A diastereoselective synthesis of 7α-nitromethyl steroid derivative and its use for an efficient synthesis of eplerenone

Article abstract of DOI:10.1016/j.steroids.2012.04.017

A novel and efficient method of stereoselectively introducing α-nitromethyl group to C-7 position of 11α-hydroxyl canrenone 4 was described. In addition, this method was successfully applied in a total synthesis of Eplerenone 8. The route was characteristic of simple operation, moderate reaction conditions with 5 steps and 55% total yield, at the same time, without any expensive or toxic reagent in use.

Full text of DOI:10.1016/j.steroids.2012.04.017

Steroids 77 (2012) 1086–1091
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Steroids
journal homepage: www.elsevier.com/locate/steroids
A diastereoselective synthesis of 7
a
-nitromethyl steroid derivative and its use
for an efficient synthesis of eplerenone
⇑
Bin Zhang, Hongli Chen, Huanyu Tang, Huijin Feng, Yuanchao Li
Shanghai Institute of Materia Medica, Chinese Academy of Science, 555 Zu Cong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient method of stereoselectively introducing a-nitromethyl group to C-7 position of 11a-
Received 3 February 2012
Received in revised form 13 April 2012
Accepted 16 April 2012
hydroxyl canrenone 4 was described. In addition, this method was successfully applied in a total synthe-
sis of Eplerenone 8. The route was characteristic of simple operation, moderate reaction conditions with 5
steps and 55% total yield, at the same time, without any expensive or toxic reagent in use.
Ó 2012 Elsevier Inc. All rights reserved.
Available online 12 May 2012
Keywords:
Nitromethane
Eplerenone
1,6-Conjugated addition
Quaternary ammonium salt
Synthesis
1. Introduction
groups were eager to install carbomethoxy group at C-7 by a con-
venient method in the total synthesis of eplerenone. In 1997, John
The reagent nitromethane or its derivatives have been used in
steroid chemistry to introduce C-7 nitromethyl group by 1,6-con-
jugated addition to steroidal 4,6-dien-3-one. However, to our
knowledge, only the corresponding 7b-nitromethyl steroid deriva-
tives 1, 2 [1,2] and nitromethylene 3 [3] were reported (Fig. 1).
When compound 4 was treated with NaOMe/MeNO2/H2O in DMF
at room temperature for 1 day [2,3], the conjugated addition gave
Ng used toxic acetone cyanohydrin to construct enamine bridge at
C4 and C7, and then converted it to carbomethoxy [9]. 6 years later,
Pearlman developed a new approach to the furan degradation [10]
and used it in the synthesis of eplerenone with higher yield and
better selectivity, but this approach needed as low as ꢀ50 °C and
five steps to degrade furan, which was not atom efficient and prob-
lematic in industrial use. Recently, Wuts chose dehydroepiandros-
terone as start material by allylic substitution at C7 with moderate
stereoselectivity by using expensive stoichiometric amount transi-
tion metal salt and an inert environment [11,12]. In 2011, our
group developed a new and practical method for the stereoselec-
a mixture of compound 5a and b with poor stereoselectivity (a/
b = 1.6:1) and very low yield (trace). This result intrigued us to
optimize the reaction conditions and developed a novel method
to stereoselectively introduce 7
nitromethyl group on steroid 5
carboxy by Nef reaction without the corresponding configuration
changing [4–6]. The idea to apply steroid 5 in a synthesis of epl-
a-nitromethyl group, for the 7
a-
a
was very easy to be converted into
tive construction of a steroid 5a,7b-oxymethylene derivative via
1,6-Michael conjugate addition of steroidal 4,6-dien-3-one at as
low as ꢀ68 °C and applied it in the synthesis of eplerenone [13].
We finally found, when 4 was treated with K2CO3/MeNO2 in
DMF in the presence of a catalytic amount of octadecyl dimethyl
benzyl ammonium chloride at 90 °C for two days, it was result in
1,6-conjugated addition and a stereochemical conversion at C-7
a
erenone also impelled us to optimize reaction conditions.
Eplerenone is cardiovascular drug, an aldosterone antagonist
used as an adjunct in the management of chronic heart failure,
marketed by Pfizer under the trade name Inspra [7]. In the total
synthesis of eplerenone, the most principal challenge was the
introduction of the carbomethoxy substituent. In 1984, Grob
accomplished the first synthesis of eplerenone by employing Nag-
position in one step to afford the 7
a-nitromethyl steroid 5
a with
90% yield and 96% de (Scheme 1). With compound 5
a
in hand,
we succeeded in a total synthesis of Eplerenone 8 with 5 steps
and 55% total yield.
ata hydrocyanation of
D
9(11)-canrenone as the key step [8], but
with moderate stereoselectivity, tedious column chromatography
and using toxic cyanide. After that, many companies and research
2. Experimental
⇑
All melting points were determined on a Büchi 510 melting
point apparatus and were uncorrected. 1H and 13C NMR spectra
Corresponding author. Tel.: +86 21 50806600x3502; fax: +86 21 50807288.
E-mail address: ycli@mail.shcnc.ac.cn (Y. Li).
0039-128X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2012.04.017

B. Zhang et al. / Steroids 77 (2012) 1086–1091
1087
Fig. 1. 7b-Nitromethyl-4,5-dihydrocanrenone; 7b-nitromethyl-D9(11)-4,5-dihydrocanrenone and 6b,7b-methylene-(10S)-nitro-3-oxo-17
a-pregn-4-en-21-carboxylic acid, c-
lactone.
were run on Bruker AM-300, Bruker AM-400 spectrometer using
tetramethyl silane as the internal standard (d = 0). Splitting pat-
terns were designated as ‘‘s, d, t, q, and m’’; these symbols indicated
‘‘singlet, doublet, triplet, quartet, and multiplet’’, respectively. X-ray
crystallographic data were obtained on a CAD-4 diffractometer.
Optical rotations were recorded on a Jasco-Dip-181 polarimeter.
Mass spectra and high-resolution mass spectra were measured on
a Finnigan MAT-95 mass spectrometer. High performance liquid
chromatograms (HPLC) were taken on Agilent 1100 instruments
1274, 1192; UVmax: 242 nm; 1H NMR (300 MHz,CDCl3) d5.82 (s,
1H), 4.38–4.20 (m, 2H), 4.10 (tt, J = 10.29, 10.29, 4.95, 4.95 Hz,
1H), 2.81 (td, J = 13.99, 4.16, 4.16 Hz, 1H), 2.73–2.27 (m, 10H),
2.07–1.70 (m, 7H), 1.68–1.59 (m, 2H), 1.50 (ddd, J = 24.57, 12.19,
5.69 Hz, 1H), 1.38 (s, 3H), 1.04 (s, 3H); 13C NMR(100 MHz,CDCl3)
d 199.092, 176.239, 164.980, 128.330, 94.707, 74.029, 68.710,
53.387, 46.162, 45.170, 43.219, 39.867, 37.704, 37.471, 36.477,
35.951, 35.328, 34.207, 31.127, 29.087, 22.276, 18.343, 15.679; EI
MS(70 eV, m/z): 417(M+, 21%), 399(17%), 370(44%), 111(100%);
HR-MS(EI) calcd for C23H31NO6(M+) 417.2151, Found 417.2153;
Anal. Calc. for C23H31NO6: C, 66.17; H, 7.48; N, 3.35. Found: C,
66.35; H, 7.63; N, 3.31%.
and Waters 2998 with column Venusii MP™ C18, 5
lm, 100 Å,
10 ꢁ 250 mm and SunFine™ C18, 5 m,4.6 ꢁ 150 mm. Silica gel
l
60 H (200–300 mesh) manufactured by Qingdao Haiyang Chemical
Co. (China) was generally used for chromatography. N,N-dimethyl
formamide (DMF) and MeNO2 were distilled and dried by 4 Å
molecular sieves overnight. K2CO3 was well ground into a powder,
baked at 145 °C for 10 h and then cooled in desiccator with P2O5.
TMG, TEA and DIPEA were short for trimethylglycine, triethyl amine
and N,N-Diisopropylethylamine, respectively. The purity of each
step product was >98%, which was determined by HPLC and H NMR.
Compound 5b: 1H NMR (300 MHz,CDCl3) d 5.73 (s, 1H), 4.73 (dd,
J = 12.72, 3.72 Hz, 1H), 4.37 (dd, J = 12.51, 7.64 Hz, 1H), 4.15–3.99
(m, 1H), 2.67–1.37 (m, 21H), 1.35 (s, 3H), 1.03 (s, 3H); 13C
NMR(100 MHz,CDCl3) d199.556, 176.137, 166.179, 125.006,
93.623, 80.058, 68.297, 58.043, 47.763, 47.027, 43.126, 41.537,
39.625, 38.306, 37.275, 37.004, 35.457, 34.181, 30.969, 29.052,
26.114, 18.600, 16.023; UVmax
z):417(M+, 17%), 111(100%), 370(37%); HR-MS(EI) calcd for
23H31NO6(M+) 417.2151, found 417.2157.
: 243 nm; EI MS(70 eV, m/
C
2.1. 11 b,17b-Dihydroxy-7
a
/b-nitromethyl-pregna-4-en-3-one-21-
and b)
carboxylic acid, -lactone (5
c
a
2.2. 11 b,17b-dihydroxy-7a-nitromethyl-pregna-4-en-3-one-21-
To a solution of compound 4 (1.07 g, 3 mmol) in MeNO2 (10 ml),
1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU) (0.8 ml, 5.3 mmol) was
added at room temperature and stirred overnight. The resulting
reaction was quenched by a.q. HCl (10% w/w) to adjust the pH to
6. Then solvent was removed under vacuum and the residue was
purified by silica column chromatography eluted with EtOAc/
carboxylic acid, -lactone (5a)
c
To a solution of compound 4 (20 g, 56 mmol), octadecyl di-
methyl benzyl ammonium chloride (2.32 g, 6 mmol) and MeNO2
(60 ml, 1120 mmol) in DMF (190 ml) equipped with a CaCl2 drying
tube and a reflux condenser, K2CO3 (78 g, 565 mmol) was added at
90 °C with stirring. The mixture was stirred at this temperature for
48 h. The resulting mixture was cooled to room temperature, and
then filtered. The filter cake was washed with dichloride methane
(DCM) for three times. The organic layers were combined with the
filtrate, and adjusted pH to 6 with a.q. HCl (10%, w/w). The HPLC
cyclohexane (1:4, v/v) to afford diastereomers 5
yield) and b (192 mg, 15% yield). The compound 5
recrystallized from EtOAc to afford colorless crystals.Compound
: mp:281–282 °C; [ ]20D: 51° (c 0.24, CHCl3); IR max(KBr)
3467, 2950, 1766, 1662, 1550, 1458, 1441, 1419, 1382, 1344,
a
(308 mg, 25%
a
was readily
5a
a
m
Scheme 1. Synthesis of 5a and its application in synthesis Eplerenone 8.

1088
B. Zhang et al. / Steroids 77 (2012) 1086–1091
analysis suggested the ratio of diastereomer 5
a
to b was 48:1. The
combined organic layers were concentrated under vacuum to give
crude product as brown solid. The crude product was washed with
water three times and then filtered. The residue was diluted with
DCM, and then filtered. The filtrate was washed with a.q. HCl
(10%, w/w), brine and dried by Na2SO4 to afford crude powder
product 5
purification. The crude was readily recrystallized from EtOAc to af-
ford pure product 5 (21 g, 90% yield).
a (23 g), which was used directly for next step without
Fig. 2. Ionic bond and p–p stacking interaction.
a
1.40 (m, 2H), 1.35 (s, 3H), 1.00 (s, 3H); HR-MS(EI) calcd for
24H32O6 (M+) 416.221 found 416.225; Anal. Calc. for C24H32O6:
C,69.21, H,7.74. Found: C, 68.32; H, 7.72%. UVmax: 244 nm.
2.3. 11 b,17b-dihydroxy-7
a- methoxycarbonyl -pregna-4-en-3-one-
C
21-carboxylic acid, -lactone (6)
c
To a solution of 5a (5 g, 12 mmol) in DMF (40 ml), AcOH (2.9 ml,
51 mmol) was added at 45 °C with stirring. 30mins later, NaNO2
(2.484 g, 36 mmol) was slowly added in batches to the mixture.
1 h later, a solution of AcOH (2.9 ml, 51 mmol) in DMF (3 ml)
was added dropwise to the mixture. After 4 h, the reaction was
cooled to 0 °C and then quenched by sat. Na2SO3 solution (54 ml,
89 mmol). It was allowed to warm to room temperature and stir-
red overnight. The solvent was removed completely under vacuum
to give powder solid. The solid was diluted with acetone and fil-
tered. The filter cake was washed with acetone for three times.
The organic layers were combined with filtrate and then concen-
trated to 100 ml. To the result solution, MeI (1.5 ml, 24 mmol)
and K2CO3 (5 g, 36 mmol) were added at 0 °C. The mixture was al-
lowed to warm to room temperature and stirred overnight. The
mixture was filtered and the filter cake was washed with DCM
for three times. The organic layers were combined with filtrate
and then the solvent was completely removed. The residue was di-
luted with DCM and washed with a.q HCl (10%, w/w), sat. NaHCO3,
brine and dried by Na2SO4, then filtered and the filtrate was con-
centrated to afford crude product 6, which could be purified by
recrystallization from DCM/toluene to afford colorless crystals 6
(4 g, 80% yield) [14]: mp.:230–232 °C; 1H NMR (300 MHz,CDCl3)
d 5.68 (s, 1H), 4.04 (dt, J = 10.23, 9.84, 3.98 Hz, 1H), 3.64 (s, 3H),
2.85–2.71 (m, 2H), 2.68–2.18 (m, 8H), 2.10–1.57 (m, 9H), 1.49–
2.4. 17b-Hydroxy-7
a-carbomethoxy-3-oxo-pregna-4,9(11)-diene-21-
carboxylic acid, -lactone (7)
c
Compound 7 was prepared from 6 according to the reference
[12]. mp.: 204–2061 °C; 1H NMR (300 MHz,CDCl3) d 5.67 (s, 1H),
5.60 (d, J = 5.84 Hz, 1H), 3.54 (s, 3H), 2.93 (dd, J = 4.48, 2.00 Hz,
1H), 2.78 (ddd, J = 14.93, 5.15, 1.64 Hz, 1H), 2.61–2.36 (m, 6H),
2.33–2.05 (m, 5H), 1.99–1.75 (m, 4H), 1.51–1.38 (m, 2H), 1.35 (s,
3H), 0.90 (s, 3H); 13C NMR(100 MHz,CDCl3) d 198.805, 176.667,
172.828, 166.858, 142.504, 125.871, 119.134, 95.252, 51.605,
44.638, 43.935, 43.250, 40.719, 40.526, 35.902, 35.586, 34.359,
33.912, 33.068, 31.616, 29.378, 27.354, 23.448, 14.234.
2.5. Eplerenone (8)
Compound 8 was prepared from 7 according to the reference
[10]. [a a
]20D:+2.2o(c 0.415, CHCl3) (lit. [8] [ ] = +5o (c = 0.437,
CHCl3)); mp. 242–244 °C (lit. [8] 240–242 °C); UVmax: 240 nm;
Anal. Calc. for C24H30O6: C,69.54; H,7.30. Found: C, 69.25; H,
7.30%. X-ray data of Eplerenone 8 was included in Supplementary
data.
Table 1
1,6-Conjugated addition of MeNO2 to dienone 4.
O
O
O
O
O
O
HO
HO
HO
H
H
H
H
H
H
H
H
H
O
O
CH2NO2
O
CH2NO2
5α
4
5β
Entry
Base
Catal.
Sol.
Temp. (°C)
Time (h)
Yield (%)a
a
:bb
1
2
3
4
5
6
7
8
NaOMe
K3PO4
K3PO4
K3PO4
K2CO3
K3CO3
K2CO3
K2CO3
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
RT
RT
40
80
90
90
90
90
9
9
9
6
9
9
48
48
Trace
5
1.6:1
1.6:1
4:1
5:1
5:1
1:1
10:1
48:1
Ac
A
60
50
80
30
88
90
A
A
Bd
A
Ce
a
b
c
The yields were determined by column chromatography purification.
The ratios of crude products were determined by HPLC and 1H NMR.
A was benzyl triethyl ammonium chloride (10% mol).
B was tetraethyl ammonium chloride (10% mol).
C was octadecyl dimethyl benzyl ammonium chloride (10% mol).
d
e

B. Zhang et al. / Steroids 77 (2012) 1086–1091
1089
Scheme 2. Compound 5 was used in synthesis of Eplerenone 8. Reagents and conditions: (a) (1) NaNO2/DMF/AcOH, 35–40 °C; (2) K2CO3/MeI/acetone, RT; (b) (1) MsCl/Et3N/
CH2Cl2, 0 °C; (2) HCOOK/HCOOH/Ac2O, 100 °C; (c) Cl3CCONH2/H2O2 (30% w/w)/CH2Cl2/K2HPO4, 10–20 °C.
2.6. The convertion of compound 5b into 5
a
dichloride methane (DCM) for three times. The organic layers
were combined with the filtrate and all the solvent was removed
To a solution of compound 5b (1 g, 2.4 mmol), octadecyl di-
methyl benzyl ammonium chloride (93 mg, 0.22 mmol) and
MeNO2 (2 ml, 37 mmol) in DMF (6 ml) equipped with a CaCl2 dry-
ing tube and a reflux condenser, K2CO3 (3.3 g, 24 mmol) was
added at 90 °C with stirring. The mixture was stirred at this tem-
perature for 48 h. The resulting mixture was cooled to room tem-
perature, and then filtered. The filter cake was washed with
under reduced pressure to afford crude product 5a. There was no
compound 5b in crude product detected by HPLC and H NMR. The
crude product was placed under vacuum to afford brown powder.
The crude powder product was washed with water in sonic wash-
ing machine and then filtered for three times. The residue was
readily recrystallized from EtOAc to afford pure product 5
a
(980 mg, 98% yield).
Fig. 3. The mechanism of stereochemical conversion of a steroid 7b-nitromethyl derivative into 7a.

1090
B. Zhang et al. / Steroids 77 (2012) 1086–1091
structure of quaternary ammonium salts also had effect on the
yield and the stereoselectivity. A quaternary ammonium salts con-
taining benzyl group was required to ensure the better yield and
the better stereoselectivity. There was screening of many commer-
cial alkyl quaternary ammonium salts. For examples, tetrabutyl
ammonium bromide, methyl trioctyl ammonium chloride or stea-
ryl trimethyl ammonium chloride gave moderate yield and poor
stereoselectivity similarly as tetraethylammonium chloride did
(entry 6). We finally found the bulky commercial benzyl quater-
nary ammonium salts, such as octadecyl dimethyl benzyl ammo-
nium chloride, was the best phase transfer catalyst. Compound 4
with MeNO2 and K2CO3 under catalysis of octadecyl dimethyl ben-
zyl ammonium chloride (10% mol) at 90 °C afforded compound 5
a
in satisfactory yield (90%) and good de (96%) (entry8).
We envisioned the mechanism of stereochemical inversion of
7b-nitromethyl group into more thermodynamically stable 7
one was that the elimination of nitromethane from compound 5b
was much more easily than that from compound 5 . The formation
a
a
of six-membered-ring pre-transition state accounted for preferred
elimination of nitromethane from compound 5b at high tempera-
ture (Fig. 2). The exclusive formation of compound 5
a was quite
likely the result of a thermodynamic control. It was supported by
the fact when compound 5b was treated with MeNO2, K2CO3 and
octadecyl dimethyl benzyl ammonium chloride (10% mol) at
90 °C for 2 days, which were the same conditions as entry 8
Fig. 4. X-ray crystallographic structure of Eplerenone 8.
showed, compound 5b was almost completely converted into 5a,
meanwhile there was a trace amount of compound 4 detected by
HPLC. The ammonium salt catalyzed this procedure maybe by
exposure of oxygen on nitromethyl group. The reason was that if
without the octadecyl dimethyl benzyl ammonium chloride, the
inversion of the configuration would be unable to happen even
stirring for a week.
3. Results and discussions
Our synthetic efforts began with preparation of 7a-nitromethyl
canrenone by using commercial 11
starting material. The results of 1,6-conjugated addition to 11
droxy canrenone 4 in different conditions are summarized in Table
1. Because NaOMe (5 eq.)/MeNO2 (11 eq.)/H2O (11 eq.) in DMF at
room temperature were found as the most frequently used condi-
tions, it was initially employed (entry 1). Indeed, under these con-
a
-hydroxy canrenone 4 as the
a
-hy-
All the intermediate compounds were fully characterized by 1H
NMR, 13C NMR and mass spectral data. The structural assignments
of the 7a
- and 7-isomers were determined by 1H NMR. It had been
reported that the equatorial 7b-nitromethyl derivative 1 and 2
showed 1H NMR signal for C-7 b nitromethyl group (–CH2NO2) at
4.76 (dd, J = 12.16, 2.60 Hz, 1H), 4.35 (dd, J = 12.36, 8.70 Hz, 1H)
[2] and 4.70 (dd, J = 12.38, 4.26 Hz, 1H), 4.37 (dd, J = 12.40,
ditions, there were trace amounts of compound 5
a and b found.
We tried to increase the reaction temperature. But when it was
as high as 50 °C, the reaction became complex. A lot of NaCH2NO2
was precipitated from the solution when NaOMe was added, and
9.06 Hz, 1H) [1], respectively. Compound 5
a
and 5b showed 1H
HPLC analysis indicated there was no compound 5
a
or b detected
NMR signal for C-7 nitromethyl group at 4.38–4.20 (m, 2H) and
4.73 (dd, J = 12.72, 3.72 Hz, 1H), 4.37 (dd, J = 12.51, 7.64 Hz, 1H),
respectively.
even for 2 days if without water adding. We thought water helped
make NaCH2NO2 dissolve in DMF. Different solvents were
screened, such as nonpolar and polar ones and different bases,
including organic and inorganic bases, but all failed.
With the important compound 5
tive from compound 5 was achieved by modified Henry reaction
[4], without purification, followed by methylation of 7 -carboxy
a in hand, 7a-carboxyl deriva-
a
Quaternary ammonium salts were usually used in improving
a
MeNO2 conjugate addition to
a
,b-unsaturated ketone [15,16]. The
group to afford ester 6 with 80% yield, without detecting any C-
7b methyl carboxyl diastereomer of compound 6 by 1H NMR or
HPLC analysis. The ester 6 was converted into Eplerenone 8 by a se-
quence same to that was previously developed for the construction
of 9(11)epoxide [10](Scheme 2). The structure assignment of Epl-
erenone 8 was confirmed by X-ray (Fig. 3).
pre-transition state of the enantioselective Michael addition of
nitromethane to ketone catalyzed by a chiral quaternary ammo-
nium salts was described by Corey [17]. We envisioned the benzyl
group or ArCH2-substituent was necessary in quaternary ammo-
nium salt to improve the nucleophilicity of nitromethane anion
by ionic bond and a
p–p
stacking interaction [18] between benzyl
In conclusion, we succeeded in an introduction of nitromethyl
group and nitromethane anion (Fig. 2).
group at C-7 from commercial available 11
4 and a stereochemical conversion of 7b-nitromethyl group into
in one step with 90% yield and 96% de. An efficient route for
the synthesis of Eplerenone 8 was established with easy operation,
five steps and 55% total yield and without any expensive or toxic
reagent in use Fig. 4.
a-hydroxy canrenone
The commercially available benzyl triethyl ammonium chloride
was chose as the phase transfer catalyst at very beginning. Increas-
ing reaction temperature could significantly improve the yield and
slightly improve the diastereomeric ratio (entry 2 and 3). But when
the temperature was increased to higher than 80 °C in the presence
of K3PO4, the reaction became complex and the yield was obviously
decreased even in 6 h (entry 4). So we turned to much weaker
bases, such as K2HPO4, KHCO3, CsF etc., and found reaction proceed
with better yield only in the presence of K2CO3 at 90 °C (entry 5).
The reaction time was another key factor effecting on the stereose-
lectivity. A longer extension time could dramatically increase the
diastereomeric ratio and slightly improve the yield (entry 7). The
7a
Acknowledgement
This work was supported by the National Science & Technology
Major Project ‘‘Key New Drug Creation and Manufacturing Pro-
gram’’, China (No. 2009ZX09102-026).

B. Zhang et al. / Steroids 77 (2012) 1086–1091
1091
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Appendix A. Supplementary data
aldosterone antagonists. Increased selectivity of 9
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a,11-epoxy derivatives. Helv
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.steroids.
2012.04.017.
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