 63.69 (C4Ј), 73.13 (C2),

(C7a), 50.72, 67.44 (COTs), 69.70, 78.83 (C4ЈЈ), 80.04, 106.68 75.29 (C3), 128.63 and 128.90 (C-o and C-p), 133.31 (C-m), 138.19

(OϪCϪO), 124.82 (C4), 125.85 (Ph C-p), 127.72 (Ph C-o ), 128.07 (C-ipso) ppm. C₂₃H₃₆O₄S (408.23): calcd. C 67.61, H 8.88; found

(Ts C2,6), 129.11 (Ph C-m), 129.88 (Ts C3,5), 132.52 (Ts C4),

134.69 (Ph C-ipso), 145.12 (Ts C1), 161.30 (C3a) ppm. This mate-

rial was used for the next step without purification.

C 67.58, H 9.03.

Methyl (2E,5S)-5-[(1S,3aS,4S,7aS)-7a-Methyl-4-(phenylsulfonyl)-

ocatahydro-1H-inden-1-yl]hex-2-enoate and (2Z,5S)-5-[(1S,3aS,4S,-

(1S,5R,7aS)-7a-Methyl-4-phenylsulfonyl-1-{(1S)-2-[(4S)-2,2,5,5-tetra- 7aS)-7a-Methyl-4-(phenylsulfonyl)ocatahydro-1H-inden-1-yl]hex-

methyl-1,3-dioxolan-4-yl]-1-(tosyloxymethyl)ethyl}-2,3,5,6,7,7a- 2-enoate (56): A solution of Pb(OAc)₄(65 mg, 0.15 mmol) in di-

hexahydro-1H-inden-5-ol (53): mCPBA (50%, 231 mg, 0.67 mmol,) chloromethane (1 mL) was added dropwise to a stirred mixture of

was added to a solution of sulfide 52 (134 mg, 0.223 mmol) in di-

chloromethane (7 mL) at 0 °C. The mixture was warmed to room

diol 55 (47 mg, 0.12 mmol), powdered K₂CO₃(115 mg, 0.84 mmol)

and dichloromethane (3 mL) at Ϫ15 °C. The mixture was warmed

temperature, and, after 2 h, was poured into 10% aqueous Na₂SO₃to room temperature, and, after 1 h, it was filtered through a pad

(10 mL). The products were extracted with dichloromethane (4 ϫ

15 mL). The extract was dried and the solvent was evaporated. The

of Celite. The Celite was washed with dichloromethane and the

combined filtrates were evaporated. The residue was dissolved in

dry CH₃CN (1.5 mL), and Ph₃PϭCHCOO₂Me (98 mg, 0.29 mmol)

residue was purified by chromatography on silica gel (15 g, hexanes/

1

EtOAc, 1:1) to give the sulfone 53 (135 mg, 96%). H NMR: δ ϭ in CH₃CN (1.5 mL) was added. The mixture was heated under re-

0.96 (s, 3 H, Me), 1.05 (s, 3 H, Me), 1.07 (s, 3 H, Me), 1.29 (s, 3 flux for 3 h. The solvent was evaporated and the residue was puri-

H, Me), 2.41 (s, 3 H, PhMe), 3.35 (dd, J ϭ 1.9, 11.2 Hz, 1 H, C4ЈЈ-

H), 3.95Ϫ4.0 (m, 3 H, CH₂OTs and OH), 4.68 (t, J ϭ 7.9 Hz, 1

fied by chromatography (5 g, hexanes/EtOAc, 2:1) to give 56

(48 mg, 98%, E:Z, 10:1 by ¹H NMR). (E)-56 (from the mixture):

H, C5-H), 7.3Ϫ7.9 (m, 9 H, arom. H) ppm. ¹³C NMR: δ ϭ 17.98 ¹H NMR: δ ϭ 0.68 (s, 3 H, C7Јa-Me), 0.91 (d, J ϭ 6.6 Hz, 3 H,

(C7a-Me), 21.55 (MePh), 22.88 (3), 25.54 (3), 25.98 (C2), 26.45 (3),

C6-H), 3.03 (dt, J ϭ 3.1, 11.2 Hz, 1 H, CHSO₂), 3.70 (s, 3 H,

27.45 (2), 27.78 (2), 28.12 (2), 28.38 (3), 34.22 (2), 34.70 (C1Ј), MeO), 5.80 (d, J ϭ 15.5 Hz, 1 H, C2-H), 6.89 (m, 1 H, C3-H),

47.33 (C7a), 49.54 (1), 65.59 (C5), 69.60 (COTs), 78.73 (C4ЈЈ), 79.87

(C5ЈЈ), 106.59 (OϪCϪO), 126.90 (Ph C2,6), 127.84 (Ts C2,6),

7.5Ϫ7.7 and 7.8Ϫ7.9 (m, 5 H, Ph) ppm. ¹³C NMR: δ ϭ 11.85 (C6),

18.94 (C7a-Me). 21.02 (2), 25.29 (2), 27.29 (2), 27.88 (2), 35.34

128.97 (Ph C3,5), 129.80 (Ts C3,5), 132.24 (Ts C4), 133.14 (Ph C4), (C5), 38.52 (2), 38.85 (2), 44.64 (C7Јa), 48.02 (C3Јa), 51.33 (MeO),

133.24 (C4), 141.18 (Ph C1), 145.08 (Ts C1), 167.76 (C3a) ppm. 54.48 (C1Ј), 63.64 (CϪSO₂Ph), 122.33 (C2), 128.64 and 128.88 (C-

This material was used for the next step without purification.

o and C-p), 133.30 (C-m), 138.13 (C-ipso), 147.75 (C3), 166.76 (C1)

1

ppm. (Z)-56: H NMR: δ ϭ 6.20 (m, C3-H), 3.67 (s, MeO) ppm.

(4S)-2,2,5,5-Tetramethyl-4-{(2S)-2-[(1S,3aS,4S,7aS)-7a-methyl-4-

(phenylsulfonyl)octahydro-1H-inden-1-yl]propyl}1,3-dioxolane (54):

LiAlH₄(120 mg, 3.2 mmol) was added to a solution of 53 (0.61 g,

0.96 mmol) in THF (4 mL). The mixture was heated under reflux

for 20 min. After cooling, methanol (2 mL) and then 10% aqueous

HRMS (liquid SIMS) calcd. for C₂₃H₃₂O₄SNa [M^ϩϩ Na]:

427.1984; found 427.1914.

Methyl (2E,5S)-5-[(1S,3aS,4S,7aS)-7a-Methyl-4-(phenylsulfonyl)-

ocatahydro-1H-inden-1-yl]hex-2-enoate and (2Z,5S)-5-[(1S,3aS,4S,

tartaric acid (20 mL) were added. The products were extracted with 7aS)-7a-Methyl-4-(phenylsulfonyl)ocatahydro-1H-inden-1-yl]hexa-

Eur. J. Org. Chem. 2004, 783Ϫ799

www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 797

E. Gorobets, V. Stepanenko, J. Wicha

FULL PAPER

noate (57): A solution of 56 (46 mg, 0.11 mmol) in EtOAc (4 mL) (s, 9 H, Me₃C), 3.35Ϫ3.60 (m, 1 H, CHOϪ), 3.63 (s, 2 H, CH₂S),

containing 10% Pd on charcoal (4 mg) was stirred under hydrogen

for 4 h, and the product was isolated in the usual way. The dihydro

derivative 57 was obtained (46 mg, 100%): [α]²_D⁰ϭ ϩ2.6 (c ϭ 2.4).

3.95Ϫ4.25 (m, 2 H, CH₂OϪ), 7.1Ϫ7.4 (m, 5 H, Ph) ppm. ¹³C

NMR: δ ϭ 18.53 and 18.56 (C7aЈЈ-Me), 22.82, 22.95, 25.45, 25.51,

26.81, 27.01, 29.35 (Me₃C), 29.05, 29.40, 35.65, 35.78, 36.32, 36.38,

¹H NMR: δ ϭ 0.67 (s, 3 H, C7Јa-Me); 0.89 (d, J ϭ 6.4 Hz, 3 H, 43.07, 43.53, 43.81 (CH₂ϪSPh), 48.92 and 48.95, 51.14, 51.22,

C6-H), 2.24 (dt, J ϭ 2.0, 7.0 Hz, 2 H, C2-H), 3.03 (dt, J ϭ 3.1, 51.39, 51.91, 69.19, 69.65, 72.87, 73.32, 108.72 and 108.77, 126.58

11.2 Hz, 1 H, CHϪSO₂), 3.63 (s, 1 H, MeO), 7.5Ϫ7.7 and 7.8Ϫ7.9 (C-p), 128.89 (C-o ), 129.61 (C-m), 134.74 (C-ipso), 201.64 and

(m, 5 H, Ph) ppm. ¹³C NMR: δ ϭ 11.79 and 18.56 (C7a-Me and 203.06 (C1), 204.23 (C3ЈЈЈ), 220.85 and 221.1 (C3ЈЈ) ppm. HRMS

C6); 21.04, 21.37, 25.28, 27.29, 27.78, 34.32, 35.22, 38.64, 44.57,

48.06 (C7Јa), 51.36 (MeO), 54.70, 63.69 (CSO₂Ph), 128.62 and

128.84 (C-o and C-p), 133.24 (C-m), 138.19 (C-ipso),174.03 (C1)

ppm. HRMS (liquid SIMS) calcd. for C₂₃H₃₄O₄SNa [M^ϩϩ Na]:

429.2076; found 429.2101.

calcd. for C₂₈H₄₀O₅S₂[M^ϩ]: 520.23172; found 520.23262.

S-tert-Butyl (3R,5S)-5-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-

3-carbothioate (60):

A solution of ketene acetal 58 (1.48 g,

4.63 mmol) in dichloromethane (3 mL) was added to a solution

of cyclopent-2-en-1-one (0.42 g, 5.1 mmol) and TrSbCl₆(140 mg,

0.24 mmol) in dichloromethane (7 mL) at Ϫ78 °C. The mixture was

stirred at Ϫ78 °C for 1 h, and then warmed to room temperature.

The product was isolated as described above and purified by chro-

matography on silica gel (20 g, hexanes/EtOAc, 2:1). The fraction

corresponding to the unknown product (TLC) was collected

(0.65 g) and distilled in a kugelrohr apparatus (160 °C/0.1 Torr).

(6S)-2-Methyl-6-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulf-

onyl)octahydro-1H-inden-1-yl)heptan-2-ol (ent-8): A solution of

MeMgI in Et₂O was prepared from Mg (0.61 g, 0.025 gram atom)

and MeI (1.25 mL, 20 mmol) in Et₂O (15 mL), and cooled to Ϫ20

°C. A solution of ester 57 (44 mg, 0.108 mmol) in Et₂O (1.5 mL)

was added dropwise. The mixture was warmed to room tempera-

ture, and after 2 h, it was poured into ice-cold 40% aqueous

The pyran derivative 60 was obtained: [α]²_D⁵ϭ ϩ35.1 (c ϭ 5.1). H

1

NH₄Cl. The product was extracted with dichloromethane (4 ϫ NMR: δ ϭ 1.38 and 1.19 (2s, 6 H, Me₂C), 1.45 (s, 9 H, Me₃C),

5 mL). The combined extracts were dried and the solvents evapo- 2.10Ϫ1.95 (m, 1 H, C4-H_eq), 2.4Ϫ2.15 (m, 2 H, C4-H_ax, OH), 2.96

rated. The residue was purified by chromatography on silica gel (dd, J ϭ 8.7, 7.7 Hz, 1 H, C-3 H), 3.57 (dd, J ϭ 11.7, 5.0 Hz, 1 H,

(6 g, hexanes/EtOAc, 4:1, 2:1) to give crystalline alcohol ent-8

C6-H_eq), 3.76 (dd, J ϭ 11.7, 2.9 Hz, 1 H, C6-H_ax), 4.0Ϫ4.15 (m, 1

(39 mg, 88% yield): [α]²_D⁰ϭ Ϫ0.9 (c ϭ 2.1); ¹H and ¹³C NMR spec-

H, C5-H) ppm. ¹³C NMR: δ ϭ 28.49 and 24.43 (CMe₂), 29.30

tra with identical with those of 8.^[62]Since specific rotation of the (Me₃C), 30.49 (C4), 47.94 (CMe₃), 61.53 (C3), 64.31 (C6), 77.06

enantiomers is too low for any comparisons, CD spectra of 8 and

ent-8 were taken.

(C5), 82.03 (C2), 198.56 (CϭO) ppm. C₁₂H₂₂O₃S (246.37): calcd.

C 58.50, H 9.00; found C 58.07, H 8.95.

Figure 4. Diagnostic values from a nuclear Overhauser effect

(NOE) experiment for 60

Figure 3. CD spectra of 8 (solid line) and epi-8 (dashed line)

Acknowledgments

We thank Prof. David M. Piatak for his comments on the manu-

script and help in idiomatic English. We are indebted to Prof. Zofia

S-tert-Butyl (2ξ)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-[(1ξ,2ξ)-2-

methyl-3-oxo-2-(3-oxo-4-phenylthiobutyl)cyclopentyl]propanethioate

(59): A solution of ketene acetal 58 (2.32 g, 7.3 mmol) in dichloro-

methane (3 mL) was added to a solution of 10 (0.77 g, 8.03 mmol)

and TrSbCl₆(250 mg, 0.43 mmol) in dichloromethane (15 mL) at

Ϫ78 °C. The mixture was stirred for 30 min, after which time 9

(1.3 g, 7.3 mmol) was added. After 1 hour, the mixture was warmed

to room temperature, and the reaction was quenched with water

(1 mL). After 15 min, some MgSO₄and hexanes (20 mL) were ad-

ded, and the solution was filtered through a pad of silica gel (6 g).

The silica gel was washed with dichloromethane (20 mL). The com-

bined filtrates were evaporated, and the residue was purified by

chromatography on silica gel (120 g, hexanes/EtOAc, 4:1) to give a

mixture of diones 59 (1.48 g, 39% yield) as two diastereomers in a

´

Urbanczyk-Lipkowska and to the late Dr. Anderjs Kemme for X-

ray analysis of compound 29, and to Prof. Jadwiga Frelek for CD

measurements. Financial support from the State Committee for

Scientific Research, Grant No. 3 T09A 134 18 is acknowledged.

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Received September 30, 2003

Eur. J. Org. Chem. 2004, 783Ϫ799

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799

Article Doi

Enantioselective total synthesis of a trans-hydrindane rings/side-chain building-block of vitamin D - Asymmetric induction in an acid-catalyzed conjugate-addition reaction

DOI: 10.1002/ejoc.200300611

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Article abstract of DOI:10.1002/ejoc.200300611

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