A new route to stereoselective construction of 6β,7β-methylene unit from androst-5-en-7-one

Article abstract of DOI:10.1016/j.tet.2007.03.110

By extending the Winstein cyclization method to the steroid system, we developed a simple and efficient method for highly stereoselective construction of 6β,7β-methylene unit. This method involves an initial Grignard reaction with the 7-carbonyl group of

Full text of DOI:10.1016/j.tet.2007.03.110

Tetrahedron 63 (2007) 4630–4635
A new route to stereoselective construction of 6b,7b-methylene
unit from androst-5-en-7-one
*
Gang Deng, Zheng Li, Shu-Ying Peng, Li Fang and Yuan-Chao Li
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China
Received 30 December 2006; revised 16 March 2007; accepted 19 March 2007
Available online 21 March 2007
Abstract—By extending the Winstein cyclization method to the steroid system, we developed a simple and efficient method for highly
stereoselective construction of 6b,7b-methylene unit. This method involves an initial Grignard reaction with the 7-carbonyl group of
3b,17b-bis(tert-butyldimethylsilyloxy)androst-5-en-7-one (8) and then stereoselective reduction of the tertiary alcohol followed by a tandem
oxidation/cyclopropanation reaction. The excellent yield, high stereoselectivity, and relatively mild reaction conditions should make this an
attractive method for the preparation of 6b,7b-methylene derivatives in steroid.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
structure, few syntheses have been stereoselective, with
good yield.
In steroid, 6b,7b-methylene unit represents a key sub-
structure of many biologically active natural products and
medicinal entities.1 Various methods have been developed
for the construction of this 6b,7b-methylene unit. Most
commonly used are methylenation of the D6,7-unsaturated
bond with Corey reagent,2 Simmons–Smith reagent,3 or
diazomethane.4 Although these developments have
allowed accessing to the construction of 6b,7b-methylene
The Winstein cyclization,5 which represents Ar-30 spiro-
cyclization of the structure with 2-p-hydroxyphenyl-1-ethyl
halides under basic condition, has been widely studied and
established as an useful method for the construction of the
cyclopropylcyclohexadienones6 (Scheme 1, path A). Based
on our earlier studies,7 we found that it might be possible
to extend the Winstein cyclization method to the steroid
Path A: Winstein Cyclization (R=halides):
base
HO
O
O
R
R
3
1
2
Path B: Extending of Winstein Cyclization to Steroids (R=halides):
1
1
1
10
HO
3
5
7 CH2R
3
7
CH2R
3
7
CH2R
O
O
O
5
5
4
5
6
7
Scheme 1.
Keywords: Winstein cyclization; Stereoselective; Synthesis; 6b,7b-Methylene unit.
* Corresponding author. Tel.: +86 21 50806600x3502; fax: +86 21 50807288; e-mail: ycli@mail.shcnc.ac.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.110

G. Deng et al. / Tetrahedron 63 (2007) 4630–4635
4631
CH3
system by constructing the 7b-halidemethylene-3,5-diene-
CH3
H
OR
3-ol 6 structure as outlined in path B of Scheme 1. Taking
into account the instability of the enolate, we expected it to
be a tandem reaction by enolization of compound 5, which
was generated in situ, followed by a cyclopropanation reac-
tion. The key intermediate 7b-halidemethyl-5-ene-3-ol 4
could be synthesized by stereoselective reduction of 7-ter-
tiary alcohol. Herein, we report the details of this synthesis.
RO
CH2OH
H
Et
Et
Si
Et
Figure 1. Plausible intermediate for ionic hydrogenation reduction, R¼OH
or TBS.
2. Results and discussion
Our synthesis began with the preparation of 7a-hydroxy-
methyl-5-androsten-7b-ol (10), a model tertiary alcohol
needed for further stereoselective reduction, using 3b,17b-
bis(tert-butyldimethylsilyloxy)-5-androsten-7-one (8) as the
starting material (Scheme 2).7a When compound 8 was
treated with isopropoxydimethylsilylmethylmagnesium
chloride8 in THF at 0 ꢀC, nucleophilic addition proceeded
smoothly providing b-hydroxysilane intermediate 9, which,
without purification, was subjected to oxidative cleavage of
the corresponding Si–C bond by potassium fluoride and 30%
hydrogen peroxide to give 1,2-diol 10 as a single stereo-
isomer. We then turned our attention to the stereoselective
reduction of 7-tertiary alcohol 10. Ionic hydrogenation,9
which was an effective method to reduce tertiary alcohols
and has been used in many organic synthetic procedures,10
was chosen as our first reduction system. Treatment of 10
with BF3$Et2O and Et3SiH in CH2Cl2 at 0 ꢀC for 10 min
stereoselectively gave 7b-hydroxymethyl-3,17-deprotection
compound 11 as the sole product, no byproduct such as
7a-isomer was found. The plausible mechanism may be
that the relatively bulky triethylsilane attacking the less hin-
dered a face of the in situ produced 7-carbocation to give the
desired 7b-hydroxymethyl-5-androstene (11) (Fig. 1).
3b,17b-bis(tert-butyldimethylsilyloxy)-7b-hydroxymethyl-
5-androstene 12 as the sole product in 65% isolated yield
(98% based on recovered starting material). This reduction
condition was mild and compatible with many sensitive
groups such as cyclopropane, which should make it a com-
plement to ionic hydrogenation reduction system while the
synthesis of 6b,7b-methylene unit in sterid. Deprotection of
the TBS group was achieved with TBAF to give 11 in 99%
yield.
With 7b-configuration derivative in hand, we set out to
realize our intended Winstein cyclization. According to the
literature reports,5,6 we chose chloride as the leaving group.
We changed the basic reaction condition of Winstein cycliza-
tion into Oppenauer oxidation12 condition just because it
could oxidize the 3-hydroxy group to carbonyl 14, an impor-
tant intermediate for our enolation procedure. Selective
mesylation of the primary alcohol 11 followed by chlorina-
tion with LiCl in refluxing DMF gave 13a in 82% yield
(two steps, Scheme 3). To our satisfaction, the tandem oxida-
tion/cyclopropanation reaction of 13a was carried out in the
presence of Al(O-i-Pr)3 and cyclohexanone in refluxing
toluene to cleanly afford the desired 6b,7b-methylene-4-
androsten-3,17-dione 16 in 58% yield (Table 1, entry 1).
We also investigated the influence of some other commonly
used leaving groups (R) on the yield of compound 16 (Table
1). To our surprise, we found that when the sulfonates were
used as the leaving group (entries 4–6), higher yields of
cyclopropanation was obtained and shorter reaction steps
were employed than that of halides (entries 1–3). The best
result was achieved when the methylsulfonyl group was
used as the leaving group (13d, entry 4), which gave com-
pound 16 in 78% yield. The relative configuration of 16 was
determined by ROESY studies and X-ray crystallography
(Fig. 2).
Considering about the harsh reaction condition utilized in
the ionic hydrogenation reduction (incompatible with
many groups such as cyclopropane9a), we explored another
more mild reduction system for stereoselective reduction
of 7-tertiary alcohol, which is important for our further re-
search on the synthesis of 6b,7b-methylene derivatives in
steroid. The ZnI2/NaBH3CN system11 has been reported as
a mild reagent for the reduction of tertiary alcohols. There-
fore, we treated our model tertiary alcohol 10 with standard
ZnI2/NaBH3CN reduction condition. Fortunately, we found
that it was a clean and stereoselective reaction giving
OTBS
a
OTBS
OTBS
OH
b
c
OH
OH
CH2OH
TBSO
O
TBSO
TBSO
HO
CH2OH
OTBS
Si
O
8
9
10
11
e
d
TBSO
CH2OH
12
Scheme 2. Reagents and conditions: (a) Me2(i-PrO)SiCH2Cl, Mg, THF, 0 ꢀC; (b) KF, KHCO3, 30% H2O2, THF, MeOH, rt (84% for two steps); (c) Et3SiH,
BF3$Et2O, CH2Cl2, 0 ꢀC, 96%; (d) ZnI2, NaBH3CN, 1,2-dichloroethane, rt, 65% (98% based on recovered starting material); (e) TBAF, THF, 99%.

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G. Deng et al. / Tetrahedron 63 (2007) 4630–4635
OH
OH
a
HO
CH2OH
HO
CH2R
13(a-g)
11
O
O
O
b
R
O
O
CH2R
O
C
H2
14
15
16
Scheme 3. Reagents and conditions: (a) 13a (R¼Cl): (1) MsCl, collidine, THF, 0 ꢀC; (2) LiCl, DMF, reflux, 82% (two steps); 13b (R¼Br): (1) MsCl, collidine,
THF, 0 ꢀC; (2) NaBr, DMF, reflux, 78% (two steps); 13c (R¼I): (1) MsCl, collidine, THF, 0 ꢀC; (2) NaI, acetone, reflux, 87% (two steps); 13d (R¼OMs): MsCl,
collidine, THF, 0 ꢀC; 99%; 13e (R¼p-TsO–): p-TsCl, Py, 0 ꢀC, 98%; 13f (R¼C6H5SO3–): benzenesulfonyl chloride, Py, 0 ꢀC, 97%; 13g (R¼OAc): Ac2O, Py,
0 ꢀC, 98%; (b) Al(O-i-Pr)3, cyclohexanone, toluene, reflux.
Table 1. Influence of the leaving group on the course of the cyclopropana-
tion reaction
analysis was performed on a Carlo Erba 1106 instrument.
Melting points were determined on a Buchi 510 melting
16 yielda (%)
point apparatus and are uncorrected. Optical rotations were
recorded on a Jasco-Dip-181 polarimeter. IR spectra were
recorded on a Nicollet Magna FTIR-750 spectrometer using
KBr pellets. 1H and 13C NMR spectra were run on a Bruker
AM-400 spectrometer using tetramethylsilane as the internal
standard (chemical shifts in d parts per million). Splitting
patterns are designated as ‘s, d, t, q, and m’, these symbols
indicate ‘singlet, doublet, triplet, quartet, and multiplet’, re-
spectively. Silica gel 60H (200–300 mesh) manufactured by
Qing-dao Haiyang Chemical Group Co. (China) was used
for flash chromatography.
Entry
Substrate
R (leaving group)
1
2
3
4
5
6
7
13a
13b
13c
13d
13e
13f
Cl
Br
I
58
62
61
78
71
68
–OMs
p-TsO–
C6H5SO3–
–OAc
13g
No 16 was detected
a
Isolated yield after silica gel chromatography.
4.2. 3b,17b-Bis(tert-butyldimethylsilyloxy)-7a-hydroxy-
methyl-5-androsten-7b-ol (10)7b
A solution of 8 (0.533 g, 1.0 mmol) in THF (6.0 mL) was
added to the Grignard reagent [prepared from chloromethyl-
dimethylisopropoxysilane (0.627 mL, 3.5 mmol), 1,2-dibro-
moethane (two drops), and Mg (0.096 g, 4.0 mmol) in THF
(4.0 mL) according to the Tamao’s procedure8] under Ar at-
mosphere. After stirring at 0 ꢀC for 2 h, the mixture was
quenched with an aqueous NH4Cl solution (10%) and ex-
tracted with EtOAc. The organic layer was washed with
brine and dried over Na2SO4, and concentrated at 0 ꢀC to
give an unstable single adduct as colorless oil. To a stirred
mixture of colorless crude adduct, MeOH (5.0 mL), THF
(5.0 mL), KHCO3 (0.150 g, 1.5 mmol), and KF (0.282 g,
3.0 mmol) was added H2O2 (30%, 0.5 mL, 5.0 mmol) at
room temperature. The mixture was stirred at room tem-
perature until starting material disappeared. An aqueous
Na2S2O3 solution (50%) was added slowly to the mixture
and stirred until a negative starch/iodide test was observed.
The mixture was extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and concen-
trated. The residue was purified via column chromatography
(25% EtOAc/PE) to provide compound 10 (0.478 g, 84%) as
white solid: [a]2D0 ꢁ28 (c 0.93, acetone); mp 148–152 ꢀC
Figure 2. X-ray crystallographic structure of 16.
3. Conclusions
In conclusion, we have successfully extended the Winstein
cyclization method to the steroid system for the construction
of 6b,7b-methylene unit, and further developed two methods
for stereoselective introduction of b-RCH2 (R¼leaving
group) group at the C-7 position of 5-androstene. This
method would be applicable to the synthesis of other mem-
bers of the 6b,7b-methylene family in steroid.
4. Experimental
4.1. General
1
(lit.7b mp 148–150 ꢀC); H NMR (DMSO-d6, 300 MHz)
d 5.28 (s, 1H), 3.63–3.55 (m,2H), 3.51 (d, J¼3.6 Hz, 2H),
1.04 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.71 (s, 3H), 0.05
(s, 6H), 0.03 (d, J¼3.0 Hz, 6H); 13C NMR (DMSO-d6,
100 MHz) d 142.2, 129.1, 81.8, 73.7, 72.6, 66.6, 46.4,
Mass spectra and high-resolution mass spectra were mea-
sured on a Finnigan MAT-95 mass spectrometer. Elemental

G. Deng et al. / Tetrahedron 63 (2007) 4630–4635
4633
44.3, 43.9, 42.9, 42.5, 37.5, 37.4, 36.9, 32.5, 31.3, 27.0, 25.8,
4.5. 3b,17b-Dihydroxy-7b-methanesulfonyloxymethyl-
5-androstene (13d)
21.1, 18.8, 18.2, 18.2, 10.9, ꢁ4.6, ꢁ4.7, ꢁ5.0; IR (KBr)
3429, 2955, 2933, 2856, 1637 cmꢁ1; MS (EI) m/z (%) 564
(M+, <1), 533 (100), 489 (38), 265 (22), 75 (39). Anal. Calcd
for C32H60O4Si2: C, 68.03; H, 10.70. Found: C, 68.09; H,
10.98.
At 0 ꢀC, fresh distilled collidine (0.089 mL, 0.669 mmol)
was added to a solution of 11 (0.107 g, 0.334 mmol) in
THF (3.0 mL) followed by the addition of methanesulfonyl
chloride (0.031 mL, 0.401 mmol). The reaction mixture was
allowed to warm up slowly to room temperature and stirred
for 2 h. The mixture was treated with saturated aqueous
solution of Na2CO3 and extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, and con-
centrated. The residue was purified via column chro-
matography (EtOAc/PE¼3:1) to provide compound 13d
(0.132 g, 99%) as white solid: [a]2D2 +23 (c 1.05, MeOH);
4.3. 3b,17b-Bis(tert-butyldimethylsilyloxy)-7b-hydroxy-
methyl-5-androstene (12)
To a solution of 10 (0.113 g, 0.2 mmol) in 1,2-dichloro-
ethane (5.0 mL) at room temperature were added zinc iodide
(0.128 g, 0.4 mmol) and sodium cyanoborohydride (0.101 g,
1.6 mmol). The reaction mixture was stirred at room temper-
ature for 12 h, and filtered through a pad of Celite. The Celite
was washed with EtOAc. The combined filtrate was washed
with brine, dried over Na2SO4, and concentrated. The resi-
due was purified via column chromatography (10%
EtOAc/PE) to provide compound 12 (0.071 g, 65%) with re-
covery of the starting material 10 (0.037 g). Compound 12:
[a]2D4 ꢁ10 (c 0.77, CHCl3); mp 138–139 ꢀC; 1H NMR
(CDCl3, 300 MHz) d 5.19 (s, 1H), 3.69–3.58 (m, 1H),
3.57–3.39 (m, 3H), 0.98 (s, 3H), 0.89 (s, 9H), 0.87 (s, 9H),
0.73 (s, 3H), 0.05 (d, J¼3.9 Hz, 6H), 0.00 (d, J¼3 Hz,
6H); 13C NMR (CDCl3, 100 MHz) d 145.8, 123.0, 81.4,
72.1, 65.5, 51.8, 50.9, 44.3, 44.0, 42.7, 37.3, 37.2, 35.9,
32.4, 32.1, 30.9, 29.7, 25.9, 25.8, 21.2, 19.3, 18.1, 11.6,
1
mp 102–103 ꢀC; H NMR (acetone-d6, 400 MHz) d 5.28
(s, 1H), 4.38–4.33 (dd, J¼9.6, 3.1 Hz, 1H), 4.00–3.95 (dd,
J¼9.7, 6.7 Hz, 1H), 3.58–3.53 (dd, J¼9.3, 8.3 Hz, 1H),
3.44–3.36 (m, 1H), 3.07 (s, 1H), 1.00 (s, 3H), 0.76 (s, 3H);
13C NMR (acetone-d6, 100 MHz) d 144.5, 122.3, 80.8,
73.7, 70.6, 52.3, 51.2, 44.1, 42.5, 41.8, 37.5, 37.3, 36.8,
36.2, 33.4, 32.0, 30.4, 25.8, 21.5, 19.0, 11.4; IR (KBr)
3475, 3251, 2933, 2866, 1657, 1466 cmꢁ1; MS (EI) m/z
(%) 398 (M+, <1), 380 (6), 302 (100), 284 (86), 271 (56);
HRMS (EI) calcd for C21H34O5S: 398.2127 (M+), found:
398.2145.
4.6. 3b,17b-Dihydroxy-7b-chloromethyl-5-androstene
(13a)
ꢁ4.5, ꢁ4.6, ꢁ4.8; IR (KBr) 3386, 2929, 2856, 1471 cmꢁ1
;
MS (EI) m/z (%) 548 (M+, <1), 491 (100), 267 (53), 75
(38); HRMS (EI) calcd for C32H60Si2O3: 548.4081 (M+),
found: 548.4075.
To a solution of 13d (0.100 g, 0.251 mmol) in DMF
(3.0 mL) was added LiCl (0.046 g, 0.754 mmol). The result-
ing suspension was refluxed for 2 h. After cooling to room
temperature, the reaction mixture was extracted with EtOAc.
The organic layer was washed with brine, dried over
Na2SO4, and concentrated. The residue was purified via
column chromatography (50% EtOAc/PE) to provide com-
pound 13a (0.071 g, 83%) as white solid: [a]2D5 +2 (c 0.85,
CHCl3); mp 135–136 ꢀC; 1H NMR (CDCl3, 300 MHz)
d 5.26 (s, 1H), 3.70–3.58 (m, 2H), 3.57–3.39 (m, 2H), 1.00
(s, 3H), 0.78 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 143.0, 123.1, 81.0, 70.9, 51.5, 50.3, 49.5, 43.5, 41.7,
36.8, 36.5, 35.6, 34.0, 31.3, 30.1, 26.7, 25.5, 20.9, 18.8,
11.1; IR (KBr) 3365, 2939, 1716, 1668 cmꢁ1; MS (EI) m/z
(%) 338 (M+, 13), 320 (30), 271 (100), 253 (60); HRMS
(EI) calcd for C20H31ClO2: 338.2013 (M+), found:
338.2015.
4.4. 3b,17b-Dihydroxy-7b-hydroxymethyl-5-andro-
stene (11)7b
4.4.1. Method A. To a solution of 10 (0.113 g, 0.2 mmol)
and Et3SiH (0.2 mL, 1.2 mmol) in dry CH2Cl2 (5.0 mL)
was added fresh distilled BF3$Et2O (1.23 mL, 10.0 mmol)
at 0 ꢀC and stirred for 10 min. The mixture was quenched
with an aqueous Na2CO3 solution (10%) and extracted
with CH2Cl2. The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was
purified via column chromatography (EtOAc/PE¼3:1) to
provide compound 11 (0.061 g, 96%) as white solid.
4.4.2. Method B. To a solution of 12 (0.110 g, 0.2 mmol) in
THF (4.0 mL) was added TBAF (1 M in THF, 1.0 mL,
1.0 mmol). The reaction mixture was stirred at room temper-
ature for 12 h and extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and concen-
trated. The residue was purified via column chromatography
(EtOAc/PE¼3:1) to provide compound 11 (0.063 g, 99%) as
white solid. Compound 11: [a]2D0 ꢁ15 (c 1.13, MeOH); mp
181–183 ꢀC (lit.7b mp 181–183 ꢀC); 1H NMR (CD3OD,
400 MHz) d 5.38 (s, 1H), 3.68 (dd, J¼10.8, 3.2 Hz, 1H),
3.55 (t, J¼8.0 Hz, 1H), 3.36–3.44 (m, 1H), 3.22 (dd,
J¼7.2, 3.2 Hz, 1H), 1.00 (s, 3H), 0.76 (s, 3H); 13C NMR
(CD3OD, 100 MHz) d 143.8, 126.2, 82.7, 72.5, 67.0, 54.1,
52.9, 46.1, 45.3, 43.5, 39.0, 38.8, 37.4, 34.8, 33.0, 31.2,
27.3, 22.9, 20.1, 12.4; IR (KBr) 3311, 2928, 2874,
1635 cmꢁ1; MS (EI) m/z (%) 320 (M+, 4), 302 (4), 289
(76), 271 (100), 253 (82), 159 (48) 91 (35). Anal. Calcd
for C20H32O3: C, 74.96; H, 10.06. Found: C, 74.53; H, 10.19.
4.7. 3b,17b-Dihydroxy-7b-bromomethyl-5-androstene
(13b)
To a solution of 13d (0.100 g, 0.251 mmol) in DMF
(3.0 mL) was added NaBr (0.078 g, 0.754 mmol). The
resulting suspension was refluxed for 2 h. After cooling to
room temperature, the reaction mixture was extracted with
EtOAc. The organic layer was washed with brine, dried
over Na2SO4, and concentrated. The residue was purified
via column chromatography (50% EtOAc/PE) to provide
compound 13b (0.076 g, 79%) as white solid: [a]2D4 +4
(c 0.56, CHCl3); mp 146–147 ꢀC; 1H NMR (CDCl3,
300 MHz) d 5.20 (s, 1H), 3.68–3.58 (m, 1H), 3.57–3.42
(m, 2H), 3.39–3.30 (m, 1H), 1.01 (s, 3H), 0.77 (s, 3H); 13C
NMR (CDCl3, 100 MHz) d 143.1, 123.8, 81.0, 70.9, 51.5,
50.3, 43.6, 43.2, 41.7, 36.9, 36.6, 35.7, 35.3, 31.4, 30.1,

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G. Deng et al. / Tetrahedron 63 (2007) 4630–4635
26.7, 25.5, 21.0, 18.9, 11.1; IR (KBr) 3396, 2937, 1718,
1666 cmꢁ1; MS (EI) m/z (%) 382 (M+, 7), 364 (5), 285
(100), 271 (67), 267 (46), 253 (43); HRMS (EI) calcd for
C20H31BrO2: 382.1508 (M+), found: 382.1516.
as white solid: [a]D26 +33 (c 0.50, CHCl3); mp 97–98 ꢀC;
1H NMR (CDCl3, 300 MHz) d 7.94–7.85 (d, J¼8.1 Hz,
2H), 7.71–7.62 (dt, J¼8.2, 0.9 Hz, 1H), 7.61–7.52 (t,
J¼8.1 Hz, 2H), 5.06 (s, 1H), 4.14–4.08 (dd, J¼9.3, 2.5 Hz,
1H), 3.82–3.75 (dd, J¼9.1, 6.7 Hz, 1H), 3.61–3.52 (t,
J¼8.2 Hz, 1H), 3.52–3.41 (m, 1H), 0.92 (s, 3H), 0.68 (s,
3H); 13C NMR (CDCl3, 100 MHz) d 143.4, 135.6, 133.6,
129.1, 129.1, 127.7, 127.7, 121.5, 80.8, 73.3, 70.7, 51.4,
50.2, 43.4, 41.7, 40.9, 36.7, 36.5, 35.4, 32.7, 31.3, 29.9,
25.1, 20.8, 18.7, 11.1; IR (KBr) 3396, 2937, 2874, 1448,
1360 cmꢁ1; MS (ESI) m/z (%) 483 ([M+Na]+, 100); HRMS
(ESI) calcd for C26H36O5SNa: 483.2181 ([M+Na]+), found:
483.2192.
4.8. 3b,17b-Dihydroxy-7b-iodomethyl-5-androstene
(13c)
To a solution of 13d (0.100 g, 0.251 mmol) in acetone
(8.0 mL) was added NaI (0.141 g, 0.754 mmol). The result-
ing suspension was refluxed for 2 h. After cooling to room
temperature, the reaction mixture was extracted with EtOAc.
The organic layer was washed with brine, dried over
Na2SO4, and concentrated. The residue was purified via
column chromatography (50% EtOAc/PE) to provide
compound 13c (0.095 g, 88%) as white solid: [a]2D5 +17
(c 0.52, CHCl3); mp 163–164 ꢀC; 1H NMR (CDCl3,
300 MHz) d 5.09 (s, 1H), 3.64–3.57 (t, J¼8.6 Hz, 1H),
3.56–3.46 (m, 1H), 3.37–3.31 (dd, J¼9.4, 2.4 Hz, 1H),
3.20–3.26 (dd, J¼9.5, 5.7 Hz, 1H), 1.05 (s, 3H), 0.79 (s,
3H); 13C NMR (CDCl3, 100 MHz) d 143.0, 125.5, 81.2,
71.0, 51.4, 50.2, 43.6, 42.4, 41.7, 37.4, 36.9, 36.6, 35.9,
31.4, 30.2, 25.4, 21.0, 19.2, 17.9, 11.2; IR (KBr) 3377,
2935, 1637, 1452 cmꢁ1; MS (EI) m/z (%) 430 (M+, 10),
303 (30), 285 (100), 267 (75), 81 (63); HRMS (EI) calcd
for C20H31IO2: 430.1369 (M+), found: 430.1359.
4.11. 3b,17b-Dihydroxy-7b-acetoxymethyl-5-andro-
stene (13g)
Ac2O (0.041 mL, 0.435 mmol) was added to a solution of 11
(0.107 g, 0.334 mmol) in anhydrous pyridine (3.0 mL) un-
der Ar. The mixture was stirred at 0 ꢀC for 5 h, and then
extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated. The residue
was purified via column chromatography (50% EtOAc/PE)
to provide compound 13g (0.119 g, 98%) as white solid:
[a]2D6 +28 (c 0.85, CHCl3); mp 97–98 ꢀC; 1H NMR
(CDCl3, 300 MHz) d 5.25 (s, 1H), 4.32–4.26 (dd, J¼11.1,
3.5 Hz, 1H), 3.73–3.64 (dd, J¼10.6, 8.0 Hz, 1H), 3.64–
3.58 (m, 1H), 3.57–3.46 (m, 1H), 2.04 (s, 3H), 0.98 (s,
3H), 0.76 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 171.2,
142.5, 122.8, 81.0, 70.7, 67.5, 51.6, 50.4, 43.4, 41.7, 40.6,
36.9, 36.6, 35.5, 33.3, 31.3, 30.0, 25.4, 20.9, 20.8, 18.8,
11.1; IR (KBr) 3412, 2937, 2848, 1740, 1720, 1452,
1385 cmꢁ1; MS (ESI) m/z (%) 385 ([M+Na]+, 16), 363
([M+H]+ 31); HRMS (ESI) calcd for C22H34O4Na:
385.2355 ([M+Na]+), found: 385.2350.
4.9. 3b,17b-Dihydroxy-7b-p-toluenesulfonyloxymethyl-
5-androstene (13e)
At 0 ꢀC, to a solution of 11 (0.107 g, 0.334 mmol) in
pyridine (3.0 mL) was added p-toluenesulfonyl chloride
(0.077 g, 0.401 mmol). The reaction mixture was allowed
to warm up slowly to room temperature and stirred for 2 h.
The mixture was extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and concen-
trated. The residue was purified via column chromatography
(50% EtOAc/PE) to provide compound 13e (0.155 g, 98%)
as white solid: [a]D26 +29 (c 0.53, CHCl3); mp 97–98 ꢀC;
1H NMR (CDCl3, 300 MHz) d 7.79–7.72 (d, J¼8.4 Hz,
2H), 7.38–7.31 (d, J¼8.4 Hz, 2H), 5.08 (s, 1H), 4.12–4.04
(dd, J¼9.7, 2.8 Hz, 1H), 3.79–3.70 (dd, J¼9.3, 6.8 Hz,
1H), 3.61–3.51 (dd, J¼17.1, 8.2 Hz, 1H), 3.51–3.42 (m,
1H), 2.45 (s, 1H), 0.93 (s, 3H), 0.68 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 144.6, 143.3, 132.6, 129.6, 129.6,
127.7, 127.7, 121.6, 80.8, 73.1, 70.6, 51.3, 50.2, 43.4,
41.6, 40.9, 36.7, 36.4, 35.4, 32.7, 31.2, 29.9, 25.1, 21.4,
20.8, 18.7, 11.1; IR (KBr) 3396, 3251, 2937, 1599, 1460,
1358 cmꢁ1; MS (ESI) m/z (%) 497 ([M+Na]+, 100);
HRMS (ESI) calcd for C27H38O5SNa: 497.2338
([M+Na]+), found: 497.2341.
4.12. 6b,7b-Methylene-4-androsten-3,17-dione (16)
4.12.1. General procedure. To a solution of 13 (0.2 mmol)
in dry toluene (5.0 mL) were added cyclohexanone (0.2 mL,
2.0 mmol) and Al(O-i-Pr)3 (0.248 g, 0.3 mmol). The mix-
ture was refluxed for 1 h. After cooling to room temperature,
the reaction mixture was extracted with EtOAc and washed
with diluted sulfuric acid and brine, dried over Na2SO4, and
concentrated. The residue was purified via column chroma-
tography (EtOAc/PE¼1:2) to provide compound 16 as white
1
solid: [a]2D1 ꢁ123 (c 0.19, MeOH); mp 185–187 ꢀC; H
NMR (CDCl3, 400 MHz) d 6.02 (s, 1H), 1.10 (s, 3H), 0.90
(s, 3H), 0.85–0.79 (dd, J¼10.4, 4.9 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 219.9, 197.8, 170.9, 125.7, 51.5,
51.0, 48.0, 37.2, 37.1, 35.6, 34.9, 33.8, 31.0, 21.9, 20.4,
19.1, 18.9, 18.3, 17.7, 13.6; IR (KBr) 3444, 2942, 2854,
1732, 1657 cmꢁ1; MS (EI) m/z (%) 298 (M+, 100), 283
(18), 254 (60), 149 (43), 91 (47); HRMS (EI) calcd for
C20H26O2: 298.1933 (M+), found: 298.1918.
4.10. 3b,17b-Dihydroxy-7b-benzenesulfonyloxymethyl-
5-androstene (13f)
At 0 ꢀC, to a solution of 11 (0.107 g, 0.334 mmol) in
pyridine (3.0 mL) was added p-toluenesulfonyl chloride
(0.064 mL, 0.502 mmol). The reaction mixture was allowed
to warm up slowly to room temperature and stirred for 3 h.
The mixture was extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and concen-
trated. The residue was purified via column chromatography
(50% EtOAc/PE) to provide compound 13f (0.149 g, 97%)
4.13. X-ray structural analysis of 16
Crystallographic data (excluding structural factors) for
compound 16 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC 637078. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,

G. Deng et al. / Tetrahedron 63 (2007) 4630–4635
4635
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Acknowledgements
We thank Zhejiang Shenzhou Pharmaceutical Co., Ltd. for
providing original starting materials.
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