Journal of Medicinal Chemistry
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(3H, H-21); 3.89 m (2H, W = 36.1, OCH2); 3.97 m (2H, W = 32.8,
OCH2).
2.72 (t, 1H, J = 14.4, H-5); 7.32 (m, 5H, phenyl). Anal. (C29H36O3) C,
H.
11α-Ethynyl-3α,11β-dihydroxy-5β-pregnan-20-one (37). A
solution, prepared from methanol (1.5 mL), a methanolic solution
of sodium hydroxide (2.5 N, 0.05 mL), and a pyridine solution of
sodium borohydride (0.18 M, 1.4 mL), was added to a solution of
diketone 35 (61 mg, 0.17 mmol) in methanol (4.5 mL) at 0 °C under
nitrogen. After 10 min, an excess of hydrochloric acid was added and
the solution was extracted with ether. The extract was washed with an
aqueous solution of potassium hydrogen carbonate, water and dried
over sodium sulfate. Evaporation of the solvent and chromatography
of the residue on three preparative plates (toluene/ethyl acetate, 6:4)
gave compound 37 (40 mg, 66%), mp 195−197 °C (acetone/
heptane). [α]D +133 (CHCl3, c 0.1). IR: 3599, 3457, 1030, 1115
(OH); 1701, 1359, 593 (CO); 3304, 2105, 636 (CC). 1H NMR: δ
0.81 (s, 3H, H-18); 1.22 (s, 3H, H-19); 2.14 (s, 3H, H-21); 2.53 (s,
1H, H−CC); 3.72 (m, 1H, W = 32, H-3). Anal. (C23H34O3) C, H.
3α,11β-Dihydroxy-11α-phenylethynyl-5β-pregnan-20-one
(38). Diketone 36 (74 mg, 0.17 mmol) was reduced in position 3 as
described above. Compound 38 (46 mg, 62%) forms white crystals,
mp 199−202 °C (acetone/heptane). [α]D +207 (CHCl3, c 0.1). IR:
3603, 1235, 1114 (OH); 2222 (CC); 1700, 1358, 594 (CO); 1491,
1448, 1179, 1164, 1073, 1029, 691 (phenyl). 1H NMR: δ 1.00 (s, 3H,
H-18); 1.40 (s, 3H, H-19); 2.30 (s, 3H, H-21); 3.87 (m, 1H, W = 31,
H-3); 7.43 and 7.52 (2 × m, 5H, phenyl). Anal. (C29H38O3) C, H.
3α,11α-Dihydroxy-5α-pregnan-20-one (39). Diketone 27 (85
mg, 0.26 mmol) was treated with hydrogen hexachloroiridate hydrate
and 2-propanol as in the preparation of compound 15. The product
was purified by PLC. The major component was identified as the diol
39 (ref 63, 40 mg, 47%). 1H NMR: δ 0.62 (s, 3H, H-18); 0.93 (s, 3H,
H-19); 2.13 (s, 3H, H-21); 2.56 (t, 1H, J = 8.0, H-17); 3.92 (m, 1H, W
= 36, H-11); 4.02 (m, 1H, W = 16, H-3).
General Method for the Grignard Reaction. A solution of the
Grignard reagent in THF (0.5 M, 24 mL, 12 mmol) was added to a
ketone (1.20 mmol) under stirring. The reaction mixture, monitored
by TLC, was kept at 65 °C for 10−18 h. When complete, the mixture
was poured into a saturated aqueous ammonium chloride solution.
The precipitate was extracted with ether, washed with brine, and dried
over magnesium sulfate. The solvent was evaporated, and the residue
was purified by preparative thin-layer chromatography:
3α,11β-Dihydroxy-5β-pregnan-20-one (31). 31 was prepared
from ketal 30 by reduction with LAH in THF and deprotection
1
according to ref 35. H NMR: δ 0.84 (s, 3H, H-18); 1.17 (s, 3H, H-
19); 2.12 (s, 3H, H-21); 2.46 (t, J = 8.9, H-17); 3.69 (m, W = 38 Hz,
1H, H-3); 4.26 (m, 1H, W = 18, H-11).
3β,11α-Bis-ethynyl-3α,11β-dihydroxy-5β-pregnan-20-one
(32). Following the general procedure, 20,20-ethylenedioxy-5β-
pregnane-3,11-dione (ref 16, 30, 80 mg, 0.22 mmol) was treated
with ethynyl magnesium bromide (0.5 M solution in THF, 40 mL) for
16 h. After the usual workup and chromatography (toluene/ethyl
acetate, 6:4), the ketal obtained was hydrolyzed in position 20 by
treatment with p-toluenesulfonic acid (15 mg) in acetone (15 mL) at
55 °C for 15 min. The usual workup and chromatography on two
preparative plates (toluene/ethyl acetate, 6:4) gave compound 32 (25
mg, 30%) as white crystals, mp 235−238 °C (acetone/heptane). [α]D
+109 (CHCl3, c 0.2). IR: 3594, 1106 (OH); 3305, 2223, 651 (CC);
1702, 594 (CO). 1H NMR: δ 0.81 (s, 3H, H-18); 1.26 (s, 3H, H-19);
2.13 (s, 3H, H-21); 2.50 (s, 1H, H−CC); 2.53 (s, 1H, H−CC).
Anal. (C25H34O3) C, H.
3α,11β-Dihydroxy-3β,11α-bis-phenylethynyl-5β-pregnan-
20-one (33). Following the general procedure, ketal 30 (100 mg, 0.27
mmol) was treated with phenylethynylmagnesium bromide (1.0 M
solution in THF, 2.4 mL) for 10 h. After the usual workup and
deprotection, chromatography (elution with toluene/ethyl acetate,
6:4) gave compound 33 (49 mg, 34%) as white crystals, mp 220−222
°C (acetone/heptane). [α]D +33 (CHCl3, c 0.1). IR: 3593, 1105
(OH); 2223 (CC); 1701,1356, 594 (CO); 1490, 1444, 1329, 1028,
11,20-Dioxo-pregna-3,5-dien-3-yl Acetate (40). 40 was
prepared from 11α-hydroxyprogesterone (25) according to ref 36.
1H NMR: δ 0.63 (s, 3H, H-18); 1.19 (s, 3H, H-19); 2.12 (s, 3H, H-
21); 2.13 (s, 3H, OAc); 2.70 (t, 1H, J = 9.0, H-17); 5.35 (m, 1H, W =
7.3, H-4); 5.68 (m, 1H, W = 2.0, H-6).
3β-Hydroxy-5α-pregnane-11,20-dione (41). Enol acetate 40
(6.0 g, 16.2 mmol) was hydrogenated in a mixture of ethanol (200
mL) and ethyl acetate (50 mL) in the presence of palladium on
charcoal (2.5 g, 10%). The product was dissolved in methanol (300
mL) and boiled with a solution of potassium carbonate (6.0 g, 43.4
mmol) in water (30 mL). After 1 h, acetic acid was added (5 mL) and
the solvent was partly evaporated in a vacuum and the product
precipitated after addition of water. Flash chromatography of the
product on silica gel in a mixture of toluene/ether, 4:2, yielded
compound 41 (2.2 g, 41%) as white crystals, mp 192−194 °C
1
692 (phenyl). H NMR: δ 0.86 (s, 3H, H-18); 1.32 (s, 3H, H-19);
2.16 (s, 3H, H-21); 7.31 (m, 5H, phenyl); 7.37 (m, 5H, phenyl). Anal.
(C37H42O3) C, H.
3α-Hydroxy-5β-pregnane-11,20-dione (34). Ketal 30 (90 mg,
0.24 mmol) was reduced with sodium borohydride in pyridine and
deprotected as in the preparation of compound 28. PLC yielded white
crystals of compound 34 (31 mg, 39%), mp 172−174 °C (acetone/
heptane). Mancera32 gives 168−171 °C. H NMR: δ 0.57 (s, 3H, H-
1
18); 1.15 (s, 3H, H-19); 2.10 (s, 3H, H-21); 2.47 and 2.57 (2H, AB
system, J = 11.5, H-12); 2.76 (t, 1H, J = 9.1, H-17); 3.65 (m, 1H, W =
36, H-3).
(acetone/heptane). Djerassi64 recorded the same value. H NMR δ
1
0.57 (s, 3H, H-18); 1.01 (s, 3H, H-19); 2.09 (s, 3H, H-21); 2.71 (t,
11α-Ethynyl-11β-hydroxy-5β-pregnane-3,20-dione (35). Fol-
lowing the general procedure, 3,3,20,20-bisethylenedioxy-5β-pregnan-
11-one (29, 0.5 g, 1.20 mmol) was treated with ethynylmagnesium
bromide (0.5 M solution in THF, 24 mL, 12 mmol) for 18 h. The
product was deprotected by treatment with p-toluenesulfonic acid (30
mg) in acetone (30 mL) at 55 °C for 15 min. The usual workup and
chromatography (elution with toluene/ethyl acetate, 7:3) gave
compound 35 (102 mg, 24%) as white crystals, mp 192−195 °C
(acetone/heptane). [α]D +150 (CHCl3, c 0.1). IR: 3627, 3593, 1112
1H, J = 9.2, H-17); 3.57 (m, 1H, W = 35.4, H-3).
11,20-Dioxo-5α-pregnan-3β-yl Mesylate (42). Methanesulfon-
yl chloride (4 mL, 51.7 mmol) was slowly added to a cold (0 °C)
solution of compound 41 (2.1 g, 6.3 mmol) in pyridine (8 mL) under
stirring. After 2 h, a mixture of crushed ice and water (50 g) was
added. After 2 h, the solid was filtered off, washed with water, and
dissolved in CH2Cl2. The extract was dried over sodium sulfate and
concentrated in a vacuum. On addition of ether, compound 42 (2.1 g,
81%) crystallized as white needles, mp 155−156 °C. [α]D +86 (c 0.4,
CHCl3). IR (CHCl3): 1704 (CO); 1357, 1172, 935, 926 (MsO). 1H
NMR: δ 0.57 (s, 3H, H-18); 1.03 (s, 3H, H-19); 2.10 (s, 3H, H-21);
2.72 (t, 1H, J = 9.1, H-17); 3.00 (s, 3H, Ms); 4.60 (m, 1H, W = 33.1,
H-3). Anal. (C22H34O5S) C, H, S.
1
(OH); 3303, 2103, 637 (CC); 1703, 1422, 1359, 594 (CO). H
NMR: δ 1.00 (s, 3H, H-18); 1.45 (s, 3H, H-19); 2.28 (s, 3H, H-21);
2.69 (s, 1H, H−CC). Anal. (C23H32O3) C, H.
11β-Hydroxy-11α-phenylethynyl-5β-pregnane-3,20-dione
(36). Analogously, ketone 29 (0.5 g, 1.20 mmol) was treated with
phenylethynylmagnesium bromide (1.0 M solution in THF, 12 mL, 12
mmol) for 10 h and deprotected as above. After the usual workup and
chromatography (toluene/ethyl acetate, 9:1), compound 36 (145 mg,
28%) was obtained as white crystals, mp 181−183 °C (acetone/
heptane). [α]D +190 (CHCl3, c 0.2). IR: 3593, 1112, 1236 (OH);
3α-Hydroxy-5α-pregnane-11,20-dione (3). Mesylate 42 (2.05
g, 5.0 mmol) underwent solvolysis as in the preparation of compound
8. The mixture was separated using column chromatography. The
major fraction (0.93 g, 56%) was crystallized from acetone, mp 170−
171 °C. [α]D +97 (c 0.2). Nagata65 recorded 172 °C and +113.4. H
1
NMR: δ 0.57 (s, 3H, H-18); 1.00 (s, 3H, H-19); 2.10 (s, 3H, H-21);
2.57 and 2.50 (AB system, 2H, J = 11.6, 2H-11); 2.73 (t, 1H, J =9.0,
H-17); 4.05 (m, 1H, W = 8.0, H-3).
1
2220 (CC); 1703, 594 (CO); 1491, 1444, 1161, 691 (phenyl). H
NMR: δ 0.90 (s, 3H, H-18); 1.35 (s, 3H, H-19); 2.16 (s, 3H, H-21);
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dx.doi.org/10.1021/jm3016365 | J. Med. Chem. 2013, 56, 2323−2336