766 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
MHz) 0.82 (s, 18-Me), 3.80-4 (OCH2CH2O), 5.54 (H6, H11),
Lesuisse et al.
1608 cm-1; HRMS calcd for C23H28O2S 368.18102, found
368.179820. Anal. (C23H28O2S) H,S; C: calcd, 74.96; found,
73.5.
6.76 (t, CHF2, J ) 56.5); IR (CHCl3) 1638, 1615 cm-1
.
This compound (90 mg, 0.19 mmol) was hydrolyzed as
described previously with 1 mL of 6 N HCl in 5 mL of 99%
ethanol. After 30 min at room temperature, the mixture was
worked up (methylene dichloride/aqueous saturated sodium
bicarbonate) to afford after drying 61.7 mg of a yellow oil. This
was chromatographed with ethyl acetate:cyclohexane, 1:1, to
give 46.5 mg of a colorless oil crystallizing in pure phase: Rf
) 0.39 (cyclohexane:AcOEt, 1:1); NMR (CDCl3, 300 MHz) 0.88
(s, 18-Me), 5.59 (m, H11), 5.82 (s, H4), 6.8 (t, J ) 55.5, CHF2);
IR (CHCl3) 1736, 1666, 1614, 1060, 1030, 867 cm-1; HRMS
calcd for C21H26O2F2S 380.162159, found 380.161827. Anal.
(C21H26F2O2S) C,H,S; F: calcd, 9.99; found, 9.2.
3,17-Dioxo-19-[[[(m et h ylt h io)m et h yl]t h io]m et h yl]a n -
d r osta -4,9(11)-d ien e (23). Thiol 19 (1 g, 2.4 mmol) was
dissolved in 20 mL of degassed anhydrous THF and introduced
in a 100 mL flask equipped with magnetic stirring and an
argon inlet; 322 mg (2.9 mmol) of potassium tert-butoxide were
then added portionwise. After 15 min of stirring at room
temperature, 0.4 mL (4.8 mmol, 2 equiv) of methylchloro-
methyl sulfide was added rapidly and the reaction mixture
was stirred for 5 min at room temperature The reaction
mixture was hydrolyzed with a saturated aqueous solution of
ammonium chloride, and the aqueous phase was extracted
with methylene chloride (3 × 15 mL). The organic phase was
dried, concentrated, and chromatographed (cyclohexane:
AcOEt, 8:2) to afford 850 mg (74%) of the expected material
as a white foam: Rf ) 0.8 (cyclohexane:ethyl acetate, 8:2);
NMR (CDCl3, 1 drop of C5D5N, 300 MHz) 0.85 (s, 18-Me), 2.13
(s, SMe), 3.62 (s, SCH2S), 3.8-4 (OCH2CH2), 5.53 (m, H6, H11);
3,17-Dioxo-19-[[[(2,4-d in itr op h en yl)th io]th io]m eth yl]-
a n d r osta -4,9(11)-d ien e (21). Thiol 19 (416 mg, 1 mmol) and
0.081 mL (1 mmol) of pyridine were dissolved in 15 mL of
methylene dichloride and introduced in
a 100 mL flask
equipped with magnetic stirring and an argon inlet; 235 mg
(1 mmol) of 2,4-dinitrobenzenesulfenyl chloride in 5 mL of
methylene chloride was then added dropwise to the room
temperature stirred solution. After 30 min of stirring, the
reaction mixture was poured into 100 mL of water and 100
mL of ethyl acetate. The organic phase was dried, concen-
trated, and chromatographed (cyclohexane:methylene dichlo-
ride:AcOEt, 45:45:15) to afford 500 mg (81%) of the expected
material 25 as a yellow foam: Rf ) 0.5 (cyclohexane:dichlo-
romethane:AcOEt, 45:45:15); NMR (CDCl3, 300 MHz) 0.6 (s,
18-Me), 3.8-4.0 (OCH2CH2O), 5.46 and 5.53 (2d, H6, H11),
8.47 (2H, Ar), 9.11 (1H, Ar); IR (CHCl3) 1594, 1526 cm-1; MS
M+ 616 (FD).
IR (CHCl3) 1732, 1670, 1634 cm-1
.
The next fraction was characterized as the disulfide of the
starting thiol 19 (200 mg, 10%): Rf ) 0.1 (cyclohexane:ethyl
acetate, 8:2); NMR (CDCl3, 300 MHz) 0.83 (s, 18-Me), 3.8-4
(OCH2CH2), 5.49 and 5.53 (2d, H6, H11); IR (CHCl3) 1670,
1635 cm-1; MS M+ 834.
The previous compound 350 mg, 0.7 mmol) was dissolved
in 12 mL of ethanol, the solution was introduced in a 30 mL
flask, and 6 mL of 6 N hydrochloric acid was added. After 1.5
h of stirring at room temperature, the reaction mixture was
hydrolyzed by a saturated solution of sodium bicarbonate and
the aqueous phase was extracted with methylene dichloride
(3 × 10 mL). The organic extracts were dried, concentrated,
and chromatographed with cyclohexane:ethyl acetate, 8:2, to
afford the expected material as a white foam (270 mg, 93%):
Rf ) 0.5 (cyclohexane:AcOEt, 8:2); NMR (CDCl3, 250 MHz) 0.91
(s, 18-Me), 2.13 (s), 3.63 (s, SCH2S), 5.58 (m, H11), 5.82 (d,
H4); IR (CHCl3) 1736, 1664, 1613 cm-1. Anal. (C22H30O2S2)
C,H; S: calcd, 16.42; found, 16.0.
3,17-Dioxo-19-[(a llylt h io)m et h yl]a n d r ost a -4,9(11)-d i-
en e (24). The previous procedure was applied to 400 mg (1
mmol) of thiol 19 in 10 mL of THF, 129 mg (1.2 mmol, 1.2
equiv) of potassium tert-butoxide, and 0.16 mL (2 mmol, 2
equiv) of allyl bromide. After 30 min of stirring at room
temperature, the same workup was applied to afford after
chromatography (cyclohexane:ethyl acetate, 8:2) the expected
material as a white foam (325 mg, 74%): Rf ) 0.6 (cyclohexane:
ethyl acetate, 1:1); NMR (CDCl3, 1 drop of C5D5N, 300 MHz)
0.82 (s, 18-Me), 3.11 (d, SCH2), 3.8-4 (OCH2CH2), 5.05-5.15
(CH2d), 5.50 (m, H6, H11), 5.76 (m, CHd); IR (CHCl3) 1675,
The previous compound (1.25 g, 2 mmol) was dissolved in
150 mL of methanol, the solution was introduced in a 100 mL
flask, and 10 mL of 6 N chlorhydric acid was added. The
resulting suspension was stirred for 2 h at room temperature
in an ultrasonic bath. The crude mixture was concentrated
on the rotavap and then partitioned between aqueous sodium
bicarbonate and ethyl acetate. The organic phase was dried,
concentrated, and chromatographed (gradient of dichlo-
romethane:ethyl ether, 100:0-90:10) to afford 1 g (100%) of
the expected material as a yellow solid: mp 111.5 °C; Rf )
0.38 (cyclohexane:ethyl acetate, 1:1); NMR (CDCl3, 300 MHz)
0.63 (s, 18-Me), 5.51 (m, H11), 5.82 (s, H4), 8.48 (2H, Ar), 9.1
(1H, Ar); IR (CHCl3) 1737, 1668, 1638, 1613, 1595, 1528 cm-1
MS MH+ 529 (FD). Anal. (C26H28O6S2N2) C,H,N,S.
;
3,17-D io x o -19-[(p r o p a r g y lt h io )m e t h y l]a n d r o s t a -
4,9(11)-d ien e (22). Thiol 19 (800 mg, 2 mmol) and 0.39 mL
(3 mmol) of tetramethylethylenediamine were dissolved in 4
mL of THF and introduced in a 100 mL flask equipped with
magnetic stirring and an argon inlet. The reaction mixture
was cooled to -78 °C and 2.25 mL (2 mmol) of nBuLi (0.85 M
solution in hexane) then added dropwise. After 30 min of
stirring at this temperature, 0.205 mL (1.2 equiv) of propargyl
bromide was added dropwise and the reaction mixture was
stirred for 1.5 h at -78 °C. The reaction mixture was
hydrolyzed with a saturated solution of ammonium chloride,
and the aqueous phase was extracted with methylene chloride
(3 × 10 mL). The organic phase was dried, concentrated, and
chromatographed (cyclohexane:ethyl acetate, 8:2) to afford 462
mg (53%) of the expected material as a white foam: Rf ) 0.59
(cyclohexane:ethyl acetate, 1:1); NMR (CDCl3, 1 drop of C5D5N,
300 MHz) 0.85 (s, 18-Me), 2.21 (t, HC), 3.23 (m, CH2), 5.53
1635, 989, 919 cm-1
.
The same hydrolyzing procedure as the one described for
22 was applied to 300 mg (0.7 mmol) of the previous compound
dissolved in 10 mL of ethanol and 5 mL of 6 N HCl. After 1
h at room temperature, the reaction mixture was worked up
and chromatographed (cyclohexane:ethyl acetate, 8:2) to afford
the expected material as an oil (230 mg, 95%). One precipita-
tion with pentane gave the expected analytically pure material
as a white solid (170 mg): Rf ) 0.5 (cyclohexane:ethyl acetate,
8:2); mp 99 °C; NMR (CDCl3, 250 MHz) 0.88 (s, 18-Me), 3.13
(dd, J ) 1, 7), 5.05-5.11 (CH2Cd), 5.54 (m, H11), 5.73 (CHd),
5.81 (H4); IR (CHCl3) 1736, 1665, 1634, 1613, 921 cm-1. Anal.
(C23H30O2S) C,H,S.
3,17-Dioxo-19-[(vin ylth io)m eth yl]a n d r osta -4,9(11)-d i-
en e (26). The starting steroid 21 (265 mg, 0.5 mmol) dissolved
in 50 mL of THF was introduced into a 250 mL flask equipped
with a magnetic stirrer and an argon inlet. The flask was
cooled to -78 °C, and vinylmagnesium bromide (1 mL of a 1
M solution in THF (Fluka), 1 mmol) was slowly added. The
resulting black mixture was stirred for 1 h at this temperature
and then brought to room temperature. After 30 min at room
temperature, the reaction mixture was hydrolyzed with a
saturated solution of ammonium chloride and concentrated on
the rotavap, and the aqueous phase was extracted with ethyl
acetate. The organic extracts were dried and concentrated.
The crude material was crystallized from diisopropyl ether to
(m, H6, H11); IR (CHCl3) 3207, 2105 cm-1
.
The previous compound (460 mg, 1 mmol) was dissolved in
10 mL of ethanol, the solution was introduced in a 30 mL flask,
and 2 mL of 6 N hydrochloric acid was added. The precipitate
formed was filtered, washed with ethyl ether, redissolved in
methylene dichloride, and chromatographed with cyclohexane:
ethyl acetate, 8:2, to afford the expected material as a white
solid (265 mg, 72%). This material was contaminated with
5% of thioacetate 13 and 8% of methylene dichloride: mp 190
°C; Rf ) 0.56 (cyclohexane:ethyl acetate, 1:1); NMR (CDCl3,
300 MHz) 0.9 (s, 18-Me), 2.23 (t, J ) 2.5, CH), 3.26 (m, CH2),
5.58 (m, H11), 5.82 (H4); IR (CHCl3) 3307, 1735, 1665, 1630,