Diastereoselective approaches to trans-hydrindane derivatives - Total synthesis of 8-(phenylsulfonyl)de-A,B-cholestane precursors to 25-hydroxyvitamin D3

Article abstract of DOI:10.1002/1099-0690(200208)2002:16<2727::AID-EJOC2727>3.0.CO;2-1

The total diastere os elective synthesis of the C,D rings/side chain building block for the synthesis of 1α,25 -dihydroxyvitain D₃ is described. Two tandem Mukaiyama-Michael additions involving silylated ketene acetals derived from tert-butyl 6-methylhept-5-enethioate or tert-butyl 6-methylhept-6-enethioate, 2-methylcyclopent-2-en-1-one, and 1-(phenylthio)but-3-en-2-one afforded the corresponding intermediates with the complete carbon framework of the target compound. The further transformation of these key intermediates involved cyclization, oxidation with m -CPBA, and reduction of the vinylic sulfone moiety to afford the trans-hydindane ring system. The synthesis comprises five operations and afforded the product in ca. 30% yield. The application of 2-[(phenylthio)methyl]-2-vinyl[1,3]dioxolane and 2-(phenylsulfonylmethyl)-2-vinyl[1,3] dioxoIane as Michael acceptors was also examined. c Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200208)2002:16<2727::AID-EJOC2727>3.0.CO;2-1

FULL PAPER
Diastereoselective Approaches to trans-Hydrindane Derivatives ؊ Total
Synthesis of 8-(Phenylsulfonyl)de-A,B-cholestane Precursors to
25-Hydroxyvitamin D3
Igor Prowotorow,[a] Wiaczesław Stepanenko,[a] and Jerzy Wicha*[a]
Keywords: Diastereoselectivity / MukaiyamaϪMichael addition / Steroids / Sulfides / Sulfones
The total diastereoselective synthesis of the C,D rings/side
chain building block for the synthesis of 1α,25-dihydroxyvita- duction of the vinylic sulfone moiety to afford the trans-hyd-
min D3 is described. Two tandem Mukaiyama−Michael addi- rindane ring system. The synthesis comprises five operations
tions involving silylated ketene acetals derived from tert-bu- and afforded the product in ca. 30% yield. The application
diates involved cyclization, oxidation with m-CPBA, and re-
tyl 6-methylhept-5-enethioate or tert-butyl 6-methylhept-6-
enethioate, 2-methylcyclopent-2-en-1-one, and 1-(phenyl-
thio)but-3-en-2-one afforded the corresponding interme-
diates with the complete carbon framework of the target
compound. The further transformation of these key interme-
of 2-[(phenylthio)methyl]-2-vinyl[1,3]dioxolane and 2-
(phenylsulfonylmethyl)-2-vinyl[1,3]dioxolane as Michael
acceptors was also examined.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
vinyl ketone (4) with its sulfur-bearing equivalent, in the
form of one of the derivatives 8 or 11Ϫ13 (Scheme 2),
should allow for simple transformation of the respective
Michael adduct into 2. None of the compounds 8 or 11Ϫ13
had previously been used as a Michael acceptor. We also
addressed the question of more efficient incorporation of
the tertiary hydroxy group in the side chain of intermediate
2, which required alterations in the structure of the starting
ketene acetal 6. We now present a full account of our study
of diastereoselective approaches to the de-A,B-cholane de-
rivative rac-2.[11]
The MukaiyamaϪMichael conjugate addition reaction[1]
with subsequent trapping of the immediate adduct with a
carbon electrophile provides an effective method for a sim-
ultaneous generation of two carbonϪcarbon bonds and, if
applicable, two or more stereogenic centres. In natural prod-
ucts synthesis, this conjugate addition has been used in tan-
dem with the Tsuji alkylation[2Ϫ4] and aldol[5] and imino
aldol reactions.[6] In certain systems, intermolecular conjug-
ate addition reactions have triggered sequential transforma-
tions giving rise to complex annulation products.[7] We
have recently reported on the application of two
MukaiyamaϪMichael reactions in tandem[8] for a conver-
gent synthesis of the hydrindane derivative 2 (Scheme 1),
which served as the key building block for a synthesis of
1α,25-dihydroxyvitamin D3 (1). Treatment of ketene acetals
6 with 2-methylcyclopent-2-en-1-one (5) in the presence of
trityl hexachloroantimonate as catalyst gave the interme-
diate adduct, which was treated in situ with methyl vinyl
ketone (4) as the second Michael acceptor.[9] The obtained
intermediate 3, which included all the requisite carbon
atoms and three stereogenic centres of the target com-
pound, was further transformed into compound 2. This
synthetic route was short and efficient in comparison with
those previously reported.[10] However, some important
methodological questions called for further attention. In
particular, it was thought that the replacement of methyl
Scheme 1
Results and Discussion
[a]
Institute of Organic Chemistry, Polish Academy of Sciences
ul. Kasprzaka 44, 01-224 Warsaw, Poland
Fax: (internat.) ϩ 48-22/632-6681
E-mail: jwicha@icho.edu.pl
Our attention first focused on the application of the eas-
ily accessible Michael acceptor 8, bearing the phenylthio
Eur. J. Org. Chem. 2002, 2727Ϫ2735  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0816Ϫ2727 $ 20.00ϩ.50/0
2727

I. Prowotorow, W. Stepanenko, J. Wicha
FULL PAPER
ketone, for which multiple additions present a notorious
problem. Cyclization of 9 smoothly afforded the hydrindane
derivative 10.
Our next objectives included the reduction of the thioes-
ter functionality and the oxo group, and stereoselective re-
duction of the double bond at the ring junction. Since it
could be anticipated that the ketone 10 should be selectively
transformable into each of the epimeric alcohols, we ini-
tially focused on the diastereoselective preparation of com-
pounds 17 and 19 (Scheme 3). Reduction of 10 with the
NaBH4/CeCl3 system in MeOH/THF[17] at Ϫ78 °C almost
quantitatively afforded the hydroxy ester 14, which was fur-
ther reduced with LiAlH4 in refluxing THF to give diol 15
in 88% overall yield after chromatography (ca. 3% of epi-
meric alcohol was also isolated). Kinetically controlled es-
terification of the diol 15 with tosyl chloride in dichlorome-
thane in the presence of triethylamine and a catalytic
amount of DMAP gave monotosylate 16 (86% yield). This
was subjected to reduction with LiAlH4 to yield the re-
quired alcohol 17. Finally, alcohol 17 was subjected to Mit-
Scheme 2
group,[12,13] in a three-component construction of the dione sunobu inversion[18] (PPh3/DEAD, BzOH) followed by DI-
9 (Scheme 2). The ketene acetal 6 [a mixture of (E) and (Z) BALH reduction of benzoate 18 to afford 19 in 85% over-
isomers in a ratio of 95:5] prepared as described earlier[8] all yield.
was treated with 2-methylcyclopent-2-one (5) in the pres-
ence of trityl hexachloroantimonate (TrSbCl6, ca. 5 mol%)
and the adduct 7 was subsequently treated in situ with the
α,β-unsaturated ketone 8. After the usual isolation, crystal-
line adduct 9 was obtained in a 72% yield. The relative con-
figurations at the three new asymmetric centres formed
during these reactions were ascribed on the grounds of the
Mukaiyama stereochemical model,[2] observations on the
reaction of silylated cyclopentanone enols with elec-
trophiles,[14] and our own experiences.[3]
Some approaches that would allow utilization of a
Michael acceptor bearing the phenylsulfonyl group were ex-
amined next. In an attempt to prepare phenylsulfonylmethyl
vinyl ketone (11) by oxidation of 8, only polymeric material
was obtained. To circumvent these difficulties, 8 was trans-
formed into 12 (67% yield) with ethylene glycol and a cata-
lytic amount of p-TsOH in benzene at reflux. Surprisingly,
treatment of 8 with the (TMSOCH2)2/TMSOTf system,
viewed as a milder ketalization reagent (the Noyori re-
agent[15]), was less effective (53% yield). Sulfide 12 was
smoothly oxidized into sulfone 13 with Oxone in the pres-
Scheme 3
ence of sodium hydrogen carbonate. However, all our at-
tempts to achieve reaction between silyl enol ether 7 and
acetal 13 failed. In further investigations along these lines,
treatment of acetal 12 with 7 in the presence of an equimo-
Our plans for generating the trans-hydrindane system
lar mixture of TiCl4/Ti(iPrO)4 as a catalyst,[16] followed by from hydrinadane allylic alcohols 17 and/or 19 first re-
hydrolysis of the crude product (Amberlyst 15H/acetone), quired the oxidation of the sulfanyl group to the sulfonyl
afforded the expected adduct 9 but in low yield (41%).
group, and then conjugate reduction of the respective vinyl
The experiments described had shown that, of the scru- sulfones with LiAlH4. Model experiments on the reduction
tinized candidates, (phenylthio)methyl vinyl ketone (8) was of an analogous vinyl sulfone located in a decalin ring sys-
the Michael acceptor of choice. It was important that the tem (a cholestane derivative) were encouraging and showed
adduct 9 was formed as the dominant product, easy to pur- that (1) the steric course of reduction might depend upon
ify by chromatography. No side products arising from addi- the orientation of the hydroxy group and (2) the hydroxy
tion of two or more molecules of 8 could be detected. In group (in the 1,2-position to the phenylsulfonyl group)
that respect, 8 was found to be superior to methyl vinyl could ultimately be reduced to yield the corresponding sat-
2728
Eur. J. Org. Chem. 2002, 2727Ϫ2735

Diastereoselective Approaches to trans-Hydrindane Derivatives
FULL PAPER
urated sulfone.[19] However, application of this reaction se- could be isolated and purified. After accomplishing the
quence to vinyl sulfides 17 and 19 appeared somewhat more stepwise synthesis of sulfone 2, we were able to improve the
complex, due to the presence of the additional double bond, whole synthetic approach with regard to the number of
oxidation of which would produce diastereomers. We there- steps and the overall yield. The following combination of
fore decided to proceed with oxidation and reduction steps steps emerged as the optimum: The enone 10 was reduced
without isolation of intermediates.
A vinyl sulfide with the hydroxy group in the α orienta- brief chromatography, a mixture of diol 15 and its 9α epi-
tion (19, Scheme 4) was treated with m-CPBA (ca. 3.5 mol- mer in a ratio of ca. 7:3 (by H NMR, 94% yield). The
with DIBALH (CH2Cl2/hexane, Ϫ78 °C) to afford, after
1
equiv.) in dichloromethane. The crude product was isolated diols were then treated with tosyl chloride and, after a brief
in the usual way and then, without purification, reduced purification, a mixture of the monotosylates 16 and the 9α
with an excess of LiAlH4. Sulfone 2 was obtained in 73% epimer was oxidized with m-CPBA. The product was
yield after chromatography. A small amount of a side prod- treated with an excess of LiAlH4 to give, after chromato-
uct was also isolated and identified as the alcohols 22 (mix- graphy, sulfone 2 along with 22 in 55 and 12% overall yields,
ture of diastereomers), apparently arising from reduction of respectively, from 10. In this way the synthesis of the sul-
the epoxide moiety with addition of a hydride ion at the fone 2 was achieved in five operations and in 31% overall
tertiary centre. It should be noted that the use of MeOH to yield from 6.
destroy the excess of LiAlH4 (see Exp. Sect.) was important
Although sulfone 2 was obtained in a high yield, forma-
for the generation of only one epimer of 2, with the sulfonyl tion of the side product 22 was a drawback. In the final
group in an equatorial (α) orientation; the axial sulfone approach, we chose to alter the side-chain building block
group (β) could, if present, be epimerized to 2 under alkal- in order to secure selectivity for incorporation of the C-25
ine conditions.[20] With regard to the ring junction, the re- hydroxy group. Ethyl 6-methylhept-6-enoate[21] was trans-
duction of 21 was completely selective, affording the trans- formed[22] into S-tert-butyl 6-methylhept-6-enethioate and
fused hydrindane system.
then into ketene acetal 23 [(E)/(Z) ϭ 9:1] (Scheme 5). Con-
jugate addition between 23 and acceptors 5 and 8, consecut-
ively, afforded the key intermediate 24 in 63% yield, along
with a small amount of its cyclization product 25. Base-
catalysed cyclization of 24 gave enone 25. This was reduced
with the Luche reagent to the allylic alcohol 26, which was
in turn further reduced to diol 27. Selective tosylation fol-
lowed by m-CPBA oxidation provided epoxy sulfone 29 as a
mixture of diastereomers in a ratio of ca. 2:1 (by 1H NMR).
Reduction of 29 with an excess of LiAlH4 provided sulfone
2 as the only product.
Scheme 4
When this reaction sequence was applied to the hydroxy
sulfide 17, the same product, sulfone 2, was obtained. These
experiments showed that, contrary to our initial predic-
tions, the orientation of the hydroxy group had no con-
sequences for the steric course of the double bond reduc-
tion. In practice, the 9β-hydroxy isomer 17 (steroid num-
bering) turned out to be a somewhat more convenient syn-
Scheme 5
Sulfone 2 was crystalline (m.p. 109Ϫ110 °C) and easy to
thetic intermediate, since the corresponding sulfone 20 purify. However, all our attempts to produce a single crystal
Eur. J. Org. Chem. 2002, 2727Ϫ2735
2729

I. Prowotorow, W. Stepanenko, J. Wicha
FULL PAPER
C4-Hcis), 5.23 (dd, J ϭ 10.4, 1.8 Hz, 1 H, C4-H trans), 4.14 (m, 4
H, CH2CH2), 3.29 (s, 2 H, C1-H) ppm. 13C NMR: δ ϭ 137.1 (C-
ipso), 136.5 (C1Ј), 129.1 (C-o), 128.6 (C-m), 125.8 (C-p), 116.4
(C2Ј), 107.6 (OϪCϪO), 65.3 (2C acetal.), 42.3 (CSPh) ppm. MS
EI (70 eV): m/z (%) ϭ 222 (8) [Mϩ], 99 (100), 55 (30). C12H14O2S
(222.30): calcd. C 64.83, H 6.35; found C 64.72, H 6.39. Procedure
b: TMSOCH2CH2OTMS (2.2 mL, 8.99 mmol) was added at Ϫ78
°C to a solution of Et3SiOTf (0.068 mL, 0.3 mmol) in dichlorome-
thane (1 mL), followed by ketone 8 (1.08 g, 6.06 mmol) in dichloro-
methane (4 mL). The mixture was stirred at Ϫ20 °C for 18 h, pyrid-
ine (0.1 mL) was added, and the whole mixture was poured into
aqueous NaHCO3. The product was extracted with dichlorome-
thane. The extract was dried with Na2SO4 containing powdered
NaHCO3, and the solvent was evaporated. The residue was chro-
matographed on SiO2 (40 g, hexane/EtOAc, 25:1). Ketal 12
(713 mg, 53%) was obtained.
suitable for X-ray analysis failed. The following relay syn-
thesis was therefore performed in order to confirm the
structure of 2. A sample of the known[23] optically active
ketone 30 (Scheme 6) was treated with thiophenol and
BF3·2H2O by the procedure developed by Craig and co-
workers.[24] The sulfide 31 was oxidized to the sulfone 32
with m-CPBA. Reduction of 32 (LiAlH4) gave optically act-
ive sulfone (Ϫ)-2 (m.p. 128 °C), which displayed 1H and 13
C
NMR spectra identical with those of the racemic product 2.
2-[(Phenylsulfonyl)methyl]-2-vinyl[1,3]dioxolane (13): Oxone (Ald-
rich, 2.22 g, 3.61 mmol) was added at 0 °C to a stirred mixture of
thiol 12 (232 mg, 1.05 mmol), THF (6 mL), methanol (2 mL), water
(4 mL), and NaHCO3 (1 g). The mixture was set aside for 14 h and
then poured into water. The product was extracted with EtOAc.
The solvent was evaporated, and the residue was chromatographed
on SiO2 (18 g, hexane/EtOAc, 5:1). Sulfone 13 (261 mg, 98%) was
obtained. 1H NMR: δ ϭ 7.96Ϫ7.87 (m, 2 H, H-m aromat.),
7.67Ϫ7.47 (m, 3 H, H-o, -p aromat.), 5.83 (dd, J ϭ 17.1, 10.4 Hz,
1 H, C3-H), 5.41 (dd, J ϭ 17.1, 1.5 Hz, 1 H, C4-H cis), 5.20 (dd,
J ϭ 10.4, 1.5 Hz, 1 H, C4-H trans) ppm. 13C NMR: δ ϭ 140.8 (C-
ipso), 135.5 (C-p or C1Ј), 133.3 (C1Ј or C-p), 128.7 (C-o), 128.0 (C-
m), 116.9 (C2Ј), 105.0 (OϪCϪO), 64.7 (C acetal.), 62.3 (CSO2Ph)
ppm. MS EI (70 eV): m/z (%) ϭ 227 (21) [M Ϫ C2H3]ϩ, 99 (100),
55 (26); LSIMS (ϩ) (NBA, 6 s, 5 kHz): m/z (%) ϭ 277 (7) [M ϩ
Na]ϩ, 255 (31) [M ϩ H]ϩ. C12H14O4S (254.30): C 56.68, H 5.55;
found C 56.63. H, 5.65.
Scheme 6
In conclusion, the application of the sulfur-containing
acceptors 8, 12, and 13 in tandem MukaiyamaϪMichael
reactions involving ketene acetals 6 or 23 and 2-methyl-
cyclopent-2-en-1-one (5) has been scrutinized. Expeditious
new approaches to rac-hydroxy sulfone 2, a key building
block in the total synthesis of 1α,25-dihydroxyvitamin D3,
have been developed.
S-tert-Butyl 6-Methylhept-5-enethioate: Trimethylaluminium (2.0 
in hexane, 36 mL, 72.00 mmol) was diluted with dichloromethane
(120 mL) and cooled to 0 °C. 2-Methyl-2-propanethiol (6.36 g,
72 mmol) was added dropwise to this solution. The mixture was
stirred at 0 °C for 15 min and was then allowed to warm to room
temperature (in ca. 10 min), maintained at this temperature for a
further 30 min and cooled again to 0 °C. To this thus prepared
Weinreb reagent,[22] ethyl 6-methylhept-5-enoate (prepared from
the corresponding acid, 7.7 g, 36.0 mmol) was added dropwise, and
the mixture was set aside at 0 to 5 °C for 14 h. The reaction was
quenched at 0 °C by careful addition of water (100 mL) and then
2% HCl (50 mL). The layers were separated. The aqueous layer
was extracted with CH2Cl2. The combined organic solutions were
washed with water and dried, and the solvent was evaporated. The
residue was distilled at 90Ϫ91 °C/3 Torr to give the title compound
(5.3 g, 70%).[8]
Experimental Section
General: Reactions involving silyl enol ethers or organometallic re-
agents were carried out in flame-dried glassware under argon. THF
was dried with Na/K alloy and distilled under argon. NMR spectra
were recorded at 200 MHz (1H) and 50 MHz (13C). Column chro-
matography was performed on Merck 60 silica gel, 230Ϫ400 mesh,
and TLC on Merck aluminium sheets, 60 S254 silica gel. Organic
extracts were dried with anhydrous Na2SO4 and the solvents were
removed in a rotary evaporator. Optical rotations were measured
for CHCl3 solutions.
S-tert-Butyl rac-(2R*)-6-Methyl-2-{(1R*,2S*)-2-methyl-3-oxo-2-[3-
2-[(Phenylthio)methyl]-2-vinyl[1,3]dioxolane (12). Procedure a: A
oxo-4-(phenylthio)butyl]cyclopentyl}hept-5-enethioate (9). Procedure
mixture of ketone 8[13] (640 mg, 3.60 mmol), ethylene glycol (5 mL), a: Ketene acetal 6[8] (3.93 g, 13.6 mmol) in dichloromethane (6 mL)
p-TsOH (25 mg), and benzene (20 mL) was heated under reflux for
4 h in a flask equipped with a DeanϪStark adapter. After the mix-
ture had cooled, triethylamine (0.25 mL) was added, and the solu-
tion was filtered through a pad of SiO2 (5 g). The solvent was re-
moved, and the residue was chromatographed on SiO2 (30 g, hex-
ane/EtOAc, 25:1). The main fraction was collected and distilled in
a Kugelrohr apparatus (225 °C/0.1 Torr). Ketal 12 (538 mg, 67%)
was obtained. 1H NMR: δ ϭ 7.38Ϫ7.12 (m, 2 H, H-m aromat.),
was added at Ϫ78 °C, over 20 min, to a stirred solution of enone
5 (1.18 mL, 11 mmol) and TrSbCl6 (350 mg, 0.6 mmol) in dichloro-
methane (30 mL). After 1.5 h, 1-(phenylthio)but-3-en-2-one (8,
1.95 g, 11 mmol) in dichloromethane (6 mL) was added dropwise.
The mixture was set aside at Ϫ78 °C for 3 h and then allowed to
warm to room temp. (in ca. 1 h), and the reaction was then
quenched with water (2 mL). After 30 min, the solvent was evapor-
ated. The residue was dried by repeated coevaporation with ben-
7.31Ϫ7.11 (m, 3 H, H-o, -p aromat.), 5.56 (dd, J ϭ 17.1, 10.4 Hz, zene and then chromatographed on SiO2 (140 g, hexane/EtOAc,
1 H, C3-H, steroid numbering), 5.49 (dd, J ϭ 17.1, 1.75 Hz, 1 H, 10:1). Diketone 9 (3.86 g, 72%) was obtained. M.p. 89Ϫ90 °C
2730
Eur. J. Org. Chem. 2002, 2727Ϫ2735

Diastereoselective Approaches to trans-Hydrindane Derivatives
FULL PAPER
(methanol). IR (KBr) ν˜ ϭ 1731, 1708, 1666, 1584 cmϪ1. 1H NMR:
(C8), 67.9 (C9), 63.0 (C21), 50.9, 46.1 (C13), 40.6, 35.0, 29.1, 28.4,
δ ϭ 7.38Ϫ7.12 (m, 5 H, SPh), 5.07 (br. t, J ϭ 7.1 Hz, C24-H),3.62 25.8, 25.7, 25.2, 18.0, 17.7 ppm. C24H34O2S (386.59): calcd. C
(s, 2 H, S-C8-H), 2.76Ϫ0.90 (m, 14 H), overlapping 1.69 (s, 3 H, 74.56, H 8.86; found C 74.29, H 8.96. rac-(1R*,5R*,7aR*)-1-[(1R*)-
C27-H cis), 1.59 (s, 3 H, C26-H trans), 1.41 (s, 9 H, tBuS), 0.98 (s, 1-(Hydroxymethyl)-5-methylhex-4-en-1-yl]-7a-methyl-4-(phenyl-
3 H, C18-H) ppm. 13C NMR: δ ϭ 221.1 (C14), 204.2 (C9 or 21),
202.9 (C21 or 9), 135.0 (C-ipso), 132.2 (C25), 129.8 (C-o), 128.9 hexane, 1:1). H NMR: δ ϭ 7.30Ϫ7.08 (m, 5 H, SPh), 5.11 (br. t,
thio)-2,3,5,6,7,7a-hexahydro-1H-inden-5-ol: m.p. 113 °C (benzene/
1
(C-m), 126.6 (C-p), 123.5 (C24), 54.1, 51.2, 48.6, 43.9, 43.3, 36.5,
35.7, 31.8, 29.5 (3 C-1, tBuS), 29.2, 25.7, 25.2, 22.9, 18.6, 17.7.
J ϭ 7.0 Hz, C24-H), 3.99 (br. d, 1 H, J ϭ 1.4 Hz, C9-H), 3.76Ϫ3.60
(m, 2 H, J ϭ 4.0 Hz, C21-H), 2.75Ϫ0.82 (m, 14 H), overlapping
C28H40O3S2 (488.76): calcd. C 68.81, H 8.25; found C 68.65, H 1.69 and 1.61 (2 s, 3H each, C26 and C27), 1.00 (s, 3 H, C18-H)
8.38. Procedure b: Compound 6 (361 mg, 1.26 mmol) was added at
ppm. 13C NMR: δ ϭ 162.6 (C14), 135.7 (C-ipso), 131.5 (C25), 128.9
Ϫ78 °C, over 20 min, to a solution of 5 (0.107 mL, 1.00 mmol) and (C-o), 127.6 (C-m), 125.5 (C-p), 124.4 (C24), 122.5 (C8), 66.2 (C9),
TrSbCl6 (40 mg) in dichloromethane (3 mL). After 45 min, ketal 12
(220 mg, 1.15 mmol) in dichloromethane (5 mL) was added, fol-
62.9 (C21), 50.6, 45.9 (C13), 40.5, 30.6, 28.9, 27.8, 27.7, 25.6, 25.1,
24.9, 17.6, 17.2 ppm. C24H34O2S (386.59): calcd. C 74.56, H 8.86;
lowed by a solution of TiCl4 (0.064 mL, 0.58 mmol) and Ti(iPrO)4 found C 74.50, H 8.95. Procedure b: DIBALH (0.7  in hexane,
(0.171 mL, 0.58 mmol) in dichloromethane (3 mL). The mixture 4.4 mL, 3.08 mmol) was added at Ϫ78 °C to a solution of ketone
was set aside at Ϫ78 °C for 18 h and the reaction was then
quenched with saturated aqueous NaHCO3 (3 mL). The mixture
was poured into water, and the product was extracted with hexane.
The extract was evaporated and the residue was dissolved in acet-
10 (205 mg, 0.44 mmol) in dichloromethane (10 mL). The mixture
was stirred at Ϫ78 °C for 1 h, and then set aside at room temp. for
24 h. Methanol (4 mL) was added, and the whole mixture was
poured into 10% aqueous tartaric acid. The product was extracted
one (15 mL). Amberlyst 15-H (70 mg) was added. The mixture was with dichloromethane. The solvent was evaporated, and the residue
stirred for 24 h and filtered, and the solvent was evaporated. The
residue was chromatographed on SiO2 (40 g, hexane/EtOAc, 10:1).
Diketone 9 (201 mg, 41%) was obtained, and was identical with the
sample described above.
was chromatographed on SiO2 (18 g). Elution with hexane/EtOAc
(5:1) gave 15 (118 mg, 69%) and then its 9α epimer (38 mg, 22%).
rac-(2R*)-2-[(1R*,5S*,7aR*)-5-Hydroxy-7a-methyl-4-(phenylthio)-
2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-6-methylhept-5-enyl Toluene-
4-sulfonate (16): A solution of diol 15 (110 mg, 0.28 mmol) in
S-tert-Butyl rac-(2S*)-6-Methyl-2-[(1R*,7aR*)-7a-methyl-5-oxo-4-
(phenylthio)-2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]hept-5-enethioate
(10): KOH (30% in methanol, 0.3 mL) was added to a solution of
diketone 9 (2.839 g, 5.82 mmol) in methanol (150 mL). The mixture
was stirred for 1 h and the solvent was evaporated, and the residue
was chromatographed on SiO2 (100 g, hexane/EtOAc, 20:1). Enone
10 (2.137 g, 78%) was obtained. M.p. 88Ϫ89 °C (methanol). 1H
NMR: δ ϭ 7.34Ϫ7.03 (m, 5 H, SPh), 5.09 (br. t, J ϭ 7.0 Hz, 1 H,
C24-H), 2.85Ϫ0.80 (m, 13 H), overlapping 1.63 (s, 3 H,C27-H cis),
1.54 (s, 3 H, C26-H trans), 1.44 (s, 9 H, StBu), 1.18 (s, 3 H, C-H)
ppm. 13C NMR: δ ϭ 202.8 (C21), 193.2 (C9), 184.9 (C14), 135.7
(C-ipso), 131.9 (C25), 128.5 (C-o), 126.7 (C-m), 125.0 (C-p), 124.7
(C8), 123.1 (C24), 53.8, 52.0, 48.2, 46.9, 34.3, 33.7, 32.5, 30.2, 29.2,
25.6, 25.4, 24.9, 17.4, 16.3 ppm. C28H38O2S2 (470.74): calcd. C
71.43, H 8.15; found C 71.25, H 8.25.
dichloromethane
(1.5 mL),
containing
DMAP
(8.5 mg,
0.07 mmol), triethylamine (0.5 mL) and pyridine (0.5 mL), was co-
oled to 0 °C and p-TsCl (106 mg, 0.56 mmol) was added. The mix-
ture was set aside at room temp. for 14 h and then poured into 3%
sulfuric acid. The product was extracted with dichloromethane. The
extract was washed with aqueous NaHCO3 and water, and the solv-
ent was evaporated. The residue was chromatographed on SiO2
(15 g, hexane/EtOAc, 20:1). Tosylate 16 (130 mg, 86%) was ob-
1
tained. H NMR: δ ϭ 7.79 (d, J ϭ 8.3 Hz, 2 H, H-o aromat. Ts),
7.33 (d, J ϭ 8.0 Hz, 2 H, H-m aromat. Ts), 7.32Ϫ7.09 (m, 5 H,
SPh), 4.94 (br. t, J ϭ 6.9 Hz, C24-H), 4.16Ϫ3.87 (m, 3 H, C21-H2
and C9-H), 2.75Ϫ0.89 (m, 14 H), overlapping 2.67 (s, 1 H, C9-
OH), 2.43 (s, 3 H, CH3 Ts), 1.65 (s, 3 H, C27-H (cis), 1.49 (s, 3 H,
C26-H trans), 0.95 (s, 3 H, C18-H) ppm. 13C NMR: δ ϭ 161.1
(C14), 144.7 (C-ipso, Ts), 134.7(C-ipso, Ph), 132.6 (C-p, Ts), 131.8
(C25), 129.6 (C-o,Ts), 128.9 (C-o, Ph), 127.8 (C-m, Ts or Ph), 127.5
(C-m, Ph or Ts),125.6(C-p, Ph), 124.5 (C8), 123.5 (C24), 70.2 (C9),
67.4 (C21), 50.3, 45.8 (C13), 37.8, 34.7, 28.7, 28.2, 28.0, 25.7, 25.5,
24.5, 21.5, 17.7, 17.5 ppm. C31H40O4S2 [Mϩ]: 540.23685; found
540.23661 (HRMS).
rac-(1R*,5S*,7aR*)-1-[(1R*)-1-(Hydroxymethyl)-5-methylhex-4-en-
1-yl]-7a-methyl-4-(phenylthio)-2,3,5,6,7,7a-hexahydro-1H-inden-5-ol
(15). Procedure a: NaBH4 (11.4 mg, 0.300 mmol) was added at Ϫ78
°C to a stirred solution of ketone 10 (120 mg, 0.255 mmol) and
CeCl3·7H2O (47 mg, 0.126 mmol) in methanol (3 mL) and THF
(2 mL). After 2 h, the mixture was allowed to warm to room temp.,
stirring was continued for an additional 30 min, and the whole mix-
ture was poured into 10% aqueous tartaric acid. The product 14 rac-(1R*,5S*,7aR*)-7a-Methyl-1-[(1R*)-6-methylhept-5-en-2-yl]-4-
was extracted with dichloromethane and the solvent was evapor- (phenylthio)-2,3,5,6,7,7a-hexahydro-1H-inden-5-ol (17): LiAlH4
ated. The residue was dissolved in THF (6 mL), and LiAlH4 (0.25 (0.25  in THF, 2 mL, 0.500 mmol) was added to a solution of
 in THF, 1.5 mL, 0.750 mmol) was added. The mixture was
heated at reflux temperature for 40 min. After the mixture had co-
oled, methanol (0.5 mL) was added, and the whole mixture was
poured into 10% aqueous tartaric acid. The product was extracted
with dichloromethane. The solvent was evaporated and the residue
tosylate 16 (101 mg, 0.187 mmol) in THF (1 mL). The mixture was
heated at reflux temperature for 1 h. After the mixture had cooled,
methanol (0.5 mL) was added, and the whole mixture was poured
into 10% aqueous tartaric acid. The product was extracted with
dichloromethane. The extract was concentrated, and the residue
was chromatographed on SiO2 (15 g, hexane/EtOAc, 5:1). Diol 15 was chromatographed on SiO2 (5 g, hexane/EtOAc, 10:1, 5:1). Al-
(87 mg, 88%) and its 9α epimer (3 mg, 3%) were obtained. 15: M.p.
cohol 17 (64 mg, 92%) was obtained. 1H NMR: δ ϭ 7.31Ϫ7.07 (m,
5 H, SPh), 5.09 (br. t, J ϭ 7.1, C24-H), 4.14Ϫ4.02 (m, 1 H, C9-
97 °C (benzene/hexane, 1:1). 1H NMR: δ ϭ 7.30Ϫ7.08 (m, 5 H,
SPh), 5.11 (br. t, J ϭ 7.1 Hz, C24-H), 4.15Ϫ4.03 (m, 1 H, C9-H), H), 2.65Ϫ0.80 (m, 15 H), overlapping 1.69 (d, J ϭ 1.1 Hz, 3 H,
3.70 (d, J ϭ 4.0 Hz, 2 H, C21-H), 2.69Ϫ0.85 (m, 14 H), overlapping C27-H cis), 1.61 (s, 3 H, C26-H trans), 1.05 (s, 3 H, C18-H), 0.98
1.69 (s, 3 H, C27-H cis), 1.61 (s, 3 H, C26-H trans), 1.06 (s, 3 H, (d, J20,21 ϭ 6.4 Hz, 3 H, C21-H) ppm. 13C NMR: δ ϭ 163.1 (C14),
C18-H) ppm. 13C NMR: δ ϭ 162.4 (C14), 135.0 (C-ipso), 131.8
135.1 (C-ipso), 131.7(C25), 128.9 (C-o), 127.4 (C-m), 125.5 (C-p),
(C25), 129.0 (C-o), 127.7 (C-m), 125.7 (C-p), 124.4 (C24), 124.2 124.7 (C24), 123.7 (C8), 67.8(C9), 56.3, 46.3 (C13), 35.8, 35.5, 34.3,
Eur. J. Org. Chem. 2002, 2727Ϫ2735
2731

I. Prowotorow, W. Stepanenko, J. Wicha
FULL PAPER
28.4, 28.3, 26.7, 25.6, 24.6, 18.6, 17.6, 17.5 ppm. C24H34OS [Mϩ]:
for 25 min. After the mixture had cooled, methanol (0.5 mL) was
370.23304; found 370.23214; calcd. for C24H32S [Mϩ Ϫ H2O]: added and the whole mixture was poured into 10% aqueous tartaric
352.22248; found 352.22218 (HRMS).
acid. The product was extracted with dichloromethane. The extract
was concentrated. TLC analysis of this product indicated the pres-
ence of 2 and a small amount of a side product identified as 22.
The crude product was chromatographed on SiO2 (3 g, hexane/
EtOAc, 10:1, 5:1) to give sulfone 2 (17 mg, 73%). M.p. 109 °C
(methanol). 1H NMR: δ ϭ 7.91Ϫ7.77 (m, 2 H, H-m Ph), 7.69Ϫ7.48
(m, 3 H, H-o, -p Ph), 3.03 (br. td, J ϭ 11.4, 3.3 Hz, C8-H),
2.12Ϫ0.82 (m, 20 H), overlapping 1.20 (s, 6 H, C27-H and C26-H),
0.91 (d, 3 H, J20,21 ϭ 6.5 Hz, C21-H), 0.69 (s, 3 H, C18-H) ppm.
13C NMR: δ ϭ 138.2 (C-ipso), 133.2 (C-p), 128.8 (C-o), 128.6 (C-
m), 70.9 (C25), 63.7, 54.9, 48.0, 44.5 (C14), 44.2, 38.6, 36.2, 35.4,
29.2, 29.1, 27.8, 27.3, 25.2, 21.0, 20.6, 18.6, 11.7. C24H38O3S
(406.62): calcd. C 70.89, H 9.42; found C 70.87, H 9.45. Procedure
b (from Alcohol 19 via Epoxide 21): m-CPBA (60%, 62 mg,
0.216 mmol) was added to a solution of 19 (23 mg, 0.062 mmol) in
dichloromethane (2 mL). After 2 h, the mixture was poured into
aqueous NaHCO3, and the product 21 was extracted with dichloro-
methane. The extract was washed consecutively with aqueous
Na2SO3 and water. The solvent was evaporated, and the residue was
dissolved in THF (1 mL). LiAlH4 (0.25  in THF, 1.0 mL,
0.25 mmol) was added, and the mixture was heated at reflux tem-
perature for 20 min. After the mixture had cooled, methanol
(0.5 mL) was added, and the whole mixture was poured into 10%
aqueous tartaric acid. The product was extracted with dichlorome-
thane. The extract was concentrated, and the residue was chromato-
graphed on SiO2 (2 g, hexane/EtOAc, 50:1, 10:1, 5:1). Sulfone 2
(16 mg, 64%) was obtained. Procedure c (from 10 without Isolation
rac-(1R*,5R*,7aR*)-7a-Methyl-1-[(2R*)-6-methylhept-5-en-2-yl]-4-
(phenylthio)-2,3,5,6,7,7a-hexahydro-1H-inden-5-ol (19): DEAD
(0.057 mL, 0.360 mmol) in THF (0.2 mL) was added at Ϫ78 °C to
a stirred solution of alcohol 17 (27 mg, 0.073 mmol), Ph3P (95 mg,
0.360 mmol) and benzoic acid (40 mg, 0.360 mmol) in THF (1 mL).
The mixture was set aside at room temp. for 2 h, and the solvent
was evaporated. The residue was chromatographed on SiO2 (2 g,
hexane/EtOAc, 100:1, 50:1, 20:1). Benzoate 18 (31 mg, 90%) was
1
obtained. H NMR: δ ϭ 7.94Ϫ7.01 (m, 10 H, H aromat. PhS and
Bz), 5.51Ϫ5.45 (m, C9-H), 5.11 (br. t, J ϭ 7.0 Hz, C24-H),
2.85Ϫ0.89 (m, 14 H), overlapping 1.70 (s, 3 H, C27-H cis), 1.63 (s,
3 H, C26-H trans), 1.05 (s, 3 H, C18-H), 1.01 (d, J20,21 ϭ 6.0 Hz,
C21-H) ppm. 13C NMR: δ ϭ 166.5 (CO Bz), 166.0 (C14), 136.1,
132.5, 131.2, 130.5, 129.5 (C-o, Bz), 128.7 (C-o, PhS), 128.0 (C-m,
Bz or PhS), 127.7 (C-m, PhS or Bz),127.4, 125.3, 124.7, 118.5, 70.6
(C9), 56.3, 46.1 (C13), 35.5, 34.4, 32.2, 28.2, 26.8, 26.3, 25.6, 24.5,
18.6, 17.6, 16.9. DIBALH (0.7  in hexane, 0.2 mL, 0.140 mmol)
was added at Ϫ78 °C to a stirred solution of 18 (31 mg,
0.065 mmol) in dichloromethane (3 mL). After 1 h, the mixture was
allowed to warm to room temp. The reaction was quenched with
methanol (0.5 mL) and the whole mixture was poured into 10%
aqueous tartaric acid. The product was extracted with dichlorome-
thane. The solvent was evaporated, and the residue was chromato-
graphed on SiO2 (1.5 g, hexane/EtOAc, 100:1, 50:1, 20:1). Alcohol
1
19 (23 mg, 95%) was obtained. H NMR: δ ϭ 7.32Ϫ7.07 (m, 5 H,
SPh), 5.09 (br. t, J ϭ 7.0, C24-H), 3.98 (br. s, 1 H, C9-H),
2.76Ϫ0.82 (m, 14 H), overlapping 2.19 (br. s, 1 H, C9-OH), 1.69
(d, J ϭ 1.1 Hz, 3 H, C27-H cis), 1.61 (s, 3 H, C26-H trans), 1.01
(s, 3 H, C18-H), 0.99 (d, J20,21 ϭ 5.1 Hz, 3 H, C21-H) ppm. 13C
NMR: δ ϭ 163.7 (C14), 136.1 (C-ipso), 131.3(C25), 129.1 (C-o),
127.8 (C-m), 125.7 (2 C-p), 124.9 (C24), 122.5 (C8), 66.3(C9), 56.3,
46.4 (C13), 35.7, 34.5, 31.73, 28.1, 28.0, 26.4, 25.8, 24.7, 18.8,
17.8, 17.2.
of Intermediates): DIBALH (0.7
 in hexane, 10.32 mL,
7.224 mmol) was added at Ϫ78 °C to a solution of 10 (485 mg,
1.032 mmol) in dichloromethane (15 mL). Stirring at Ϫ78 °C was
continued for 1 h, and the mixture was then set aside at room temp.
for 24 h. Methanol (5 mL) was added, and the whole mixture was
poured into 10% aqueous tartaric acid. The product was extracted
with dichloromethane. The extract was concentrated and the residue
was chromatographed on SiO2 (40 g, hexane/EtOAc, 10:1, 5:1). A
mixture of diol 15 and its 9α epimer (378 mg, 94%, in a ratio of ca.
7:3 by 1H NMR) was obtained. This (374 mg, 0.969 mmol) was
dissolved in dichloromethane (35 mL). DMAP (35 mg, 0.287 mmol)
and triethylamine (1.5 mL) were added, and the solution was cooled
to Ϫ20 °C. p-TsCl (476 mg, 2.497 mmol) in dichloromethane
(1.5 mL) was then added dropwise, and the mixture was set aside
at 0 °C for 8 h. The solvent was evaporated and the residue was
chromatographed on SiO2 (40 g, hexane/EtOAc, 20:1, 10:1). A mix-
ture of tosylate 16 and its 9α epimer (485 mg) was obtained. To a
solution of this product (485 mg, 0.898 mmol) in dichloromethane
(25 mL), m-CPBA (50%, 1.146 g, 3.323 mmol) was added at 0 °C.
The mixture was set aside at room temp. for 3 h and then poured
into aqueous NaHCO3. The product was extracted with dichloro-
methane. The extract was washed with saturated aqueous Na2S2O3
and water, and the solvent was evaporated. The residue was dis-
solved in THF (11 mL), LiAlH4 (1.0  in THF, 7 mL, 7.00 mmol)
was added, and the mixture was heated at reflux temperature for
30 min. After the mixture had cooled, methanol (2 mL) was added,
and the whole mixture was poured into 10% aqueous tartaric acid.
The product was extracted with dichloromethane. The extract was
concentrated and the residue was chromatographed on SiO2 (25 g,
hexane/EtOAc, 5:1). (3ξ,6R*)-6-[(1R*,3aR*,4R*,7aR*)-4-(Phenyl-
sulfonyl)-7a-methyloctahydroinden-1-yl]-2-methylheptan-3-ol (22,
51 mg, 12% yield from 10) and then sulfone 2 (232 mg, 55% yield
rac-(6R*)-6-[(1R*,3aR*,4R*,7aR*)-4-(Phenylsulfonyl)-7a-
methyloctahydroinden-1-yl]-2-methylheptan-2-ol (2). Procedure
a
(from Alcohol 17 via Epoxide 20): m-CPBA (60%, 58 mg,
0.202 mmol) was added at 0 °C to a solution of sulfide 17 (21 mg,
0.057 mmol) in dichloromethane (2 mL). The mixture was set aside
at room temp. for 2 h and then poured into aqueous NaHCO3. The
product was extracted with dichloromethane. The extract was
washed with saturated aqueous Na2SO3 and water. The solvent was
evaporated, and the residue was chromatographed on SiO2 (2 g,
hexane/EtOAc, 10:1, 5:1). Epoxy sulfone 20 (21 mg, 88%) was ob-
1
tained. H NMR: δ ϭ 7.79Ϫ7.90 (m, 2 H, H-mSO2Ph), 7.67Ϫ7.48
(m, 3 H, H-o and -p SO2Ph), 4.76 (br. t, J ϭ 7.8 Hz, 1 H, C9-H),
4.04 (br. s, C9-OH), 2.96Ϫ2.73 (m, 1 H, C15-αH), 2.71Ϫ2.62 (m, 1
H, C24-H), 2.40Ϫ2.14 (m, 2 H), 2.06Ϫ1.81 (m, 3 H), 1.74Ϫ0.82 (m,
8 H), overlapping 1.30 (s, 3 H, C27 or 26-H), 1.26 (s, 3 H, C26 or
27-H), 1.01 (s, 3 H, C18-H), 0.95 (d, J20,21 ϭ 6.6 Hz, 3 H, C21-H)
ppm. 13C NMR: δ ϭ 169.3 (C14), 141.5, 141.5, 133.0 (C-p), 128.9
(C-o), 126.9 (C-m), 65.7 (C9), 64.5, 64.3, 58.3, 58.0, 54.9, 54.7, 47.5,
35.1, 33.7, 33.5, 32.1, 31.9, 27.8, 27.4, 26.7, 25.6, 25.1, 24.7, 18.7,
18.6, 18.5, 17.7 ppm. MS EI (70 eV): m/z (%) ϭ 416 (1.5) [M Ϫ
H2]ϩ, 400 (9) [M Ϫ H2O]ϩ, 385 (22) [M Ϫ CH3, Ϫ H2O]ϩ, 277
(100) [M Ϫ SO2Ph]ϩ, 273 (89), 259 (48) [M Ϫ SO2Ph, Ϫ H2O]ϩ,
173 (45), [TsOH2]ϩ. LSIMS (ϩ) (NBA, 8 kV): m/z (%) ϭ 441 (21)
[M ϩ Na]ϩ, 417 (11) [M Ϫ H]ϩ, 401 (29). Epoxy sulfone 20 was
dissolved in THF (1 mL), LiAlH4 (0.25  in THF, 1.5 mL,
0.375 mmol) was added, and the mixture was heated at reflux temp.
1
from 10) were obtained. Sulfone 22: H NMR: δ ϭ 7.90Ϫ7.77 (m,
2 H, H-m Ph), 7.68Ϫ7.47 (m, 3 H, H-o, -p Ph), 3.37Ϫ3.21 (m, 1 H,
C24-H), 3.02 (br. td, J ϭ 11.2, 3.2 Hz, C8-H), 2.12Ϫ0.82 (m, 18 H),
2732
Eur. J. Org. Chem. 2002, 2727Ϫ2735

Diastereoselective Approaches to trans-Hydrindane Derivatives
FULL PAPER
overlapping 0.93Ϫ0.85 (m, 9 H, C21-H, C26-H, and C27-H), 0.68 NMR: δ ϭ 221.5 (C14), 204.4 (C9), 203.2 (C21), 145.1 (C25), 134.9
(s, 3 H, C18-H) ppm. 13C NMR: δ ϭ 138.2 (C-ipso), 133.2 (C-p), (C-ipso), 129.8 (C-o), 128.9 (C-m), 126.7 (C-p), 110.3 (C26), 54.1,
128.8 (C-o), 128.6 (C-m), 76.8 (C24), 63.6 (C8), 54.9 and 54.8, 48.0,
51.2, 48.7, 43.9, 43.2, 37.6, 36.5, 35.8, 31.0, 29.5 (tBuS), 29.1, 24.2,
44.5 (C14), 38.6, 35.5 and 35.3, 33.4 and 33.1, 30.4 (split), 27.7, 22.9, 22.1, 18.7. EI MS: m/z (%) ϭ 488 (68), 398 (31), 309 (21), 275
25.2, 21.0, 18.9, 18.7 (split), 18.5, 17.1 and 16.6 (C21), 11.7 (C18). (86), 196 (43), 179 (22), 167 (21), 147 (22), 135 (23), 123 (66), 57
LSIMS (ϩ) (NBA, 8 kV): m/z (%) ϭ 831 (1.2) [2 M ϩ Na]ϩ, 427 (100). C28H40O3S2 (488.76): calcd. C 68.81, H 8.25; found C 68.74,
(32) [M ϩ Na]ϩ, 405 (1.2) [M ϩ H]ϩ. C24H36NaO3S [M ϩ Na]ϩ: H 8.24. 25: M.p. 85Ϫ86 °C (methanol). IR (KBr): ν˜ ϭ 1677, 1601,
1
427.22829; found 427.22822 (HR LSIMSMS).
1584 cmϪ1. H NMR: δ ϭ 7.30Ϫ7.00 (m, 5 H, SPh), 4.70 (br. s, 1
H, C26-H), 4.66 (br. s, 1 H, C26-H), 2.80Ϫ1.10 (m, 16 H), overlap-
ping 1.69 (s, 3 H, C27-H), 1.48 (s, 9 H, StBu), 1.24 (s, 3 H, C18-
H) ppm. 13C NMR: δ ϭ 203.2 (C21), 193.6 (C9), 185.2 (C14), 145.1
(C25), 135.9 (C-ipso), 128.8 (C-o), 127.1 (C-m), 125.4 (C-p), 125.1
(C8), 110.3 (C26), 54.2 (C20), 52.4 (C17), 48.7 (StBu), 47.3 (C13),
37.6, 34.6, 34.1, 32.1, 30.5, 29.6 (StBu), 26.0, 24.3, 22.2 (C27), 16.7
(C18) ppm. MS EI: m/z (%) ϭ 470 (100), 414 (11), 353 (22), 305
(27), 271 (13), 256 (20), 255 (25), 243 (22), 149 (26), 147 (45), 95
(25), 91 (30), 57 (77). C28H38O2S2 (470.74): C 71.44, H 8.14; found
71.42, H 8.17.
S-tert-Butyl 6-Methylhept-6-enethioate: This compound was pre-
pared from ethyl 6-methylhept-6-enoate[21] in a way analogous to
that described above for the thioester corresponding to 6. The
1
product was distilled at 100Ϫ102 °C/1.0 Torr. H NMR: δ ϭ 4.67
(m, 1 H, ϭCH), 4.64 (m, 1 H, ϭCH), 2.43 (t, J ϭ 7.3 Hz, 2 H, C2-
H), 1.99 (t, J ϭ 7.1 Hz, 2 H, C5-H), 1.75Ϫ1.15 (m, 4 H, C3-H and
C4-H), overlapping 1.68 (s, 3 H, ϭCCH3), 1.43 (s, 9 H, SCCH3)
ppm. 13C NMR: δ ϭ 200.3 (C1), 145.3 (C6), 110.1 (C7), 47.7
(SϪC), 44.4, 37.3, 29.7, 26.7, 25.2, 22.2 ppm. MS: m/z (%) ϭ 158
(25), 125 (100), 97 (50), 96 (27), 82 (24), 57 (24), 55 (17). C12H22OS
(214.37): calcd. C 67.24, H 10.34; found C 67.00, H 10.26.
S-tert-Butyl rac-(2R*)-6-Methyl-2-[(1R*,7aR*)-7a-methyl-5-oxo-4-
(phenylthio)-2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]hept-6-enethioate
(25): A solution of KOH in methanol (20%, 0.03 mL) was added
to a solution of dione 24 (300.0 mg, 0.61 mmol) in methanol
(15.0 mL). After 1 h, the solvent was evaporated at room temp. and
the residue was chromatographed on SiO2 (15.0 g, hexane/EtOAc,
20:1, 9:1). Enone 25 (233 mg, 0.49 mmol, 81%), identical with the
sample described above, was obtained.
(E)- and (Z)-[1-(tert-Butylthio)-6-methylhepta-1,6-dienyloxy]tri-
methylsilane (23): The thioester described above (1.0 g, 4.7 mmol)
was added at Ϫ78 °C to a solution of LDA (6.3 mmol) [prepared
from iPr2NH (0.713 mg, 7.0 mmol) and BuLi (2.0  in hexane,
3.15 mL, 6.3 mmol)] in THF, followed after 30 min by TMSCl
(1.02 g, 9.4 mmol). The mixture was stirred at Ϫ78 °C for 4 h, and
was then set aside at room temp. for 12 h. The solvent was evapor-
ated, and the residue was diluted with dry hexane and filtered. The
filtrate was concentrated and the residue was distilled in a Kugel-
rohr apparatus (150 °C/4 Torr). Ketene acetal 23 (1.15 g, 85%) was
obtained as a mixture of (E)/(Z) isomers in a ratio of 9:1 (by 1H
S-tert-Butyl rac-(2R*)-2-[(1R*,5S*,7aR*)-5-Hydroxy-7a-methyl-4-
(phenylthio)-2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-6-methylhept-6-
enethioate (26): NaBH4 (20.0 mg) was added at Ϫ78 °C to a solu-
tion of enone 25 (208.0 mg, 0.44 mmol) and CeCl3·7H2O (82.0 mg)
NMR, StBu signals). (E) isomer: 1H NMR: δ ϭ 5.21 (t, J ϭ 7.4 Hz, in methanol (5.25 mL) and THF (3.5 mL). The mixture was stirred
1 H, C2-H), 4.67 (m, 2 H, C7-H2), 2.17 (m, 2 H, C3-H), 2.02 (m, at Ϫ78 °C for 2 h, allowed to warm to room temp., and poured
2 H, C5-H), 1.70 (s, 3 H, C6-CH3), 1.46 (m, 2 H, C4-H), 1.36 (s, 9
into 10% aqueous tartaric acid. The product was extracted with
H, StBu), 0.22 (s, 9 H, Si-CH3) ppm. 13C NMR: δ ϭ 145.9 (C1), dichloromethane. The extract was dried with Na2SO4 and the solv-
145.3 (C6), 120.4 (C2), 109.7 (C7), 46.3 (S-C), 37.4 (C5), 31.8 ent was evaporated. The residue was chromatographed on SiO2
1
(SCCH3), 28.9 (C3), 28.1 (C4), 22.4 (C6), 0.35 (Si-CH3). (Z) isomer
(6.0 g, hexane/EtOAc, 9:1) to give alcohol 26 (192.0 mg, 93%). H
(diagnostic signals): H NMR: δ ϭ 1.33 (s, 9 H, StBu) ppm. 13C NMR: δ ϭ 7.31Ϫ7.10 (m, 5 H, SPh), 4.69 (br. s, 1 H, C26-H), 4.65
NMR: δ ϭ 125.2 (C2), 109.9 (C7), 37.6 (C5), 31.4 (SCCH3), 27.4 (br. s, 1 H, C26-H), 4.05 (t, J ϭ 6.8 Hz, 1 H, C9-H), 2.63Ϫ1.20
(C3), 26.8 (C4), 0.76 (Si-C) ppm. MS EI: m/z (%) ϭ 286 (0.2), 229 (m, 16 H), overlapping 1.69 (s, 3 H, C27-H), 1.48 (s, 9 H, StBu),
1
(74), 161 (19), 133 (22), 95 (16), 75 (16), 73 (100), 57 (44), 55 (29),
45 (15), 41 (37). C15H30OSSi (286.56): calcd. C 62.87, H 10.55; 145.2 (C25), 134.7 (C-ipso), 128.9 (C-o), 127.5 (C-m), 125.6 (C-p),
1.12 (s, 3 H, C18-H) ppm. 13C NMR: δ ϭ 203.5 (C21), 161.4 (C14),
found C 62.87, H 10.74.
124.4 (C8), 110.1 (C26), 67.6 (C9), 54.5 (C20), 52.6 (C17), 48.4
(StBu), 46.1 (C13), 37.6, 34.3, 32.1, 29.6 (StBu), 28.4, 27.1, 25.8,
24.4, 22.2 (C27), 17.8 (C18) ppm. MS EI: m/z (%) ϭ 472 (100)
[M]ϩ, 395 (31), 227 (21), 181 (27), 149 (23), 147 (21), 131 (34), 95
(30), 57 (44). C28H40S2O2 [Mϩ]: 472.2469; found 472.2466 (HR
MS).
S-tert-Butyl rac-(2R*)-6-Methyl-2-{(1R*,2R*)-2-methyl-3-oxo-2-[3-
oxo-4-(phenylthio)butyl]cyclopentyl}hept-6-enethioate (24) and S-
tert-Butyl
rac-(2R*)-6-Methyl-2-[(1R*,7aR*)-7a-methyl-5-oxo-4-
(phenylthio)-2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]hept-6-enethioate
(25): Acetal 23 (0.868 g, 3.03 mmol) in dichloromethane (1.5 mL)
was added at Ϫ78 °C over 15 min to a stirred solution of enone 5
(0.306 g, 3.19 mmol) and TrSbCl6 (101 mg, 0.17 mmol) in dichloro-
methane (8.5 mL). After 1 h, enone 8 (0.56 g, 3.19 mmol) in dichlo-
romethane (1.5 mL) was added over 15 min. The mixture was set
rac-(1R*,5S*,7aR*)-1-[(1R*)-1-Hydroxymethyl-5-methylhex-5-
enyl]-7a-methyl-4-(phenylthio)-2,3,5,6,7,7a-hexahydro-1H-inden-5-ol
(27): LiAlH4 (1.3 mg) was added to a solution of thioester 26
(16.0 mg, 0.034 mmol) in THF (1.5 mL). The mixture was heated
aside at Ϫ78 °C for 2 h, and was then allowed to warm to room at reflux temperature for 30 min. After the mixture had cooled to
temp. (ca. 1 h), and the reaction was quenched with water (1.0 mL).
The mixture was diluted with hexane and filtered through a pad of
Celite. The filtrate was dried with Na2SO4, the solvent was evapor-
ated, and the residue was chromatographed on SiO2 (100 g, hexane/
room temperature, methanol (0.3 mL) was added and the whole
mixture was poured into 10% aqueous tartaric acid. The product
was extracted with dichloromethane. The organic extract was dried
with Na2SO4 and the solvent was evaporated. The residue was
EtOAc, 9:1) to give dione 24 (980 mg, 2.01 mmol, 63%) and enone chromatographed on SiO2 (1.8 g, hexane/EtOAc, 5:1, 4:1) to give
1
25 (60.0 mg, 0.12 mmol, 4.0%). 24: M.p. 63Ϫ64 °C (methanol). IR diol 27 (11.0 mg, 84%). H NMR: δ ϭ 7.45Ϫ7.10 (m, 5 H, SPh),
(KBr): ν˜ ϭ 1736, 1712, 1672, 1583 cmϪ1. 1H NMR: δ ϭ 7.39Ϫ7.15 4.75 (br. s, C26-H), 4.03Ϫ4.22 (m, 1 H, C9-H), 3.61 (m, 2 H, C21-
(m, 5 H, SPh), 4.71 (br. s, 1 H, C26-Ha), 4.67 (br. s, 1 H, C26-Hb), H), 2.82Ϫ0.90 (m, 16 H), overlapping 1.76 (s, 3 H, C27-H), 1.11
3.64 (s, 2 H, C8-H), 2.78Ϫ0.90 (m, 16 H), overlapping 1.69 (s, 3 H,
(s, 3 H, C18-H) ppm. 13C NMR: δ ϭ 162.3 (C14), 145.7 (C25),
134.9 (C-ipso), 128.9 (C-o), 127.5 (C-m), 125.6 (C-p), 123.9 (C8),
C27-H), 1.40 (s, 9 H, S-C-CH3), 0.99 (s, 3 H, C18-H) ppm. 13C
Eur. J. Org. Chem. 2002, 2727Ϫ2735
2733

I. Prowotorow, W. Stepanenko, J. Wicha
109.8 (C26), 67.8 (C9), 62.8 (C21), 50.8 (C20), 46.1 (C13), 40.9 was dried (Na2SO4) and the solvent was evaporated. The residue
FULL PAPER
(C17), 38.1, 34.9, 28.8, 28.4, 25.8, 24.6, 22.4 (C27), 17.9 (C18). MS
was chromatographed on SiO2 (3.0 g, hexane/EtOAc, 4:1, 3:1, 2:1,
EI: m/z (%) ϭ 386 (100), 309 (93), 149 (25), 147 (19), 135 (20), 133
1:1). Sulfone 2 was obtained (15.2 mg, 69%). One crystallization
(37), 131 (25), 121 (20), 109 (35), 107 (24), 105 (31), 95 (35), 93 from hexane/benzene gave analytically pure material (12.5 mg),
(22), 81 (24), 79 (32), 77 (32), 69 (40), 55 (66). C24H34O2S [Mϩ]: m.p. 109Ϫ110 °C identical with a sample described above.
386.2279; found 386.2275 (HRMS).
(6R)-2-Methyl-6-[(1R,7aR)-7a-methyl-4-(phenylthio)-2,3,5,6,7,7a-
rac-(2R*)-2-{(5S*,7aR*)-[5-Hydroxy-7a-methyl-4-(phenylthio)-
hexahydro-1H-inden-1-yl]heptan-2-ol (31): BF3·2H2O (0.07 mL,
2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]}-6-methylhept-6-enyl Tolu-
1.10 mmol) was added at 0 °C to a solution of 30[25] (280 mg,
ene-4-sulfonate (28): TsCl (24.0 mg, 0.125 mmol) was added at 0 °C
to a solution of diol 27 (20.0 mg, 0.05 mmol) in dichloromethane
1.00 mmol) and PhSH (1.03 mL, 10 mmol) in dichloromethane
(6 mL). The mixture was stirred at 0 °C for 6 h and then poured
(1.2 mL), containing Et3N (0.1 mL) and DMAP (1.5 mg). The mix-
into 10% aqueous NaOH. The product was extracted with dichlor-
ture was stirred at 0Ϫ5 °C for 4 h, allowed to warm to room tem-
omethane. The extract was washed with water and the solvent was
evaporated. The residue was chromatographed on SiO2 (25 g, hex-
perature and then poured into 2% sulfuric acid. The product was
extracted with dichloromethane. The organic extract was washed
successively with aqueous NaHCO3 and water and dried (Na2SO4),
and the solvents were evaporated. The residue was chromato-
ane/EtOAc, 50:1, 20:1, 5:1). Sulfide 31 (245 mg, 66%) was obtained.
[α]2D2 ϭ ϩ23.7 (c ϭ 1.83). 1H NMR: δ ϭ 7.31Ϫ7.06 (m, 5 H, SPh),
2.50Ϫ0.89 (m, 19 H), overlapping 1.22 (s, 6 H, C27-H and C26-
H), 0.98 (d, 3 H, J20,21 ϭ 6.5 Hz, C21-H), 0.98 (s, 3 H, C18-H)
graphed on SiO2 (2.0 g, hexane/EtOAc, 5:1, 4:1, 2:1). Tosylate 28
1
was obtained (23.0 mg, 85%). H NMR: δ ϭ 7.79 (d, J ϭ 8.2 Hz,
ppm. 13C NMR: δ ϭ 157.1 (C14), 136.1 (C-ipso), 128.6 (C-
2 H, C-o-H aromat. Ts), 7.34 (d, J ϭ 8.5 Hz, 2 H, C-m-H aromat.
o),128.1(C-m),125.2 (C-p), 119.3 (C8), 70.9 (C25), 56.3, 45.3
(C13),44.2, 36.7, 36.0, 34.6, 30.2, 29.2, 29.1, 27.8, 26.5, 20.6, 20.2,
Ts), 7.60Ϫ7.05 (m, 5 H, SPh), 4.67 (br. s, C26-H), 4.57 (br. s, C26-
H), 4.20Ϫ3.95 (m, 3 H, C21-H2 and C9-H), 2.78Ϫ0.85 (m, 16 H),
18.7, 18.1 ppm. MS EI (70 eV): m/z (%) ϭ 372 (52) [Mϩ], 375 (11)
overlapping 2.44 (s, 3 H, CH3 Ts), 1.64 (s, 3 H, C27-H), 0.98 (s, 3
[M Ϫ CH3]ϩ, , 339 (20) [M Ϫ CH3, Ϫ H2O]ϩ, 295 (91) [M Ϫ Ph]ϩ,
H, C18-H) ppm. 13C NMR: δ ϭ 161.3 (C14), 145 (C25), 144.9 (C-
277 (25) [M Ϫ Ph, Ϫ H2O]ϩ, 245 (25) [M Ϫ SPh, Ϫ H2O)ϩ, 189
ipso, Ts), 134.7 (C-ipso, SPh), 132.7 (C-p, Ts), 129.8 (C-o Ts), 129.1
(14), 161 (24), 105 (13), 91 (18), 69 (19). C24H36OS [Mϩ]: calcd.
372.24869; found 372.249 (HRMS).
(C-o,Ph), 127.9 (C-m, Ts), 127.7 (C-m, Ph), 125.8 (C-p Ph), 124.7
(C8), 109.9 (C26), 70.3 (C9), 67.5 (C21), 50.3 (C20), 45.9 (C13),
38.5 (C17), 37.7, 34.8, 28.5, 28.2, 28.1, 26.0, 23.9, 22.3, 21.6, 17.8
(6R)-6-[(1R,7aR)-7a-Methyl-4-(phenylsulfonyl)-2,3,5,6,7,7a-hexa-
hydro-1H-inden-1-yl]-2-methylheptan-2-ol (32): m-CPBA (60%,
(C18). MS EI: m/z (%) ϭ 540 (100), 463 (48), 241 (24), 149 (27),
147 (22), 145 (21), 131 (30), 109 (24), 105 (26), 95 (31), 91 (49), 69
63 mg, 0.22 mmol) was added at 0 °C to a solution of 31 (37 mg,
0.10 mmol) in dichloromethane (2 mL). The mixture was set aside
at room temp. for 2 h and then poured into aqueous NaHCO3.
The product was extracted with dichloromethane. The extract was
washed with aqueous Na2S2O3 and water, and the solvent was
evaporated. The residue was chromatographed on SiO2 (6 g, hex-
ane/EtOAc, 10:1, 5:1, 2:1). Sulfone 32 (40 mg, 99%) was obtained.
(21), 55 (24). C31H40O4S2 [Mϩ]: calcd. 540.2368; found 540.2387
(HR MS).
rac-(2R*)-2-[(5S*,7aR*)-5-Hydroxy-7a-methyl-4-(phenylsulfonyl)-
2,3,5,6,7,7a-hexahydro-1H-inden-1-yl]-5-(2-methyloxiranyl)pentyl
Toluene-4-sulfonate (29): m-CPBA (70%, 62 mg, 0.25 mmol) was
added at 0 °C to a solution of tosylate 28 (30 mg, 0.06 mmol) in
dichloromethane (2.3 mL). The mixture was stirred at room tem-
perature for 2 h, and was then poured into aqueous NaHCO3
(4 mL). The product was extracted with dichloromethane. The or-
ganic extract was washed successively with aqueous Na2S2O3
(10 mL) and water and then dried (Na2SO4), and the solvents were
evaporated. The residue consisted of epimeric epoxy sulfones 29
[α]2D2 ϭ ϩ16.3 (c ϭ 1.70). H NMR: δ ϭ 7.89Ϫ7.77 (m, 2 H, H-m
1
Ph), 7.63Ϫ7.43 (m, 3 H, H-o, -p Ph), 3.07Ϫ2.61 (m, 2 H),
2.43Ϫ0.79 (m, 17 H), overlapping 1.20 (s, 6 H, C27-H and C26-
H), 0.93 (d, 3 H, J20,21 ϭ 6.5 Hz, C21-H), 0.89 (s, 3 H, C18-H)
ppm. 13C NMR: δ ϭ 163.2 (C14), 141.2 (C-ipso), 132.7 (C-p), 128.8
(C-o), 128.6 (C8), 127.0 (C-m), 70.8 (C25), 54.7, 46.7 (C13), 44.1,
35.9, 35.2, 33.9, 29.2, 29.1, 27.5, 26.8, 24.3, 20.6, 18.8, 18.6, 18.2
ppm. MS EI (70 eV): m/z (%) ϭ 402 (0.3) [M Ϫ H2]ϩ, , 389 (19)
[M Ϫ CH3]ϩ, 386 (44) [M Ϫ H2O]ϩ, 371 (6) [M Ϫ CH3, Ϫ H2O]ϩ,
331 (14), 274 (29), 245 (100) [M Ϫ H2O, Ϫ SO2Ph]ϩ, 161 (53), 149
(59), 133 (76), 109 (35), 69 (34). LSIMS (ϩ) (NBA, 8 kV): m/z
(%) ϭ 831 (1.2) [2 M ϩ Na]ϩ, 427 (32) [M ϩ Na]ϩ, 405 (1.2) [M ϩ
H]ϩ. C24H36O3SNa [M ϩ Na]ϩ: calcd. 427.22829; found 427.22822
(LSIMS HRMS).
1
1
(32.0 mg, 98%) in a ratio of 2:1 (by H NMR). Major isomer: H
NMR: δ ϭ 8.05Ϫ7.30 (m, 9 H, H-arom.), 4.69 (t, 1 H, C9-H), 3.97
(m, 2 H, C21-H), 2.82Ϫ0.85 (m, 16 H), overlapping 2.51 (s, 3 H,
CH3 Ts), 1.21 (s, 3 H, CH3 Ts), 0.92 (s, 3 H, C18-H) ppm. 13C
NMR: 167.8 (C14), 145.0 (C-ipso Ts), 141.3 (C-ipso Ph), 134.5,
133.3, 132.6, 130.2, 129.9, 129.1, 127.9, 127.1, 70.1 (C21), 65.7
(C9), 56.5 (C25), 53.6 (C26), 49.3 (C20), 47.2 (C13), 37.7, 36.4,
34.2, 28.9, 27.5, 25.8, 21.8, 21.6, 20.8, 18.0 (C18). Diagnostic sig-
nals of the minor isomer: 1H NMR: δ ϭ 2.44 (s, 3 H, CH3 Ts),
1.24 (s, 3 H, C27-H) ppm. 13C NMR: δ ϭ 134.4, 129.7, 53.7, 37.7,
36.6, 29.0, 27.8, 20.8 ppm. C31H40NaO7S2 [Mϩ]: calcd. 611.2108;
found 611.2124 (HR MS). This mixture was further used without
separation.
(؊)-(6R)-6-[(1R,3aR,4R,7aR)-7a-Methyl-4-(phenylthio)octahydro-
inden-1-yl]-2-methylheptan-2-ol [(؊)-2]: LiAlH4 (0.25  in THF,
0.6 mL, 0.150 mmol) was added to a solution of 32 (50 mg,
0.124 mmol) in THF (2 mL), and the mixture was heated at reflux
temperature for 20 min. After the mixture had cooled, methanol
(0.5 mL) was added, and the whole mixture was poured into 10%
aqueous tartaric acid. The product was extracted with dichlorome-
rac-(6R*)-2-Methyl-6-[(4R*,7aR*)-7a-methyl-4-(phenylthio)octa-
hydroinden-1-yl]heptan-2-ol (2): LiAlH4 (8.2 mg) was added to a so-
lution of epoxysulfone 29 (32.0 mg, 0.054 mmol) in THF (0.5 mL), thane. The solvent was evaporated and the residue was chromato-
and the mixture was heated at reflux temperature for 35 min. After
the mixture had cooled, methanol (0.5 mL MeOH) was added, and
the whole mixture was poured into 10% aqueous tartaric acid. The
product was extracted with dichloromethane. The organic extract
graphed on SiO2 (2 g, hexane/EtOAc, 50:1, 10:1, 5:1). Sulfone (ϩ)-
2 (32 mg, 63%) was obtained. M.p. 128 °C (benzene/hexane, 1:5).
[α]2D2 ϭ Ϫ0.35 (c ϭ 0.6). 1H and 13C NMR spectra are identical
with those of a racemic sample.
2734
Eur. J. Org. Chem. 2002, 2727Ϫ2735

Diastereoselective Approaches to trans-Hydrindane Derivatives
FULL PAPER
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[11]
Acknowledgments
We thank Prof. A. R. Daniewski of HoffmannϪLa Roche, Natley,
USA, for providing us with compound 30. Financial support from
the State Committee for Scientific Research (Grant No. 3 T09A
134 18) is gratefully acknowledged.
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with the cis-hydrinadane system: (1R,3aS,7aR)-1-[(2R)-6-hy-
droxy-6-methylhept-2-yl]-7a-methyloctahydroinden-4-one (30):
1H NMR: δ ϭ 1.18 (s, 6 H, C26, C27-H), 1.02 (s, 3 H, C18-H),
0.90 (d, J ϭ 6.3 Hz, 3 H, C21-H). Ref.[23] 1H NMR: (300 MHz,
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Received March 19, 2002
[O02150]
Eur. J. Org. Chem. 2002, 2727Ϫ2735
2735