D. Renard et al. / Bioorg. Med. Chem. 17 (2009) 8123–8137
8133
ether/EDMA 7:3:0.2) (132 mg, 85%). Mp 96 °C. 1H NMR (CDCl3,
500 MHz): d 5.14 (m, 1H, H-7), 3.58 (m, 1H, H-3), 2.61 (ddd, 1H,
H-10a, J = 11.6 Hz, J = 3.7 Hz), 2.54 (m, 2H), 2.29 (dd, 1H, H-10b,
J = 11.6 Hz, J = 8.8 Hz), 2.02 (dm, 2H, H-12, J = 12.6 Hz), 1.89–1.20
(m, 23H), 1.12 (ddd, 1H, H-1b, J = J = 13.0 Hz, J = 3.2 Hz), 0.99 (d,
3H, H-21, J = 6.4 Hz), 0.90 (t, 3H, H-400, J = 7.2 Hz), 0.80 (s, 3H, H-
19), 0.54 (s, 3H, H-18). 13C NMR (CDCl3, 125 MHz): d 139.4 (8-
CH), 117.5 (7-CH), 71.0 (3-CH), 55.3 (10-CH2), 54.8 (CH), 54.2
(CH), 49.8 (100-CH2), 49.4 (CH), 43.5 (13-C), 40.2 (CH), 39.5 (CH2),
38.0 (CH2), 37.1 (CH2), 36.6 (CH), 34.2 (10-C), 31.8 (200-CH2), 31.4
(CH2), 30.0 (CH2), 27.7 (CH2), 23.0 (CH2), 21.5 (CH2), 20.5 (300-
CH2), 18.0 (21-CH3), 14.0 (400-CH3), 13.0 (19-CH3), 12.0 (18-CH3).
HRMS Found 387.3501 (Calcd 387.3501). Anal. Calcd: C, 80.56; H,
11.70; N, 3.61. Found: C, 80.40; H, 11.63; N, 3.52. IR (KBr, cmꢀ1):
3396, 3316, 2937, 2874, 2850, 1468, 1446, 1380, 1050, 784.
J = 6.6 Hz), 0.99 (d, 3H, H-21, J = 6.6 Hz), 0.94 (d, 3H, H-1000,
J = 6.4 Hz), 0.93 (d, 3H, H-1000, J = 6.4 Hz), 0.89 (d, 3H, H-300,
J = 6.7 Hz), 0.88 (d, 3H, H-300, J = 6.7 Hz), 0.86 (d, 3H, H-300,
J = 6.6 Hz), 0.84 (d, 3H, H-300, J = 6.6 Hz), 0.78 (s, 6H, H-19), 0.54
(s, 6H, H-18). 13C NMR (CDCl3, 125 MHz): d 139.4 (8-CH), 117.5
(7-CH), 71.04 and 70.99 (3-CH), 58.9 and 58.1 (100-CH2), 54.9
(CH), 54.3 (CH), 53.1 and 52.7 (10-CH2), 49.48 and 49.43 (CH),
43.51 and 43.49 (13-C), 40.2 (CH), 39.50 and 39.48 (CH2), 38.0
(CH2), 37.3 (CH), 37.19 and 37.13 (CH2), 36.7 (CH), 34.3 and 34.2
(10-C), 32.5 and 31.6 (200-CH), 31.53 and 31.47 (CH2), 29.68 and
29.63 (CH2), 27.72 and 27.69 (CH2), 23.0 (CH2), 21.5 (CH), 19.53
and 19.49 (300-CH3), 18.04 and 17.91 (21-CH3), 17.5 and 17.0 (300-
CH3), 16.3 and 16.0 (1000-CH3), 13.0 (19-CH3), 11.9 (18-CH3). HRMS
Found 358.3140 (Calcd 358.3110 for C24H40NO). Anal. Calcd: C,
80.74; H, 11.79; N, 3.49. Found: C, 80.53; H, 11.89; N, 3.51. IR
(KBr, cmꢀ1): 3427, 2947, 2873, 1471, 1444, 1381, 1099, 1052.
5.4.2.8. (3S,20S)-20-(Pentylamino-methyl)-pregn-7-en-3-ol (5h).
Ester 4h (188 mg, 0.42 mmol) was treated as described in pro-
cedure B. The crude product was subjected to SCC (pentane/diethyl
ether/EDMA 5:5:0.5) (132 mg, 78%). Mp 98 °C. 1H NMR (CDCl3,
500 MHz): d 5.16 (m, 1H, H-7), 3.59 (m, 1H, H-3), 2.58 (m, 3H),
2.29 (dd, 1H, H-10b, J = 11.4 Hz, J = 8.7 Hz), 2.00 (ddd, 1H, H-12a,
J = 12.6 Hz, J = J = 3.3 Hz), 1.89–1.21 (m, 27H), 1.08 (ddd, 1H, H-
1b, J = J = 13.3 Hz, J = 3.2 Hz), 0.99 (d, 3H, H-21, J = 6.4 Hz), 0.90 (t,
3H, H-500, J = 6.9 Hz), 0.79 (s, 3H, H-19), 0.55 (s, 3H, H-18). 13C
NMR (CDCl3, 125 MHz): d 139.4 (8-CH), 117.5 (7-CH), 71.0 (3-
CH), 55.6 (10-CH2), 54.9 (CH), 54.3 (CH), 50.4 (100-CH2), 49.4 (CH),
43.5 (13-C), 40.2 (CH), 39.5 (CH2), 38.0 (CH2), 37.1 (CH2), 36.9
(CH), 34.2 (10-C), 31.5 (CH2), 29.8 (CH2), 29.6 (CH2), 27.7 (CH2),
23.0 (CH2), 22.6 (CH2), 21.5 (CH2), 17.9 (21-CH3), 14.0 (500-CH3),
13.0 (19-CH3), 11.9 (18-CH3). HRMS Found 401.3694 (Calcd
401.3658). Anal. Calcd: C, 80.74; H, 11.79; N, 3.49. Found: C,
80.51; H, 11.87; N, 3.48. IR (KBr, cmꢀ1): 3421, 2930, 2870, 2800,
1448, 1376, 1130, 1096,1046, 726.
5.4.2.11. (3S,20S)-20-(Dodecylamino-methyl)-pregn-7-en-3-
ol (5k). Ester 4k (158 mg, 0.29 mmol) was treated as described in
procedure B. The crude product was subjected to SCC (pentane/
diethyl ether/EDMA 6:4:0.5) (109 mg, 75%). Mp 76 °C. 1H NMR
(CDCl3, 500 MHz): d 5.16 (m, 1H, H-7), 3.58 (m, 1H, H-3), 2.63–
2.47 (m, 3H, H-100, H-10a), 2.28 (dd, 1H, H-10b, J = 11.7 Hz,
J = 8.6 Hz), 2.01 (ddd, 1H, H-12a, J = 12.5 Hz, J = 4.0 Hz, J = 2.9 Hz),
1.89–1.19 (m, 41H), 1.07 (ddd, 1H, H-1b, J = J = 13.4 Hz,
J = 3.5 Hz), 0.99 (d, 3H, H-21, J = 6.6 Hz), 0.88 (t, 3H, H-1200,
J = 6.9 Hz), 0.79 (s, 3H, H-19), 0.54 (s, 3H, H-18). 13C NMR (CDCl3,
125 MHz): d 139.4 (8-CH), 117.6 (7-CH), 71.0 (3-CH), 55.5 (10-
CH2), 54.8 (14-CH), 54.2 (17-CH), 50.4 (100-CH2), 49.4 (9-CH), 43.5
(13-C), 40.2 (5-CH), 39.5 (12-CH2), 38.0 (4-CH2), 37.1 (1-CH2),
36.8 (20-CH), 34.2 (10-C), 31.9 (CH2 side chain), 31.5 (2-CH),
30.1, 29.65, 29.62, 29.61, 29.58 (CH2 side chain and 6-CH2), 29.3
(CH2 side chain), 27.7 (16-CH2), 27.4 (CH2 side chain), 23.0 (15-
CH2), 22.7 (CH2 side chain), 21.5 (11-CH2), 17.9 (21-CH3), 14.1
(1200-CH3), 13.0 (19-CH3), 12.0 (18-CH3). HRMS Found 499.4768
(Calcd 499.4753). Anal. Calcd: C, 80.74; H, 11.79; N, 3.49. Found:
C, 80.53; H, 11.89; N, 3.51. IR (KBr, cmꢀ1): 3418, 2918, 2849,
1635, 1472, 1372, 1051, 1040.
5.4.2.9. (3S,20S)-20-[(2-Methylpropyl)amino-methyl]-pregn-7-
en-3-ol (5i). Ester 4i (200 mg, 0.46 mmol) was treated as de-
scribed in procedure B. The crude product was subjected to SCC
(pentane/diethyl ether/EDMA 8:2:0.5) (141 mg, 79%). Mp 117 °C.
1H NMR (CDCl3, 400 MHz): d 5.15 (m, 1H, H-7), 3.58 (m, 1H, H-
3), 2.62 (dd, 1H, H-10a, J = 11.6 Hz, J = 3.1 Hz), 2.41 (dd, 1H, H-100a,
J = 11.6 Hz, J = 7.0 Hz), 2.32 (dd, 1H, H-100b, J = 11.6 Hz, J = 6.8 Hz),
2.25 (dd, 1H, H-10b, J = 11.6 Hz, J = 2.9 Hz), 2.00 (ddd, 1H, H-12a,
J = 12.5 Hz, J = J = 3.3 Hz), 1.89–1.20 (m, 22H), 1.07 (ddd, 1H, H-
1b, J = J = 13.0 Hz, J = 3.3 Hz), 0.99 (d, 3H, H-21, J = 6.4 Hz), 0.89
(d, 6H, 2 CH3, J = 6.8 Hz), 0.80 (s, 3H, H-19), 0.54 (s, 3H, H-18).
13C NMR (CDCl3, 100 MHz): d 139.4 (8-CH), 117.5 (7-CH), 71.0
(3-CH), 58.2 (100-CH2), 55.4 (10-CH2), 54.8 (CH), 54.3 (CH), 49.4
(CH), 43.5 (13-C), 40.2 (CH), 39.4 (CH2), 37.9 (CH2), 37.1 (CH2),
36.7 (CH), 34.2 (10-C), 31.4 (CH2), 29.6 (CH2), 28.0 (200-CH), 27.7
(CH2), 23.0 (CH2), 21.5 (CH2), 20.68 and 20.63 (2 CH3), 17.8 (21-
CH3), 13.0 (19-CH3), 11.9 (18-CH3). HRMS Found 387.3528 (Calcd
387.3501). IR (KBr, cmꢀ1): 3409, 2951, 2869, 1471, 1444, 1378,
1365, 1097, 1039, 749.
5.4.3. (3S,20S)-20-[(N-Butyl-N-methyl-amino)-methyl]-pregn-
7-en-3-yl acetate (6)
To a stirred solution of ester 4g (1.80 g, 4.10 mmol) in dichloro-
methane (10 mL) was successively added, at 0 °C, formaldehyde
solution (37% in water, 4.0 mL, 49 mmol) and formic acid
(566 mg, 12.3 mmol). The reaction mixture was then heated at
80 °C for 2 h. After cooling to ambient temperature aqueous NaOH
[2 N] (6 mL) was slowly added and the mixture was stirred for
10 min at ambient temperature. Then it was extracted with dichlo-
romethane (3 ꢁ 10 mL), the combined organic layers were dried
over sodium sulfate, and evaporated to dryness under reduced
pressure. The crude product was subjected to SCC (pentane/diethyl
ether/EDMA 9:1:0.1) to afford 6 as a white solid (1.7 g, 94%). Mp
128 °C. 1H NMR (CDCl3, 500 MHz): d 5.15 (m, 1H, H-7), 4.69 (m,
1H, H-3), 2.37 (ddd, 1H, H-100a, J = 12.0 Hz, J = 8.6 Hz, J = 6.3 Hz),
2.14 (s, 3H, CH3N), 2.11 (m, 2H), 2.05 (ddd, 1H, H-12a,
J = 12.9 Hz, J = J = 3.3 Hz), 2.02 (s, 3H, CH3CO), 1.97 (dd, 1H, H-10b,
J = 12.0 Hz, J = 10.4 Hz), 1.91–1.11 (m, 22H), 1.12 (m, 2H), 0.99 (d,
3H, H-21, J = 6.6 Hz), 0.90 (t, 3H, H-400, J = 7.3 Hz), 0.80 (s, 3H, H-
19), 0.54 (s, 3H, H-18). 13C NMR (CDCl3, 100 MHz): d 170.7 (CO),
139.4 (8-CH), 117.4 (7-CH), 73.4 (3-CH), 64.1 (10-CH2), 58.3 (100-
CH2), 55.2 (CH), 54.7 (CH), 49.2 (CH), 43.6 (13-C), 43.2 (CH3N),
40.0 (CH), 39.4 (CH2), 36.8 (CH2), 35.4 (CH), 34.2 (10-C), 33.8
(CH2), 29.7 (CH2), 29.5 (CH2), 27.9 (CH2), 27.5 (CH2), 23.1 (CH2),
21.5 (CH2, CH3CO), 20.7 (300-CH2), 18.2 (21-CH3), 14.1 (400-CH3),
12.9 (19-CH3), 12.0 (18-CH3). HRMS Found 443.3769 (Calcd
443.3763). Anal. Calcd: C, 78.50; H, 11.13; N, 3.16. Found: C,
5.4.2.10. (3S,20S)-20-[(1R,S)-(1,2-Dimethyl-propylamino)-
methyl]-pregn-7-en-3-ol (5j) (mixture of diastereomers). Ester
4j (220 mg, 0.50 mmol) was treated as described in procedure B.
The crude product was subjected to SCC (pentane/diethyl ether/
EDMA 9:1:0.5) (164 mg, 82%). Mp 141 °C. 1H NMR (CDCl3,
500 MHz): d 5.15 (m, 2H, H-7), 3.58 (m, 2H, H-3), 2.67 (dd, 1H,
H-10a, J = 11.2 Hz, J = 2.8 Hz), 2.61 (dd, 1H, H-10a, J = 11.8 Hz,
J = 3.1 Hz), 2.37 (m, 2H, H-100), 2.27 (dd, 1H, H-10b, J = 11.8 Hz,
J = 8.6 Hz), 2.17 (dd, 1H, H-10b, J = 11.2 Hz, J = 8.8 Hz), 2.00 (ddd,
2H, H-12a, J = 12.5 Hz, J = J = 3.3 Hz), 1.88–1.18 (m, 44H), 1.06
(ddd, 2H, H-1b, J = J = 12.7 Hz, J = 3.1 Hz), 1.00 (d, 3H, H-21,