The regio- and stereo-selective reduction of steroidal 4-en-3-ones using Na2S2O4/NaHCO3 and CuCl/NaBH 4

Article abstract of DOI:10.1016/j.steroids.2013.09.011

This paper describes the regio- and stereoselective reduction of a.

Full text of DOI:10.1016/j.steroids.2013.09.011

Steroids 78 (2013) 1339–1346
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Steroids
journal homepage: www.elsevier.com/locate/steroids
The regio- and stereo-selective reduction of steroidal 4-en-3-ones using
Na2S2O4/NaHCO3 and CuCl/NaBH4
1
⇑
Chunli Wang, Xiaoyu Chen, Yaoqing Huang, Jesse Yang , Ying Chen
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
4
Article history:
Received 22 April 2013
Received in revised form 19 September 2013
Accepted 29 September 2013
Available online 12 October 2013
This paper describes the regio- and stereoselective reduction of 4 -3-keto moiety in certain steroids
using Na2S2O4/NaHCO3 and CuCl/NaBH4, respectively. Using either one of the two reduction agents in
the reaction, the 17-substituents in the D ring were observed to have clearly influenced the stereoselec-
tive reduction of 4-ene in the A ring by the so-called conformational transmission effect. Na2S2O4/
NaHCO3 regioselectively reduced C@C at 4-position of 17-substituted-androst-4-en-3-one derivatives
to 5a-H-3-one as the main isomer. And as an extended application, Epiandrosterone (11) was further
Keywords:
4-En-3-one
Conjugated reduction
Sodium dithionite
Cuprous chloride
synthesized from androst-4-en-3,17-dione (AD) via four steps. The total yield from this was about 45%.
4
In the presence of CuCl/NaBH4, 4 -3-keto conjugated reduction of 17-spirocyclic ethylene ketal protected
androst-4-en-3-one derivatives mainly produced 3a-hydroxy-5b-H isomers, at a yield around 81%.
Considering the scaffold configuration of 3a-hydroxy-5b-H moiety coincided with that of bile acid
analogs, this selective reduction could also be used as an alternative method for the synthetic study of
bile acids using AD and its derivatives, which are from the microorganism degradation of natural sterols,
as the potential materials. Meanwhile, configurations of the reductive compounds 5b, 6b, 9, 10 and 17e
were identified by X-ray diffraction.
Ó 2013 Elsevier Inc. All rights reserved.
1. Introduction
two common reduction systems, Na2S2O4/NaHCO3 and CuCl/
NaBH4, to reduce steroidal 4-en-3-one and 1,4-dien-3-one.
Finding a new natural resource for the semi-synthesis of
steroidal drugs has been an important research topic. Since and-
rost-4-en-3,17-dione (AD) and androsta-1,4-dien-3,17-dione
(ADD, Fig. 1) have been obtained from the degradation of natural
sterols by microorganisms with a relatively good yield, using AD
and ADD as the starting materials to synthesize various steroidal
drugs has attracted the attention of many organic synthetic chem-
ists [1–5]. Because many sterols are available from industrial
waste, the synthesis of valuable steroidal drugs from this resource
will have great economic and scientific advantages. However, due
to the lack of effective and highly stereoselective reduction method
for 4-ene in the conjugated enone, synthesizing steroidal drugs
using saturated A ring from AD and ADD is still a great challenge.
Although several hydrogenation catalysts were reported for the
selective reduction of conjugated enone-steroids such as catalytic
systems based on Pd, Cu/Al2O3, Pt/TiO2, homogeneous rhodium
catalysts and so on [6–10], most of them have no practical use in
industrial manufacturing due to their high cost, harsh reaction
condition or low stereo-selectivity, etc. In this paper, we explored
Akamanchi [11] reported that AD could be reduced to
-androstane-3,17-dione with a yield of 88% by refluxing a solu-
5a
tion of steroid in toluene with an aqueous solution of Na2S2O4/
NaHCO3 in the presence of PTC (Aliquat 336). The high stereoselec-
tivity, good yield, inexpensive reductant, mild condition and easy
operation of this phase transformation reaction presented a strong
attraction to us. However, when we repeated their work, the exper-
iments resulted in a product that was a 2:1 mixture of 5
isomer. It was not a pure 5 -androstane-3,17-dione, as was ex-
pected. Since 5 - and 5b-androstane-3,17-dione isomers show
a- and 5b-
a
a
very similar physical properties, including very close Rf values on
thin-layer chromatography (TLC), similar chemical shifts on 1H
NMR spectra and same melting points, it was thus suspected that
the author might not have separated those two isomers, and re-
ported them as a single product in the literature.
Coupled with our attempt to synthesize Epiandrosterone from
AD and to improve the stereoselectivity of 5a-isomer, six different
17-O-substituted cyanohydrins (3a–c, 4a–c) and one 17-spirocy-
clic ethylene ketal AD (14) were prepared to conduct the stereose-
lective reduction of 4-ene using Na2S2O4/NaHCO3. The experiments
showed that the yield and stereoselectivity of the reduction are
⇑
Corresponding author. Tel.: +86 021 51980116.
E-mail address: yingchen71@fudan.edu.cn (Y. Chen).
closely related to 17-substituents. The highest ratio of 5
a-:5b-iso-
1
mer was 2.2:1, which was in agreement with that of other catalytic
Intern from Henry M. Gunn High School, Palo Alto, CA, USA.
0039-128X/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2013.09.011

1340
C. Wang et al. / Steroids 78 (2013) 1339–1346
washed with diethyl ether and then poured into 0.2 N HCl
O
O
(30 mL). After stirring for 3 h, the product was collected by filtra-
tion, washed with water and dried to give 1 (3.9 g, 89%). m.p.
171–174 °C; Recrystallization from acetone gave white crystal:
m.p. 177–178 °C. 1H NMR (400 MHz, CDCl3) d 5.73 (1H, s, 4-CH),
1.20 (3H, s, 19-CH3), 0.98 (3H, s, 18-CH3). ESI-MS m/z (%): 313 [M]+.
O
O
ADD
AD
Fig. 1. The structures of AD and ADD.
2.1.2. 17a-Cyano-17b-hydroxyandrost-4-en-3-one (2)
AD (2.4 g, 8.4 mmol) was dissolved in acetone cyanohydrin
(3.6 mL, 39.4 mmol). The mixture was stirred at 40 °C for 8 h and
then a few drops of triethylamine were added to adjust pH to
8.8–9.0. Stirring was continued for another 0.5 h. The solid was fil-
tered, washed with diethyl ether, followed with acetone adjusted
by p-toluenesulfonic acid to pH = 6, and dried to give 2 (1.7 g,
65%), m.p. 162–164 °C. ESI-MS m/z (%): 313 [M]+.
reduction based on Pd [7]. Applying one of the 5a-isomers (5b) as
key intermediates, Epiandrosterone was further synthesized with a
yield of 92%.
Moreover, many literatures reported that a number of complex
Cu–H reagents can reduce the C@C of
a,b-unsaturated carbonyl
compound selectively [12,13], but rarely for steroidal 4-en-3-one.
NaBH4–CuCl/MeOH is a Cu–H reagent formed in situ, which can
selectively reduce the C@C of a,b-unsaturated esters but does not
attack the ester group [14]. This inspired us to explore the C@C
selective reduction of 4-en-3-one in AD and ADD derivatives under
the NaBH4–CuCl condition. Interestingly enough, with this reagent,
both C@C and C@O of 4-en-3-one were directly saturated into 5b-
H-3a-hydroxy as main isomer by conjugated reduction. It is no-
ticed that the spatial structures of 17-substituents in AD and
ADD derivatives, seemingly by a conformational transmission ef-
2.1.3. 17b-Cyano-17
cyano-17b-acetoxyandrost-4-en-3-one (4b)
a-acetoxyandrost-4-en-3-one (3b) and 17a-
Acetic anhydride (6.0 mL, 64 mmol) was added under nitrogen
to a solution of 1 (4.0 g, 12.8 mmol) and dimethylaminopyridine
(DMAP) (0.5 g, 4.1 mmol) in dry pyridine (40 mL). The resulting
mixture was refluxed for 3 h and poured into ice water (150 mL).
The resulting brown solid was filtered, washed with water till neu-
tral, dried to give 3b (4.35 g, 96%), m.p. 219–222 °C. 1H NMR
(400 MHz, CDCl3) d 5.77 (1H, s, 4-CH), 2.11 (3H, s, –COCH3), 1.22
(3H, s, 19-CH3), 1.12 (3H, s, 18-CH3). ESI-MS m/z (%): 356.2 (M+1).
The synthesis procedure of 4b was the same as that used for the
preparation of 3b. Yield: 93%, m.p. 157–160 °C. 1H NMR (400 MHz,
CDCl3) d 5.75 (1H, s, 4-CH), 2.11 (3H, s, –COCH3), 1.20 (3H, s, 19-
CH3), 0.98 (3H, s, 18-CH3). ESI-MS m/z (%): 356.2 (M+1).
fect [15,16], markedly influenced the ratio of 5
and 5b-H-3 -hydroxy isomers. With the 17-O-acyl cyanohydrin
protected group, 4-en-3-one of AD was reduced to 5b-H-3 -hydro-
xy- and 5 -H-3b-hydroxy-androstane isomers with ratios around
2.8:1–1:1. While the AD and ADD derivatives with 17-spirocyclic
ethyleneketal protected were reduced to 5b-H-3 -hydroxy- and
-H-3b-hydroxy-androstane isomers at a 9:1 predominant ratio,
a-H-3b-hydroxy
a
a
a
a
5a
and nearly 80% diastereo-selectivity. And the configuration of
one reduction product 17e was identified by X-ray diffraction.
2.1.4. 17b-Cyano-17
cyano-17b-benzoyloxyandrost-4-en-3-one (4c)
a-benzoyloxyandrost-4-en-3-one (3c) and 17a-
The 3a-hydroxy-5b-androstane isomer with two chiral centers at
Trifluoroacetic anhydride (4.5 mL, 32 mmol), p-toluenesulfonic
acid (0.5 g, 2.9 mmol) and benzoic acid (4.0 g, 32 mmol) were
added to CHCl3 (15 mL). After stirring for 0.5 h at room tempera-
ture, compound 1 (2.0 g, 6.4 mmol) was added. The reaction was
stirred at room temperature and monitored by TLC until the sub-
strate disappeared. Then the mixture was alkalized to pH 7–8 with
saturated sodium bicarbonate solution and extracted with CHCl3
(3 ꢀ 15 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated in vacuum to give the crude product, which was puri-
fied by column chromatography using CH2Cl2 as eluent to give a
white solid 3c (1.5 g, 56%), m.p. 200–202 °C. 1H NMR (400 MHz,
CDCl3) d 7.49–8.08 (5H, m, –COC6H5), 5.77 (1H, s, 4-CH), 1.22
(3H, s, 19-CH3), 1.16 (3H, s, 18-CH3). ESI-MS m/z (%): 418.2 (M+1).
The synthesis procedure of 4c was the same as that used for the
preparation of 3c. Yield: 62%, m.p. 246–249 °C. 1H NMR (400 MHz,
CDCl3) d 7.49–8.08 (5H, m, –COC6H5), 5.77 (1H, s, 4-CH), 1.22 (3H,
s, 19-CH3), 1.16 (3H, s, 18-CH3). ESI-MS m/z (%): 418.2 (M+1).
3- and 5-position is the common structural pattern of bile acid
derivatives. Because of the low cost of reagents and easy acquisi-
tion of AD and ADD as starting materials, this reduction method
has great potential in the synthetic investigation of bile acid
analogs.
Herein, we would like to report the details of this research.
2. Experimental
Melting points were measured with a microscope (SGW X-4)
melting apparatus without correction. The 1H NMR was measured
on a Bruker-DPX spectrometer operating at 400 MHz for 1H and
101 MHz for 13C, expressed in ppm. 1H assignments were made
using 2D gCOSY experiments, while 13C assignments were made
using 2D gHSQC and gHMBC experiments. The solvents used were
CDCl3 and DMSO-d6. Mass spectrum was measured with HP5973N
analytical mass spectrometers. Optical rotation was measured on a
WZZ-2S polarimeter. Column chromatography (CC) was carried
out on silica gel (300–400 mesh, Shanghai Sanpont, Co., Ltd, China)
and TLC analyses were carried out on silica gel GF254 glass plates
2.1.5. Synthesis of 14, 15e, 15f and 18
The compound 14 was prepared by the ketalization of AD (1.0 g,
3.5 mmol) in refluxing toluene (10 ml) using ethylene glycol
(0.7 mL, 12.3 mmol). After 2 h, p-toluenesulfonic acid (0.05 g,
0.3 mmol) was added to the mixture. The reaction mixture was
worked up after another 1 h and then alkalized to pH 7–8 with sat-
urated sodium bicarbonate solution. The organic layer was dried
(Na2SO4), filtered, and concentrated in vacuum to give the crude
product, which was purified by column chromatography using
17% ethyl acetate in petroleum ether as eluent to give a white solid
14 (0.53 g, 46%), m.p. 178–181 °C. 1H NMR (400 MHz, CDCl3) d 5.73
(s, 1H, 4-H), 3.89 (m, 4H, (OCH2)2), 1.22 (s, 3H, 19-CH3), 0.79 (s, 3H,
18-CH3). ESI-MS m/z (%): 331.2 (M+1). The data were compared
with that of the literature [17].
(20 ꢀ 20 cm with 250
lm layer, Yantai Jiangyou Company, China).
2.1. General protection procedure of 17-one
2.1.1. 17b-Cyano-17a-hydroxyandrost-4-en-3-one (1)
AD (4.0 g, 14 mmol) was dissolved in the mixture of methanol
(20 mL) and water (2 mL). To the solution, sodium carbonate
(150 mg, 1.4 mmol) and acetone cyanohydrin (4.1 mL, 44.9 mmol)
were added. The reaction mixture was stirred at 40 °C for 4 h and
then water (6 mL) was added. The mixture was stirred for another
5 h and kept overnight at room temperature. Solid was filtered,

C. Wang et al. / Steroids 78 (2013) 1339–1346
1341
The synthesis procedure of 15e was the same as that used for
2.2.3. Reduction of 17b-cyano-17a-benzoyloxyandrost-4-en-3-one
the preparation of 14 with ADD as the starting material, and the
product was purified by crystallizing from acetone with a yield
of 73%, m.p. 170–172 °C. 1H NMR (400 MHz, CDCl3) d 7.12 (d,
J = 9.5 Hz, 1H, 2-H), 6.20 (d, J = 10.5 Hz, 1H, 1-H), 6.02 (s, 1H,
4-H), 3.89 (m, 4H, (OCH2)2), 1.24 (s, 3H, 19-CH3), 0.85 (s, 3H,
18-CH3). ESI-MS m/z (%): 329.2 (M+1). The data were compared
with that of the literature [18].
(3c) and 17 -cyano-17b-benzoyloxyandrost-4-en-3-one (4c)
a
Compound 3c was reduced by the general procedure, and
yielded 5c and 6c in 80% with the ratio of 2.2:1.
Compound 5c: m.p. 207–209 °C. Optical rotation: ½a D25
ꢁ
= +6.8°
(CH2Cl2, 0.01 g/mL). 1H NMR (400 MHz, CDCl3) d 7.51–8.02 (5H,
m, –COC6H5), 1.12 (3H, s, 19-CH3), 1.09 (3H, s, 18-CH3), 0.92 (1H,
m, 9-H). ESI-MS m/z (%): 420.2 (M+1).
The synthesis procedure of 15f was the same as that used for
Compound 6c: m.p. 211–213 °C. Optical rotation: ½a D25
ꢁ
= +5.8°
the preparation of 15e with 11a-hydroxy-androsta-1,4-diene-
(CH2Cl2, 0.01 g/mL). 1H NMR (400 MHz, CDCl3) d 7.49–8.01 (5H,
m, –COC6H5), 1.12 (3H, s, 19-CH3), 1.09 (3H, s, 18-CH3). ESI-MS
m/z (%): 420.2 (M+1).
3,17-dione as the starting material, and the product was
crystallized from methanol with a yield of 88%, m.p. 250–252 °C.
ESI-MS m/z (%): 345.2 (M+1).
The synthesis procedure of 18 was the same as that used for the
preparation of 15e with 6-methyleneandrost-4-en-3,17-dione as
the starting material, and the product was crystallized from meth-
anol with a yield of 90%, m.p. 170–172 °C. 1H NMR (400 MHz,
CDCl3) d 5.98 (s, 1H, 4-H), 5.05 (s, 1H, 6-CH2), 4.93 (s, 1H, 6-CH2),
3.89 (m, 4H, (OCH2)2), 1.14 (s, 3H, 19-CH3), 0.89 (s, 3H, 18-CH3).
ESI-MS m/z (%): 343.2 (M+1).
Compound 4c was reduced by the general procedure, and
yielded 7c and 8c in 89% (7c:8c = 1.8:1).
Compound 7c: m.p. 264–267 °C. Optical rotation: ½a D25
ꢁ
= +39.7°
(CH2Cl2, 0.01 g/mL). 1H NMR (400 MHz, CDCl3) d 7.47–8.01 (5H,
m, –COC6H5), 1.06 (6H, d, J = 8.9 Hz, 18-CH3, 19-CH3), 0.94 (1H,
m, 9-H). ESI-MS m/z (%): 420.1 (M+1).
Compound 8c: m.p. 245–247 °C. Optical rotation: ½a D25
ꢁ
= +37.9°
(CH2Cl2, 0.01 g/mL). 1H NMR (400 MHz, CDCl3) d 7.47–8.01 (5H,
m, –COC6H5), 1.07 (6H, d, J = 8.9 Hz, 18-CH3, 19-CH3). ESI-MS m/z
(%): 420.1 (M+1).
2.2. General reduction procedure with sodium dithionite
2.2.4. Reduction of 17-ethylendioxyandrost-4-en-3-one (14)
Compound 14 was reduced by the general procedure, and the
original product was then added to 2 N HCl solution to form 17-ke-
tone. Products 9 and 10 were obtained with the yield of 77% and
with the ratio of 1:1.4.
A solution of steroidal substances AD, 3a–c, 4a–c, 14 (1 equiv)
in toluene, together with a solution of sodium dithionite (9 equiv)
and sodium bicarbonate (9 equiv) in water in presence of PTC (5%
equiv), was refluxed and stirred for 3 h. The aqueous layer was sep-
arated and organic phase was concentrated in vacuum. Products
were purified by the column chromatography using 9–10% ethyl
acetate in petroleum ether.
2.2.5. Reduction of 17b-cyano-17a-(1-butoxy-ethoxy)-androst-4-en-
3-one (3a) and 17a-cyano-17b-(1-butoxy-ethoxy)-androst-4-en-3-
one (4a)
2.2.1. Reduction of androst-4-en-3,17-dione (AD)
Compound 1 (1.0 g, 3 mmol) and n-Butyl vinyl ether (4.2 mL,
30 mmol) were added to anhydrous tetrahydrofuran containing
PTS (0.07 g). The mixture was stirred for 0.5 h at room temperature
under nitrogen atmosphere. The reaction solution was adjusted to
pH 8–9 with triethylamine and concentrated in vacuum to get a
brown oil. Then toluene (10 mL) together with a solution of sodium
dithionite (5.0 g, 28.7 mmol) and sodium bicarbonate (2.4 g,
28.7 mmol) in water (15 mL) in presence of PTC (0.07 g,
0.17 mmol) were added into the brown oil and refluxed with stir-
ring for 3 h. Monitored by TLC, but no product was appeared.
The reduction procedure of 4a was same as that used for the
preparation of 3a. But the mixture of 7a and 8a was obtained with
the yield of only 10%. Further study on their ratio was not
conducted.
AD was reduced following the general reduction procedure, and
yielded 9 and 10 in 78% with the ratio of 2:1.
Compound 9: m.p. 134–137 °C. Optical rotation: ½a D25
ꢁ
= +159.7°
(CH2Cl2, 0.01 g/mL). IR (KBr):
m .
1452, 1713, 1746, 2832, 2939 cmꢂ1
1H NMR (400 MHz, CDCl3) d 1.03 (3H, s, 19-CH3), 0.88 (3H, s, 18-
CH3), 0.79 (1H, m, 9-H). ESI-MS m/z (%): 289.3 (M+1).
Compound 10: m.p. 134–137 °C. Optical rotation: ½a D25
ꢁ
= +97.2°
(CH2Cl2, 0.01 g/mL). IR (KBr):
m .
1446, 1708, 1734, 2862, 2928 cmꢂ1
1H NMR (400 MHz, CDCl3) d 1.05 (3H, s, 19-CH3), 0.89 (3H, s, 18-
CH3). ESI-MS m/z (%): 289.3 (M+1).
2.2.2. Reduction of 17b-cyano-17
a-acetoxyandrost-4-en-3-one (3b)
and 17 -cyano-17b-acetoxyandrost-4-en-3-one (4b)
a
Compound 3b was reduced by the general reduction procedure,
and yielded 5b and 6b in 85% with the ratio of 2:1.
2.3. Synthesis of Epiandrosterone (11)
Compound 5b: m.p. 226–230 °C. Optical rotation: ½a D25
ꢁ
= +32.9°
(CH2Cl2, 0.01 g/mL). 1H NMR (400 MHz, CDCl3) d 2.11 (3H, s,
–COCH3), 1.03 (6H, d, J = 1.8 Hz, 18-CH3, 19-CH3), 0.79 (1H, m, 9-
H). ESI-MS m/z (%): 358.3 (M+1).
A solution of sodium borohydride (17 mg, 0.45 mmol) in meth-
anol (4 mL) was added slowly into the methanol (10 mL) solution
of 5b (0.16 g, 0.45 mmol) at ꢂ10 °C. After stirring for 0.5 h at this
temperature, the mixture was added with 20% KOH (12 mL) aque-
ous solution, stirred for additional 1 h at 40 °C and then poured
into water (15 mL). The resulting solid was filtered, washed with
water till neutral, and dried to give the target compound 11
(0.12 g, 92%), m.p. 170–173 °C. 1H NMR (400 MHz, CDCl3) d 3.61
(1H, s, 3-H), 0.85 (6H, d, J = 10.4 Hz, 18-CH3, 19-CH3), 0.75 (1H,
m, 9-H); ESI-MS m/z (%): 291.3 (M+1).
Compound 6b: m.p. 225–229 °C. Optical rotation: ½a D25
ꢁ
= +19.3°
(CH2Cl2, 0.01 g/mL). 1H NMR (400 MHz, CDCl3)
d 2.14 (3H,
s, –COCH3), 1.04 (6H, d, J = 6.7 Hz, 18-CH3, 19-CH3). ESI-MS m/z
(%): 375.2 (M+18).
Compound 4b was reduced by the general reduction procedure,
and yielded 7b and 8b in 94% (7b:8b = 1:1).
Compound 7b: m.p. 205–207 °C. Optical rotation: ½a D25
ꢁ
= +6.6°
(CH2Cl2, 0.01 g/mL). 1H NMR (400 MHz, CDCl3) d 2.11 (3H, s,
–COCH3), 1.02 (3H, s, 19-CH3), 0.92 (3H, s, 18-CH3), 0.84 (1H, m,
9-H). ESI-MS m/z (%): 358.2 (M+1).
2.4. General reduction procedure with CuCl/NaBH4
Compound 8b: m.p. 167–170 °C. Optical rotation: ½a D25
ꢁ
= ꢂ1.2
Steroidal substances (AD, 3b–c, 4b, 14, 15e–f, 18, 1 equiv) and
CuCl (1–2 equiv) were added to dry ethanol. The mixture was stir-
red for 2 h at room temperature under nitrogen atmosphere.
NaBH4 (2–6 equiv) was added slowly to the solution. Monitored
(CH2Cl2, 0.01 g/mL). 1H NMR (400 MHz, CDCl3) d 2.10 (3H, s,
–COCH3), 1.04 (3H, s, 19-CH3), 0.92 (3H, s, 18-CH3). ESI-MS m/z
(%): 358.2 (M+1).

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C. Wang et al. / Steroids 78 (2013) 1339–1346
by TLC and stop the reaction when the substrate disappeared. The
black solution was then filtered and concentrated in vacuum to
give original product. The original product was then added to sat-
urated NaOH solution (3b–c, 4b) or 2 N HCl (14, 15e–f, 18) solution
to form 17-ketone. The resulting white solid was filtered, washed
with water till neutral, and dried. The crude solid was chromato-
graphed by using 9–10% ethyl acetate in petroleum ether as eluent
to obtain eight target compounds.
38.18, 36.82, 35.95, 35.84, 34.49, 31.69, 27.34, 25.13, 23.54,
21.86, 14.02.
2.4.8. 3b-hydroxy-6-methyl-androst-5-en-17-one (19) and 3
hydroxy-6-methylen-5b-androstan-17-one (20)
a-
Compound 18 was reduced by the general procedure, and
yielded 19 (57%) together with 20 (30%).
Compound 19: m.p. 152–155 °C. 1H NMR (400 MHz, CDCl3) d
3.55 (s, 1H, 3-H), 1.82 (s, 3H, 6-CH3), 1.04 (s, 3H, 19-CH3), 0.90 (s,
3H, 18-CH3). ESI-MS m/z (%): 303.3 (M+1). 13C NMR (101 MHz,
CDCl3) d 221.20, 132.59, 125.21, 70.86, 51.44, 50.35, 47.47, 37.75,
37.49, 36.93, 35.90, 35.24, 31.61, 31.50, 31.32, 21.88, 20.47,
19.64, 19.56, 13.58.
2.4.1. 3b,17b-dihydroxy-5
5b-androstane (13)
a-androstane (12) and 3a,17b-dihydroxy-
AD was reduced by the general procedure, and yielded 12 and
13 in 73% with the ratio of 4:3.
Compound 12: m.p. 158–160 °C ESI-MS m/z (%): 315.1 (M+23).
1H NMR (400 MHz, CDCl3) d 3.60 (dt, J = 11.1, 7.3 Hz, 2H, 3-H, 17-
H), 0.83 (s, 3H, 19-CH3), 0.77(s, 3H, 18-CH3), 0.63 (m, 1H, 9-H).
13C NMR (101 MHz, DMSO-d6) d 79.99, 69.24, 54.01, 50.53,
44.39, 42.49, 38.80, 38.11, 36.63, 36.57, 35.12, 31.28, 29.78,
28.27, 23.03, 20.39, 12.09, 11.27.
Compound 13: m.p. 241–243 °C ESI-MS m/z (%): 315.1 (M+23).
1H NMR (400 MHz, CDCl3) d 3.60 (dt, J = 11.1, 7.3 Hz, 2H, 3-H, 17-
H), 0.98 (s, 3H, 19-CH3), 0.83 (s, 3H, 18-CH3). 13C NMR (101 MHz,
DMSO-d6) d 80.00, 69.77, 50.60, 42.57, 41.53, 40.17, 36.74, 36.22,
35.44, 35.18, 34.26, 30.30, 29.87, 26.72, 25.76, 23.22, 23.05,
19.95, 11.23.
Compound 20: m.p. 113–116 °C. 1H NMR (400 MHz, CDCl3) d
4.80 (s, 1H, 6-CH2), 4.50 (s, 1H, 6-CH2), 3.62 (s, 1H, 3-H), 1.04 (s,
3H, 19-CH3), 0.90 (s, 3H, 18-CH3). ESI-MS m/z (%): 303.3 (M+1).
13C NMR (101 MHz, CDCl3) d 220.90, 148.52, 106.62, 71.31, 54.75,
51.37, 49.31, 47.88, 40.74, 37.82, 36.97, 36.49, 35.81, 33.67,
31.46, 31.22, 21.88, 20.47, 13.83, 12.47.
3. Results and discussion
3.1. Regioselective reduction C@C of 4-En-3-one moiety with Na2S2O4/
NaHCO3
2.4.2. 3b-hydroxy-5a-androstane-17-one (16e) and 3a-hydroxy-5b-
androstane-17-one (17e)
Compound 3b was reduced by the general procedure, and
yielded 16e and 17e in 95% with the ratio of 2.8:1.
With the desire of regio- and stereo-selectively reducing C@C
double band of 4-en-3-one steroids in mind, androst-4-en-3,17-
dione (AD) was selected as model substrate to repeat its reduction
with Na2S2O4/NaHCO3 according to Akamanchi’s method men-
tioned in the literature [11]. Unexpectedly, two configuration
Compound 16e: m.p. 180–183 °C. 1H NMR (400 MHz, CDCl3) d
3.65 (s, 1H, 3-H), 0.90 (s, 3H, 19-CH3), 0.77 (s, 3H, 18-CH3), 0.83
(m, 1H, 9-H). ESI-MS m/z (%): 291.3 (M+1). 13C NMR (101 MHz,
CDCl3) d 221.43, 71.10, 54.38, 51.39, 47.75, 44.79, 38.02, 36.89,
35.81, 35.60, 35.00, 31.51, 31.39, 30.84, 28.35, 21.74, 20.46,
13.77, 12.26.
isomers, 5
duced at a 2:1 ratio with a total yield of 78%. This is different from
only 5 -androstane-3,17-dione isomer formed at 88% yield as re-
ported in the literature. The configurations of 5 - and 5b-andro-
a- and 5b-androstane-3,17-dione (9 and 10) were pro-
a
a
Compound 17e: m.p. 143–145 °C. 1H NMR (400 MHz, CDCl3) d
3.65 (s, 1H, 3-H), 0.90 (s, 3H, 19-CH3), 0.77 (s, 3H, 18-CH3). ESI-
MS m/z (%): 291.3 (M+1). 13C NMR (101 MHz, CDCl3) d 221.36,
71.90, 51.51, 47.87, 42.04, 40.40, 36.35, 35.90, 35.69, 35.39,
34.77, 31.75, 30.52, 26.91, 25.38, 23.29, 21.83, 20.10, 13.80.
stane-3,17-diones (9, 10) were confirmed by the X-ray crystal
diffraction analysis (Fig. 2). Duax et al [15,16] had reported that
the 17-substituents of 17a-acetoxy progesterone could change
the A-ring conformation by conformational transmission, which
then affect the achieved reaction at the ring A. In order to investi-
gate and improve the ratio of 5a-androstane-3,17-dione isomer in
2.4.3. Reduction of 17
The procedure was same as that of 3b, and produced 16e and
17e with 1:1 ratio in the total yield of 50%.
a
-cyano-17b-acetoxyandrost-4-en-3-one (4b)
the synthesis of Epiandrosterone, six different O-substituted
17-cyanohydrin (3a–c, 4a–c) and one 17-spirocyclic ketal of AD
(14) were further prepared as substrates to monitor their stereose-
lective reduction with Na2S2O4/NaHCO3.
2.4.4. Reduction of 17b-cyano-17
(3c)
a-benzoyloxyandrost-4-en-3-one
As Scheme 1 shown, in the Na2CO3/MeOH-H2O solvent of ace-
tone cyanohydrin and pure acetone cyanohydrin, the configuration
Compound 3c was reduced by the general procedure and
yielded 16e and 17e in 29% without being separated.
of pure 17a-hydroxy-17b-cyano-androst-4-en-3-one (1) and 17a-
cyano-17b-hydroxy-androst-4-en-3-one (2) were synthesized with
yields of 89% and 65%, respectively. Then two 17-ether-protected
cyanohydrins (3a, 4a), four 17-O-acyl-protected cyanohydrins
(3b–c, 4b–c) and one 17-spirocyclic ketal (14) were prepared fur-
ther to undergo PTC reduction. The results were shown in Table 1.
Surprisingly, 4a yielded only 10% of reductive products, while 3a
had no reaction at all. This implied that the bulky 17-substituent
might hinder the reduction of 4-ene in A ring. As for the others,
the 3b and 3c produced 5b, 5c and 6b, 6c with ratios of 2:1 and
2.4.5. Reduction of 17-ethylendioxyandrost-4-en-3-one (14)
Compound 14 was reduced by the general procedure, and
yielded 16e and 17e in 90% with the ratio of 1:9 (16e:17e).
2.4.6. Reduction of 17-ethylendioxyandrosta-1,4-dien-3-one (15e)
The procedure was same as that of 14, and yielded 16e and 17e
in 89% with the ratio of 1:9 (16e:17e).
2.2:1 for 5
The 4b and 4c resulted in 7b, 7c and 8b, 8c at ratios of 1:1 and 1.8:1
for 5 -:5b-isomer and with yields of 94% and 89%, respectively.
And the substrate 14 also created 5 -:5b-isomer at a ratio of
1:1.4 and with the yield of 77%. The configurations of 5b (5 -iso-
mer) and 6b (5b-isomer) were confirmed by crystal X-ray diffrac-
tion (Fig. 3). The configurations of other reduction products were
confirmed via 17-deprotection to form 17-ketone. They were then
a-:5b-isomer and at yields of 85% and 80%, respectively.
2.4.7. 3
a,11a-dihydroxy-5b-androstane-17-one (17f)
The reduction procedure of 15f was same as that of 14, and
a
yielded 17f in 81% with no 5
a
-isomer (16f) obtained.
a
Compound 17f: m.p. 99–102 °C. 1H NMR (400 MHz, CDCl3) d
3.95 (s, 1H, 11-H), 3.62 (s, 1H, 3-H), 1.04 (s, 3H, 19-CH3), 0.90 (s,
3H, 18-CH3). ESI-MS m/z (%): 329.2 (M+23). 13C NMR (101 MHz,
CDCl3) d 219.50, 71.91, 68.02, 50.39, 48.08, 47.12, 43.61, 43.22,
a

C. Wang et al. / Steroids 78 (2013) 1339–1346
1343
O
O
O
O
H
H
9
10
Fig. 2. X-ray diffraction crystal structures of 9 and 10.
CN
OR
CN
OH
CN
OR
O
O
O
H
H
5a,b,c
6a,b,c
CN
OR
i
iiia,b,c
iv
O
O
O
AD
1
3a, b,c
iv
O
ii
OR
CN
O
O
O
H
OH
CN
iiia,b,c
OR
CN
9
O
O
+
H
H
v
O
iv
7a,b,c
8a,b,c
O
iv
OR
CN
14
O
O
4a,b,c
CH(CH )OC H ; b. R=COCH ; c. R=COC H
6 5
2
O
H
10
a. R=
3
4
9
3
Scheme 1. Reagents and conditions: (i). (CH3)2C(OH)CN, Na2CO3, MeOH-H2O, 40 °C for 9 h, 0.2 N HCl for 3 h, RT; (ii). (CH3)2C(OH)CN, 40 °C for 8 h, N(Et)3, 0 °C for 0.5 h; (iiia).
C2H3OC4H9, PTS, THF; (iiib). (CH3CO)2O, Py, DMAP, refluxed for 3 h; (iiic). (CF3CO)2O, PTS, C6H5COOH; (iv). Na2S2O4, NaHCO3, toluene-water, refluxed for 3 h; (v). 2 N HCl aq,
RT.
Table 1
The selective PTC reduction of 4-ene-3-one with sodium dithionite.
Entry
Substrate
R
T
Ratioa (mol)
Time (h)
Yield (%)
5-a:5-b
1
2
3
4
5
6
7
8
4-AD
3a
3b
3c
4a
–
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
1:9:9
1:9:9
1:9:9
1:9:9
1:9:9
1:9:9
1:9:9
1:9:9
3
3
3
3
3
3
3
3
78
0
2:1
–
2:1
2.2:1
–
1:1
CH3CHOC4H9
COCH3
COC6H6
CH3CHOC4H9
COCH3
COC6H6
–
85
80
10
94
89
77
4b
4c
1.8:1
1:1.4
14b
a
The molar ratio refers to substrate: Na2S2O4: NaHCO3 = 1:9:9.
The 17-one was protected by ethylendioxy group.
b
compared with 9 and 10, of which the configurations were mea-
sured by single crystal X-ray diffraction (Fig. 2).
The data in Table 1 showed that the structural pattern at
17-position has considerable effect on the yield and stereose-
lectivity of 4-ene reduction. The 17-position in steroidal skele-
ton is far from the reaction center of 4-ene reduction. This
remote effect should have been resulted from the so-called
conformation transmission effect. The conformation change of
D ring caused by different 17-substitutes or structural patterns
could have transmitted to A ring and therefore resulted in its
conformation change, which might influence the stereoselectiv-
ity of reduction.

1344
C. Wang et al. / Steroids 78 (2013) 1339–1346
CN
O
CN
O
O
O
O
O
H
H
6b
5b
Fig. 3. X-ray diffraction crystal structures of 5b and 6b.
O
CN
OH
CN
OAc
iii
i
ii
96%
57%
89%
O
O
O
O
AD
3b
1
CN
OAc
O
iv
92%
HO
H
H
5b
Epiandrosterone(11)
Scheme 2. Synthesis of Epiandrosterone. (i). (CH3)2C(OH)CN, Na2CO3, MeOH-H2O, 40 °C for 9 h, 0.2 N HCl for 3 h, RT; (ii). (CH3CO)2O, Py, DMAP, refluxed for 3 h; (iii). Na2S2O4,
NaHCO3, toluene-water, refluxed for 3 h; (iv). NaBH4, MeOH, ꢂ10 °C for 0.5 h, 20% KOH in water, 40 °C for 1 h.
As an extended use of C@C stereoselective reduction product in
4-en-3-one steroids, 3b was selected as an intermediate product for
further synthesizing Epiandrosterone (11), which was a key starting
material for synthesizing a series of steroidal drugs, such as Rocuro-
nium Bromide, Vecuronium Bromide, etc. As Scheme 2 below
showed, the overall yield of the 4-step synthesis from AD was 45%.
Acetyloxy-17b-cyano-androst-4-en-3-one (3b) reacted with CuCl/
NaBH4 in ethanol to produce 3b-hydroxy-5 -androstane-17-one
(16e) and 3 -hydroxy-5b-androstane-17-one (17e) at the ratio of
2.8:1 and a total yield of 95%. Similarly, 17b-acetyloxy-17 -cyano
isomer (4b) generated those two isomers at the ratio of 1:1 and the
yield of 50%. On the other hand, 17 -benzoyloxy-17b-cyano deriv-
a
a
a
a
ative (3c) was converted into corresponding 16e and 17e with a
yield of 29% only. Interestingly, the conjugated reduction of 14
and 15e bearing 17,17-ethylendioxy spiro-ketal as protecting
3.2. Conjugated reduction of 4-En-3-one moiety with CuCl/NaBH4
AD, three 17-ester-protected cyanohydrins (3b, 3c and 4b) and
four 17-spirocyclic ketal (14, 15e, 15f and 18) compounds were
used as the substrates to perform their reduction with CuCl/NaBH4.
The general procedure was described in Scheme 3 below. At room
temperature, the mixture of substrate and CuCl in absolute ethanol
was added with NaBH4 slowly and stirred for a couple of hours
with TLC monitoring. After hydrolysis of 17-protected group, 17-
ketone was formed in the aqueous solution of NaOH or HCl. The
products were isolated by common workup mentioned in the
experimental section.
group produced 5b-androstane-3
high stereoselectivity, but formed only 9% of 5
hydroxy isomer (16e) at a ratio of 9:1 (17e:16e). In particular,
the introduction of 11 -hydroxy and 6-double bond also dramati-
cally increased the ratio of 5b-androstane-3 -hydroxy isomer.
Based on these facts, it was believed that compound 15f was al-
most reduced into the desired isomer 17f at a yield of 81%, and
18 was reduced to 3b-hydroxy-6-methyl-androst-5-en-17-one
a
-hydroxy compound (17e) at
a
-androstane-3b-
a
a
(19) and 3
a
-hydroxy-6-methylen-5b-androstane-17-one (20) at a
-isomer was sep-
yield of 86%. In both of these two reactions, no 5
a
The experimental data and results listed in Table 2 above illus-
trate that the reduction of 4-en-3-one was a little bit complicated.
In the reduction reaction, AD was reduced to 3b,17b-dihydroxy-
arated. The above indicates that the 17-spirocyclic ketal protecting
group was more favorable to stereoselectively form 5b-configura-
tion products by using CuCl/NaBH4 as reduction agent.
5a-androstane (12) and 3a,17b-dihydroxy-5b-androstane (13) at
The two isomers 12 and 13 obtained were identified by 1H NMR,
13C NMR, HSQC and HMBC. Nunes [10] reported that the H-3
a ratio of 4:3 and with a yield of 73%. Due to conformational trans-
mission, the spatial orientation and bulk of 17-substituent in D
chemical shifts of the axial alcohols in 5b-H-3b-hydroxyand 5
H-3 -hydroxy isomers tended to move to low field due to lack of
diaxial 3Ja, a couplings, presenting a peak at 4.0 ppm. On the other
a-
ring remarkably influenced the ratio and yield of 5
a
and 5b-H iso-
a
mers again for selective reduction of 4-en-3-one in A ring. 17
a
-

C. Wang et al. / Steroids 78 (2013) 1339–1346
1345
O
OH
OH
i
+
O
HO
HO
H
H
13
AD
12
O
CN
O
O
X
H
OR
O
O
HO
O
O
O
3b, R=COCH3
3c, R=COC6H5
16e,f
iii
i
14
ii
i
X
OR
O
CN
+
X
15e,f
O
HO
e. X=H, f. X=OH
4b, R=COCH3
H
17e,f
O
O
O
O
i
iii
+
O
HO
HO
H
20
19
18
Scheme 3. Reagents and conditions: (i).CuCl/NaBH4, dry ethanol; (ii). NaOH aq, RT; (iii).2 N HCl aq, RT.
Table 2
The conjugate reduction of steroids by CuCl/NaBH4.
Entry
Substrate
T (°C)
Ratio (S:CuCl:NaBH4)
Time (h)
Yield (%)
Ratio
1
2
3
4
5
6
7
8
AD
3b
3c
4b
14
15e
15f
18
rt
1:1:4
1:2:2
1:2:4
1:2:2
1:2:4
1:2:4
1:2:4
1:2:6
2.5
4
2.5
2.5
4
4
4
4
73 (12 + 13)
95 (16e + 17e)
29 (16e + 17e)
50 (16e + 17e)
90 (16e + 17e)
89 (16e + 17e)
81 (17f)
4:3 (12:13)
2.8:1 (16e:17e)
–
1:1 (16e:17e)
1:9 (16e:17e)
1:9 (16e:17e)
–
ꢂ10
rt
0
rt
rt
rt
rt
86 (19 + 20)
1.9:1 (19:20)
hand, the corresponding C-3 chemical shifts tended to move to
high field, presenting a peak at 66.1 ppm. While the thermody-
O
namically more stable alcohols, 5b-H-3a-hydroxy and 5a-H-3b-
hydroxy isomers, presented 1H NMR peak at d = 3.6 (m, 3-CH) with
13C NMR at d = 71 (C3) around. Furthermore, Kanchithalaivan [19]
reported that the 13C NMR of 5
a-H-3b-hydroxy isomer presented
HO
C-9 peak at 54.6 ppm. In this study, the 1H NMR of 12 presented
a peak at d = 3.60 (dt, J = 11.1, 7.3 Hz, 2H, 3&17-H) with diaxial
3Ja, a couplings and 13C NMR at d = 79.99 (C17), 69.24 (C3). 1H
NMR of 13 also showed peaks at d = 3.60 (dt, J = 11.1, 7.3 Hz, 2H,
3&17-H) and 13C NMR at d = 80.00 (C17), 69.77 (C3). The HSQC of
12 showed that the C-9 carbon signal at 54.01 ppm assigned a mul-
tiplet at 0.63 ppm to H-9 proton; and in the HSQC of 13, the chem-
ical shift of C-9 moved to 40.17 ppm assigned a multiplet to H-9 at
1.38 ppm. Furthermore, the HMBC of 12 showed the H-19 correla-
tion with a carbon signal at 54.01 ppm (C-9), and the H-9 at
0.63 ppm had a correlation with C-1 at 35.12 ppm. Analyzing all
the data mentioned above, it was assumed that the structure of
H
17e
Fig. 4. X-ray diffraction crystal structure of 17e.
NMR of all 5b isomers. Meanwhile, the configuration of 17e was
confirmed by X-ray spectrum (Fig. 4), and the structures of the oth-
ers were also confirmed by comparing their 1H and 13C NMR spec-
tra with 12, 13, 17e and the data reported in the literatures [10,19].
The two chiral centers, 3a-hydroxyl and 5b-H, associated with
that of bile acid analogs, were introduced simultaneously in one-
step reaction with CuCl/NaBH4. The reduction system might be
an alternative method for the synthetic investigation of bile acid
analogs from AD, ADD and their derivatives.
12 was 3b,17b-dihydroxy-5
droxy-5b-androstane. Summarizing all the 1H NMR spectrum of
the 5 steroids synthesized in our previous studies, the chemical
shift of H-9 was observed to present a peak at 0.63–0.94 ppm with
a clear multiplet signal in all of the 5 -isomers, including the 5a-
a-androstane and 13 was 3a,17b-dihy-
a
4. Conclusion
a
androstane (5b–c, 9, 7b–c, 11, 12, 16e) reported in this study,
The two reduction systems, Na2S2O4/NaHCO3 and CuCl/NaBH4,
were studied to regio- and stereoselectively reduce 4-en-3-one ste-
whereas there was no corresponding chemical shift signals in 1H

1346
C. Wang et al. / Steroids 78 (2013) 1339–1346
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Acknowledgement
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This research was supported by Zhejiang Xianju Pharmaceutical
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Conformational
transmission
and
receptor
binding
of
Appendix A. Supplementary data
a
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.steroids.2013.09.
011.
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