Journal of Medicinal Chemistry
Article
MHz, CDCl ): δ 71.8 (C-3), 50.1, 44.2 (C-17), 42.3, 42.1, 40.8, 37.4,
0.93 (3H, s, H-19), 2.22 (1H, dtt, J = 17.7, J = 8.8, J = 2, H-16a),
3
1
2
3
3
7.1, 36.5, 35.5, 34.8, 34.4, 30.6, 27.1, 26.5, 25.5, 23.4, 20.6, 17.1. IR
2.47 (1H, dddd, J = 16.9, J = 10, J = 4.4, J = 2.2. H-16b), 3.62 (1H,
1 2 3 4
13
spectrum (CHCl ): 3609 (OH); 1031 (C−O); 606 (C−I). MS ESI:
m/z 425.1 (25%, M + Na). HR-MS (ESI) m/z: for C H OINa [M +
m, H-3), 4.50−4.62 (2H, m, CH ). C NMR (101 MHz, CDCl ):
3
2
3
δ 162.0 (C-17), 100.7 (C-20), 71.9 (C-3), 54.6, 44.3, 42.3, 40.8, 36.5,
19
31
Na] calcd, 425.1322; found, 425.1306.
7β-Iodo-5β-androstan-3α-yl 3-Sulfate Pyridinium Salt (12).
Compound 12 was prepared according to General Procedure for
Sulfation. Starting from compound 11 (255 mg, 0.63 mmol),
36.0, 35.9, 35.5, 34.8, 30.6, 29.6, 27.2, 26.5, 24.3, 23.5, 20.8, 18.6. IR
1
spectrum (CHCl ): 3609, 3451, 1031 (OH); 1653 (CC). MS
3
(ESI): m/z 311.3 (100%, M + Na). HR-MS (ESI) m/z: for
C H ONa [M + Na] calcd, 311.2345; found, 311.2344.
20
32
compound 12 (298 mg, 72%) was obtained as a white solid: mp
17-Methylene-5β-androstan-3α-yl 3-Sulfate Pyridinium Salt (17).
Compound 17 was prepared according to General Procedure for
Sulfation. Starting from compound 16 (50 mg, 0.17 mmol),
1
1
18−120 °C; [α] +58.5 (c 0.39, CHCl /MeOH 1.94:0.20). H NMR
D
3
(
400 MHz, CDCl ): δ 0.79 (3H, s, H-18), 0.92 (3H, s, H-19), 3.76
3
(
1H, t, J = 9.4, H-17α), 4.39 (1H, tt, J = 11.0, J = 5.0. H-3), 7.32 (2H,
compound 17 (63 mg, 81%) was obtained as a white solid: mp
1
2
1
ddd, J = 7.6, J = 4.3, J = 1.5. H-2′ and H-4′, pyridinium), 7.72 (1H,
155−159 °C; [α]D +41.6 (c 0.25, CHCl ). H NMR (400 MHz,
1
2
3
3
tt, J = 7.7, J = 1.8, H-3′, pyridinium), 8.64 (2H, dt, J = 4.6, J = 1.7,
CDCl ): δ 0.73 (3H, s, H-18), 0.91 (3H, s, H-19), 2.22 (1H, dt, J =
1
2
1
2
3
1
13
H-1′ and H-5′, pyridinium). C NMR (101 MHz, CDCl ): δ 149.6
17.3, J = 8.7, H-16a), 2.47 (1H, m, H-16b), 4.44 (1H, m, H-3), 4.59
3
2
(
C-1′ and C-5′, pyridinium), 136.4 (C-3′, pyridinium), 128.6 (C-2′
and C-4′, pyridinium), 78.8, 50.1, 46.4, 44.2, 42.3, 42.1, 40.6, 37.2,
5.5, 34.7, 34.4, 33.4, 27.9, 27.0, 26.4, 25.5, 23.1, 20.5, 17.0. IR
(2H, m, CH ), 7.51 (2H, ddd, J = 7.7, J = 4.7, J = 1.4, H-2′ and
2
1
2
3
H-4′, pyridinium), 7.93 (1H, tt, J = 7.7, J = 1.7, H-3′, pyridinium),
1
2
13
3
8.74 (2H, d, J = 4.5, H-1′ and H-5′, pyridinium). C NMR (101 MHz,
spectrum (CHCl ): 3434, 3608 (OH); 1385 (CH ); 1027, 1034 (C−
CDCl ): δ 162.0 (C-17), 147.4 (C-1′ and C-5′, pyridinium), 139.2 (C-
3
3
3
O). MS (ESI): m/z 481.2 (100%, M − pyH). HR-MS (ESI) m/z: for
3′, pyridinium), 124.9 (C-2′ and C-4′, pyridinium), 100.7 (C-20), 79.5
C H O IS [M-pyH] calcd, 481.0904; found, 481.0908.
(C-3), 54.6, 44.3, 42.3, 40.8, 36.0, 35.8, 35.4, 34.7, 33.4, 29.5, 27.8,
19
30
4
5
β-Androstan-3α-ol (14). Trimethylsilyl chloride (84 mL, 0.65
27.0, 26.4, 24.2, 23.4, 20.8, 18.6. IR spectrum (CHCl ): 3140, 3093,
3
mol) was added dropwise to a stirred solution of compound 13 (6 g,
.02 mol) and zinc powder (42 g, 0.38 mol) in dichloromethane and
1490, 826 (pyridinium); 1653 (CC). MS ESI: m/z 367.1 (100%, M
0
− pyH). HR-MS (ESI) m/z: for C H O S [M − pyH] calcd,
20
32
4
methanol (1:1, 180 mL) at 0 °C. The reaction mixture was stirred at
room temperature. After 4 h, heterogeneous zinc pellets were removed
by filtration and to the filtrate was added a saturated solution of
sodium bicarbonate (to pH 7). To clear the white emulsion,
chloroform (3 × 50 mL) and an aqueous solution of hydrochloric
acid (5%, 30 mL) was added. The now transparent organic and
aqueous layers were separated, and the organic phase was separated,
washed with brine, and dried. Solvents were evaporated, and the
residue was purified by column chromatography (4% of acetone in
367.1948; found, 367.1946.
7β-Methyl-5β-pregn-3α-ol (18). Compound 18 was prepared in
the same manner as compound 6. Starting from compound 16 (100
mg, 0.34 mmol), a mixture of 17α- and 17β-isomers (1:10) was
obtained. Further crystallization from acetone/n-heptane compound
afforded 17β-methyl derivative 18 (75 mg, 75%): mp 151−153 °C
1
(acetone/n-heptane); [α]D +18.1 (c 0.21, CHCl ). H NMR (400
3
MHz, CDCl ): δ 0.52 (3H, s, H-18), 0.82 (3H, d, J = 6.8, 17-Me), 0.92
3
13
(3H, s, H-19), 3.62 (1H, m, H-3). C NMR (101 MHz, CDCl ): δ
3
petroleum ether) to afford white solids of 14 (4.5 g, 79%): mp 143−
72.0 (C-3), 56.0, 45.3, 42.4, 42.3, 41.0, 37.9, 36.7, 36.2, 35.6, 34.9, 30.7,
1
1
44 °C (acetone/n-heptane); [α] +10.9 (c 0.27, CHCl ). H NMR
30.4, 27.4, 26.8, 24.9, 23.5, 20.7, 13.9, 12.1. IR spectrum (CHCl ):
D
3
3
(
400 MHz, CDCl ): δ 0.68 (3H, s, H-18), 0.92 (3H, s, H-19), 3.58−
3610, 1034 (OH); 1379 (CH ). MS (ESI): m/z 313.2 (100%, M +
3
3
13
3
4
2
2
.67 (1H, m, H-3). C NMR (101 MHz, CDCl ): δ 72.0 (C-3), 54.7,
Na). For C H O (290.5) calcd: 82.69%, C; 11.80%, H. Found:
3
20 34
2.2, 41.0, 40.9, 40.6, 39.2, 36.6, 36.3, 35.6, 34.8, 30.7, 27.3, 26.9, 25.7,
82.62%, C; 11.37%, H.
3.5, 20.9, 20.7, 17.6. IR spectrum (CHCl ): 3608, 3446 (OH); 2972,
17β-Methyl-5β-pregn-3α-yl 3-Sulfate Pyridinium Salt (19).
Compound 19 was prepared according to General Procedure for
Sulfation. Starting from compound 18 (50 mg, 0.17 mmol),
3
887, 1377 (CH ); 2935, 2865, 1450 (CH ); 1081, 1065, 1034 (CO).
3
2
For C H O (276.2) calcd: 82.55%, C; 11.67%, H. Found: 82.31% C,
19
32
1
1.82% H.
β-Androstan-3α-yl 3-Sulfate Pyridinium Salt (15). Compound 15
compound 19 (66 mg, 85%) was obtained as a white solid: mp
1
5
174−175 °C; [α]D +21.6 (c 0.18, CHCl ). H NMR (400 MHz,
3
was prepared according to General Procedure for Sulfation. Starting
CDCl ): δ 0.51 (3H, s, H-18), 0.81 (3H, d, J = 6.8, 17-Me). 0.91 (3H,
3
from compound 14 (200 mg, 0.72 mmol), compound 15 (211 mg,
s, H-19), 4.46 (1H, m, H-3), 8.00 (2H, m, H-2′ and H-4′, pyridinium),
6
7%) was obtained as a white solid: mp 180−182 °C (chloroform);
8.48 (1H, t, J = 7.8, H-3′, pyridinium), 8.97 (2H, d, J = 5.4, H-1′ and
1
13
[α] +16.0 (c 0.28, CHCl /MeOH, 2:0.1). H NMR (400 MHz,
H-5′, pyridinium). C NMR (101 MHz, CDCl ): δ 145.8 (C-1′ and
D
3
3
CDCl ): δ 0.67 (3H, s, H-18), 0.92 (1H, s. H-19), 4.48 (1H, tt, J =
C-5′, pyridinium), 142.3 (C-3′, pyridinium), 127.2 (C-2′ and C-4′,
pyridinium), 79.9 (C-3), 56.0, 45.2, 42.3, 42.3, 40.9, 37.8, 36.1, 35.5,
34.7, 33.4, 30.3, 27.8, 27.1, 26.7, 24.8, 23.4, 20.6, 13.9, 12.1. IR
3
1
1
8
1.3, J = 4.9, H-3), 7.94−8.04 (2H, m, H-2′ and H-4′, pyridinium),
2
.47 (1H, tt, J = 7.9, J = 1.6, H-3′, pyridinium), 8.97 (2H, dt, J = 5.6,
1
2
1
13
J = 1.5, H-1′ and H-5′, pyridinium). C NMR (101 MHz, CDCl /
spectrum (CHCl ): 3140, 3100, 1490, 1028 (pyridinium); 1263, 1172
2
3
3
CD OD): δ 145.5 (C-1′ and C-5′, pyridinium), 142.3 (C-3′,
(SO ); 1486, 1379 (CH ). MS ESI: m/z 369.2 (100%, M − pyH).
3
3
3
pyridinium), 127.0 (C-2′ and C-4′, pyridinium), 79.7 (C-3), 54.6,
HR-MS (ESI) m/z: For C H O S [M − pyH] calcd, 369.2105;
20
33
4
4
2
2.2, 40.9, 40.7, 40.5, 39.1, 36.2, 35.4, 34.6, 33.3, 27.8, 27.1, 26.8, 25.5,
found, 369.2103.
(17Z)-5β-Pregn-17(20)-en-3α-ol (20). Compound 20 was prepared
3.3, 20.8, 20.6, 17.5. IR spectrum (CHCl ): 1260, 1178, 1050, 970
3
2
1
1
(
OSO ). MS (EI): m/z 355.2 (100%, M − pyH). HR-MS (ESI) m/z:
according to the literature. H NMR (400 MHz, CDCl ): δ 0.85
3
3
for C H O S [M − pyH] calcd, 355.1949; found, 355.1949.
(3H, s, H-18), 0.93 (3H, s, H-19), 1.64 (3H, dt, J = 7.1, J = 2.0, H-
19
31
4
1
2
1
3
1
7-Methylene-5β-androstan-3α-ol (16). Sodium hydride (50% in
21), 3.62 (1H, bm, H-3), 5.11 (1H, qt. J = 7.1, J = 2.0, H-20). C
1 2
parafine oil, 80 mg, 1.70 mmol) was added to a solution of
methyltriphenylphosphonium bromide (619 mg, 1.73 mmol) in dry
DMSO (4 mL) under inert atmosphere, and the reaction mixture was
stirred at room temperature for 1 h. Then, a solution of 13 (100 mg,
NMR (101 MHz, CDCl ): δ 150.4 (C-20), 113.2 (C-20), 71.8 (C-3),
56.3, 44.4, 42.1, 40.5, 37.4, 36.4, 35.4, 35.3, 34.6, 31.5, 30.5, 27.1, 26.3,
24.4, 23.3, 21.0, 16.8, 13.0.
(17Z)-5β-Pregn-17(20)-en-3α-yl 3-Sulfate Pyridinium Salt (21).
Compound 21 was prepared according to the General Procedure for
Sulfation. Starting from compound 20 (100 mg, 0.33 mmol),
3
0
7
.34 mmol) in dry DMSO (3 mL) was added. After 1.5 h of stirring at
0 °C, an aqueous solution of ammonium chloride was added. The
product was extracted with chloroform (2 × 20 mL), and the
combined organic extracts were washed with brine and dried. Solvents
were evaporated, and the residue was purified by chromatography on
pre-TLC plates (40% ether in petroleum ether) to afford compound
compound 21 (95 mg, 63%) was obtained as a white solid: mp
1
171−173 °C (chloroform); [α]D +35.1 (c 0.21, CHCl ). H NMR
3
(400 MHz, CDCl ): δ 0.84 (3H, s, H-18), 0.91 (3H, s, H-19), 1.64
3
(3H, dt, J = 7.1, J = 2.0, H-21), 4.45 (1H, tt, J = 10.9, J = 4.9, H-3),
1
2
1
2
1
6 (90 mg, 90%): mp 147−149 °C (acetone/n-heptane); [α] +30.5
5.10 (1H, qt, J = 7.1, J = 2.1, H-20), 8.01 (2H, m, H-2′ and H-4′,
D
1
2
1
(c 0.22, CHCl ). H NMR (400 MHz, CDCl ): δ 0.75 (3H, s, H-18),
pyridinium), 8.47 (1H, tt, J = 7.9, J = 1.6, H-3′, pyridinium), 8.99
3
3
1
2
5
960
J. Med. Chem. 2015, 58, 5950−5966