Synthesis of 12-oxa, 12-aza and 12-thia cholanetriols

Article abstract of DOI:10.1016/j.steroids.2010.12.003

An efficient synthesis of 12-hetero steroids was achieved via a Baeyer-Villiger oxidation and a photolysis as the key steps. We set out to describe in this paper the first synthesis of 12-aza steroids. The characteristic ¹H and ¹³C N

Full text of DOI:10.1016/j.steroids.2010.12.003

Steroids 76 (2011) 324–330
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Steroids
journal homepage: www.elsevier.com/locate/steroids
Short communication
Synthesis of 12-oxa, 12-aza and 12-thia cholanetriols
Malika Ibrahim-Oualia,∗, Khalil Hamzea, Luc Rocheblaveb
a Institut des Sciences Moléculaires de Marseille UMR 6263 CNRS, 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:
An efficient synthesis of 12-hetero steroids was achieved via a Baeyer–Villiger oxidation and a photolysis
as the key steps. We set out to describe in this paper the first synthesis of 12-aza steroids. The characteristic
1H and 13C NMR spectroscopic features of the synthesized compounds are reported.
© 2010 Elsevier Inc. All rights reserved.
Received 15 September 2010
Received in revised form
29 November 2010
Accepted 8 December 2010
Available online 14 December 2010
Keywords:
Cholic acid
Baeyer–Villiger oxidation
Microwave
Photolysis
1. Introduction
known classes of xenobiotics [15], and several have been described
as inhibitors of 5␣-reductase [16,17].
The steroid system, selected by the evolutionary process to per-
form some of the most fundamental biological functions, has not
only inspired biochemists and endocrinologists, but also become
the basis of many important discoveries in organic chemistry [1].
Steroids can regulate a variety of biological processes and thus
have the potential to be developed as drugs for the treatment of
a large number of diseases including cardiovascular [2], autoim-
mune diseases [3], brain tumours, breast cancer, prostate cancer,
osteoarthritis, etc. [4].
Modified steroids have attracted a great deal of attention these
last years. Their preparation is a stimulating challenge to the
organic chemist, often demanding the development of new and
generally useful reactions [5–7]. Moreover, the biological proper-
ties of modified steroids have proved to be of interest [8–11].
The replacement of one or more carbon atoms of a steroid
molecule by a heteroatom affects the chemical properties of a
steroid and often results in useful alterations to its biological activ-
ity. The potential of heterosteroids in general, and azasteroids in
particular, as novel drugs and the challenge of their synthesis
prompted numerous research groups to undertake studies in this
field. Particularly, the biological activity of azasteroids has been the
subject of some reviews [12–14]. Those steroids are one of the best-
Azasteroids are by far the most common heterocyclic steroids.
This is probably due to the fact that a –NH– group has approx-
imately the same size as a methylene group. Consequently, the
insertion of a nitrogen atom into the steroid nucleus does not distort
the shape of the molecule to any great extent.
We have recently reported a synthetic route to 3-hetero steroids
from cholic acid [18,19]. We were now interested by the synthe-
sis of 12-hetero derivatives of steroid and particularly of 12-aza
steroids using the same starting material. Indeed, though many
azasteroids have been reported, curiously and much to our sur-
prise, 12-aza steroids have never been reported. So, in connection
with our ongoing interest in the synthesis of heterosteroids, here
we wish to report the extension of our method for the preparation
of 12-heterosteroids (Scheme 1).
2. Experimental
All reactions were run under argon in oven-dried glassware.
1H and 13C NMR spectra were recorded at 200 or 400 and 50
and 100 MHz respectively, in CDCl3 solutions. Chemical shifts (ı)
are reported in ppm with tetramethylsilane as internal standard.
IR spectra were recorded on a Perkin-Elmer 1600 spectropho-
tometer. Optical rotations were determined on a Perkin-Elmer
343 polarimeter. Flash chromatography was performed on sil-
ica gel (Merk 60 F254) and TLC on silica gel. Dichloromethane
was distilled over calcium hydride and tetrahydrofuran (THF) over
sodium/benzophenone. Triethylamine and pyridine were distilled
∗
Corresponding author. Tel.: +33 491288416; fax: +33 49128828345.
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.2010.12.003

M. Ibrahim-Ouali et al. / Steroids 76 (2011) 324–330
325
O
HO
OH
OH
X
12
H
H
H
3
7
HO
OH
HO
OH
H
H
X = O, S, N
cholic acid
Scheme 1.
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.
evaporation of the solvent, was purified by flash chromatography
on silica gel (CH2Cl2/MeOH: 95/5) to afford 0.25 g of pure lactone 5
(97%) as an oil. 1H NMR (300 MHz, CDCl3): 0.86 (s, 3H, H-19), 1.05
(d, J = 6.4, 3H, H-21), 1.34 (s, 3H, H-18), 3.20 (s, 3H, OCH3), 3.25 (m,
2H, H-3 and H-7), 3.31 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 3.35 (m,
1H, H-24); 13C NMR (75 MHz, CDCl3): 14.5, 15.3, 17.7, 22.3, 24.2,
25.2, 26.1, 26.5, 27.5, 31.6, 32.8, 34.6, 35.2, 35.9, 36.3, 41.2, 42.7,
50.1, 55.7, 58.5, 58.9, 65.9, 73.3, 76.9, 80.2, 86.9, 174.8. HRMS (EI)
for C27H46O5 [M+] calcd 450.3345 found 450.3348.
Compound
2 was prepared according to the previously
described procedure [20].
2.1. 3˛,7˛,24-Trimethoxy-5ˇ-cholan-12˛-ol (3)
To a stirred suspension of NaH (0.1 g, 4.4 mmol) in THF (10 mL) at
0 ◦C under argon was added a solution of tetrol 2 (0.5 g, 1.26 mmol)
in 5 mL of THF. The reaction mixture was stirred for 15 min, and then
iodomethane (274 ␮L, 4.4 mmol) was added dropwise. 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 combined
organic extracts (3 × 10 mL) were washed with 30 mL of brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography on silica gel (Et2O: 100%)
to give 7 (0.45 g, 82%) as an oil. 1H NMR (300 MHz, CDCl3): 0.86 (d,
J = 6.5, 3H, H-21), 0.89 (s, 3H, H-19), 1.21 (s, 3H, H-18), 2.10 (bs, 1H,
OH), 3.02 (m, 2H, H-24), 3.14 (m, 1H, H-12), 3.21 (s, 3H, OCH3), 3.24
(m, 1H, H-3), 3.28 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 3.34 (m, 1H, H-
7); 13C NMR (75 MHz, CDCl3): 10.6, 16.9, 20.1, 24.9, 27.6, 28.2, 28.5,
29.5, 32.1, 32.8, 34.7, 34.9, 35.9, 36.9, 37.4, 39.2, 40.5, 44.6, 47.8,
50.8, 57.4, 57.6, 59.8, 74.9, 79.4, 82.2, 88.9. HRMS (EI) for C27H48O4
[M+] calcd 436.3553 found 436.3558.
2.4. 3˛,7˛-Dimethoxy-13-oxa-C-homo-5ˇ-cholan-12-ol (6)
To
a solution of lactone 5 (100 mg, 0.2 mmol) in dry
dichloromethane (20 mL) at −78 ◦C diisobutyl-aluminium hydride
(DIBAL) (1.0 M in hexane) (1.5 mL) [19] was added dropwise over
the course of 10 min. The solution was stirred for 2 h at −78 ◦C
and poured into ice water. After removal of the precipitates, the
solution was washed with water (10 mL) and dried over anhydrous
magnesium sulfate. Evaporation of the solvent gave lactol 6, which
was purified by chromatography on silica gel with CH2Cl2/MeOH
(95/5), to yield an oily product 6 (95 mg, 95%). 1H NMR (300 MHz,
CDCl3: 0.87 (s, 3H, H-19), 1.06 (d, J = 6.6, 3H, H-21), 1.35 (s, 3H, H-
18), 2.16 (m, 2H, H-11), 3.21 (s, 3H, OCH3), 3.25 (m, 1H, H-3), 3.32
(s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.36 (m, 1H, H-7), 5.22 (m, 1H,
H-12), 5.36 (m, 1H, H-12); 13C NMR (75 MHz, CDCl3): 14.5, 17.7,
22.3, 23.3, 24.3, 26.1, 27.5, 29.9, 31.6, 32.1, 32.8, 34.7, 35.9, 36.4,
42.2, 42.7, 50.1, 53.5, 55.4, 55.7, 58.5, 65.5, 73.3, 76.9, 80.3, 86.8,
93.3. HRMS (EI) for C27H48O5 [M+] calcd 452.3502 found 452.3506.
2.2. 12-Oxo-3˛,7˛,24-trimethoxy-5ˇ-cholane (4)
Alcohol 3 (200 mg, 0.4 mmol) was mixed in a mortar with pyri-
dinium chlorochromate (PCC) (0.13 g, 0.6 mmol). The mixture was
transferred to a pressure-resistant tube (pyrex) and irradiated with
MW at 170 ◦C for 15 min. The reaction mixture was filtered through
a Celite pad and the filtrate and washings (CH2Cl2, 3 × 10 mL) were
combined and evaporated under reduced pressure. The residue was
chromatographed on silica gel (diethyl ether/petroleum ether: 7/3),
2.5.
11-Iodo-C-nor-11,12-seco-3˛,7˛,24-trimethoxy-cholan-5ˇ-yl
formate (7)
To the lactol 6 (200 mg, 0.4 mmol) in dry benzene (25 mL) con-
taining pyridine (0.7 mL) mercury(II) oxide (214 mg) and iodine
(251 mg) was added. The solution was irradiated in a Pyrex vessel
with a 100-W high-pressure mercury arc (EIKOSHA, PIH-100), for
2 h under an argon atmosphere [21]. The solution was filtered and
the filtrate was washed with saturated aqueous NaHCO3 (20 mL).
The organic layer was dried with MgSO4, filtered and concentrated
to give a crude oily product. This product was purified by flash chro-
matography on silica gel (diethyl ether/petroleum ether: 9/1) to
afford 0.22 g of formate 7 (88%) as an oil. 1H NMR (300 MHz, CDCl3):
1.06 (d, J = 6.5, 3H, H-21), 1.16 (s, 3H, H-19), 1.50 (s, 3H, H-18), 2.78
(m, 1H, H-3), 2.79 (m, 1H, H-7), 3.21 (m, 2H, CH2-I), 3.24 (s, 3H,
to afford 0.12 g (71% yield) of 12-oxo steroid 4 as a colorless oil. 1
H
NMR (300 MHz, CDCl3): 0.85 (d, J = 6.5, 3H, H-21), 0.89 (s, 3H, H-
19), 1.24 (s, 3H, H-18), 3.00 (m, 2H, H-24), 3.20 (s, 3H, OCH3), 3.26
(m, 1H, H-3), 3.30 (s, 3H, OCH3), 3.31 (s, 3H, OCH3), 3.32 (m, 1H,
H-7); 13C NMR (75 MHz, CDCl3): 11.5, 18.9, 22.4, 23.8, 26.4, 26.7,
27.6, 28.0, 29.3, 31.8, 34.7, 36.0, 37.5, 37.9, 39.4, 41.5, 46.6, 52.8,
53.8, 55.4, 56.0, 56.8, 58.5, 73.4, 76.9, 80.2, 214.3. HRMS (EI) for
C27H46O4 [M+] calcd 434.3396 found 434.3401.
OCH3), 3.25 (s, 3H, OCH3), 3.37 (m, 2H, H-24), 8.04 (s, 1H, CHO); 13
C
2.3. 3˛,7˛-Dimethoxy-13-oxa-C-homo-cholan-12-one (5)
NMR (75 MHz, CDCl3): 6.9, 13.8, 19.5, 19.7, 23.5, 24.4, 29.9, 30.8,
31.6, 32.0, 33.8, 34.1, 35.7, 38.3, 38.4, 41.5, 42.8, 46.2, 46.3, 57.1,
57.4, 59.3, 74.9, 82.4, 82.9, 89.2, 160.9. HRMS (EI) for C27H47IO5
[M+] calcd 578.2468 found 578.2475.
To
a solution of ketone 4 (0.26 g, 0.6 mmol) in dry
dichloromethane (30 mL) containing p-toluenesulfonic acid
(90 mg, 0.6 mmol) m-CPBA (12 mg) was added [19]. The solution
was stirred for 12 h at room temperature. The solution was
then diluted with water and extracted with dichloromethane
(3 × 15 mL). The solution was washed successively with a 5%
Na2S2O3 solution, saturated brine, and water and was dried over
anhydrous magnesium sulfate. The oily product, obtained by
2.6. 3˛,7˛,24-Trimethoxy-12-oxa-5ˇ-cholane (8)
A solution of the formate 7 (270 mg, 0.4 mmol) in dry THF
(20 mL) was cooled at −78 ◦C. To this solution methyllithium in

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M. Ibrahim-Ouali et al. / Steroids 76 (2011) 324–330
diethyl ether (1 M, solution) (1.1 mL) was added dropwise while
stirring [19]. After the solution was stirred for 3 h at −78 ◦C, the
temperature of the solution rose to room temperature. Evaporation
of the solvent left a residue which was dissolved in diethyl ether
(15 mL). The organic layer was washed with water (15 mL) and
extracted with diethyl ether (3 × 15 mL). The extracts were dried
over MgSO4, filtered and then concentrated under vacuum to yield
a crude oily product. This product was purified by flash chromatog-
raphy on silica gel (diethyl ether/petroleum ether: 1/9) to afford
pure 12-oxa steroid 8 (0.15 g, 75%) as an oil. 1H NMR (300 MHz,
CDCl3): 1.06 (d, J = 6.4, 3H, H-21), 1.16 (s, 3H, H-19), 1.31 (s, 3H, H-
18), 2.16 (m, 2H, H-11), 2.78 (m, 1H, H-3), 2.79 (m, 1H, H-7), 3.21
(s, 3H, OCH3), 3.24 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 3.37 (m, 2H,
H-24), 3.43 (m, 1H, H-11), 3.68 (m, 1H, H-11); 13C NMR (75 MHz,
CDCl3): 19.4, 20.7, 20.8, 23.5, 24.2, 27.6, 29.9, 32.0, 32.1, 32.2, 32.8,
33.8, 35.7, 37.5, 41.6, 43.5, 50.7, 57.1, 57.4, 58.5, 59.3, 61.8, 74.9,
80.6, 82.9, 90.4. HRMS (EI) for C26H46O4 [M+] calcd 422.3396 found
422.3401.
43.2, 44.3, 48.6, 50.2, 57.1, 57.3, 59.3, 74.8, 82.6, 89.9. HRMS (EI) for
C26H46O3S [M+] calcd 438.3168 found 438.3172.
2.9. 12-Thia-3˛,7˛,24-trimethoxy-5ˇ-cholan-12-oxide (12)
Thia steroid 11 (100 mg, 0.2 mmol) was dissolved in CH2Cl2
(20 mL), under argon. The solution was cooled at 0 ◦C and m-CPBA
(36 mg, 0.2 mmol) was added [19]. After stirring at this tempera-
ture for 4 h, the mixture was hydrolysed with a saturated solution
of NaHCO3 (10 mL). 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 chro-
matography on silica gel (petroleum ether/ethyl acetate, 9/1 to
5/5) to give an inseparable 1/3 mixture of two diastereoisomers
12␣/12␤ (60 mg, 66%) as an oil. Major isomer: 1H NMR (300 MHz,
CDCl3): 0.76 (s, 3H, H-18), 0.88 (d, J = 6.4, 3H, H-21), 0.95 (s, 3H, H-
19), 2.56 (m, 2H, CH2–S O), 3.02 (m, 2H, H-3 and H-7), 3.21 (s, 3H,
OCH3), 3.22 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 3.36 (m, 2H, H-24);
13C NMR (75 MHz, CDCl3): 19.6, 20.4, 20.6, 26.4, 26.9, 27.4, 29.9,
32.1, 32.4, 33.6, 33.8, 34.5, 34.9, 35.6, 38.2, 38.4, 44.2, 45.8, 48.4,
2.7. Reduction of iodo formate 7
57.2, 57.6, 59.3, 67.8, 74.2, 82.9, 89.1. HRMS (EI) for C26
calcd 454.3117 found 454.3122.
H
46O4S [M+]
To a solution of iodo formate 7 (540 mg, 0.8 mmol) in dry toluene
(20 mL) DIBAL (1.0 M in hexane, 7 mL) [19] was added 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 solvent
was then evaporated and the product extracted with diethyl ether
(3 × 20 mL). The solution was washed with water and dried over
anhydrous magnesium sulfate. Evaporation of the solvent gave an
oily product which was purified by chromatography on silica gel
(petroleum ether/ethyl acetate: 1/9), to yield iodo alcohol 9 (0.36 g,
82%) as a yellow oil. 1H NMR (300 MHz, CDCl3): 0.92 (s, 3H, H-18),
0.98 (d, J = 7.4, 3H, H-21), 1.02 (s, 3H, H-19), 2.0 (bs, 1H, OH), 2.78
(m, 2H, H-3 and H-7), 3.05 (t, J = 6.8 Hz, 2H, CH2I), 3.20 (s, 3H, OCH3),
3.22 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 3.42 (m, 2H, H-24); 13C NMR
(75 MHz, CDCl3): 6.9, 19.3, 19.6, 23.3, 24.1, 24.2, 27.6, 29.8, 30.9,
31.2, 31.9, 32.4, 33.8, 33.9, 35.8, 38.7, 46.3, 49.5, 57.1, 57.4, 59.6,
61.2, 74.9, 75.6, 82.6, 89.7. HRMS calcd for C26H47IO4 550.2519,
found 550.2523.
2.10. 12-Thia-3˛,7˛,24-trimethoxy-5ˇ-cholan-12,12-dioxide
(13)
Thia steroid 11 (100 mg, 0.2 mmol) was dissolved in CH2Cl2
(15 mL), under argon. The solution was cooled at 0 ◦C and m-
CPBA (70 mg, 0.4 mmol) was added [19]. After stirring at room
temperature for 24 h, the mixture was hydrolysed with a satu-
rated solution of NaHCO3 (10 mL). 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 (CH2Cl2/MeOH: 100/0 to 95/5)
to afford 80 mg (85% yield) of sulfone 13 as colorless needles.
Mp = 161–162 ◦C. 1H NMR (300 MHz, CDCl3): 0.82 (s, 3H, H-18), 0.88
(d, J = 6.5, 3H, H-21), 0.97 (s, 3H, H-19), 2.78 (m, 2H, H-3 and H-7),
3.20 (s, 3H, OCH3), 3.21 (s, 3H, OCH3), 3.24 (s, 3H, OCH3), 3.26–3.48
(m, 4H, H-24 and CH2–SO2); 13C NMR (75 MHz, CDCl3): 14.8, 19.2,
20.8, 25.6, 26.4, 27.2, 28.4, 28.9, 30.9, 31.7, 32.0, 32.2, 33.4, 34.2,
35.7, 37.8, 39.4, 43.5, 52.2, 57.1, 57.3, 59.0, 64.2, 74.5, 82.2, 89.8.
HRMS (EI) for C26H46O5S [M+] calcd 470.3066 found 470.3068.
2.8. 3˛,7˛,24-Trimethoxy-12-thia-5ˇ-cholane (11)
To a solution of iodo alcohol 9 (300 mg, 0.6 mmol) in pyridine
(20 mL) methanesulfonyl chloride (1.2 mL, 1.8 g, 15 mmol) [19] was
added at 0 ◦C under a nitrogen atmosphere. The solution was stirred
for 24 h at room temperature; the solvent was then evaporated and
the product extracted with diethyl ether (3 × 15 mL). The combined
extracts were dried over MgSO4, filtered and then concentrated
under vacuum to give the crude mesylate 10 (0.28 g, 68%). The latter
was then used in the next step without further purification. 1H NMR
(300 MHz, CDCl3): 0.92 (s, 3H, H-18), 0.96 (d, J = 6.8, 3H, H-21), 1.02
(s, 3H, H-19), 2.77 (m, 2H, H-3 and H-7), 2.94 (s, 3H, CH3SO2), 3.10
(m, 2H, CH2I), 3.21 (s, 3H, OCH3), 3.24 (s, 3H, OCH3), 3.26 (s, 3H,
OCH3), 3.48 (m, 2H, H-24).
To a solution of mesylate 10 (280 mg, 0.44 mmol) in acetonitrile
(20 mL) sodium sulfide nonahydrate (865 mg) was added. The solu-
tion was heated under reflux for 3 days. The solvent was evaporated
and the product dissolved in diethyl ether. The solution was washed
with water and dried over anhydrous magnesium sulfate. Evapo-
ration of the solvent gave a crude product, which was purified by
chromatography on silica gel (petroleum ether/ethyl acetate: 1/9),
to give thia steroid 11 (70 mg, 36%) as an oil. 1H NMR (300 MHz,
CDCl3): 1.03 (d, J = 6.4, 3H, H-21), 1.16 (s, 3H, H-19), 1.38 (s, 3H,
H-18), 2.36 (m, 1H, H-11), 2.62 (m, 1H, H-11), 2.76 (m, 2H, H-3
and H-7), 3.21 (s, 3H, OCH3), 3.23 (s, 3H, OCH3), 3.24 (s, 3H, OCH3),
3.42 (m, 2H, H-24); 13C NMR (75 MHz, CDCl3): 18.8, 19.9, 22.6, 24.6,
26.2, 26.8, 27.6, 28.3, 29.9, 31.3, 31.4, 34.7, 35.7, 38.2, 39.2, 42.4,
2.11.
11,13-Diiodo-C-nor-11,12-seco-7˛,7˛,24-trimethoxy-5ˇ-cholane
(14)
To a solution of iodo formate 7 (290 mg, 0.5 mmol) in dry carbon
tetrachloride (5 mL) iodotrimethylsilane (213 ␮L, 1.5 mmol) was
added dropwise over a period of 5 min under an argon atmosphere.
The solution was heated at 60–70 ◦C for 2 days and diethyl ether
was added (15 mL). The organic layer was washed with 5% aque-
ous sodium hydrogen carbonate, 5% aqueous sodium thiosulfate,
and saturated brine successively and then dried over anhydrous
sodium sulfate. Evaporation of the solvent in vacuo left a red oil,
which was passed through a short silica gel column (petroleum
ether) to give pure diiodide 14 (0.3 g, 92%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): 1.06 (d, J = 6.4, 3H, H-21), 1.12 (s, 3H, H-19), 2.10
(s, 3H, H-18), 2.76 (m, 2H, H-3 and H-7), 2.96 (m, 1H, H-11), 3.19 (m,
1H, H-11), 3.21 (s, 3H, OCH3), 3.23 (s, 3H, OCH3), 3.24 (s, 3H, OCH3),
3.38 (m, 2H, H-24); 13C NMR (75 MHz, CDCl3): 6.7, 18.1, 19.2, 27.6,
28.0, 28.7, 29.9, 30.5, 30.7, 31.2, 31.4, 33.5, 35.7, 36.5, 37.2, 38.6,
41.0, 46.3, 48.8, 52.0, 57.1, 57.4, 59.1, 74.8, 82.9, 88.3. HRMS (EI) for
C
26H46I2O3 [M+] calcd 660.1536 found 660.1541.

M. Ibrahim-Ouali et al. / Steroids 76 (2011) 324–330
327
O
O
H
S
S
O
N
S
S
(CH2)n
H
H3CO
H3CO
H
a: n = 1
b: n = 2
Fig. 1. Literature examples of 12-oxa [22] and 12-thia steroids [23].
2.12. N-Benzyl 3˛,7˛,24-trimethoxy-12-aza-5ˇ-cholane (15)
2.15. 12-Thia-3˛,7˛-dihydroxy-5ˇ-cholan-12-oxide-24-ol (18)
To a solution of diiodide 14 (305 mg, 0.46 mmol) in dioxane
(2 mL) benzylamine (125 ␮L, 122 mg, 1.15 mmol) was added. The
solution was heated under reflux for 24 h and extracted with
dichloromethane (3 × 20 mL). The extract was washed with water,
saturated brine, dried over anhydrous magnesium sulfate, filtered
and concentrated in vacuo. The residue was purified by flash chro-
matography on silica gel (petroleum ether/ethyl acetate: 9/1), to
afford aza steroid 15 (0.16 g, 68%) as an oil. 1H NMR (300 MHz,
CDCl3): 1.02 (d, J = 6.4, 3H, H-21), 1.12 (s, 3H, H-19), 1.16 (s, 3H,
H-18), 2.16 (m, 2H, H-11), 2.78 (m, 2H, H-3 and H-7), 3.20 (s, 3H,
OCH3), 3.23 (s, 3H, OCH3), 3.24 (s, 3H, OCH3), 3.45 (m, 2H, H-24),
3.60 (s, 2H, NCH2Ph), 7.20–7.35 (m, 5H, H aromatic); 13C NMR
(75 MHz, CDCl3): 19.0, 19.5, 20.6, 25.0, 25.5, 26.6, 27.8, 28.3, 29.4,
29.9, 33.6, 34.6, 35.4, 35.8, 39.2, 42.6, 43.2, 44.3, 45.2, 49.8, 57.0,
57.3, 59.1, 63.6, 74.8, 76.9, 82.6, 127.3, 128.5, 128.9, 135.8. HRMS
(EI) for C33H53NO3 [M+] calcd 511.4025 found 511.4029.
The same procedure described above was used [19]. Reaction
of 110 mg (0.24 mmol) of 12 in chloroform (20 mL) and 0.2 mL of
ISi(CH3)3 gave, after 24 h of reaction and after purification by flash
chromatography on silica gel (CH2Cl2/MeOH: 9/1), 65 mg (65%) of
an inseparable 1/3 mixture of two diastereoisomers 18␣/18␤ as an
oil. Physical data for the mixture: ˛2D0 = +36.68◦ (c = 0.892, CHCl3)
and HRMS (EI) for C23H40O4S [M+] calcd 412.2647 found 412.2650;
NMR data for the major isomer (from spectra of the isomer mix-
ture): 1H NMR (300 MHz, CDCl3): 0.88 (s, 3H, H-18), 1.07 (d, J = 6.5,
3H, H-21), 1.16 (s, 3H, H-19), 2.02 (bs, 1H, OH), 2.41 (m, 1H, H-11),
2.64 (m, 1H, H-11), 3.18 (m, 2H, H-3 and H-7), 3.52 (m, 2H, H-24);
13C NMR (75 MHz, CDCl3): 19.6, 20.6, 20.9, 26.3, 26.8, 30.2, 31.6,
32.0, 32.4, 32.9, 34.6, 34.8, 36.2, 37.8, 38.2, 40.5, 44.3, 45.8, 48.2,
63.2, 67.6, 68.8, 69.9.
2.16. 12-Thia-3˛,7˛-dihydroxy-5ˇ-cholan-12,12-dioxide-24-ol
(19)
The same procedure described above was used [19]. Reaction
of 100 mg (0.21 mmol) of 13 in chloroform (20 mL) and 0.2 mL of
ISi(CH3)3 gave, after 24 h of reaction and after purification by flash
chromatography on silica gel (CH2Cl2/MeOH: 9/1), 60 mg (67%) of
19 as an oil. ˛2D0 = +36.10◦ (c = 0.563, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.89 (s, 3H, H-18), 1.04 (d, J = 6.4, 3H, H-21), 1.12 (s, 3H,
H-19), 2.01 (bs, 1H, OH), 3.16 (m, 2H, H-3 and H-7), 3.22 (m, 1H,
H-11), 3.45 (m, 1H, H-11), 3.52 (m, 2H, H-24); 13C NMR (75 MHz,
CDCl3): 15.4, 19.1, 20.4, 25.6, 26.4, 28.1, 30.2, 31.0, 31.4, 31.8, 32.2,
32.5, 34.4, 36.3, 38.4, 39.1, 40.6, 43.5, 52.4, 63.2, 64.1, 68.5, 69.7.
HRMS (EI) for C23H40O5S [M+] calcd 428.2596 found 428.2600.
2.13. 12-Oxa-3˛,7˛-dihydroxy-5ˇ-cholan-24-ol (16)
To a solution of 12-oxa steroid 8 (100 mg, 0.24 mmol) in chlo-
roform (20 mL) trimethylsilyl iodide (0.2 mL) [19] was added. The
solution was left overnight at room temperature. Methanol (1 mL)
was then added to decompose any excess trimethylsilyl iodide. The
solution was extracted with diethyl ether (3 × 10 mL), washed with
water and saturated brine, and dried over anhydrous magnesium
sulfate. Evaporation of the solvent gave a crude product, which was
purified by chromatography on silica gel (CH2Cl2/MeOH: 9/1), to
give triol 16 (55 mg, 60%) as an oil. ˛2D0 = +52.55◦ (c = 0.310, CHCl3);
1H NMR (300 MHz, CDCl3): 0.86 (s, 3H, H-18), 1.06 (d, J = 6.4, 3H, H-
21), 1.08 (s, 3H, H-19), 2.01 (bs, 1H, OH), 2.03 (bs, 1H, OH), 3.18 (m,
2H, H-3 and H-7), 3.40 (m, 1H, H-11) 3.52 (m, 2H, H-24), 3.62 (m,
1H, H-11); 13C NMR (75 MHz, CDCl3): 19.4, 20.4, 20.9, 23.2, 24.2,
30.4, 31.4, 31.8, 32.7, 32.8, 32.9, 36.6, 37.2, 38.2, 41.6, 46.2, 50.7,
58.5, 61.9, 63.2, 70.1, 71.4, 79.6. HRMS (EI) for C23H40O4 [M+] calcd
380.2927 found 380.2932.
2.17. N-Benzyl 12-aza-3˛,7˛-dihydroxy-5ˇ-cholan-24-ol (20)
The same procedure described above was used [19]. Reaction of
100 mg (0.19 mmol) of 15 and 0.2 mL of ISi(CH3)3 gave, after 24 h
of reaction and after purification by flash chromatography on silica
gel (CH2Cl2/MeOH: 9/1), 55 mg (62%) of 20 as an oil. ˛2D0 = +77.83◦
(c = 0.415, CHCl3); 1H NMR (300 MHz, CDCl3): 0.86 (s, 3H, H-18),
1.08 (d, J = 6.4, 3H, H-21), 1.12 (s, 3H, H-19), 2.01 (bs, 1H, OH),
2.12 (m, 1H, H-11), 2.34 (m, 1H, H-11), 3.10 (m, 2H, H-3 and H-7),
3.51 (m, 2H, H-24), 3.62 (s, 2H, NCH2Ph), 7.21 (m, 5H, H aromatic);
13C NMR (75 MHz, CDCl3): 19.1, 19.6, 20.1, 25.0, 25.4, 30.0, 30.8,
31.4, 32.2, 33.6, 34.1, 35.6, 36.1, 38.1, 42.9, 48.9, 53.6, 56.6, 62.1,
62.9, 63.1, 69.8, 71.0, 71.4, 127.3, 127.9, 128.4, 134.9. HRMS (EI) for
2.14. 12-Thia-3˛,7˛-dihydroxy-5ˇ-cholan-24-ol (17)
The same procedure described above was used [19]. Reaction
of 200 mg (0.46 mmol) of 11 in chloroform (20 mL) and 0.4 mL of
ISi(CH3)3 gave, after 24 h of reaction and after purification by flash
chromatography on silica gel (CH2Cl2/MeOH: 9/1), 120 mg (66%) of
17 as an oil. ˛2D0 = +46.41◦ (c = 0.540, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.84 (s, 3H, H-18), 1.06 (d, J = 6.4, 3H, H-21), 1.12 (s, 3H,
H-19), 2.01 (bs, 1H, OH), 2.32 (dd, J = 5.4 and 13.8, 1H, H-11), 2.58
(dd, J = 5.6 and 13.4, 1H, H-11), 3.16 (m, 2H, H-3 and H-7), 3.48 (m,
2H, H-24); 13C NMR (75 MHz, CDCl3): 18.6, 20.2, 23.2, 24.5, 26.8,
26.9, 30.4, 30.7, 31.2, 31.8, 32.5, 34.7, 34.8, 36.4, 37.9, 38.2, 42.1,
44.4, 48.6, 50.2, 63.4, 69.2, 69.8. HRMS (EI) for C23H40O3S [M+] calcd
396.2698 found 396.2703.
C
30H47O3N [M+] calcd 469.3556 found 469.3561.
3. Results and discussion
There are very few syntheses of 12-oxa [22] and 12-thia [23]
steroids reported in the literature before (Fig. 1).
And firstly, we turned our attention to the synthesis of 12-oxa
and 12-thia cholanols. The key reactions leading to these new het-
erosteroids are schematically depicted in Schemes 2 and 3. Taking
into account the cis A/B ring junction of the final product, cholic acid

328
M. Ibrahim-Ouali et al. / Steroids 76 (2011) 324–330
O
HO
HO
HO
OH
OH
a
b
HO
OH
HO
MeO
MeO
OH
H
H
1
2
O
OMe
OMe
c
d
OMe
MeO
MeO
OMe
H
H
3
4
HO
O
O
O
OMe
OMe
e
f
OMe
OMe
H
H
5
6
OHC
O
OMe
I
O
OMe
g
MeO
OMe
MeO
OMe
H
H
7
8
Reaction conditions : (a) LiAlH4, THF, 0 °C, 87%; (b) CH3I, NaH, THF, r.t., 82%;
(c) PCC, MW, 15 min, 71%; (d) m-CPBA, PTSA, CH2Cl2, 97%; (e) DIBAL,
CH2Cl2, 95%; (f) HgO-I2, pyridine, C6H6, hν, 88%; (g) MeLi, THF, - 78 °C, 75%.
Scheme 2. Synthesis of a 12-oxa-5␤-steroid 8 through a seven-step sequence.
1, a commercial bile acid both inexpensive and readily available,
was our choice of starting material. We adopted a more attractive
way for the synthesis of 12-heterosteroids. Hydroxyls at different
positions on the nucleus have different reactivities towards alkylat-
ing agents, generally in the order C-3 > C-7 > C-12 [19,24]. Since the
photochemical cleavage of lactol 6 to the seco-steroid 7 does not
tolerate free hydroxy groups, 3␣,7␣,12␣-tetrol 2 was selectively
tri-methoxylated leaving only the 12␣-hydroxy group unprotected.
Thus, we proceeded firstly to an easy reduction [20] of the side
chain acid function of 1 with LiAlH4 in tetrahydrofuran at room
temperature. Tetrol 2 was then isolated in good yield. This lat-
ter was selectively methylated [25] with methyl iodide-sodium
hydride in THF, leading to the 3␣,7␣,24-trimethoxy cholan-12␣-ol
3, in 82% yield. Microwave (MW) [26] irradiation of 3 with pyri-
dinium chlorochromate furnished ketone 4 very quickly, in a few
minutes, and in 71% yield.
R
O
OMe
S
I
OMe
c
MeO
OMe
MeO
OMe
H
H
11
7
9
R = CHO
R = H
a
b
10 R = Ms
Reaction conditions : (a) DIBAL, CH2Cl2, - 78 °C to r.t., 12 h, 82%; (b) CH3SO2Cl, pyridine,
r.t., 24 h, 68%; (c) Na2S.H2O, CH3CN, Δ, 3 days, 36%.
Scheme 3. Synthesis of 12-thia-5␤-steroid 11.

M. Ibrahim-Ouali et al. / Steroids 76 (2011) 324–330
329
O
S
O O
S
OMe
OMe
b
a
11
MeO
OMe
MeO
OMe
H
H
12
13
Reaction conditions : (a) m-CPBA, 1 equiv, CH2Cl2, 0 °C, 1 h, 66%;
(b) m-CPBA, 2 equiv, CH2Cl2, r.t., 24 h, 85%.
Scheme 4. Synthesis of sulfoxide 12 (1/3 mixture of 12␣ and 12␤ diastereomers) and sulfone 13.
Ph
OMe
I
R
N
OMe
b
MeO
OMe
MeO
OMe
H
H
7
R = OCHO
15
a
14 R = I
Reaction conditions : (a) Me3SiI-CCl4, r.t., 48 h, 92%; (b) PhCH2NH2, dioxane, Δ, 24 h, 68%.
Scheme 5. First synthesis of an 12-aza steroid 15.
In the next step, we undertook the formation of the lactone 5
from ketone 4 [27,28]. The Baeyer–Villiger [29] oxidation of the lat-
ter, was done using the experimental conditions applied recently
[19], and 13-oxa-C-homo-5␤-cholestan-12-one 5 was obtained as
a single product in excellent yield (97%). The reduction of lactone
5 with DIBAL in toluene at −78 ◦C for 4 h readily gave lactol 6,
which was subjected to the hypoiodide photolysis under the con-
ditions described by Suginome and Yamada [21], to give formate
7 in 88% yield. The cyclization of formate 7 with methyllithium in
THF afforded a novel 12-oxa steroid 8 in an optimized yield of 75%.
We turned then our attention to the introduction of a sulfur
atom at the same position of the steroidal skeleton. The synthe-
sis of 12-thia-5␤-steroid 11 was achieved in three steps from iodo
formate 7 (Scheme 3). Treatment of 7 with DIBAL in toluene at
−78 ◦C gave iodo alcohol 9 in 82% yield. Its mesylation with mesyl-
chloride/pyridine to the corresponding mesylate 10, followed by
treatment of the latter with sodium sulfide in acetonitrile gave 12-
thia steroid 11 in 36% yield. The structure of 11 was determined
by a series of 1D NMR, COSY and NOESY experiments (400 MHz)
and confirmed by the NOE effects. The NOE contacts observed in
the NOESY spectra showed cross-peaks between the 7␣-methoxy
protons and the protons 14␣, 6␣ and 11␣. The ␣-geometry of all,
which was derived from some peaks, indicates a spatial proximity
between the 18-methyl protons and the protons at positions 11␤,
5␤, 16␤. These interactions suggested a ␤ stereochemistry for the
18-methyl protons.
12 shows shifts for the major peaks corresponding to the ␣-
configurated sulfoxide.
In order to obtain the sulfone as the sole product, oxidation on
compound 11 was carried out with 2 equiv. of m-CPBA in CH2Cl2 at
room temperature. The corresponding steroid 13 bearing a sulfone
moiety was isolated in 85% yield (Scheme 4).
Surprisingly and to the best of our knowledge, no previous
successful formation of 12-aza steroids has been reported in the
literature. We turned then our attention to the introduction of
a nitrogen atom at the C-12 position of the steroidal skeleton
(Scheme 5). Iodo formate 7 was converted into its diiodo derivative
14, by treatment with trimethylsilyl iodide [35,36] in carbon tetra-
chloride, in 92% yield. This latter was treated with benzylamine in
dioxane under reflux for 48 h to afford N-benzyl 12-aza-5␤-steroid
19 in good yield. The structure of 15 was confirmed by spectro-
scopic methods. It is worth pointing out that here too, we observed
retention of configuration at C-13.
Finally, in order to obtain the free alcohols we undertook differ-
ent attempts of deprotection on steroids 8, 11–13 and 15. Thus,
methoxy groups of compounds 8, 11–13 and 15 were removed
easily by using trimethylsilyl iodide. These demethylation reac-
tions were carried out in chloroform at room temperature for 24 h,
and afforded the expected deprotected hetero steroids 16–20 in
satisfactory yields as indicated in Scheme 6.
OMe
OH
X
X
Compounds containing a sulfide, sulfoxide or sulfone moiety
are not only of synthetic interest but also are some of them of
medicinal relevance [30,31]. So, we envisaged to oxidize this latter
chemically [32,33]. And (Scheme 3), oxidation of 11 with 1 equiv.
of 3-chloroperbenzoic acid in dichloromethane led to a 1/3 mix-
ture of the corresponding sulfoxide 12␣ and 12␤ in good yield. The
equatorial sulfoxide is the major isomer in accord with the known
behaviour of peroxy acids with cyclic sulfides [34]. Indeed, the
configuration at sulfur was allocated on the basis of the tendency
of thianes to be oxidized predominantly to equatorial sulfoxides
by peroxy acids. Thus, the 13C NMR spectrum of the compound
ISi(CH3)3
CHCl3
r.t., 24 h
MeO
OMe
HO
OH
H
H
8
X = O
16 X = O; 60%
17 X = S; 66%
11 X = S
12 X = SO
18 X = SO; 58%
13 X = SO2
19 X = SO2; 67%
20 X = NCH2Ph; 62%
15 X = NCH2Ph
Scheme 6. Final step of deprotection.

330
M. Ibrahim-Ouali et al. / Steroids 76 (2011) 324–330
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Acknowledgements
This work has been financially supported by the CNRS, INSERM
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