On reduction of α,β-unstaurated ketones and the respective allylic alcohols, bearing a phenylsulfonyl or phenylsulfanyl group in the a position. Hydroxy group-controlled stereoselective reduction of 3α- And 3β-hydroxy-4-(phenylsulfonyl)cholest-4-ene

Article abstract of DOI:10.1039/b000600i

Reduction reactions of chplest-4-en-3-one derivatives bearing the phenylsulfonyl or phenylsulfanyl group at C-4 with various metal hydrides are studied. Lithium aluminohydride reduction of 4-(phenylsulfonyl)cholest-4-en-3β-ol 13a and 4-(phenylsulfonyl)cholest-4-en-3α-ol 15a occurs with saturation of the double bond and deoxygenation to give 4β-phenylsulfonyl-5β-cholestane 8 and 4α-phenylsulfonyl-5α-cholestane 7a, respectively. Reduction of 4-(phenylsulfonyl)cholest-4-en-3-one 2 with lithium aluminohydride yields compound 8. Reduction of compounds 2, 13a and 15a with other metal hydrides affords mixtures of diastereomeric products. Metal hydride reductions of 4-(phenylsulfanyl)cholest-4-en-3-one 1 affect the carbonyl group only. Catalytic hydrogenation of compound 2 gives a mixture of 5α- and 5β- dihydro derivatives. Mechanistic and stereochemical aspects of the reduction reactions are discussed. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b000600i

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On reduction of ꢀ,ꢁ-unstaurated ketones and the respective allylic
alcohols, bearing a phenylsulfonyl or phenylsulfanyl group in the
ꢀ position. Hydroxy group-controlled stereoselective reduction of
3ꢀ- and 3ꢁ-hydroxy-4-(phenylsulfonyl)cholest-4-ene
1
Karol Michalak, Wiaczesław Stepanenko and Jerzy Wicha*
Institute of Organic Chemistry, Polish Academy of Sciences, POB 58, 01-224 Warsaw, Poland
Received (in Cambridge, UK) 21st January 2000, Accepted 17th March 2000
Published on the Web 19th April 2000
Reduction reactions of cholest-4-en-3-one derivatives bearing the phenylsulfonyl or phenylsulfanyl group at C-4
with various metal hydrides are studied. Lithium aluminohydride reduction of 4-(phenylsulfonyl)cholest-4-en-3β-ol
13a and 4-(phenylsulfonyl)cholest-4-en-3α-ol 15a occurs with saturation of the double bond and deoxygenation
to give 4β-phenylsulfonyl-5β-cholestane 8 and 4α-phenylsulfonyl-5α-cholestane 7a, respectively. Reduction of
4-(phenylsulfonyl)cholest-4-en-3-one 2 with lithium aluminohydride yields compound 8. Reduction of compounds 2,
13a and 15a with other metal hydrides affords mixtures of diastereomeric products. Metal hydride reductions of
4-(phenylsulfanyl)cholest-4-en-3-one 1 affect the carbonyl group only. Catalytic hydrogenation of compound 2 gives
a mixture of 5α- and 5β- dihydro derivatives. Mechanistic and stereochemical aspects of the reduction reactions are
discussed.
was expected that we would gain insight into the multistep
reduction mechanism and, eventually, develop stereoselective
approaches to trans- and cis-decalin derivatives.
Introduction
Metal hydride reduction reactions of α,β-unsaturated ketones,1,2
α-phenylsulfonyl ketones3 and vinyl sulfones4–6 have been exten-
sively studied. However, there are no reports on the reduction
Results and discussion
of α,β-unsaturated ketones bearing in the α-position a phenyl-
sulfonyl or a phenylsulfanyl group. In such derivatives relative
rates of reduction of the carbonyl group and the double bond
may differ from those in the parent compound, and, con-
sequently, the steric outcome of the reaction may be different.
Some consecutive reactions due to the presence of the sulfur-
containing group may also occur. Recently, we have shown7,8
that the complex hydrindane derivative i with oxo and vinyl
sulfone functions, in reaction with lithium aluminohydride was
transformed stereoselectively into product iii with trans-fused
hydrindane rings. We have also noted that the steric course of
the carbon–carbon double-bond reduction doesn’t depend
upon the orientation of the hydroxy group (α or β) in the inter-
mediate ii. It was thought of interest to examine in some detail
the reduction of easily available α,β-unsaturated ketones 1 and
2, and the corresponding 3-hydroxy derivatives that are likely
immediate products of the carbonyl compounds’ reduction. It
Sulfide 1 was prepared by treatment of 4β,5-epoxy-5β-
cholestan-4-one9 with thiophenol and potassium hydroxide in
ethanol.10 Sulfone 2 was obtained by oxidation of sulfide 1 with
MCPBA. In order to prepare some reference compounds,
the known11,12 3α,4α-epoxy-5α-cholestane 3 (Scheme 1) was
Scheme 1 Reagents and yields: (a) PhSH, EtOH, 83% yield; (b) MsCl,
Et3N, CH2Cl2; (c) MCPBA, 100%; (d) DBU, PhH, 95% in 2 steps; (e)
Et3BLiH, 99%; (f) tert-BuOK–tert-BuOH, 100%.
allowed to react with sodium thiophenolate in ethanol to give
diaxial hydroxy sulfide 4, by analogy to the procedure
developed for related hydrindane derivatives.13 Compound 4
was treated consecutively with mesyl chloride, MCPBA, and
DBU to afford vinylic sulfone 6. Reduction of 6 with Et3BHLi
and chromatographic separation of the products afforded
DOI: 10.1039/b000600i
J. Chem. Soc., Perkin Trans. 1, 2000, 1587–1594
This journal is © The Royal Society of Chemistry 2000
1587

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4α- and 4β-phenylsulfonyl derivatives 7a and 7b in 79 and 20%
yield, respectively. Alternatively, oxidation of hydroxy sulfide
4 with MCPBA provided sulfone 5, which on treatement with
mesyl chloride and then with Et3BHLi gave a mixture of 7a
and 7b. Compound 7b with an axially oriented phenylsulfonyl
group was transformed into its epimer 7a quantitatively with
potassium tert-butoxide in tert-butyl alcohol.14
Reduction of sulfone 2 with an excess of LiAlH4 in THF at
room temperature afforded saturated sulfone 8 with cis con-
figuration at the ring junction, isolated in 78% yield. The struc-
ture of compound 8 was confirmed by its reduction with
sodium amalgam, which afforded 5β-cholestane.
Reduction of compound 2 with NaBH4 in methanol afforded
a mixture of hydroxy sulfones 9 (5α-H) and 10 (5β-H) (83%
yield). The mixture could not be separated by either chrom-
atography or crystallization; however, a sample of pure com-
pound 9 was isolated by precipitation. Oxidation of the crude
mixture of 9 and 10 with Jones reagent followed by chrom-
atography afforded oxo sulfones 11 and 12 in 58% and 41%
yield, respectively. Configuration at C-5 in compounds 11 and
12 was established by their reduction to 5α- and 5β-cholestan-3-
one, respectively.
smoothly reduced under analogous conditions to give alcohol
9. This experiment shows that the reduction reaction occurs
along two mechanistic paths: (1) with reduction of the carbonyl
group preceding the reduction of the carbon–carbon double
bond and (2) with reduction of the carbon–carbon double bond
occurring first, followed by reduction of the carbonyl group
(or providing a saturated ketone 12). In practical terms, selec-
tivity with regard to the ring-junction configuration was poor,
providing, in total, 5α and 5β isomers in the ratio 65:35.
Reduction of 2 with a system, CuCN–n-BuLi–DIBAH, that
is known to reduce steroidal and related 4-en-3-ones selectively
to the corresponding 5α-H saturated ketones,15,16 afforded a
mixtute of ketones 11 (39%) and 12 (22%) and unsaturated
alcohol 13a (10%). Reduction of 2 with DIBAH in methylene
dichloride affected the carbonyl group only and yielded quanti-
tatively alcohol 13a.
Allylic alcohol 13a was thought to be a likely intermediate in
reduction of phenylsulfonyl enone 2 to sulfone 8 by means of
LiAlH. Since a directive effect of the hydroxy group appeared
to be possible it was of interest to compare the steric courses
of reduction of epimeric alcohols 13a and 15a. Accordingly,
alcohol 13a was subjected to the Mitsunobu inversion which
afforded 3α-hydroxy sulfone 15a in 64% overall yield, via
benzoate 15b. In parallel experiments 15a was prepared from
3β-hydroxy sulfide 14 (see below) via 16b and 16a in a somewhat
better overall yield (68%).
Reduction of 3β-hydroxy sulfone 13a with LiAlH4 afforded
5β-H sulfone 8 in 78% yield. Reduction of 3α-hydroxy sulfone
15a with LiAlH4 afforded 5α-H sulfone 7a in 82% yield.
In light of the clear directing effect exerted by the hydroxy
group in the reduction of hydroxy sulfone 13a, it was of interest
to examine the effect of an alkoxy group. To this end, the meth-
oxymethyl derivative 13b, prepared from 13a in the usual way,
was treated with LiAlH4. Three products, 8, 7a and 7b, were
obtained; a ratio of 5α- to 5β-H products was estimated as
≈1:1. The above results for the reduction reactions of vinylic
sulfones 2, 13a and 15a are compiled in Table 1.
Reduction of sulfide 1 with various reducing agents afforded
mixtures of 3-hydroxy-4-(phenylsulfanyl)cholest-4-enes 14 and
16a. Some results are shown in Table 2. No carbon–carbon
double-bond reduction was observed. Only Luche reduction17
(NaBH4–CeCl3) was virtually selective with respect to 3β-
hydroxy derivative 14.
Catalytic hydrogenation of sulfone 2 in the presence of 10%
palladium on carbon was examined for completeness of our
study. Compound 2 was practically unchanged under hydro-
genation conditions in EtOH at room temperature. However, at
reflux temperature the reaction was complete in ca. 5 h to yield
trans and cis products, 11 and 12 in the ratio 6.5:1. Hydrogen-
ation of 2 in EtOH at room temperature in the presence of
CF3COOH afforded 11 and 12 in the ratio 5.5:1. Our attempts
to achieve stereoselective reduction of the carbon–carbon
double bond in 2 by varying the solvent in the catalytic hydro-
genation reaction failed.
The above described experiments allow for some mechanistic
comments. It is likely that reduction of 2 to 5β-H saturated
sulfone 8 commences with hydride ion addition to the carbonyl
group from the α-side to form intermediate iv, Scheme 2.
Further reduction occurs with intramolecular hydride ion
delivery and elimination of the metal-bonded oxygen atom.
The intermediate vinylic sulfone v with cis ring junction under-
goes further reduction to 8. This mechanism is corroborated by
stereoselective reduction of the allylic alcohol with β-oriented
hydroxy group, 13a (Table 1, entry 2). Intramolecular hydride
anion delivery presumably occurs in a similar fashion in
reduction of 3α-hydroxy derivative 15a (via intermediate vi) to
yield 5α-H sulfone 7a (Table 1, entry 3). The importance of the
hydroxy group for stereoselective introduction of the hydrogen
at C-5 is also shown by the reduction of the MOM ether 13b
in which a mixture of 5α- and 5β-H products was formed
The configuration around C-3 and C-4 in compound 9
follows from the results of nuclear Overhauser effects (NOE)
experiments involving C-19, C-4 and C-3 protons (see Experi-
mental section). Configuration around C-3 and C-4 in 10 was
1
deduced from the H NMR spectrum of the mixture of 9 and
10 in which the signals of the C-3 proton (δ 3.91, broad singlet)
and the C-4 proton (δ 3.15, doublet of doublets, J = 12.1 and
2.0 Hz) in 10 could be seen. It was assumed that the value J = 2
Hz corresponds to C-3–C-4 proton coupling (cis) and that the
value J = 12.1 Hz reflects coupling of C-4 and C-5 protons in a
trans configuration (4α,5β). The assignment of structures of 9
1
and 10 was corroborated by the H NMR spectrum of previ-
ously prepared hydroxy sulfone epimer 5 which differs from
that of 9 in the orientation of the phenylsulfonyl group. It is
noteworthy that in both alcohols 9 and 10 the hydroxy group
occupies an axial position whereas the sulfonyl group is in an
equatorial position.
Next, reduction of 2 with NaBH4 in THF in the presence of
DMPU as a polar co-solvent was examined. Treatment of 2
with NaBH4 in THF–DMPU (a suspension) at room tempera-
ture afforded a mixture of hydroxy sulfones 9 and 10 in 74%
yield in a ratio of ≈5.5:1, and oxo sulfone 12 in 23% yield. Oxo
sulfone 12 resisted further reduction under the reaction con-
ditions. It is noteworthy that isomeric oxo sulfone 11 was
1588
J. Chem. Soc., Perkin Trans. 1, 2000, 1587–1594

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Table 1 Reduction of oxo sulfone 2 and hydroxy sulfones 13a and 15a with metal hydrides
Entry
Compound
Reducing system
Product (yield %), ratio
5α:5β
1
2
3
4
5
6
7
8
2
13a
15a
13b
2
LiAlH4–THF
LiAlH4–THF
LiAlH4–THF
LiAlH4–THF
NaBH4–MeOH
NaBH4–THF–DMPU
CuCN–n-BuLi–DIBAH
DIBAH–CH2Cl2
8 (78)
5β-H only
5β-H only
5α-H only
1:1
3:2
2:1
8 (78)
7a (82)
8, 7a, 7b
9, 10 (83)
2
9, 10 (74) and 12 (23)
11 (39), 12 (22), 13a (10)
13a (100)
2
2
2:1
Table 2 Reduction of oxo sulfide 1 with metal hydrides
Entry
Reducing agent
Solvent
Temp.
Product (yield %, ratio)
1
2
3
4
DIBAH
CH2Cl2–hexane
THF
THF–MeOH
THF
Ϫ78 ЊC
Ϫ78 ЊC
Ϫ78 ЊC to rt
rt
14 (69) and 16a (21)
14 and 16a (79, 82:18)a
14 (91)b
L-Selectride
NaBH4–CeCl3
LiAlH4
14 and 16a (91, 84:16)
a Ratio of products was determined by 1H NMR spectroscopy. b Some 15a, less than 5%, could be detected by 1H NMR analysis.
suggestions regarding the multistep reduction have been
made.
Experimental
Mps were determined on a Kofler hot-stage melting point
apparatus and are uncorrected. 1H and 13C NMR spectra were
performed for samples in CDCl3 on a Varian Gemini 200 MHz
spectrometer using residual CHCl3 as an internal standard
(δ 7.26 and 77.0, respectively). Signal multiplicities in 13C
spectra were assigned using DEPT sequence and are given in
brackets. J-Values are given in Hz. Mass spectra were taken at
an ionizing voltage of 70 eV; peak (m/z) relative intensities are
given in parentheses. Air-sensitive reactions were performed in
oven- or flame-dried glassware under argon. Bulk solution of
LiAlH4 (1 M) was prepared using freshly purchased reagent
(Aldrich) and Na/K alloy-dried THF. Organic extracts were
dried over Na2SO4 and the solvents were evaporated on a rotary
evaporator.
4-(Phenylsulfanyl)cholest-4-en-3-one 1
This compound was prepared from 4β,5-epoxy-5β-cholestan-3-
one9 following the described procedure;10 mp 105 ЊC (Found:
C, 80.62; H, 9.70. Calc. for C33H48OS: C, 80.43; H, 9.82%);
λmax(EtOH)/nm 321.3, 250.4, 202.5; νmax(KBr)/cmϪ1 1679, 1581,
1557; δH 7.24–7.02 (5 H, m, ArH), 3.62 (1 H, dtd, J 14.5, 3.0,
0.5), 2.54 (2 H, dd, J 9.9, 4.5), 2.23 (1 H, td, J 14.2, 5.3), 1.29
(3 H, s, 19-H3), 0.91 (3 H, d, J20,21 6.5, 21-H3), 0.86 (6 H, d,
J25,26 and 25,27 6.6, 26- and 27-H3), 0.71 (3 H, s, 18-H3); δC 194.1,
177.9, 137.23, 128.7, 126.9, 125.1, 56.0, 55.7, 54.2, 42.3, 41.6,
39.5, 39.4, 36.0, 35.6, 35.2, 34.6, 34.4, 32.0, 31.0, 28.1, 27.9,
24.0, 23.7, 22.7, 22.5, 21.1, 18.6, 18.3, 11.9. Physical constants
were in agreement with those described, with the exception of
1H NMR signal at δ 3.62 (1 H) which has been not recorded in
the original characterization.
Scheme 2
(Table 1, entry 4). The hydroxy group-directing effect has not
been observed in the reduction of a related hydrindane system.7
This difference suggests that in the hydrindane system reduction
of the vinyl sulfone unit occurs by intermolecular hydride anion
delivery. It is noteworthy that LiAlH4 reduction of the carbon–
carbon double bond at the ring junction in a hydrindane-related
vinylic sulfone lacking an oxygen function afforded the
trans-hydrindane derivative only.6 NaBH4–methanol reduction
of 2 affording a mixture of 9 and 10 shows little selectivity
with respect to the configuration at the ring junction (Table 1,
entry 5).
In conclusion, it was shown that readily available sulfonyl
ketone 2 may be stereoselectively transformed into 5α- or
5β-cholestane derivatives, 7 or 8. Reduction of the sulfur-
containing α,β-unsaturated ketones 1 and 2, and of the
respective alcohols, has been scrutinized. Some mechanistic
4-(Phenylsulfonyl)cholest-4-en-3-one 2
To a stirred solution of sulfide 1 (604 mg, 1.23 mmol) in CH2Cl2
(10 cm3) was added MCPBA (60%; 734 mg, 2.55 mmol) in por-
tions. After 2 h, the mixture was partitioned between aq.
Na2SO3 and CH2Cl2. The organic solution was washed with
water and the solvent was evaporated. The residue was crystal-
lized from acetone–hexane to give sulfone 2 (528 mg, 82%), mp
146–148 ЊC; λmax(EtOH)/nm 253.3, 221.7, 199.6; νmax(KBr)/
cmϪ1 1688; δH 8.02–7.92 (2 H, m, ArH), 7.58–7.42 (3 H, m,
ArH), 4.32 (1 H, dt, J 14.1, 2.8), 2.38–0.82 (26 H, m) over-
J. Chem. Soc., Perkin Trans. 1, 2000, 1587–1594
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lapping with 1.25 (3 H, s, 19-H3), 0.89 (3 H, d, J20,21 7.0, 21-H3),
0.85 (6 H, d, J25,26 7.0, 26- and 27-H3), 0.70 (3 H, s,
mmol). After 8 h the mixture was partitioned between benzene
and aq. Na2SO3. The organic layer was washed succes-
sively with aq. Na2SO3 and water. Evaporation of the solvent
gave 3ξ-chloro-4β-phenylsulfonyl-5α-cholestane (239 mg,
100%), δH 7.94–7.86 (2 H, m, ArH), 7.69–7.51 (3 H, m, ArH),
4.53 (1 H, br s, 3-H), 3.42 (1 H, br d, J4,5 4.3, 4-H), 2.74–2.56
(1 H, m), 2.41–2.23 (2 H, m), 1.21 (3 H, s, 19-H3), 0.90 (3 H, d,
J20,21 8.1, 21-H3), overlapping with 0.86 (6 H, d, J25,26 and 25,27 6.6,
26- and 27-H3), 0.67 (3 H, s, 18-H3); δC 141.1 (C-i)(0), 133.6
(C-o)(1), 129.3 (C-m)(1), 127.7 (C-p)(1), 71.4 (C-3)(1), 56.3 (1),
56.2 (1), 55.3 (1), 44.7 (1), 42.4 (0), 39.8 (2), 39.5 (2), 36.1 (2),
35.9 (1), 35.7 (1), 35.4 (1), 33.2 (2), 32.1 (2), 28.2 (2), 28.0 (1),
27.1 (2), 26.6 (2), 24.1 (2), 23.8 (2), 22.8 (C-26 or -27)(3), 22.5
(C-27 or -26)(3), 20.9 (2), 18.6 (C-21)(3), 13.6 (C-19)(3), 12.0
(C-18)(3).
A solution of the later product (239 mg, 0.44 mmol) in benz-
ene (10 cm3) containing DBU (0.07 cm3, 0.46 mmol) was heated
under reflux for 30 min and then cooled and partitioned
between benzene and 3% HCl. The organic layer was washed
with water and the solvent was evaporated to give vinylic sulfone
6 (220 mg, 99%), δH 7.83–7.76 (2 H, m, ArH), 7.60–7.44 (3 H,
m, ArH), 7.14 (1 H, br d, J2,3 3.1, 3-H3), 0.87 (3 H, d, J20,21 5.0,
and 25,27
18-H3); δC 192.0 (C-3), 181.2 (C-4 or -5), 142.6 (C-5 or -4), 136.1
(C-ipso), 132.7 (C-o), 128.4 (C-m), 127.7 (C-p), 55.9, 55.5,
54.7, 42.8, 42.3, 39.4, 39.3, 36.0, 35.6, 35.1, 34.1, 33.4, 32.6,
28.1, 27.9, 27.6, 23.9, 23.7, 22.7, 22.5, 21.3, 18.5, 18.4, 11.9
(C-18); m/z (EI) 524.332 34 (Mϩ, 22%. C33H48O3S requires M,
524.332 41), 509 [(M Ϫ CH3)ϩ, 2)], 460 [(M Ϫ SO2)ϩ, 100], 445
(13), 383 [(M Ϫ SO2Ph)ϩ, 83].
4ꢁ-Phenylsulfanyl-5ꢀ-cholestan-3ꢀ-ol 4
To anhydrous EtOH (30 cm3) was added sodium (214 mg, 9.3
mg-atom). After the reaction was complete, thiophenol (0.94
cm3, 9.15 mmol) was added, followed by 3α,4α-epoxy-5α-
cholestane 311,12 (1.80 g, 4.6 mmol). The mixture was heated
under reflux for 24 h, cooled and partitioned between water
and benzene. The organic extract was washed with water and
evaporated. The residue was chromatographed on SiO2 (10 g;
hexane–EtOAc, 9:1) to give compound 4 (1.93 g, 83%), mp
133 ЊC (from EtOH); δH 7.41–7.12 (5 H, m, ArH), 4.02 (1 H, br
d, J3,4 2.2, 3-H3), 3.17 (1 H, br dd, J3,4 2.2, J4,5 2.2, 4-H3), 0.97
(3 H, s, 19-H3), 0.91 (3 H, d, J20,21 7.1, 21-H3) overlapping with
21-H) overlapping with 0.84 (6 H, d, J25,26
6.3, 26- and
and 25,27
0.87 (6 H, d, J25,26
6.7, 26- and 27-H3), 0.66 (3 H, s,
and 25,27
27-H3), 0.70 (3 H, s, 19-H3), 0.59 (3 H, s, 18-H3); δC 141.7 (C-4
or -i)(0), 141.1 (C-i or -4)(0), 140.3 (C-3)(1), 132.6 (C-o)(1),
128.8 (C-m)(1), 127.1 (C-p)(1), 56.1 (1), 56.1 (1), 52.8 (1), 45.8
(1), 42.4 (0), 39.9 (2), 39.4 (2), 36.1 (2), 35.7 (1), 34.8 (1), 32.8
(2), 31.4 (2), 28.2 (2), 27.9 (1), 23.9 (2), 23.8 (2), 23.6 (2), 23.4
(2), 22.8 (C-26 or -27)(3), 22.5 (C-27 or -26)(3), 21.4 (2), 18.6
(C-21)(3), 12.4 (C-19)(3), 12.0 (C-18)(3); m/z (EI) 510.353 64
(Mϩ, 63%. C33H50O2S requires M, 510.353 15), 495 (23), 462 (3),
445 (12), 397 (3), 369 (42), 355 (100), 341 (20), 287 (10), 275
(22), 259 (7), 235 (10), 229 (17), 213 (22), 199 (5), 171 (6), 161
(8), 147 (13), 135 (23), 121 (35), 107 (28), 95 (35), 81 (65).
18-H3); δC 137.9 (C-i), 130.5 (C-o), 120.9 (C-m), 126.3 (C-p),
70.2 (C-3), 56.7, 56.5, 56.2, 55.1, 42.8, 42.5, 39.9, 39.5, 36.5,
36.2, 35.8, 35.3, 32.3, 31.6, 28.2, 28.0, 27.5, 24.3, 24.2,
23.9, 22.8, 22.6, 20.5, 18.7, 13.7 (C-19), 12.0 (C-18); m/z (EI)
496.373 12 (Mϩ, 84%. C33H52OS requires M, 496.373 89), 386
(14), 369 (100), 353 (5), 287 (8), 273 (8), 257 (7), 243 (10),
229 (7), 215 (11), 189 (7), 175 (10), 161 (24), 147 (12), 135 (18),
121 (10), 107 (15).
4ꢁ-Phenylsulfonyl-5ꢀ-cholestan-3ꢀ-ol 5
To a solution of sulfide 4 (598 mg, 1.2 mmol) in CH2Cl2 (20
cm3) was added MCPBA (60%; 710 mg, 2.47 mmol). The mix-
ture was stirred for 2 h and then partitioned between aq.
Na2SO3 and CH2Cl2. The product was isolated in the usual way
to give sulfone 5 (627 mg, 98%), δH 7.91–7.82 (2 H, m, ArH),
7.65–7.45 (3 H, m, ArH), 4.13 (1 H, br s, 3-H), 3.26 (1 H, d,
J 5.3, 4-H), 1.19 (3 H, s, 19-H3), 0.90 (3 H, d, J20,21 7.3, 21-H3)
overlapping with 0.86 (6 H, d, J25,26 and 25,27 6.7, 26- and 27-H3),
0.66 (3 H, s, 18-H3); δC 141.6 (C-i), 133.2 (C-o), 129.1 (C-m),
127.9 (C-p), 70.6 (C-3), 65.2 (C-4), 56.4, 56.2, 55.6, 45.2, 42.4,
39.9, 39.5, 36.2, 35.8, 35.4, 33.3, 31.9, 28.2, 28.0, 27.3, 25.7,
24.2, 23.8, 22.8, 22.6, 20.9, 18.7, 13.4 (C-19), 12.0 (C-18); m/z
(EI) 528.363 67 (Mϩ, 5%. C33H52O3S requires M, 528.363 71),
510 [(M Ϫ H2O), 8], 495 (4), 445 (3), 387 (23), 369 (100), 355
(17), 341 (3), 313 (2), 287 (6), 257 (6), 247 (10), 229 (23), 215
(33), 201 (8), 175 (10), 161 (20), 147 (21), 135 (27), 121 (23), 107
(28), 95 (38), 81 (47).
4ꢀ-Phenylsulfonyl-5ꢀ-cholestane 7a and 4ꢁ-phenylsulfonyl-5ꢀ-
cholestane 7b
(a) To a stirred solution of vinyl sulfone 6 (100 mg, 0.2 mmol)
in THF (5 cm3) was added a solution of LiEt3BH (0.5 M in
THF; 0.25 cm3, 0.125 mmol). The mixture was set aside for 2 h
and then partitioned between CH2Cl2 and water. The organic
solution was evaporated and the residue was chromatographed
on SiO2 (6 g; hexane–AcOEt, 9:1) to give consecutively 7b (20
mg, 20%) and then 7a (79 mg, 79%).
(b) To a solution of hydroxy sulfone 5 (108 mg, 0.2 mmol) in
CH2Cl2 (5 cm3), stirred under argon at Ϫ20 ЊC, was added Et3N
(0.09 cm3, 0.65 mmol) followed by MsCl (0.03 cm3, 0.39 mmol).
After 1 h, water (5 cm3) was added. The mixture was allowed
to warm to room temperature and then was extracted with
CH2Cl2. The organic extract was dried and evaporated to give
the crude mesyl ester. The later product was dissolved in THF
(5 cm3) and treated with LiEtBH3 (0.5 M in THF; 0.7 cm3, 0.35
mmol). The mixture was stirred at room temperature for 0.5 h,
and then was poured into water and extracted with CH2Cl2.
The organic extract was dried and concentrated. The residue
was chromatographed on SiO2 (10 g; hexane–ethyl acetate, 9:1)
to give 7b (19 mg, 18%), 7a (80 mg, 76%) and a fraction contain-
ing both these components (5 mg, 5%).
4-Phenylsulfonyl-5ꢀ-cholest-3-ene 6
To a solution of hydroxy sulfide 5 (306 mg, 0.62 mmol) in
CH2Cl2 (10 cm3) was added Et3N (0.26 cm3, 1.9 mmol) followed
by MsCl (0.09 cm3, 1.2 mmol). The mixture was set aside for 4 h
and then partitioned between hexane and water. The hexane
layer was washed consecutively with 3% HCl and water. The
solvent was evaporated to give 3ξ-chloro-4β-phenylsulfanyl-5α-
cholestane (316 mg, 100%), δH 7.38–7.20 (5 H, m, ArH), 4.45
(1 H, br d, J3,4 2.2, 3-H), 3.43 (1 H, br dd, J3,4 2.2, J4,5 2.2,
4-H), 2.59–2.38 (1 H, m), 2.29–2.16 (1 H, m), 1.00 (3 H, s,
19-H3), 0.92 (3 H, d, J20,21 7.5, 21-H3), 0.89 (6 H, d, J25,26 and 25,27
6.8, 26- and 27-H3), 0.67 (3 H, s, 18-H3); δC 136.9 (C-i), 130.3
(C-o), 129.1 (C-m), 126.7 (C-p), 62.4 (C-3), 57.1, 56.5, 56.2,
54.8, 42.5, 42.3, 39.8, 39.5, 36.6, 36.2, 35.8, 35.3, 32.1, 31.8,
28.2, 28.0, 27.4, 25.0, 24.2, 23.9, 22.8, 22.6, 20.5, 18.7, 14.3
(C-19), 12.0 (C-18).
Compound 7b had δH 7.96–7.87 (2 H, m, ArH), 7.63–7.48
(3 H, m, ArH), 3.21 (1 H, br t, J 5.2, 4-H), 1.23 (3 H, s, 19-H),
0.89 (3 H, d, J20,21 7.0, 21-H3) overlapping with 0.86 (6 H, d,
J25,26
7.0, 26- and 27-H3), 0.66 (3 H, s, 18-H3) [lit.,14
and 25,27
δH 3.22 (4-H), 1.24 (19-H3), 0.68 (18-H3)].
Compound 7a had δH 7.87–7.78 (2 H, m, ArH), 7.66–7.47
(3 H, m, ArH), 3.04 (1 H, br t, J 10.7, 4-H), 2.43 (1 H, dd,
J 13.6, 2.4), 0.89 (3 H, d, J20,21 5.2, 21-H3) overlapping with 0.85
(6 H, d, J25,26 and 25,27 7.1, 26- and 27-H3) overlapping with 0.83
(3 H, s, 19-H3), 0.63 (3 H, s, 18-H3); δC 139.1 (C-i)(0), 133.1
(C-o)(1), 128.9 (C-m)(1), 128.5 (C-p)(1), 64.5 (C-4)(1), 56.3 (1),
56.1 (1), 54.4 (1), 46.7 (1), 42.3 (0), 39.9 (2), 39.5 (2), 37.5 (0),
To a solution of the crude chloride (226 mg, 0.44 mmol)
in CH2Cl2 (10 cm3) was added MCPBA (60%; 256 mg, 0.89
1590
J. Chem. Soc., Perkin Trans. 1, 2000, 1587–1594

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37.4 (2), 36.1 (2), 35.7 (1), 34.6 (1), 31.4 (2), 28.8 (2), 28.2 (2),
28.0 (1), 25.4 (2), 24.0 (2), 23.8 (2), 22.8 (C-26 or -27)(3), 22.5
(C-27 or -26)(3), 21.1 (2), 20.6 (2), 18.6 (C-21)(3), 13.3 (C-19)(3),
12.0 (C-18)(3) [lit.,14 δH 2.96 (4-H), 1.27 (19-H3), 0.65 (18-H3)].
12.0 (C-18)(3); m/z (EI) 528.363 68 (Mϩ, 8%. C33H52O3S
requires M, 528.363 71), 463 (3), 445 (8), 387 (86), 369 (100),
353 (5), 329 (3), 287 (5), 261 (8), 243 (10), 231 (21), 215 (12), 175
(11), 161 (14), 135 (16), 107 (7).
Compound 10: δH selected signals: 3.91 (1 H, br s), 3.15 (1 H,
dd, J 12.1, 2.0), 1.03 (3 H, s, 19-H3).
Reduction of 2 with LiAlH4. 4ꢁ-Phenylsulfonyl-5ꢁ-cholestane 8
On attempted reduction of 2 with NaBH4 in MeOH at the
reflux temp., the enol of 2 [4-(phenylsulfonyl)cholesta-3,5-dien-
3-ol] was obtained in 85% yield, λmax(EtOH)/nm 201.3, 222.5,
248.9, 286.8; δH 11.25 (1 H, s, OH), 7.84–7.77 (2 H, m, ArH),
7.67–7.43 (3 H, m, ArH), 6.08 (1 H, dd, J6,7a 5.5, J6,7b 2.7, 6-H),
2.50–2.38 (2 H, m), 0.88 (3 H, d, J20,21 6.0, 21-H3) overlapping
with 0.85 (6 H, d, J25,26 and 25,27 6.2, 26- and 27-H), 0.62 (3 H, s,
19-H3), 0.59 (3 H, s, 18-H3); δC 165.4, 140.8 (C-i), 133.1 (C-o),
131.8, 128.6 (C-m), 127.0 (C-p), 122.0, 106.6, 56.6, 56.0, 48.7,
39.6, 39.5, 42.2, 39.6, 39.5, 36.1, 35.9, 35.7, 32.1, 31.8, 30.5,
28.2, 28.0, 27.5, 24.1, 23.8, 22.8, 22.5, 21.1, 18.6, 17.3, 11.8
(C-18); m/z (EI) 524 (Mϩ, 19%), 509 (2), 460 (100), 445 (15), 427
(3), 383 (43), 369 (3), 365 (4), 271 (10), 257 (8), 247 (10), 229
(15), 213 (8), 197 (16), 173 (15), 147 (15), 135 (18), 121 (19), 105
(22), 95 (35).
To a stirred solution of compound 2 (120 mg, 0.229 mmol) in
THF (5 cm3) was added LiAlH4 (1 M in THF; 3 cm3, 3.00
mmol) dropwise. The reaction was quenched with MeOH18
(1 cm3) and the mixture was poured into 10% aq. tartaric acid.
The product was extracted with CH2Cl2. The solvent was evap-
orated and the residue was chromatographed on SiO2 (6 g;
hexane–EtOAc, 50:1, 10:1 and 5:1) to give compound 8 (92
mg, 78%), δH 7.88–7.78 (2 H, m, ArH), 7.66–7.46 (3 H, m,
ArH), 3.55 (1 H, td, J 11.1, 3.7, 4-H3), 2.51–2.37 (1 H, m), 0.99
(3 H, s, 19-H3), 0.88 (3 H, d, J20,21 6.3, 21-H3), 0.85 (3 H, d, J25,26
6.6, 26-H3), 0.85 (3 H, d, J25,27 6.6, 27-H3), 0.63 (3 H, s, 18-H3);
δC 138.9 (C-i)(0), 133.1 (C-o)(1), 128.8 (C-m)(1), 128.5 (C-p)(1),
61.1 (C-4)(1), 56.5 (1), 56.3 (1), 43.6 (1), 42.6 (0), 42.1 (1), 40.1
(2), 39.4 (2), 37.1 (0), 36.5 (2), 36.1 (2), 35.7 (1), 35.7 (1), 28.9
(2), 28.3 (2), 28.0 (1), 26.1 (2), 24.1 (C-21)(3), 23.8 (2), 23.1 (2),
22.8 (C-26)(3), 22.5 (C-27)(3), 20.8 (2), 19.5 (2), 18.6 (C-19)(3),
12.0 (C-18)(3); m/z (EI) 512.368 99 (Mϩ, 0.5%. C33H52O2S
requires M, 512.368 80), 510 (1), 495 (0.3), 447 (0.3), 397 (0.4),
371 (100), 355 (7), 245 (14), 163 (23), 149 (35), 135 (30), 109
(41), 95 (55), 81 (45).
4ꢀ-Phenylsulfonyl-5ꢀ-cholestan-3-one 11 and 4ꢁ-phenylsulfonyl-
5ꢁ-cholestan-3-one 12
A mixture of 9 and 10, as described above, (95 mg, 0.18 mmol)
was dissolved in acetone (5 cm3) and treated with Jones reagent
until the brown colour persisted (2.7 M; 0.1 cm3, 0.27 mmol),
then some propan-2-ol was added and the solution was
partitioned between water and CH2Cl2. The organic extract was
evaporated. The residue was chromatographed on SiO2 (10 g;
hexane–EtOAc, 92:8) to give consecutively ketones 12 (39 mg,
41%) and 11 (55 mg, 58%).
Desulfuration of 8
To a stirred solution of sulfone 8 (30 mg, 0.06 mmol) in THF
(2 cm3) and MeOH (10 cm3) was added 6% sodium amalgam
(310 mg) in portions during 12 h. The mixture was partitioned
between hexane and water, and the product was isolated in the
usual way. 5β-Cholestane was obtained (21 mg, 96%), δH 0.91
(3 H, s, 19-H3) overlapping with 0.90 (3 H, d, J20,21 6.5, 21-H3)
overlapping with 0.86 (6 H, d, J25,26 and 25,27 6.7, 26- and 27-H3),
0.64 (3 H, s, 18-H3); δC 56.7, 56.4, 43.8, 42.7, 40.6, 40.3, 39.5,
37.6, 36.2, 35.9, 35.8, 35.4, 28.3, 28.0, 27.6, 27.3, 27.1, 26.6,
24.3, 23.8, 22.8, 22.6, 21.4, 20.9, 18.7, 12.1 (lit.,19 δC 56.6, 56.3,
43.7, 42.7, 40.5, 40.3, 39.5, 37.6, 36.2, 35.9, 35.8, 35.3, 28.3,
28.0, 27.5, 27.2, 27.0, 26.6, 24.3, 23.8, 22.8, 22.5, 21.3, 20.8,
18.6, 12.0).
Compound 12 showed δH 7.82–7.75 (2 H, m, ArH), 7.71– 7.50
(3 H, m, ArH), 3.63 (1 H, d, J4,5 6.3, 4-H), 2.76 (1 H, br s), 2.55
(1H, dd, J 19.6, 7.1), 2.35–2.13 (1 H, m), 1.12 (3 H, s, 19-H3),
0.87 (3 H, d, J20,21 6.4, 21-H3), 0.84 (6 H, d, J25,26
6.0,
and 25,27
26- and 27-H3), 0.63 (3 H, s, 18-H3); δC 204.3 (C-3), 137.6 (C-i),
134.0 (C-o), 129.0 (C-m), 128.9 (C-p), 76.5 (C-4), 56.1, 55.9,
43.5, 42.8, 42.5, 39.5, 39.4, 36.1, 35.7, 35.0, 34.8, 34.6, 32.1,
28.2, 28.0, 26.3, 24.0, 23.8, 22.8, 22.5, 22.3, 21.4, 18.6, 11.9
(C-18); m/z (EI) 526.348 00 (Mϩ, 2%. C33H50O3S requires M,
526.348 06), 511 (1), 462 (7), 385 (100), 367 (20), 315 (13), 275
(5), 245 (12), 231 (22), 213 (8), 161 (12), 135 (12), 121 (22), 95
(32).
Compound 11 showed δH 7.82–7.74 (2 H, m, ArH), 7.69–7.48
(3 H, m, ArH), 3.49 (1 H, dd, J4,5 9.1, 1.3, 4-H), 2.87–2.53 (3 H,
m), 2.45–2.25 (2 H, m), 0.90 (3 H, d, J20,21 6.6, 21-H3) over-
lapping with 0.86 (6 H, d, J25,26 and 25,27 7.1, 26- and 27-H3), 0.74
(3 H, s, 19-H3), 0.64 (3 H, s, 18-H3); δC 204.5 (C-3), 138.0 (C-i),
133.9 (C-o), 128.9 (C-m), 128.8 (C-p), 76.2 (C-4), 58.1, 56.0,
53.8, 45.2, 42.5, 39.8, 39.5, 36.1, 35.9, 35.7, 35.6, 35.0, 34.5,
31.2, 29.1, 28.2, 28.0, 24.1, 23.8, 22.8, 22.5, 21.4, 18.6, 13.7
(C-19), 12.0 (C-18); m/z (EI) 526.348 00 (Mϩ, 8%), 462 (28), 444
(2), 392 (12), 385 (53), 369 (27), 353 (3), 315 (5), 271 (7), 245
(20), 229 (100), 215 (22), 187 (10), 161 (10).
Reduction of 2 with NaBH4 in MeOH. 4ꢀ-Phenylsulfonyl-5ꢀ-
cholestan-3ꢀ-ol 9 and 4ꢁ-phenylsulfonyl-5ꢁ-cholestan-3ꢁ-ol 10
To a stirred solution of ketone 2 (201 mg, 0.38 mmol) in MeOH
(20 cm3) was added NaBH4 (161 mg, 4.2 mmol) in portions
during 7 h. The mixture was set aside for 16 h and then was
poured into water. The product was extracted with CH2Cl2. The
extract was evaporated. The residue was chromatographed on
SiO2 (7 g; benzene–EtOAc, 85:15). A mixture of alcohols 9 and
10 was obtained (168 mg, 83%). A sample of pure isomer 9 was
obtained by dissolution of the mixture in CH2Cl2 and precipi-
tation of an amorphous solid with pentane; δH 7.96–7.88 (2 H,
m, ArH), 7.70–7.51 (3 H, m, ArH), 3.75 (1 H, br s, 3-H3), 3.10
(1 H, dd, J4,5 11.5, J3,4 1.8, 4-H), 2.38–2.20 (2 H, m), 2.01–0.81
(29 H, m) overlapping with 0.89 (3 H, d, J20,21 6.2, 21-H3), 0.85
(6 H, d, J25,26 and 25,27 7.3, 26- and 27-H3) overlapping with 0.84
(3 H, s, 19-H3), 0.64 (3 H, s, 18-H3); NOE experiments: Irradi-
ation at δ 0.84 ppm (19-H3) led to an increase of intensity of the
signal at δ 3.1 (3-H) by 1.4% being observed. Irradiation at
δ 3.10 (4-H) led to an increase of signals at δ 0.84 by 1.4% and
at δ 3.75 ppm (3-H) by 5.2%. Upon irradiation at δ 3.75 an
increase of the signal at δ 3.10 by 5.0% was observed; δC 139.5
(C-i)(0), 133.5 (C-o)(1), 129.1 (C-m)(1), 128.1 (C-p)(1), 67.8
(C-3 or -4)(1), 65.1 (C-4 or 3)(1), 56.2 (1), 56.1 (1), 54.1 (1), 42.3
(0), 40.3 (1), 39.9 (2), 39.5 (2), 37.7 (0), 36.1 (2), 35.8 (1), 34.6
(1), 31.5 (2), 31.2 (2), 28.3 (2), 28.2 (2), 28.0 (1), 25.2 (2), 24.0
(2), 23.8 (2), 22.8 (3), 22.5 (3), 21.2 (2), 18.6 (3), 12.4 (C-19)(3),
Desulfuration of 11
To a mixture of sulfone 11 (45 mg, 0.09 mmol), THF (2 cm3)
and MeOH (10 cm3) was added 6% sodium amalgam (1.2 g) in
portions until starting material was consumed (TLC, 5 days).
The mixture was partitioned between hexane and water. The
product was isolated in the usual way. 5α-Cholestan-3-one
was obtained (26 mg, 79%), identical in all respects with an
authentic sample.
Desulfuration of 12
Sulfone 12 (48 mg, 0.09 mmol) treated with sodium amalgam
under conditions analogous to those described above afforded
5β-cholestan-3-one (28 mg, 80%).
J. Chem. Soc., Perkin Trans. 1, 2000, 1587–1594
1591

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Reduction of 2 with NaBH4 in a mixture of THF and DMPU
1.17 mmol), followed by CH3OCH2Cl (90%; 0.06 cm3, 0.74
mmol) and KI (0.1 mg). The mixture was heated under reflux
for 24 h and then cooled and partitioned between water and
benzene. The organic layer was washed with water and the
solvent was evaporated. The residue was chromatographed on
SiO2 (5 g; hexane–EtOAc, 93:7) to give 13b (106 mg, 96%),
δH 7.98–7.88 (2 H, m, ArH), 7.56–7.40 (3 H, m, ArH), 4.95
(1 H, d, J 7.0, 3-H), 4.68 (2 H, d, J 6.8, OCH2O), 3.39 (3 H, s,
CH3O), 3.07 (1 H, br d, J 12.9), 1.01 (3 H, s, 19-H3), 0.86 (3 H,
To a stirred mixture of NaBH4 (10 mg, 0.26 mmol), THF (2
cm3) and 1,3-dimethylperhydropyrimidin-2(1H)-one (DMPU)
(0.3 cm3) was added ketone 2 (105 mg, 0.2 mmol) in THF
(2 cm3) at 0 ЊC. After 1 h (at 0 ЊC), the mixture was allowed
to warm to room temp. and was partitioned between benzene
and 3% HCl. The organic extract was washed successively with
water and brine, and the solvent was evaporated. The residue
was chromatographed on SiO2 (5g; hexane–EtOAc, 95:5)
to give compound 12 (23%) and a mixture of alcohols 9 and
10 (74%) in the ratio 5.5:1 (determined by 1H NMR after oxid-
ation of the mixture to a mixture of ketones 11 and 12). In an
analogous reaction carried out at Ϫ45 ЊC, ketone 12 (24%) and
alcohols 9 and 10 (73%, in the ratio 4.5:1, respectively) were
obtained.
d, J20,21 5.4, 21-H3) overlapping with 0.83 (6 H, d, J25,26
and 25,27
6.5, 26- and 27-H3), 0.62 (3 H, s, 18-H3); δC 165.2 (C-4)(0), 143.9
(C-5)(0), 133.8 (C-i)(0), 132.3 (C-o)(1), 128.6 (C-m)(1), 126.6
(C-p)(1), 97.7 (OCH2O)(2), 71.5 (C-3)(1), 55.9 (1), 55.8 (1), 55.7
(1), 50.5 (CH3O)(3), 42.5 (0), 41.1 (0), 39.6 (2), 39.4 (2), 36.0 (2),
35.6 (1), 35.3 (1), 32.8 (2), 28.5 (2), 28.2 (2), 27.9 (3), 27.6 (2),
25.6 (2), 23.9 (2), 23.7 (2), 22.7 (3), 22.5 (3), 21.9 (2), 21.5 (3),
18.5 (3), 12.0 (C-18)(3).
Reduction of 11 with NaBH4 in THF–DMPU
A mixture of 11 (48 mg, 0.09 mmol), THF (1 cm3), DMPU (0.3
cm3) and NaBH4 (4 mg, 0.1 mmol) was stirred at 0 ЊC for 1 h,
and then worked up in an analogous manner to that described
above. Alcohol 9 (47 mg, 97%) was obtained.
Attempted reduction of 12 under analogous conditions
failed.
Reduction of 13b with LiAlH4
A mixture of ether 13b (102 mg, 0.18 mmol), THF (5 cm3) and
LiAlH4 (35 mg, 0.92 mmol) was heated under reflux for 20 min
and cooled. The reagent excess was decomposed with water and
the mixture was partitioned between 3% HCl and benzene.
Product was isolated in the usual way and chromatographed on
SiO2 (5 g; hexane–EtOAc, 9:1). A mixture of sulfones 8, 7a and
Reduction of 2 with CuCN–n-BuLi–DIBAH system16,20
1
7b was obtained (70 mg, 76%) in proportions 5:4:1 by H
To a suspension of CuCN (46 mg, 0.513 mmol) in THF (5 cm3)
was added n-BuLi (1.3 M in hexane; 0.39 cm3, 0.513 mmol) at
Ϫ20 ЊC. After 30 min, the mixture was cooled to Ϫ50 ЊC and
DIBAH (0.7 M in hexane; 1.833 cm3, 1.283 mmol) and HMPA
(1 cm3) were added consecutively. Stirring at Ϫ50 ЊC was con-
tinued for 2 h, and then ketone 2 (52.5 mg, 0.100 mmol) in THF
(1 cm3) was added. After an additional 3 h, the mixture was
allowed to warm to room temp. The reaction was quenched
with MeOH (2 cm3) and the mixture was poured into 10% aq.
tartaric acid. The product was isolated with CH2Cl2 and chrom-
atographed on SiO2 (6 g; hexane–EtOAc, 40:1, then 20:1) to
give 4-(phenylsulfonyl)cholest-4-en-3β-ol 13a (5 mg, 10%), 12
(11.5 mg, 22%) and 11 (20.5 mg, 39%). Compound 13a showed
δH 7.98–7.90 (2 H, m, ArH), 7.62–7.44 (3 H, m, ArH), 4.75
(1 H, t, J2,3 5.5, 3-H3), 3.05 (1 H, dt, J 13.9, 1.8), 1.06 (3 H, s,
19-H3), 0.86 (3 H, d, J20,21 4.6, 21-H3), 0.84 (6 H, d, J25,26 and 25,27
6.6, 26- and 27-H3), 0.62 (3 H, s, 18-H3); δC 164.0 (C-4), 143.4
(C-5), 136.0 (C-i), 132.7 (C-o), 128.9 (C-m), 128.4 (C-p), 65.7
(C-3), 55.9, 55.6, 52.3, 42.4, 41.4, 39.6, 39.4, 36.0, 35.6, 35.2,
32.1, 31.0, 28.1, 27.9, 27.7, 26.6, 23.8, 23.7, 22.8, 22.5, 21.5,
20.5, 18.5, 11.9 (C-18); m/z (LSIMS) 549.337 77 (Mϩ ϩ Na.
C33H50NaO3S requires m/z, 549.337 84).
NMR. Rechromatography of the mixture gave pure products 8
and 7a and 7b.
4-(Phenylsulfonyl)cholest-4-en-3ꢀ-ol 15a
(a) From 13a. To a solution of alcohol 13a (113 mg, 0.21
mmol) in CH2Cl2 (3 cm3) was added Ph3P (265 mg, 1.1 mmol) in
CH2Cl2 (1 cm3) at Ϫ78 ЊC. The mixture was stirred for 2 h and
then benzoic acid (135 mg, 1.1 mmol) in CH2Cl2 (2 cm3) and
diethyl azodicarboxylate (0.175 cm3, 1.1 mmol) were added. The
mixture was set aside at room temp. for 4 h and then partitioned
between saturated aq. NaHCO3 and benzene. The organic phase
was washed with water and the solvent was evaporated. The
residue was chromatographed on SiO2 (5 g; hexane–EtOAc,
95:5) to give benzoate 15b (80 mg). This crude product was
dissolved in 5% methanolic KOH (3 cm3) and set aside for 16 h.
The usual work-up and chromatography of the product on SiO2
(5 g; hexane–EtOAc, 8:2) gave alcohol 15a (72 mg, 64%).
(b) From 16a. To a solution of sulfide 16a (see below) (59 mg,
0.119 mmol) in CH2Cl2 (3 cm3) was added MCPBA (60%; 70
mg, 0.243 mmol) at 0 ЊC. The mixture was stirred at room temp.
for 1 h and poured into aq. Na2CO3. The product was extracted
with CH2Cl2. The extract was washed successively with aq.
Na2S2O3 and water, and the solvent was evaporated. The resi-
due was chromatographed on SiO2 (2 g; hexane–EtOAc, 50:1,
25:1, 10:1) to give alcohol 15a (61 mg, 97%), δH 7.97–7.90 (2 H,
m, ArH), 7.63–7.46 (3 H, m, ArH), 4.77 (1 H, s, 3-H3), 3.15
(1 H, dt, J 14.5, 3.3), 1.03 (3 H, s, 19-H3), 0.87 (3 H, d, J20,21 4.7,
21-H3) overlapping with 0.85 (6 H, d, J25,26 and 25,27 5.7, 26- and
27-H3), 0.63 (3 H, s, 18-H3); δC 163.0 (C-4)(0), 143.1 (C-5)(0),
135.6 (C-i)(0), 132.7 (C-o)(1), 128.9 (C-m)(1), 126.7 (C-p)(1),
62.9 (C-3)(1), 55.8 (1), 55.4 (1), 54.5 (1), 42.2 (0), 40.9 (0), 39.5
(2), 39.3 (2), 35.9 (1), 35.6 (1), 34.9 (1), 31.2 (2), 30.8 (2), 28.0
(2), 27.9 (1), 27.2 (2), 26.5 (2), 23.8 (2), 23.6 (2), 22.7 (3), 22.4
(2), 21.6 (2), 18.4 (2C)(3), 11.8 (C-18)(3); m/z (EI) 525 (Mϩ,
0.3%), 508.3373 [(M Ϫ H2O)ϩ, 99. C33H48O2S requires m/z,
508.3375], 493 (19), 444 (54), 429 (9), 395 (44), 385 (8), 367 (82),
351 (8), 261 (81), 247 (62), 159 (33), 147 (80), 135 (71), 119 (42),
109 (54), 105 (100), 95 (82), 91 (52), 81 (71), 69 (45), 55 (50), 43
(45).
Reduction of 2 with DIBAH. 4-(Phenylsulfonyl)cholest-4-en-3ꢁ-
ol 13a
To a solution of 2 (210 mg, 0.38 mmol) in CH2Cl2 (10 cm3),
stirred at Ϫ20 ЊC, was added DIBAH (0.7 M in hexane; 0.65
cm3, 0.46 mmol). After 1 h (at Ϫ20 ЊC) the reaction was
quenched with MeOH (0.1 cm3). The mixture was warmed to
room temp. and partitioned between 3% HCl and CH2Cl2. The
product was isolated in the usual way. Alcohol 13a (212 mg,
100%) was obtained.
Reduction of 13a with LiAlH4
A mixture of 13a (98 mg, 0.19 mmol), THF (3 cm3) and LiAlH4
(10 mg, 0.26 mmol) was stirred for 2 h at room temp. Work-up
with saturated aq. Na2SO4 and the usual isolation of product
gave 8 (70 mg, 78%).
3ꢁ-Methoxymethyl-4-(phenylsulfonyl)cholest-4-ene 13b
Reduction of 15a with LiAlH4
To a solution of alcohol 15a (70 mg, 0.13 mmol) in THF (2 cm3)
To mixture of 13a (102 mg, 0.19 mmol) in THF (5 cm3) and
HMPA (0.25 cm3) was added NaH (55% in mineral oil; 51 mg,
1592
J. Chem. Soc., Perkin Trans. 1, 2000, 1587–1594

View Article Online
was added LiAlH4 (10 mg, 0.26 mmol) and the mixture was
stirred for 2 h. The reagent excess was decomposed with satur-
ated aq. Na2SO4, and the mixture was diluted with CH2Cl2 and
dried with Na2SO4. The solid was filtered off and the solvent
was evaporated. The residue was chromatographed on SiO2
(5 g; hexane–EtOAc, 9:1) to give compound 7a (56 mg, 82%).
with CH2Cl2 and chromatographed on SiO2 (10 g; hexane–
EtOAc, 60:1 and 40:1) to give 14 (91 mg, 91%). Inspection of
1
the H NMR spectrum of this product showed the presence
of traces (≈3%) of the isomer 16a.
4-(Phenylsulfanyl)cholest-4-en-3a-yl benzoate 16b
To a solution of alcohol 14 (86 mg, 0.174 mmol), Ph3P (182 mg,
0.695 mmol) and benzoic acid (78 mg, 0.639 mmol) in THF (1.5
cm3) was added DEAD (0.11 cm3, 0.575 mmol) in THF (0.5
cm3) at Ϫ78 ЊC. The mixture set aside at room temp. for 2 h and
the solvent was evaporated. The residue was chromatographed
on SiO2 (5 g; hexane–EtOAc, 100:1, 50:1 and 20:1) to give the
title benzoate 16b (77 mg, 76%), δH 7.89–7.00 (10 H, m, ArH),
5.51 (1 H, br s, 3-H), 3.51–3.36 (1 H, m, 6 lines, 6-αH), 1.19
(3 H, s, 19-H3), 0.94 (3 H, d, J20,21 6.4, 21-H3), 0.89 (6 H, d,
Reduction of 1 with DIBAH. 4-(Phenylsulfanyl)cholest-4-en-3ꢁ-
ol 14 and 4-(phenylsulfanyl)cholest-4-en-3ꢀ-ol 16a
To a solution of 1 (450 mg, 0.91 mmol) in CH2Cl2 (10 cm3) was
added DIBAH (0.7 M in hexane; 4.4 cm3, 3.08 mmol) at
Ϫ78 ЊC. The mixture was stirred for 1 h at Ϫ78 ЊC and allowed
to warm to room temp. The reaction was quenched with MeOH
(2 cm3) and the mixture was poured into 10% aq. tartaric acid.
The product was isolated with CH2Cl2 and chromatographed
on SiO2 (45 g; hexane–EtOAc, 100:1 and 75:1) to give alcohols
14 (312 mg, 69%) and 16a (96 mg, 21%).
J25,26
6.6, 26- and 27-H3), 0.73 (3 H, s, 18-H3); δC 165.9
and 25,27
(C᎐O), 160.8 (C-5), 137.0 (C-i, SPh), 132.4 (C-p, Bz), 130.6
᎐
(C-i, Bz), 129.5 (C-o, Bz), 128.6 (C-o, SPh), 128.0 (C-m, Bz),
127.6 (C-m, SPh), 125.1 (C-p, SPh), 120.7 (C-4), 72.1 (C-3),
56.1, 55.9, 54.7, 42.3 (C-13), 40.4 (C-10), 39.7, 39.4, 36.0, 35.6,
35.5, 32.2, 32.1, 28.5, 28.1, 27.9, 25.7, 24.0, 23.7, 22.7, 22.5,
21.6, 18.5, 18.5, 11.9; m/z (EI) 598.384 14 (Mϩ, 11%. C40H54O2S
requires M, 598.384 45), 476.347 80 (Mϩ Ϫ C6H5CO2H, 100.
C33H48S requires m/z, 476.347 67), 461 [(M Ϫ CH3 Ϫ BzOH)ϩ,
21], 367 (24), 122 (BzOHϩ, 18), 105 (C6H5COϩ, 100).
Compound 14 showed δH 7.31–7.08 (5 H, m, ArH), 4.08–3.86
(1 H, m, 3-H), 3.31–3.18 (1 H, m, 8 lines, 6-αH), 2.90 (1 H, br
s, 3-OH), 1.17 (3 H, s, 19-H3), 0.92 (3 H, d, J20,21 6.6, 21-H3),
0.87 (6 H, d, J25,26 and 25,27 6.6, 26- and 27-H3), 0.70 (3 H, s, 18-H3);
δC 157.6 (C-5), 136.2 (C-i), 128.8 (C-o), 127.0 (C-m), 125.7
(C-4), 125.3 (C-p), 68.0 (C-3), 56.0, 56.0, 54.4, 42.3 (C-13),
40.6 (C-10), 39.7, 39.4, 36.0, 35.6, 35.4, 33.7, 32.7, 29.1, 28.1,
27.9, 27.3, 24.0, 23.7, 22.7, 22.4, 21.2, 19.8, 18.5, 11.9; m/z (EI)
494.358 35 (Mϩ, 100%. C33H50OS requires M, 494.358 24),
476 [(M Ϫ H2O)ϩ, 94], 461 [(M Ϫ CH3 Ϫ H2O)ϩ, 13], 399
[(M Ϫ Ph Ϫ H2O)ϩ, 6], 385 (19), 367 (65), 105 (29), 95 (34),
57 (25).
4-(Phenylsulfanyl)cholest-4-en-3a-ol 16a from 16b
To a solution of benzoate 16b (77 mg, 0.129 mmol) in CH2Cl2
(3 cm3) was added DIBAH (0.7 M in hexane; 0.4 cm3, 0.280
mmol) at Ϫ78 ЊC. The mixture was stirred for 1 h before being
allowed to warm to room temp., treated with MeOH (0.5 cm3),
and poured into 10% aq. tartaric acid. The product was isolated
with CH2Cl2 and chromatographed on SiO2 (1.5 g; hexane–
EtOAc, 100:1 and 50:1) to give 16a (59 mg, 92%).
Compound 16a showed δH 7.31–7.06 (5 H, m, ArH), 4.05–
3.98 (1 H, m, 3-H), 3.37–3.23 (1 H, m, 6 lines, 6-αH), 2.27
(1 H, br s, 3-OH), 1.14 (3 H, s, 19-H3), 0.90 (3 H, d, J20,21 8.6,
21-H3), 0.87 (6 H, d, J25,26
6.6, 26- and 27-H3), 0.70
and 25,27
(3 H, s, 18-H3); δC 157.7 (C-5), 136.7 (C-i), 128.9 (C-o),
127.5 (C-m), 125.3 (C-4), 124.4 (C-p), 67.5 (C-3), 56.0, 55.9,
54.4, 42.3 (C-13), 40.6 (C-10), 39.8, 39.4, 36.0, 35.7, 35.6, 32.2,
31.5, 28.5, 28.1, 27.9, 26.9, 24.0, 23.7, 22.7, 22.5, 21.6,
18.6, 18.5, 11.9; m/z (EI) 494.358 41 (Mϩ, 38%), 476.347 53
[(M Ϫ H32O)ϩ, 100. C33H48S requires m/z, 476.347 67], 461
[(M Ϫ CH3 Ϫ H2O)ϩ, 12], 399 [(M Ϫ Ph Ϫ H2O)ϩ, 6], 385 (5),
367 (30), 109 [(SPh)ϩ, 14], 105 (36), 95 (24), 57 (19).
Reduction of 15a with LiAlH4
To a solution of hydroxy sulfone 15a (61 mg, 0.116 mmol) in
THF (4 cm3) was added LiAlH4 (0.25 M in THF; 0.6 cm3, 0.150
mmol). The mixture was heated under reflux for 20 min. After
cooling, the reaction mixture was quenched with MeOH (0.5
cm3) and poured into 10% aq. tartaric acid. The product was
isolated with CH2Cl2 and chromatographed on SiO2 (2 g;
hexane–EtOAc 50:1, 10:1 and 5:1) to give sulfone 7a (49 mg,
82%).
Reduction of 1 with LiAlH4
To a stirred solution of LiAlH4 in THF (1.5 M; 5 cm3) was
added a solution of 1 (150 mg, 0.305 mmol) in THF (3 cm3) in
one portion. After 20 min the reaction was quenched with
MeOH (1 cm3) and the mixture was poured into 10% aq. tar-
taric acid. The product was extracted with CH2Cl2. The extract
was washed with water and evaporated. The residue was filtered
through SiO2 (15 g; hexane–EtOAc, 40:1) to give a mixture of
14 and 16a (137 mg, 91%) in the ratio 84:16, respectively, by 1H
NMR.
Catalytic hydrogenation of 2
A solution of 2 (60 mg, 0.11 mmol) in EtOH (4.5 cm3), contain-
ing 10% palladium on carbon (10 mg), was stirred under hydro-
gen at the reflux temperature for 5 h. The mixture was cooled
and diluted with CH2Cl2. The solid was filtered off and the
solvent was evaporated. A mixture of compounds 11 and 12 in
the ratio 6.5:1 (1H NMR) was obtained.
In an analogous reaction, a solution of 2 (60 mg, 0.11 mmol)
in EtOH (4.5 cm3), containing 10% palladium on carbon (10
mg), was treated with CF3COOH (0.5 mmol) and the mixture
was stirred at room temp. for 5 days. A mixture of 11 and 12 in
the ratio 5.5:1 (1H NMR) was obtained.
Reduction of 1 with L-Selectride
To a solution of 1 (105 mg, 0.213 mmol) in THF (7 cm3) was
added L-Selectride (1 M in THF; 0.25 cm3, 0.25 mmol) at
Ϫ78 ЊC. The mixture was stirred at Ϫ78 ЊC for 1 h. The reaction
was quenched with MeOH (0.5 cm3). The product was isolated
as in the above described experiments to give a mixture of 14
References
1
and 16a (83 mg 79%) in the ratio 82:18, respectively, by H
NMR.
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Reduction of 1 with NaBH4–CeCl3 system17
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18 After quenching of the reaction with MeOH only one epimer of
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J. Chem. Soc., Perkin Trans. 1, 2000, 1587–1594