Novel Neurosteroids that Modulate GABAA Receptors
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5211
2.26-1.25 (m, 22H), 4.01 (bs, 1H, 3â-H), 4.23 (bs, 1H, 20H),
7.41-7.33 (m, 6H), 7.68-7.64 (m, 4H).
was added. The slurry was cooled to 0 °C, and a solution of
alcohol 12a (100 mg, 0.14 mmol) in THF (2 mL) was added.
The reaction mixture was stirred at rt, and, after 30 min, MeI
(0.02 mL, 0.28 mmol) was added; stirring was then continued
for 5 h. The reaction was quenched by saturated aqueous NH4-
Cl and was diluted with ethyl acetate, and the organic layer
was washed with brine and was dried over anhydrous Na2-
SO4. After the evaporation of the solvent, the residue was
purified by flash column chromatography [petroleum ether
40-60 °C/dietyl ether (98:2)] to afford (20R)-3-triisopropyl-1-
methoxy-1-[3R-(tert-butyldiphenylsilyloxy)-5R-androstan-17â-
yl]-2-propyne as a white solid (70 mg, 70% yield).
(20R)-1-[3r(tert-Butyldiphenylsilyloxy)-5r-androstan-
17â-yl]-3-triisopropyllsilyl-2-propyn-1-ol (12a). A solution
of (S)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]-
oxazaborole (1 M) in toluene (0.084 mL, 0.084 mmol) was
added to a solution of ketone 11 (30 mg, 0.042 mmol) in 3 mL
of THF. The resulting solution was cooled to -30 °C, and then
0.02 mL (0.21 mmol) of borane methyl sulfide complex was
added. After the reaction was completed, it was quenched by
the slow addition of methanol (1.0 mL). The reaction mixture
was diluted with diethyl ether, and the organic layer was
washed with saturated NH4Cl, 5% NaHCO3, and brine. The
organic layer was dried over anhydrous Na2SO4 and was
concentrated in vacuo. The residue was purified by flash
column chromatography [petroleum ether 40°-60 °C/acetone
(90:10)] to afford 12a as a white solid (28 mg, 93% yield, and
100% ee). 1H NMR (δ): 0.71 (s, 6H, 18,19-CH3), 0.84-2.07 (m,
23H), 1.06 (s, 9H, C(CH3)3), 3.99 (bs, 1H, 3â-H), 4.27 (d, J )
9.54 Hz, 1H, 20-H), 7.32-7.42 (m, 6H), 7.63-7.66 (m, 4H).
17â-(3-Oxo-1-propynyl)-5r-androstan-3r-ol (13). A solu-
tion of 11 (155 mg, 0.215 mmol) in anhydrous dichloromethane
(9 mL) was treated with HF-pyridine (0.86 mmol, 0.024 mL)
at 0 °C, and the resulting mixture was stirred at rt for 2 h.
The addition of water at 0 °C was followed by an extraction
with methylene chloride. The organic layer was washed with
brine and was dried with anhydrous Na2SO4, and the solvent
was evaporated in vacuo. Subsequent purification of the
residue by flash column chromatography [dichloromethane/
ethyl acetate (95/5)] afforded the desired compound 13 in 76%
yield as a solid. mp:148-150 °C; 1H NMR (δ): 0.67 (s, 3H, CH3),
0.77 (s, 3H, CH3), 0.80-2.27 (m, 22H), 2.62 (t, J ) 8.8 Hz, 1H,
17R-H), 3.21 (s, 1H, acetylenic), 4.04 (bs, 1H, 3â-H); 13C NMR
(δ): 11.23, 13.49, 20.64, 22.39, 24.26, 28.46, 29.05, 31.97, 32.22,
35.53, 35.90, 36.17, 38.69, 39.15, 54.29, 56.84, 64.81, 66.52,
73.85, 78.65, 97.77, 197.91; Anal. (C22H32O2) C, H.
(20R)-17â-(1-Hydroxy-2-propynyl)-5r-androstan-3-ol
(14). Compound 12a (200 mg, 0.31 mmol) was treated with a
solution of 1 M (n-Bu)4N+F- (7.8 mL, 7.8 mmol) in hexanes at
rt for 24 h. The reaction was completed using the same
procedure as that used for compound 6 to afford, after
purification by flash column chromatography using dichlo-
romethane/ethyl acetate 90/10 as elution solvent, alcohol 14
in 80.5% yield. mp: 197-199 °C; 1H NMR (δ): 0.73 (s, 3H, 18-
CH3), 0.77 (s, 3H, 19-CH3), 0.80-2.10 (m, 23H), 2.41 (d, J )
1.81 Hz, 1H), 4.03 (bs, 1H, 3â-H), 4.24-4.72 (m, 1H, 20-H).
13C NMR (δ): 11.23, 12.24, 20.59, 24.30, 25.34, 28.53, 29.03,
32.03, 32.20, 35.43, 35.91, 36.15, 39.16, 39.63, 42.56, 54.45,
56.07, 56.67, 64.68, 66.01, 72.50, 85.44; Anal. (C22H34O2) C,
H.
(20S)-17â-(1-Hydroxy-2,3-butadienyl)-5r-androstane-
3-ol (15). Paraformaldehyde (20 mg), copper hypobromide (4
mg, 0.027 mmol), and diisopropylamine (0.07 mL, 0.5 mmol)
were sequentially added to a solution of alcohol 14 (83 mg,
0.25 mmol) in anhydrous dioxane (3 mL). The resulting
mixture was refluxed for 24 h. The addition of HCl 2 M and
extraction with ethyl acetate were followed by an extraction
of the organic layer with NaHCO3, water, and brine and a
drying with anhydrous Na2SO4. The solvent was evaporated
in vacuo, and the residue was purified by flash column
chromatography, using dichloromethane/ethyl acetate 85/15
as elution solvent, to afford allenic alcohol 15 (45 mg, 52%).
mp: 184-187 °C.; 1H NMR (δ): 0.76 (s, 3H, CH3), 0.78 (s, 3H,
CH3), 0.85-2.10 (m, 23H), 4.03 (bs, 1H, 3â-H), 4.07 (m, 1H,
20-H), 4.82 (dd, J ) 1.23 Hz, 2H, 23-H), 5.20 (q, J ) 6.6 Hz,
1H, 21-H).; 13C NMR (δ): 11.18, 12.42, 20.64, 24.43, 25.29,
28.54, 29.03, 32.06, 32.18, 35.39, 35.88, 36.13, 39.15, 39.85,
42.74, 54.41, 56.03, 56.75, 66.59, 72.56, 77.16, 94.89, 207.05.;
IR(cm-1): 1995 (CdCdCH2), 1255 (C-O); Anal. (C23H36O2) C,
H.
(20R)-17â-(1-Methoxy-2-propynyl)-5r-androstan-3r-
ol (16) The deprotection of 3R-OH and the removal of the
triisopropylsilyl group in 3-triisopropylsilyl-1-methoxy-1-[3R-
(tert-butyldiphenylsilyloxy)-5R-androstan-17â-yl]-2-propyne were
accomplished in one step by adding 1 M (n-Bu)4N+F- solution
in THF (1.9 mL, 1.9 mmol) to a solution of the above compound
(50 mg, 0.076 mmol) in anhydrous THF (3 mL). The resulting
solution was stirred at rt for 24 h and was then taken through
the same process used to obtain compound 6 to afford, after
purification by flash column chromatography using petroleum
ether 40-60 °C/acetone 82/18 as the elution solvent, methoxy
1
derivative 16. mp: 161-163 °C; H NMR (δ): 0.69 (s, 3H, 18-
CH3), 0.77 (s, 3H, 19-CH3), 0.79-2.24 (m, 23H), 2.44 (d, J )
1.83 Hz, 1H), 3.37 (s, 3H, OCH3), 3.70 (dd, J ) 9.8 Hz, 1H,
20-H), 4.03 (bs, 1H, 3â-H); 13C NMR (δ): 10.74, 11.94, 20.44,
23.89, 26.62, 28.54, 29.02, 32.03, 32.16, 35.17, 35.89, 36.11,
38.63, 39.14, 41.74, 54.28, 54.37, 55.90, 56.13, 66.58, 73.11,
74.59, 82.95; Anal. (C23H35O2) C, H.
(20R)-1-[3r-(tert-Butyldiphenysilyloxy)-5r-androstan-
17â-yl]-2-propyn-1-ol (17) A solution of 1 M (n-Bu)4N+F- in
THF (0.72 mL, 0.72 mmol) was added to a solution of 12a (310
mg, 0.48 mmol) in THF (10 mL), and the resulting mixture
was stirred at rt for 0.5 h. The reaction mixture was taken
through the same process used to obtain compound 6 to afford,
after purification by flash column chromatography using
petroleum ether 40-60 °C/acetone 82/18 as the elution solvent,
compound 17 (230 mg, 84%). Anal. (C38H52O2Si) C, H.
(20R)-1-{3r-(tert-Butyldiphenysilyloxy)-5r-androstan-
17â-yl-[3-(4-methoxyphenyl)-2-propynyl]}-1-ol. A solution
of 17 (100 mg, 0.176 mL) in pyrrolidine (2.5 mL) was added to
a solution of 4-iodoanisole (82.38 mg, 0.35 mmol), CuI (19 mg,
0.1 mmol), and tetrakis(triphenylphosphine) palladium (0) (58
mg, 0.05 mmol) in pyrrolidine (1.5 mL). The resulting mixture
was stirred for 24 h at rt. The quenching of the reaction by
the addition of NH4Cl was followed by an extraction with ethyl
acetate. The organic layer was washed with water and brine
and dried with (Na2SO4), and the solvent was evaporated in
vacuo. Subsequent purification of the residue with flash
column chromatography using petroleum ether 40-60 °C/
acetone 80/20 as the eluent afforded, in 84% yield, (20R)-1-
{3R-(tert-butyldiphenysilyloxy)-5R-androstan-17â-yl-[3-(4-meth-
oxy phenyl)-2-propynyl]}-1-ol as a solid. mp: 63-65 °C; Anal.
(C45H57O3Si) C, H.
(20R)-17â-[1-Hydroxy-3-(4-methoxyphenyl)-2-propynyl]-
5r-androstan-3r-ol (18). The removal of the protecting group
in (20R)-1-{3R-(tert-butyldiphenysilyloxy)-5R-androstan-17â-
yl-[3-(4-methoxyphenyl)-2-propynyl]}-1-ol was accomplished
following the same procedure as that followed for compound
6 to afford, after flash column purification using dichlo-
romethane/ethyl acetate (90/10) as the elution solvent, com-
1
pound 18 in 77% yield. mp: 185-188 °C.; H NMR (δ): 0.76
(s, 3H, 19-CH3), 0.78 (s, 3H, 18-CH3), 0.81-2.08 (m, 23H), 3.79
(s, 1H, OCH3), 4.03 (bs, 1H, 3â-H), 4.45-4.49 (m, 1H, 20-H),
6.80 (d, J ) 8.8 Hz, 2H), 7.32 (d, J ) 8.8 Hz, 2H).; 13C NMR
(δ): 11.19, 12.38, 20.58, 24.30, 25.45, 28.52, 29.02, 32.02, 32.16,
35.40, 35.87, 36.14, 39.14, 39.61, 42.56, 54.42, 55.26, 56.07,
57.07, 65.28, 66.60, 84.40, 89.22, 113.86, 114.99, 133.03,
159.52; Anal. (C29H39O3) C, H.
(20R)-3-Triisopropyl-1-methoxy-1-[3r-(tert-butyldi-
phenylsilyloxy)-5r-androstan-17â-yl]-2-propyne. Sodium
hydride (60% dispersion in mineral oil, 12 mg, 0.28 mmol) was
washed with dry hexane (2 × 2 mL), and then 1.5 mL of THF
(20S)-17â-(1-Hydroxy-2-propynyl)-5r-androstan-3-ol
(19). Compound 12b (200 mg, 0.31 mmol) was treated with a
solution of 1 M (n-Bu)4N+F- (7.8 mL, 7.8 mmol) in hexanes at
rt for 24 h. The reaction was completed using the same