First synthesis of thia steroids from cholic acid

Article abstract of DOI:10.1016/j.steroids.2010.04.006

Heterosteroids remain interesting due to their potential biological activities. This prompted us to synthesize novel thia steroids possessing the heteroatom in the A-ring. We set out to describe a new and versatile method for preparing 3-thia steroids from cholic acid via a selective oxidation of one hydroxyl group, a BaeyerVilliger oxidation and a photolysis as the key steps. The characteristic ¹H and ¹³C NMR spectroscopic features of the synthesized compounds are reported.

Full text of DOI:10.1016/j.steroids.2010.04.006

Steroids 75 (2010) 701–709
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
First synthesis of thia steroids from cholic acid
Malika Ibrahim-Oualia,∗, Luc Rocheblaveb
a Institut des Sciences Moléculaires de Marseille UMR 6263 CNRS and Université d’Aix Marseille III, Faculté des Sciences et Techniques de Saint Jérôme,
Avenue Escadrille Normandie Niémen, 13397 Marseille Cedex 20, France
b Université de Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie, INSERM U863, IFR 62, F-69373 Lyon Cedex 08, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Heterosteroids remain interesting due to their potential biological activities. This prompted us to syn-
thesize novel thia steroids possessing the heteroatom in the A-ring. We set out to describe a new and
versatile method for preparing 3-thia steroids from cholic acid via a selective oxidation of one hydroxyl
group, a Baeyer–Villiger oxidation and a photolysis as the key steps. The characteristic 1H and 13C NMR
spectroscopic features of the synthesized compounds are reported.
Received 30 October 2009
Received in revised form 20 April 2010
Accepted 22 April 2010
© 2010 Elsevier Inc. All rights reserved.
Keywords:
Thia steroids
Baeyer–Villiger oxidation
Microwave
Photolysis
Nucleophilic substitution
Steroids represent an important class of natural products due to
their high ability to penetrate cells and bind to nuclear and mem-
brane receptors.
The fact that minor changes in steroid structures can cause
extensive changes in biological activity has long intrigued medici-
nal chemists. Naturally occurring steroid nuclei have been modified
in several ways with the aim of finding more active compounds,
free from undesirable or harmful side effects, and of recognising the
structural and stereo-chemical features required for the display of
specific, selective physiological activity.
The replacement of one or more carbon atoms of a steroid
molecule with heteroatoms brings notable modifications of its bio-
logical activity [1–3]. Wolff and Zanati have reported that some
A-ring hetero-androstanes have androgenic activity similar to that
of testosterone [4,5]. An increasing number of compounds con-
taining oxygen, nitrogen or sulphur in the nucleus of the steroidal
skeleton have been prepared since 1970 and their activities studied
[6–11]. These modified steroids have been found to possess varied
biological activities, such as anti-viral [12] and analgesic properties
[13]. These results have encouraged organic chemists to get new
compounds having the potential of providing some useful drugs.
We have focussed our interest on bile acid (BA) derivatives. BAs
have been the subject of numerous pharmacological studies. Their
amphiphilic character generally increases cell membrane perme-
ability. From recent studies, they are not only considered for their
important role in lipid adsorption. In the search for such emerg-
ing tools, BA receptors have been identified as potential targets,
and are being explored to address the various aspects of metabolic
disorders [14].
We recently described the first synthesis of a 3-oxa steroid from
cholic acid [15]. We were now interested in the first synthesis of
3-thia steroids, possessing a 5␤-hydrogen, from cholic acid. To the
best of our knowledge, and much to our surprise, there is no syn-
thesis described in the literature despite their potential bioactivity.
In this article, we describe the synthesis of 3-thia-5␤ steroids also
demonstrating that the method we developed for 3-oxa steroids
[15] can be successfully transferred to that novel structural class
(Scheme 1). Our strategy involves Baeyer–Villiger oxidation of the
corresponding 3-oxo steroid to introduce the heteroatom into the
A-ring as used by Suginome et al. [16]. Moreover, in this article,
we provide the experimental details of the steroids reported by us
recently [15]. Furthermore, we show how we have optimised the
yields of two key steps of our synthesis: the selective oxidation at
C-3 and the Baeyer–Villiger oxidation.
1. Experimental
All reactions were run under argon in oven-dried glassware.
1H and 13C NMR spectra are recorded at 200 or 400, and 50
and 100 MHz, respectively, in CDCl3 solutions. Chemical shifts (␦)
are reported in ppm with tetramethylsilane as internal standard.
Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 spec-
∗
Corresponding author. Tel.: +33 491288416; fax: +33 491983865.
E-mail addresses: malika.ibrahim@univ-cezanne.fr,
malika.ibrahim@univ.u-3mrs.fr (M. Ibrahim-Ouali), luc.rocheblave@univ-lyon1.fr
(L. Rocheblave).
0039-128X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2010.04.006

702
M. Ibrahim-Ouali, L. Rocheblave / Steroids 75 (2010) 701–709
Scheme 1.
trophotometer. Flash chromatography was performed on silica gel
(Merk 60 F254) and thin layer chromatography (TLC) on silica gel.
Dichloromethane was distilled over calcium hydride and tetra-
hydrofuran (THF) over sodium/benzophenone. Triethylamine and
pyridine were distilled from potassium hydroxide and stored over
KOH under argon. MW-promoted reactions were carried out in a
Biotage Initiator MW. Temperature could be measured at the end
of the reaction with a thermocouple thermometer.
reaction was quenched with H2O and EtOAc. The aqueous layer was
acidified to pH2 with diluted HCl, and layers were separated. The
aqueous layer was further extracted with EtOAc (3× 50 ml), and
the combined organic layers were dried over anhydrous MgSO4
and evaporated to dryness. The crude product was purified by flash
chromatography on silica gel (CH2Cl2/MeOH: 9/1) to afford 1.04 g
of pure triol 6 (95%) as a white solid. mp = 201 ◦C; IR (neat) 3360,
2890 cm−1 1H NMR (CDCl3) 3.99 (1H, m, H-12␤), 3.92 (4H, bs,
;
Compounds 2 and 4 were prepared according to the previ-
ously described procedures [17,18]. The nomenclature used for
the steroids is not the nomenclature used by Chemical Abstracts
[19,20].
OCH2–CH2O), 3.85 (1H, m, H-7␤), 3.62 (2H, t, J = 6.1 Hz, H-24), 1.00
(3H, d, J = 6.4 Hz, H-21), 0.93 (3H, s, H-19), 0.71 (3H, s, H-18); 13C
NMR (CDCl3) 109.8, 73.0, 68.4, 64.2, 64.0, 63.6, 47.5, 46.6, 42.0,
40.3, 39.7, 38.6, 35.5, 34.8, 34.1, 31.9, 30.1, 29.5, 28.7, 27.2, 26.1,
25.9, 23.3, 22.4, 17.8, 12.7. HRMS Calculated for C26H44O5 436.3189,
found 436.3192.
1.1. Methyl 3-oxo-7˛,12˛-dihydroxy-5ˇ-cholan-24-oate (3)
Methyl cholate (200 mg, 0.47 mmol) was mixed in a mortar with
silver carbonate on Celite (1 g) and toluene (2.5 ml). The mixture
was transferred to a pressure-resistant tube (pyrex) and irradiated
with MW at 170 ◦C for 3 min. The reaction mixture was filtered over
a Celite pad and then concentrated under ‘vacuum’. The crude prod-
uct was recrystallised from petroleum ether, to afford 0.18 g (90%
yield) of 3-oxo steroid 3. mp = 172 ◦C; 1H NMR (CDCl3) 4.01 (1H, m,
H-12); 3.91 (1H, m, H-7), 3.66 (3H, s, OCH3), 3.39 (1H, dd, J = 15.2 Hz,
J = 13.5 Hz, H-4␤), 1.00 (3H, s, H-19), 0.98 (3H, d, J = 6.4 Hz, H-21),
0.72 (3H, s, H-18); 13C NMR (CDCl3) 203.4, 180.7, 73.0, 72.3, 68.4,
51.6, 47.3, 46.7, 45.6, 43.1, 41.8, 39.5, 36.8, 36.7, 36.2, 35.0, 34.0,
31.2, 31.0, 28.7, 27.2, 23.2, 21.7, 17.4, 12.6.
1.4. 3,3-(Ethylenedioxy)-7˛,12˛,24-trimethoxy-5ˇ-cholane (7)
To a stirred suspension of NaH (0.14 g, 5.9 mmol) in THF (10 ml)
at 0 ◦C under argon was added a solution of triol 6 (0.78 g, 1.8 mmol)
in 5 ml of THF. The reaction mixture was stirred for 15 min, and
then iodomethane (367 ␮l, 5.9 mmol) was added drop-wise. After
48 h at room temperature, the reaction was diluted with 10 ml of
Et2O and quenched by the slow addition of 10 ml of H2O. The com-
bined organic extracts were washed with 30 ml of brine, dried over
anhydrous MgSO4, and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (Et2O: 100%) to
give 7 (0.85 g, 100%) as an oil. IR (neat) 2940, 2890 cm−1 1H NMR
;
1.2. Methyl 3,3-(ethylenedioxy)-7˛,12˛-diacetate-5ˇ-cholan-
24-oate (5)
(CDCl3) 3.94 (1H, m, H-12␤), 3.87 (4H, bs, OCH2–CH2O), 3.80 (1H,
m, H-7␤), 3.30 (2H, m, H-24), 3.28 (3H, s, OCH3), 3.22 (3H, s, OCH3),
3.16 (3H, s, OCH3), 0.90 (3H, s, H-19), 0.88 (3H,d, J = 7.4 Hz, H-21),
0.63 (3H, s, H-18); 13C NMR (CDCl3) 109.8, 82.1, 73.6, 65.8, 64.1,
58.5, 55.9, 55.8, 46.6, 46.1, 42.8, 40.8, 39.6, 37.3, 35.5, 34.6, 34.1,
32.2, 30.0, 27.7, 27.6, 27.2, 26.3, 23.2, 22.6, 22.3, 17.8, 12.5. HRMS
Calculated for C29H50O5 478.3658, found 478.3663.
To a solution of (1.43 g, 2.83 mmol) in 50 ml toluene was added
ethylene glycol (0.96 ml, 16.9 mmol) and p-toluenesulphonic acid
(0.15 g, 0.87 mmol). The resulting solution was refluxed overnight
with the use of a Dean–Stark trap to remove water, and then cooled
to room temperature. The solution was transferred to a separatory
funnel. Approximately 150 mg of Na2CO3 was carefully added to the
funnel, followed by distilled water. The organic layer was dried over
MgSO4, then filtered, and the solvent was removed in vacuo to yield
the desired product 5 (1.38 g, 89%) as an oil. IR (neat) 3447, 2875,
1.5. 3,3-(Ethylenedioxy)-12˛-hydroxy-7˛,24-dimethoxy-
5ˇ-cholane (15)
1720 cm−1 1H NMR (CDCl3) 5.06 (1H, m, H-12␤), 4.88 (1H, m, H-
;
7␤), 3.9 (4H, bs, O–CH2CH2–O), 3.64 (3H, s, OCH3), 2.10 (3H, s, OAc),
2.06 (3H, s, OAc), 0.92 (3H, s, H-19), 0.79 (3H, d, J = 6.4 Hz, H-21), 0.71
(3H, s, H-18); 13C NMR (CDCl3) 175.5, 170.5, 170.1, 109.3, 75.4, 70.9,
64.1, 64.0, 53.5, 51.5, 47.3, 45.1, 43.4, 39.8, 37.9, 37.7, 34.6, 34.3,
33.6, 30.9, 30.0, 28.7, 27.2, 25.8, 22.8, 22.3, 21.7, 21.5, 17.5, 12.2.
HRMS Calculated for C31H48O8 548.3349, found 548.3353.
Using the same procedure described above for compound 7,
reaction of 1 g of 6, 0.18 g of NaH and 0.48 ml of iodomethane
resulted in, after 24 h of reaction and after purification by flash chro-
matography on silica gel (Et2O: 100%), 0.6 g (59%) of 15. IR (neat)
3400, 2880 cm−1 1H NMR (CDCl3) 3.92 (1H, m, H-12␤), 3.90 (4H,
;
bs, OCH2-CH2O), 3.80 (1H, m, H-7␤), 3.33 (2H, m, H-24), 3.26 (3H,
s, OCH3), 3.21 (3H, s, OCH3), 0.97 (3H, d, J = 7.5 Hz, H-21), 0.92 (3H,
s, H-19), 0.68 (3H, s, H-18); 13C NMR (CDCl3) 109.7, 81.9, 73.5, 68.4,
64.1, 64.0, 58.5, 55.8, 46.6, 46.4, 42.8, 42.0, 40.7, 38.4, 35.5, 34.6,
33.7, 32.1, 30.1, 28.8, 27.5, 27.1, 26.3, 23.5, 22.4, 22.0, 17.7, 12.6.
HRMS Calculated for C28H48O5 464.3502, found 464.3505.
1.3. 3,3-(Ethylenedioxy)-7˛,12˛-dihydroxy-5ˇ-cholan-24-ol (6)
A solution of methyl ester 5 (1.38 g, 2.5 mmol) in dry ether
(10 ml) was added in one portion to a suspension of LiAlH4 (0.57 g,
15.1 mmol) in dry ether (20 ml) at room temperature. After 1 h, the

M. Ibrahim-Ouali, L. Rocheblave / Steroids 75 (2010) 701–709
703
1.6. 3,3-(Ethylenedioxy)-7˛,12˛-dihydroxy-24-methoxy-
5ˇ-cholane (14)
poured into ice water. After removal of the precipitates, the solu-
tion was washed with water and dried over anhydrous magnesium
sulphate. Evaporation of the solvent resulted in lactol 10, which
was purified by chromatography on silica gel with CH2Cl2/MeOH
(95/5), to yield an oily product 10 (75 mg, 75%). IR (neat) 3615,
Using the same procedure described above for compound 7,
reaction of 0.5 g of 6, 0.09 g of NaH and 0.23 ml of iodomethane
resulted in, after 6 h of reaction and after purification by flash chro-
matography on silica gel (Et2O: 100%), 0.35 g (67%) of 14. IR (neat)
3405 cm−1 1H NMR (CDCl3) 5.10 (1H, dd, J = 7.9 Hz, J = 5.5 Hz, H-
;
4), 4.68 (1H, d, J = 5.7 Hz, H-4), 4.38 (1H, dd, J = 13.4 Hz, J = 9.8 Hz,
H-3), 3.38 (1H, m, H-12␤), 3.32 (3H, s, OCH3), 3.28 (3H, s, OCH3),
3.26 (1H, m, H-7␤), 3.19 (3H, s, OCH3), 3.06 (2H, m, H-24), 0.93
(3H, s, H-19), 0.92 (3H, d, J = 6.5 Hz, H-21), 0.65 (3H, s, H-18); 13C
NMR (CDCl3) 82.3, 77.8, 73.6, 65.8, 64.7, 64.4, 58.7, 58.5, 56.6, 56.1,
47.8, 46.8, 46.1, 42.7, 42.6; 36.4, 36.3, 35.5, 32.2, 30.1, 29.9, 27.3,
26.2, 23.5, 22.2, 18.0, 12.5. HRMS calculated for C27H48O5 452.3502,
found 452.3505.
3400, 2940, 2895 cm−1 1H NMR (CDCl3) 3.95 (1H, m, H-12␤); 3.87
;
(4H, bs, OCH2–CH2O); 3.80 (1H, m, H-7␤); 3.31 (2H, dd, J = 13.5 Hz,
J = 6.8 Hz, H-24); 3.29 (3H, s, OCH3); 0.95 (3H, d, J = 6.4 Hz, H-21);
0.89 (3H, s, H-19); 0.65 (3H, s, H-18); 13C NMR (CDCl3) 109.9; 73.4;
72.9; 68.3; 64.0; 63.9; 58.5; 47.4; 46.5; 41.7; 40.3; 39.7; 38.4; 35.5;
34.8; 34.0; 32.3; 29.9; 28.5; 28.4; 27.6; 26.3; 25.9; 23.2; 22.3; 17.7;
12.5. HRMS Calculated for C27H46O5 450.3345, found 450.3348.
1.7. 3-Oxo-7˛,12˛,24-trimethoxy-5ˇ-cholane (8)
1.10. 2-Iodo-A-nor-2, 3-seco-7˛,12˛,24-trimethoxy-
cholan-5ˇ-yl formate (11)
Ketal 7 (0.9 g, 1.8 mmol) was dissolved in acetone (100 ml) in a
250 ml round-bottom flask equipped with magnetic stirring. Con-
centrated hydrochloric acid (4 ml) was added drop-wise to the
flask. The solution was stirred at room temperature for 12 h, after
which 100 ml of distilled water was added to the solution. The
majority of the acetone was evaporated and the solution was
extracted with dichloromethane and washed with distilled water
followed by brine. The organic layer was dried over MgSO4 and the
solvent removed on a rotary evaporator to give 0.79 g (97%) of the
desired product 8 as an oil. This ketone 8 was used in the next step
To the lactol 10 (200 mg, 0.4 mmol) in dry benzene (25 ml) con-
taining pyridine (0.7 ml) was added mercury(II) oxide (214 mg) and
iodine (251 mg). The solution was irradiated for 2 h and worked
up in the usual manner to give a crude oily product. This prod-
uct was purified by flash chromatography on silica gel (Et2O/EP:
9/1) to afford 0.23 g of formate 11 (90%) as an oil. IR (neat)
3447, 1705 cm−1 1H NMR (CDCl3) 8.02 (1H, s, CHO), 4.25 (1H,
;
m, H-4), 4.00 (1H, m, H-4), 3.39 (1H, m, H-12␤), 3.27 (3H, s,
OCH3), 3.26 (3H, s, OCH3), 3.25 (1H, m, H-7␤), 3.24 (3H, s, OCH3),
3.10 (2H, t, J = 7.4 Hz, H-2), 2.28 (2H,m, H-24), 1.01 (3H, s, H-
19), 0.98 (3H, d, J = 6.5 Hz, H-21), 0.68 (3H, s, H-18); 13C NMR
(CDCl3) 161.8, 82.3, 77.8, 68.2, 58.7, 58.5, 56.5, 56.1, 52.4, 50.2,
47.8, 46.6, 42.8, 41.4, 37.5, 36.6, 36.3, 32.5, 30.2, 29.8, 27.6, 26.3,
23.8, 22.5, 19.2, 13.6, 2.3. HRMS calculated for C27H47IO5 578.2468,
found 578.2472.
without further purification. IR (neat) 2940, 1703 cm−1 1H NMR
;
(CDCl3) 3.42 (1H, m, H-12␤), 3.35 (2H, dd, J = 14.9 Hz, J = 8.7 Hz, H-
24), 3.32 (3H, s, OCH3), 3.29 (3H, s, OCH3), 3.21 (3H, s, OCH3), 0.99
(3H, s, H-19), 0.93 (2H, d, J = 7.4 Hz, H-21), 0.69 (3H, s, H-18); 13C
NMR (CDCl3) 203.2, 82.1, 73.6, 58.5, 57.3, 56.0, 46.7, 46.2, 44.5, 43.6,
42.8, 39.6, 36.9, 35.5, 34.8, 32.2, 30.9, 29.3, 28.4, 27.5, 27.2, 26.3,
23.2, 22.5, 22.0, 17.9, 12.5. HRMS calculated for C27H46O4 434.3396,
found 434.3401.
1.11. 3-Oxa-7˛,12˛,24-trimethoxy-5ˇ-cholane (12)
1.8. 3a-Oxa-A-homo-7˛,12˛,24-trimethoxy-5ˇ-
holan-3-one (9)
A solution of the formate 11 (135 mg, 0.2 mmol) in dry THF
(20 ml) was cooled at −78 ◦C. To this solution was added, drop-
wise, methyllithium in diethyl ether (1 M, solution) (0.55 ml), while
stirring. After the solution was stirred for 2 h at −78 ◦C, the temper-
ature of the solution rose to room temperature. Evaporation of the
solvent left a residue, which was dissolved in diethyl ether. The
solution was worked up in the usual manner to yield a crude oily
product. This product was purified by flash chromatography on sil-
ica gel (Et2O/EP: 1/9) to afford pure 3-oxa steroid 12 (75 mg, 76%)
To
a solution of ketone 8 (0.26 g, 0.6 mmol) in dry
dichloromethane (30 ml) containing p-toluenesulphonic acid
(90 mg, 0.6 mmol), was added meta-chloroparabenzoic acid
(MCPBA) (12 mg). The solution was stirred for 12 h at room tem-
perature in the presence of light. The solution was then diluted
with water and extracted with dichloromethane. The solution was
washed successively with a 5% Na2S2O3 solution, saturated brine,
and water and was dried over anhydrous magnesium sulphate.
The oily product, obtained by evaporation of the solvent, was
purified by flash chromatography on silica gel (CH2Cl2/MeOH:
95/5) to afford 0.2 g of pure lactone 9 (75%) as an oil. IR (neat) 2940,
as an oil. IR (neat) 3447, 2940, 1361, 1195, 1100 cm−1 1H NMR
;
(CDCl3) 3.65–3.45 (6H, m, H-2, H-4 and H-24), 3.25 (3H, s, OCH3),
3.22 (3H, s, OCH3), 3.20 (3H, s, OCH3), 2.84 (2H, m, H-7␤ and H-12␤),
1.02 (3H, s, H-19), 0.99 (3H, d, J = 6.4 Hz, H-21), 0.72 (3H, s, H-18);
13C NMR (CDCl3) 82.1, 76.7, 73.6, 68.3, 58.7, 57.3, 56.0, 46.6, 46.0,
44.3, 43.2, 42.6, 39.5, 36.8, 35.4, 34.6, 32.2, 30.9, 29.4, 28.3, 27.6,
26.5, 23.4, 22.6, 18.9, 12.8. HRMS calculated for C26H46O4 422.3396,
found 422.3400.
1780 cm−1 1H NMR (CDCl3) 4.82 (1H, dd, J = 13.7 Hz, J = 9.5 Hz,
;
H-4␤), 3.78 (1H, d, J = 13.7 Hz, H-4␣), 3.50 (1H, dd, J = 13.9 Hz,
J = 6.9 Hz, H-12␤), 3.88 (1H, m, H-7␤), 3.33 (3H, s, OCH3), 3.24 (3H,
s, OCH3), 3.17 (3H, s, OCH3), 2.36 (2H, m, H-24), 0.96 (3H, s, H-19),
0.89 (2H, d, J = 7.4 Hz, H-21); 0.64 (3H, s, H-18); 13C NMR (CDCl3)
177.4, 82.0, 76.1, 65.8, 58.3, 56.5, 55.9, 46.6, 46.0, 45.5, 42.6, 39.4,
36.3, 36.2, 35.3, 33.1; 31.9, 28.2, 28.1, 27.8, 27.3, 23.2, 23.1, 22.0,
17.7, 15.0, 12.1. HRMS Calculated for C27H46O5 450.3345, found
450.3349.
1.12. Methyl 3,3-(ethylenedioxy)-5ˇ-cholan-7,
12-dien-24-oate (13b)
Using the same procedure described above for compound 5,
reaction of 1 g (2.4 mmol) of 4 and 0.12 g of PTSA resulted in,
after 24 h of reaction, and after purification by flash chromatog-
raphy on silica gel (Et2O: 100%), 0.98 g (92%) of 13b. IR (neat) 3448,
1.9. 3a-Oxa-A-homo-7˛,12˛,24-trimethoxy-5ˇ-cholan-3-ol (10)
2880 cm−1 1H NMR (CDCl3) 5.40 (3H, m, H-7␤, H-11 and H-12␤),
;
To
a
solution of lactone
9
(100 mg, 0.2 mmol) in dry
3.89 (3H, s, OCH3), 3.87 (4H, m, OCH3), 0.85 (3H, d, J = 7.5 Hz, H-
21), 0.84 (3H, s, H-19), 0.80 (3H, s, H-18); 13C NMR (CDCl3) 175.5,
145.0, 136.2, 131.8, 121.9, 109.7, 64.4, 64.3, 62.7, 51.9, 53.7, 45.6,
42.2, 38.9, 38.1, 37.4, 35.4, 31.4, 31.3, 31.2, 29.8, 28.0, 27.5, 27.1,
dichloromethane (20 ml) at −78 ◦C was added diisobutylalu-
minium hydride (DIBAL) (1.0 M in hexane) (1.5 ml), drop-wise, over
the course of 10 min. The solution was stirred for 2 h at –78 ◦C and

704
M. Ibrahim-Ouali, L. Rocheblave / Steroids 75 (2010) 701–709
Scheme 2.
23.3, 20.9, 19.2. HRMS Calculated for C27
428.2930.
H
40O4 428.2927, found
vent was then evaporated, and the product extracted with diethyl
ether. The solution was washed with water and dried over anhy-
drous magnesium sulphate. Evaporation of the solvent resulted in
an oily product, which was purified by chromatography on silica
gel (petroleum ether/ethyl acetate: 1/9), to yield iodoalcohol 16
1.13. Reduction of iodo formate 11
(180 mg, 82%). IR (neat) 3475 (OH), 1080 cm−1 1H NMR (CDCl3)
;
To a solution of iodo formate 11 (270 mg, 0.4 mmol) in dry
toluene (20 ml) was added DIBAL (1.0 M in hexane, 3.5 ml) at −78 ◦C
under a nitrogen atmosphere. The solution was stirred for 30 min
at −78 ◦C, and an additional 6 h at room temperature. The sol-
3.45 (4H, m, H-24 and CH2OH), 3.26 (3H, s, OCH3), 3.22 (3H, s, OCH3),
3.20 (3H, s, OCH3), 3.10 (2H, t, J = 6.8 Hz, CH2I), 2.78 (2H, m, H-7␤ and
H-12␤), 2.0 (1H, bs, OH), 1.02 (3H, s, H-19), 0.98 (3H, d, J = 7.4 Hz, H-

M. Ibrahim-Ouali, L. Rocheblave / Steroids 75 (2010) 701–709
705
21), 0.92 (3H, s, H-18). 13C NMR (CDCl3) 83.6, 78.2, 68.2, 63.8, 58.3,
58.1, 56.6, 52.4, 50.4, 47.6, 46.5, 42.6, 41.2, 37.4, 36.6, 36.3, 32.3,
30.2, 29.6, 27.5, 26.2, 23.6, 22.5, 19.2, 13.8, 2.3. HRMS calculated for
(CDCl3) 3.25–3.50 (6H, m, H-24 and CH2-SO2), 3.24 (3H, s, OCH3),
3.22 (3H, s, OCH3), 3.20 (3H, s, OCH3), 2.78 (2H, m, H-7␤ and H-
12␤), 0.98 (3H, s, H-19), 0.89 (3H, d, J = 6.5 Hz, H-21), 0.82 (3H, s,
H-18); 13C NMR (CDCl3) 83.9, 78.8, 74.6, 58.8, 57.6, 57.2, 52.4, 49.2,
46.8, 46.4, 44.6, 42.9, 39.6, 37.6, 36.7, 35.8, 34.4, 32.1, 30.0, 29.4,
28.6, 27.6, 26.4, 20.4, 19.2, 12.8. HRMS Calculated for C26H46O5S
470.3066, found 470.3069.
C26H47IO4 550.2519, found 550.2524.
1.14. 3-Thia-7˛,12˛,24-trimethoxy-5ˇ-cholane (18)
To a solution of iodoalcohol 16 (150 mg, 0.3 mmol) in pyri-
dine (11 ml), was added methanesulphonyl chloride (0.6 ml) at 0 ◦C
under a nitrogen atmosphere. The solution was stirred for 24 h at
room temperature; the solvent was then evaporated and the prod-
uct extracted with diethyl ether. The ethereal solution was worked
up in the usual manner, and the crude mesylate 17 (190 mg, 92%)
was used in the next step without further purification. IR (neat)
1.17. 3-Oxa-7˛,12˛-dihydroxy-5ˇ-cholan-24-ol (21)
To a solution of 3-oxa steroid 12 (50 mg, 0.12 mmol) in chloro-
form (20 ml), was added trimethylsilyl iodide (0.1 ml). The solution
was left overnight at room temperature. Methanol was then added
to decompose any excess trimethylsilyl iodide. The solution was
extracted with diethyl ether, washed with water and saturated
brine, and dried over anhydrous magnesium sulphate. Evaporation
of the solvent resulted in a crude product, which was purified by
chromatography on silica gel (CH2Cl2/MeOH: 9/1), to give triol 21
1330, 1130 cm−1 1H NMR (CDCl3) 3.50 (4H, m, H-24 and CH2OMs),
;
3.28 (3H, s, OCH3), 3.23 (3H, s, OCH3), 3.21 (3H, s, OCH3), 3.13 (2H,
t, J = 6.9 Hz, CH2I), 2.95 (3H, s, CH3SO2), 2.77 (2H, m, H-7␤ and H-
12␤), 1.00 (3H, s, H-19), 0.98 (3H, d, J = 6.8 Hz, H-21), 0.92 (3H, s,
H-18).
(30 mg, 65%) as an oil. IR (neat) 3280 (OH), 1220, 1070 cm−1 1H
;
NMR (CDCl3) 3.65–3.40 (6H, m, H-2, H-4 and H-24), 3.18 (2H, m,
H-7␤ and H-12␤), 2.03 (1H, bs, OH), 2.01 (1H, bs, OH), 1.04 (3H,
s, H-19), 1.02 (3H, d, J = 6.4 Hz, H-21), 0.84 (3H, s, H-18); 13C NMR
(CDCl3) 78.3, 74.5, 72.6, 68.3, 63.4, 52.8, 52.1, 46.3, 41.6, 40.2, 38.5,
36.1, 34.3, 32.2, 31.9, 29.4, 28.3, 27.6, 26.4, 23.6, 21.7, 18.8, 12.9.
HRMS calculated for C23H40O4 380.2927, found 380.2930.
To a solution of mesylate 17 (190 mg, 0.27 mmol) in acetoni-
trile (20 ml) sodium sulphide nonahydrate (530 mg) was added.
The solution was heated under reflux for 3 days. The solvent was
evaporated and the product dissolved in diethyl ether. The solu-
tion was washed with water and dried over anhydrous magnesium
sulphate. Evaporation of the solvent resulted in a crude product,
which was purified by chromatography on silica gel (petroleum
ether/ethyl acetate: 1/9), to give thia steroid 18 (50 mg, 42%) as an
1.18. 3-Thia-7˛,12˛-dihydroxy-5ˇ-cholan-24-ol (22)
oil. IR (neat) 1382, 1263 cm−1 1H NMR (CDCl3) 3.34 (2H, m, H-24),
;
Using the same procedure described above for compound 21,
reaction of 100 mg (0.23 mmol) of 18 and 0.2 ml of ISi(CH3)3
resulted in, after 24 h of reaction and after purification by flash
chromatography on silica gel (CH2Cl2/MeOH: 9/1), 55 mg (60%) of
3.26 (3H, s, OCH3), 3.23 (3H, s, OCH3), 3.20 (3H, s, OCH3), 2.78 (2H,
m, H-7␤ and H-12␤), 2.50 (4H, m, CH2-S), 0.98 (3H, s, H-19), 0.89
(3H, d, J = 6.5 Hz, H-21), 0.78 (3H, s, H-18); 13C NMR (CDCl3) 84.6,
78.8, 74.6, 57.2, 56.4, 46.8, 46.2, 44.1, 43.3, 42.8, 39.5, 37.8, 36.6,
35.4, 34.5, 32.1, 30.9, 29.4, 28.4, 27.6, 26.6, 25.4, 22.6, 20.2, 18.7,
12.8. HRMS calculated for C26H46O3S 438.3168 found 438.3172.
22. IR (neat) 3270 (OH), 1260, 1085 cm−1 1H NMR (CDCl3) 3.44
;
(2H, m, H-24), 3.15 (2H, m, H-7␤ and H-12␤), 2.55–2.35 (4H, m,
CH2-S), 2.00 (1, bs, OH), 1.02 (3H, s, H-19), 0.96 (3H, d, J = 6.4 Hz, H-
21), 0.88 (3H, s, H-18); 13C NMR (CDCl3) 76.8, 74.4, 57.7, 56.2, 41.4,
39.5, 38.1, 37.9, 37.8, 36.6, 34.9, 33.5, 31.8, 30.1, 29.3, 28.6, 27.3,
26.6, 25.6, 22.3, 20.1, 18.9, 12.8. HRMS calculated for C23H40O3S
396.2698, found 396.2702.
1.15. 3-Thia-7˛,12˛,24-trimethoxy-5ˇ-cholan-3-oxide (19)
Thia steroid 18 (50 mg, 0.1 mmol) was dissolved in CH2Cl2
(15 ml), under argon. The solution was cooled at 0 ◦C and MCPBA
(18 mg, 0.1 mmol) was added. After stirring at this temperature
for 1 h, the mixture was hydrolysed with a saturated solution of
NaHCO3. The aqueous layer was extracted with CH2Cl2 (3× 25 ml).
The organic phase was dried with MgSO4, filtered and concentrated
in vacuo. The residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate, 9/1 to 5/5) to give an inseparable
3/1 mixture of two diastereoisomers 19␣/19␤ (35 mg, 77%).
1.19. 3-Thia-7˛,12˛-dihydroxy-5ˇ-cholan-3-oxide-24-ol (23)
Using the same procedure described above for compound 21,
reaction of 55 mg (0.12 mmol) of 19 and 0.1 ml of ISi(CH3)3 resulted
in, after 24 h of reaction and after purification by flash chromatog-
raphy on silica gel (CH2Cl2/MeOH: 9/1), 33 mg (66%) of 23. IR (neat)
3285 (OH), 1175, 1096 cm−1 1H NMR (CDCl3) 3.51 (2H, m, H-24),
;
Major isomer: mp = 158 ◦C; IR (neat) 1305, 1220, 790 cm−1 1H
;
3.16 (2H, m, H-7␤ and H-12␤), 2.58–2.36 (4H, m, CH2-S = O), 2.01 (1,
bs, OH), 0.99 (3H, s, H-19), 0.92 (3H, d, J = 6.4 Hz, H-21), 0.76 (3H, s,
H-18); 13C NMR (CDCl3) 77.2, 75.4, 58.2, 57.4, 54.6, 49.9, 41.2, 39.3,
38.6, 37.5, 37.4, 36.8, 34.9, 33.6, 30.2, 29.4, 28.2, 26.9, 25.1, 22.6,
20.3, 18.7, 12.9. HRMS Calculated for C23H40O4S 412.2647, found
412.2650.
NMR (CDCl3) 3.32 (2H, m, H-24), 3.28 (3H, s, OCH3), 3.24 (3H, s,
OCH3), 3.21 (3H, s, OCH3), 2.76 (2H, m, H-7␤ and H-12␤), 2.55 (4H,
m, CH2-S = O), 0.96 (3H, s, H-19), 0.90 (3H, d, J = 6.4 Hz, H-21), 0.78
(3H, s, H-18); 13C NMR (CDCl3) 84.8, 78.6, 74.3, 57.4, 56.6, 54.6,
49.8, 46.8, 46.4, 44.3, 43.2, 42.9, 39.6, 37.6, 36.7, 35.8, 34.4, 32.3,
30.8, 28.6, 26.8, 25.5, 22.6, 20.4, 18.9, 12.9. HRMS Calculated for
C26H46O4S 454.3117, found 454.3121.
1.20. 3-Thia-7˛,12˛-dihydroxy-5ˇ-cholan-3,
3-dioxide-24-ol (24)
1.16. 3-Thia-7˛,12˛,24-trimethoxy-5ˇ-cholan-3,3-dioxide (20)
Thia steroid 18 (50 mg, 0.1 mmol) was dissolved in CH2Cl2
(15 ml), under argon. The solution was cooled at 0 ◦C and MCPBA
(35 mg, 0.2 mmol) was added. After stirring at room temperature
for 24 h, the mixture was hydrolysed with a saturated solution of
NaHCO3. The aqueous layer was extracted with CH2Cl2 (3× 25 ml).
The organic phase was dried with MgSO4, filtered and concentrated
in vacuo. The residue was purified by flash chromatography on sil-
ica gel (CH2Cl2/MeOH: 100/0 to 95/5) to afford 40 mg (86% yield) of
Using the same procedure described above for compound 21,
reaction of 55 mg (0.12 mmol) of 20 and 0.1 ml of ISi(CH3)3 resulted
in, after 24 h of reaction, and after purification by flash chromatog-
raphy on silica gel (CH2Cl2/MeOH: 9/1), 40 mg (75%) of 24. IR (neat)
3292 (OH), 1095, 1040 cm−1 1H NMR (CDCl3) 3.53 (2H, m, H-24),
;
3.25–3.50 (4H, m, CH2–SO2), 3.16 (2H, m, H-7␤ and H-12␤), 2.02 (1,
bs, OH), 1.04 (3H, s, H-19), 1.02 (3H, d, J = 6.4 Hz, H-21), 0.89 (3H, s,
H-18); 13C NMR (CDCl3) 78.1, 76.3, 58.8, 57.2, 55.6, 50.1, 41.5, 39.6,
38.2, 37.9, 37.4, 36.5, 34.6, 33.9, 30.2, 29.6, 28.3, 26.7, 25.3, 22.5,
sulphone 20. mp = 166 ◦C; IR (neat) 1305, 1220, 790 cm−1 1H NMR
;

706
M. Ibrahim-Ouali, L. Rocheblave / Steroids 75 (2010) 701–709
Scheme 3.
20.2, 18.8, 12.9. HRMS Calculated for C23H40O5S 428.2596, found
428.2600.
expected, O-alkylation was dependent on reaction time. The results
of some O-alkylation attempts are reported in Table 2.
We observed that the formation of product 14 resulting from
alkylation of the primary hydroxyl group at C-24 was finished after
6 h. After 12 h, a mixture of products 14 and 15, in a 1/1 ratio was
isolated. Alkylation of the C-7 position was finished after stirring
for 24 h at room temperature, and ketal 15 was the sole product
isolated. As much as 48 h of stirring, at room temperature, was
necessary to obtain the desired 7␣,12␣,24-trimethoxy ketal 7 as
the sole product.
2. Results and discussion
Recently, we have developed the first synthesis of a 3-oxa-
5␤-steroid via 11 steps from cholic acid [15]. The synthetic
pathway is depicted in Scheme 2. The key step of the syn-
thesis is a photochemical reaction of a lactol developed by
Suginome et al. [16]. Our strategy required also a selective
oxidation of one hydroxyl group and a Baeyer–Villiger oxida-
tion of a steroidal ketone to introduce a heteroatom in the
A-ring.
Table 2
Cholic acid 1, an inexpensive bile acid, was chosen as the start-
ing material. Esterification of 1 led to methyl cholate 2 [21], which
was selectively oxidised at C-3 under microwave irradiation, using
Fetison’s reagent (Ag2CO3/celite). This result represents a novel
synthetic access [15] for the synthesis of ketone 3 [22]. This latter
was diacetylated leading to 4 [23] in so far as a direct ketalisation
of 3 led to the dehydrated product 13 as indicated in Scheme 3.
To overcome this problem, several attempts were done using p-
toluenesulphonic acid (PTSA) or pyridinium p-toluenesulphonate
(PPTS) as catalyst and benzene or toluene as solvent. Unfortunately,
we did not observe the desired product 13a, but in all cases, the
dehydrated ketal 13b was isolated (see Table 1).
Methylation of the alcohol functions at positions 7, 12 and 24.
Attempt
Times
Conditions
Yield (%)
1
6 h
67%
After acetylation of positions 7 and 12, which proved to be nec-
essary, the ketone 4 was easily transformed with ethylene glycol
and p-toluenesulphonic acid into its ketal 5, which was reduced
in 95% yield with lithium aluminium hydride in diethyl ether to
the triol 6 (Scheme 2). In the next step, methylation of triol 6
with methyl iodide–sodium hydride in THF was done. The methoxy
group was chosen as protective group of the three hydroxyl groups
because it is chemically stable under our conditions of photolysis.
Several attempts were necessary to obtain the desired product 7. As
2
12 h
24 h
48 h
60%a
3
59%
Table 1
Direct ketalisation of ketone 3a.
Attempt
Catalyst
Solvent
Product
Yieldb (%)
1
2
3
4
PTSA
PTSA
PPTS
PPTS
C6H6
Toluene
C6H6
13b
13b
13b
13b
86
92
85
78
Toluene
4
100%
a
Reaction conditions: ꢀ, 0.2 equiv. of catalyst, 24 h.
Before 12 h of reaction, too much starting material was recovered.
b
a
Ratio 14:15 = 1:1.

M. Ibrahim-Ouali, L. Rocheblave / Steroids 75 (2010) 701–709
707
Table 3
iodo formate 11 was subjected to reductive hydrolysis with DIBAL
in dichloromethane at −78 ◦C, to give iodo alcohol 16 in 88% yield.
Treatment of the latter with mesyl chloride, under standard con-
ditions, resulted in the corresponding mesylate 17 in good yield.
The first 3-thia-5␤-steroid 18, was obtained in an optimised yield
of 42% by refluxing the acetonitrile solution of mesylate 17 and
sodium sulphide.
The synthetic utility of organic sulphur compounds has been
reviewed [24]. Compounds containing a sulphide, sulphoxide or
sulphone moiety are not only of synthetic interest, they may also
significantly contribute to biological activity [25–27].
Therefore, we also synthesized the corresponding sulphoxide
and sulphone of the thia steroid 22 that are both novel. We envis-
aged to oxidise the thia steroid 18 by using a chemical method [28].
Thus (Scheme 5), oxidation of sulphide 18 with an equivalent of 3-
chloroperbenzoic acid in dichloromethane led to an inseparable 3/1
mixture of two sulphoxides, 19␣ and 19␤, in good yield. The equa-
torial sulphoxide is the major isomer, which is an expected result
when peroxy acids are used [29].
Then, we were interested to prepare the corresponding sul-
phone 20. In this case, to obtain the sulphone as the sole product,
oxidation on compound 15 was carried out with 2 equiv. of 3-
chloroperbenzoic acid in dichloromethane at room temperature.
The corresponding steroid 20 matching a sulphone moiety was
isolated in 86% yield.
Finally, to obtain the free alcohols, we undertook different
attempts of de-protection on steroids 12 and 18–20. Thus, methoxy
groups of compounds 12, 18–20 were removed easily by using
trimethylsilyl iodide. These demethylation reactions were carried
out in chloroform at room temperature for 24 h, and afforded the
expected de-protected heterosteroids 21–24 in good yields, as indi-
cated in Scheme 6.
To summarise, we have achieved a new partial synthesis of
3-thia steroids, according to the method described in this arti-
cle. The advantages of this procedure are the accessibility of the
starting material and the simplicity and the availability of the
reagents. Thus, the first synthesis of a 3-oxa-5␤-steroid 12 and a
3-thia-5␤-steroid 18 was achieved, via 11 steps (25% overall yield)
and 13 steps (9% overall yield), respectively, from cholic acid. The
biological evaluation of compounds 21–24, with respect to their
Baeyer–Villiger oxidation of ketone 8.
Attempt
Conditions
Times
8 (%)
9 (%)
1
2
3
4
5
MCPBA/AcOH/H2SO4
H2O2/AcOH/H2SO4
K2S2O8/AcOH/H2SO4
MCPBA/CH2Cl2
10 days
10 days
10 days
10 days
12 h
>50%
>50%
>50%
100%a
–
10%
10%
10%
–
MCPBA/CH2Cl2/PTSA
75%
a
Starting material recovered without purification on silica gel.
Then, a classic acid hydrolysis of seven with hydrochloric acid
in acetone at room temperature provided the desired ketone 8 in
excellent yield (Scheme 2). We turned then our attention to the
Baeyer–Villiger oxidation of ketone 8. In this key step, we under-
took several attempts to optimise the yield of the reaction. The
results of those attempts are reported in Table 3.
Using the experimental conditions described by Suginome et al.
[16] conditions of attempts 1–4 (3-chloroperbenzoic acid (MCPBA)
or potassium persulphate or hydrogen peroxide in glacial acetic
acid–concentrated sulphuric acid (3:0.5, v/v)), low yields were
obtained, even after 10 days. These yields are quite similar to those
obtained in the pregnane series. Finally, we succeeded (attempt 5)
in optimising the formation of the desired compound 9 by adding
a stoichiometric amount of p-toluenesulphonic acid in a mixture
of 8 and MCPBA in dichloromethane. Otherwise, it is worth point-
ing out that the reaction proceeded regioselectively, no isomeric
lactone was formed.
The reduction of lactone 9 with diisobutylaluminium hydride
(DIBAL) in toluene at −78 ◦C for 2 h resulted in the lactol 10,
which was converted into the corresponding iodo formate 11. The
treatment of 11 with methyllithium in THF afforded the desired
3-oxa-5␤-steroid 12 in good yield [24].
The characteristic 1H and 13C NMR spectroscopic features of
these new compounds 5–12 are reported in the experimental
part.
As a continuation of our synthetic and stereo-chemical stud-
ies on heterocyclic steroidal systems containing a heteroatom, a
similar strategy was used to obtain 3-thia-5␤-steroids (Scheme 4).
The iodo formate 11, prepared as described above in Scheme 2,
was used here as the starting material. The formyloxy group of this
Scheme 4.

708
M. Ibrahim-Ouali, L. Rocheblave / Steroids 75 (2010) 701–709
Scheme 5.
Scheme 6.
anti-leukaemic activity, is under progress and will be reported in
due course.
[11] Ibrahim-Ouali M, Rocheblave L. Recent advances in azasteroids chemistry.
Steroids 2008;73:375–407.
[12] Chorvat RJ, Pappo R. Synthesis of 2-azaestratrienes.
1976;41(17):2864–70.
J
Org Chem
[13] Taylor EC, Lenard K. Ready total synthesis of 8,13-diaza-18-norestrone methyl
ethers. Chem Commun 1967;(2):97–8.
Acknowledgements
[14] Atul T, Pranab M. TGR5: an emerging bile acid G-protein-coupled receptor
target for the potential treatment of metabolic disorders. Drug Discov Today
2009;14:523–30.
[15] Ibrahim-Ouali M, Botsi-Nkomendi N, Rocheblave L. Synthesis of heterosteroids.
First synthesis of oxa steroid from cholic acid. Tetrahedron Lett 2010;51:
93–5.
This work has been financially supported by the CNRS, INSERM
and the Ministère de l’Enseignement Supèrieur et de la Recherche.
References
[16] Suginome H, Yamada S, Wang JB. Photoinduced molecular transformations.
A versatile substitution of a carbonyl group of steroidal ketones by a het-
eroatom. The synthesis of aza-, oxa-, thia-, selena-, and tellurasteroids. J Org
Chem 1990;55:2170–6.
[17] Cravatto G, Boffa L, Turello M, Parenti M, Barge A. Chemical modifications of
bile acids under high-intensity ultrasound or microwave irradiation. Steroids
2005;70:77–83.
[18] Bonar-Law RP, Davis AP. Cholic acid as an architectural component
in biomimetic/molecular recognition chemistry. Synthesis of the first
“Cholaphanes”. Tetrahedron 1993;49:9829–44.
[19] Differences between the IUPAC names of the hydrocarbons and the cor-
responding Chemical Abstracts names are noted in the review of Loening
KL. Hydrocarbons, nomenclature. Kirk-Othmer Encycl Chem Technol 3rd ed.
1980;12:892–900.
[20] Moss GP. Nomenclature of steroids. Pure Appl Chem 1989;61:1783–822.
[21] Fieser LF, Rajagopalan S. Oxidation of Steroids. Selective Oxidations
and Acylations in the Bile Acid Series. Helv Chim Acta 1950;72:
5530–6.
[22] Tserng KY. A convenient synthesis of 3-keto bile acids by selective oxidation of
bile acids with silver carbonate–celite. J Lipid Res 1978;19:501–4.
[23] Trost B. alpha-Sulfenylated carbonyl compounds in organic synthesis. Chem
Rev 1978;78:363–82.
[1] Morand P, Lyall J. The steroidal estrogens. Chem Rev 1968;68(1):85–124.
[2] Huisman HO. Approaches to total synthesis of heterocyclic steroidal systems.
Angew Chem Int Ed Engl 1971;10(7):450–9.
[3] Huisman HO, Speckamp WN. Synthesis of heterocyclic steroidal systems. Int
Rev Sci: Org Chem Ser Two 1976;8:207–36.
[4] Wolff ME, Zanati G. Thia steroids. 2-Thia-A-nor-5-alpha-pregnan-20-one. J Med
Chem 1970;13:629.
[5] Wolff ME, Zanati G. Preparation and androgenic activity of novel heterocyclic
steroids. J Exp 1970;26:1115–6.
[6] Zanati G, Wolff ME. Heterocyclic steroids. Synthesis and androgenic activity of
A-ring oxaandrostanes. J Med Chem 1971;14:958–61.
[7] Salvi VS, Mukherjee D, RoyChowdhury MN, Engel CR. Steroids and related prod-
ucts. Synthesis of 11-Oxa steroids. 4. Synthesis of 17,21-dihydroxy-11-oxa-
4-pregnene-3,20-dione, an 11-oxa analog of 17-hydroxylated glucocorticoids.
Steroids 1976:717–25.
[8] Rosen P, Boris A, Oliva C. Synthesis and biological-activity of some 15-
oxaestranes. J Med Chem 1980;23:329–30.
[9] Ibrahim-Ouali M. Recent advances in thiasteroids chemistry. Steroids
2006;71:1025–44.
[10] Ibrahim-Ouali M. Recent advances in oxasteroids chemistry. Steroids
2007;72:475–508.
[24] Oae S. Organic Chemistry of Sulfur. New York: Plenum Press; 1977.

M. Ibrahim-Ouali, L. Rocheblave / Steroids 75 (2010) 701–709
709
[25] Winiwarter S, Roth HJ. The top ten NSAIDs: a molecular modeling study. Pharm
Acta Helv 1994;68:181–9.
[26] Testa B. The Metabolism of Drugs and Other Xenobiotics. Biochemistry of Redox
Reactions. London: Academic Press; 1995. pp. 434–437.
[27] Surapaneni SS, Clay MP, Spangle LA, Paschal JW, Lindstrom TD. In
vitro biotransformation and identification of human cytochrome P450
isozyme-dependent metabolism of tazofelone. Drug Metab Dispos 1997;25:
1383–8.
[28] Iwama T, Matsumoto H, Shimizu H, Kataoka T, Muraoka O, Tanabe G. Pummerer
reaction of 2-vinylcyclopropyl sulfoxides: generation and reactions of butadi-
enylthionium ion intermediates. J Chem Soc, Perkin Trans I 1998:1569–76.
[29] Kazunobu T, Yuko N, Satsuki M, Tetsur T, Masaya N, Tatsuta K, et al. Application
of highly stereocontrolled glycosidations employing 2,6-anhydro-2-thio sugars
to the syntheses of erythromycin A and olivomycin A trisaccharide. J Am Chem
Soc 1995;117:3717–27.