Journal of Medicinal Chemistry
ARTICLE
treated with TBAF (1 M in THF, 9.2 mL, 9.2 mmol) in THF (50 mL) as
described for the synthesis of compound 20. Purification by flash column
chromatography (hexane to hexane/EtOAc 10:1) afforded successively
the Z-isomer 35 (380 mg, 12%) and the E-isomer 34 (2.2 g, 72%) as
white powders. Compound 34: mp 85ꢀ87 °C. δH 0.86 (3H, s), 1.23
(3H, t, J 7.4), 1.30 (3H, t, J 7.1), 1.33ꢀ1.58 (6H, m), 1.85ꢀ2.00 (3H, m),
2.18ꢀ2.25 (1H, m), 2.39ꢀ2.45 (1H, m), 2.60 (2H, q, J 7.4), 2.78ꢀ2.84
(2H, m), 2.86ꢀ2.91 (2H, m), 4.16 (2H, q, J 7.1), 4.67 (1H, s), 5.59 (1H,
t, J 2.3), 6.51 (1H, s), 7.06 (1H, s). HRMS (ESþ): m/z found 369.2416;
C24H33O3þ (Mþ þ H) requires 369.2424. Anal. (C24H32O3) C, H, N.
Compound 35: mp 157ꢀ159 °C. δH 1.04 (3H, s), 1.22 (3H, t, J 7.4), 1.29
(3H, t, J 7.2), 1.36ꢀ1.62 (6H, m), 1.78ꢀ1.84 (1H, m), 1.89ꢀ1.95 (1H,
m), 2.16ꢀ2.23 (1H, m), 2.31ꢀ2.37 (1H, m), 2.41ꢀ2.49 (1H, m),
2.57ꢀ2.65 (3H, m), 2.77ꢀ2.84 (3H, m), 4.11ꢀ4.20 (2H, m), 4.60
(1H, s, br), 5.68 (1H, t, J 1.9), 6.50 (1H, s), 7.05 (1H, s). HRMS (ESþ):
m/z found 369.2419; C24H33O3þ (Mþ þ H) requires 369.2424. Anal.
(C24H32O3) C, H, N.
4.21 (1H, dd, J 12.1, 7.4), 4.35 (1H, dd, J 12.1, 7.4), 4.57 (1H, s, br),
5.32ꢀ5.37 (1H, m), 6.50 (1H, s), 7.04 (1H, s). HRMS (ESþ): m/z
found 349.2151; C22H30O2Naþ (MþþNa) requires 349.2138. Anal.
(C22H30O2) C, H
2-Ethyl-3-O-sulfamoyl-17-vinyl-estra-1,3,5(10),16-tetraene
40. Compound 38 (80 mg, 0.24 mmol) was treated with sulfamoyl
chloride (0.5 mmol) in DMA (1.0 mL) as described for the synthesis of
compound 16. Purification by flash column chromatography (hexane/
EtOAc 10:1 to 3:1) afforded compound 40 as a colorless oil (52 mg,
56%). δH 0.91 (3H, s), 1.21 (3H, t, J 7.4), 1.27ꢀ1.55 (2H, m), 1.61ꢀ1.73
(4H, m), 1.85ꢀ2.07 (2H, m), 2.18ꢀ2.39 (4H, m), 2.69 (2H, q, J 7.4),
2.83ꢀ2.92 (2H, m), 4.88ꢀ4.97 (1H, m), 4.99 (2H, s), 5.35 (1H, d, J
18.0), 5.73 (1H, s, br), 6.32 (1H, dd, J 18.0, 11.4), 7.10 (1H, s), 7.18
(1H, s). HRMS (ESþ): m/z found 388.1937; C22H30NO3Sþ (Mþ þ H)
requires 388.1941.
Treatment of 39 (80 mg, 0.24 mmol) with sulfamoyl chloride (0.5
mmol) in DMA (1.0 mL) also yielded 40 (70 mg, 74%).
(E)-2-Ethyl-3-O-sulfamoyl-17-(2-ethoxy-2-oxoethylidene)
estra-1,3,5(10)-triene 36. Compound 34 (185 mg, 0.5 mmol) was
treated with sulfamoyl chloride (1.5 mmol) in DMA (1.0 mL) as
described for the synthesis of compound 16. Purification by flash column
chromatography (hexane/EtOAc 10:1 to 3:1) afforded compound 36 as
a white powder (195 mg, 87%), mp 116ꢀ118 °C. δH 0.86 (3H, s), 1.22
(3H, t, J 7.4), 1.29 (3H, t, J 7.1), 1.38ꢀ1.64 (6H, m), 1.76ꢀ2.02 (3H, m),
2.23ꢀ2.29 (1H, m), 2.38ꢀ2.44 (1H, m), 2.67 (2H, q, J 7.4), 2.85ꢀ2.91
(4H, m), 4.16 (2H, q, J 7.1), 4.98 (2H, s), 5.59 (1H, t, J 2.3), 7.09 (1H, s),
7.20 (1H, s). HRMS (ESþ): m/z found 448.2149; C24H34NO5Sþ
(Mþ þ H) requires 448.2152. Anal. (C24H33NO5S) C, H, N
(E)-2-Ethyl-3-hydroxy-17-(2-methoxyethylidene)estra-1,3,
5(10)-triene 41. Compound 21 (0.9 g, 1.97 mmol) was treated with
lithium aluminum hydride (0.45 g, 12 mmol) in THF (30 mL) at 0 °C as
described for the synthesis of compound 25. Purification by flash column
chromatography (hexane/EtOAc 15:1 to 6:1) afforded the allylic alcohol
as a white powder (0.75 g, 89%), mp 61ꢀ62 °C. δH 0.84 (3H, s),
1.20ꢀ1.66 (9H, m), 1.82ꢀ2.02 (3H, m), 2.21ꢀ2.51 (3H, m), 2.71 (2H,
q, J 7.4), 2.82ꢀ2.89 (2H, m), 4.10ꢀ4.21 (2H, m), 5.07 (2H, s),
5.28ꢀ5.34 (1H, m), 6.66 (1H, s), 7.15 (1H, s), 7.30ꢀ7.48 (5H, m).
HRMS (ESþ): m/z found 417.2793; C29H37O2þ (Mþ þ H) requires
417.2788. Method was as for 17 using the allylic alcohol, sodium hydride
(60% dispersion in mineral oil, 80 mg, 2 mmol), and iodomethane
(0.19 mL, 3.0 mmol) in THF (10 mL) at room temperature for 18 h.
Purification by flash column chromatography (hexane/EtOAc 20:1)
afforded the methyl ether as a colorless oil (0.59 g, 91%). δH: 0.84
(3H, s), 1.24 (3H, t, J 7.4), 1.26ꢀ1.66 (6H, m), 1.82ꢀ2.02 (3H, m),
2.20ꢀ2.51 (3H, m), 2.70 (2H, q, J 7.4), 2.82ꢀ2.89 (2H, m), 3.36 (3H, s),
3.90ꢀ3.97 (2H, m), 5.06 (2H, s), 5.24ꢀ5.30 (1H, m), 6.66 (1H, s), 7.15
(1H, s), 7.31ꢀ7.48 (5H, m). HRMS (ESþ): m/z found 431.2937;
C30H39O2þ (Mþ þ H) requires 431.2945. A solution of the benzyl ether
(180 mg, 0.42 mmol) in t-BuOH (10 g) was refluxed and treated sodium
(∼50 mg). Further chunks of sodium were added every hour until
deprotection was complete by TLC (8 h). The mixture was cooled, and
the reaction was then quenched with isopropanol. The mixture was then
diluted with water. Theorganicswere extracted with ethylacetate, andthe
organic layer was washed with water, brine and then evaporated.
Purification by flash column chromatography (hexane/EtOAc 15:1 to
8:1) afforded 41 as a white powder (95 mg, 67%), mp 133ꢀ134 °C. δH
0.79 (3H, s), 1.22 (3H, t, J 7.4), 1.28ꢀ1.60 (6H, m), 1.75ꢀ1.96 (3H, m),
2.18 (1H, m), 2.39 (3H, m), 2.59 (2H, q, J 7.4), 2.79 (2H, m), 3.35
(3H, s), 3.90ꢀ3.98 (2H, m), 5.11 (1H, s), 5.21ꢀ5.28 (1H, m), 6.4þ8
(1H, s), 7.05 (1H, s). HRMS (ESþ): m/z found 341.2472; C23H33O2
(Mþ þ H) requires 341.2475. Anal. (C23H32O2) C, H
(Z)- 2-Ethyl-3-O-sulfamoyl-17-(2-ethoxy-2-oxoethylidene)
estra-1,3,5(10)-triene 37. Compound 35 (170 mg, 0.46 mmol) was
treated with sulfamoyl chloride (1.5 mmol) in DMA (1.0 mL) as
described for the synthesis of compound 16. Purification by flash column
chromatography (hexane/EtOAc 10:1 to 3:1) afforded compound 37 as
a white powder (190 mg, 92%), mp 152ꢀ153 °C. δH 1.04 (3H, s), 1.22
(3H, t, J 7.4), 1.29 (3H, t, J 7.2), 1.34ꢀ1.64 (6H, m), 1.77ꢀ1.85 (1H, m),
1.91ꢀ1.97 (1H, m), 2.18ꢀ2.27 (1H, m), 2.31ꢀ2.38 (1H, m), 2.40ꢀ2.49
(1H, m), 2.56ꢀ2.74 (3H, m), 2.79ꢀ2.88 (3H, m), 4.10ꢀ4.18 (2H, m),
4.92 (2H, s), 5.69 (1H, t, J 2.1), 7.08 (1H, s), 7.19(1H, s). HRMS (ESþ):
m/z found 448.2143; C24H34NO5Sþ (Mþ þ H) requires 448.2152.
Anal. (C24H33NO5S) C, H, N
(E)-2-Ethyl-3-hydroxy-17-(2-hydroxyethylidene)estra-1,3,
5(10)-triene 38. A solution of 34 (370 mg, 1.0 mmol) in THF (5 mL)
stirred under nitrogen was cooled to ꢀ78 °C, and DIBAL-H (1 M in
THF, 2.2 mL, 2.2 mmol) was added dropwise. The mixture was stirred at
ꢀ78 °C for 1 h and then slowly warmed to room temperature and stirred
for 30 min. Ammonium chloride (saturated, 5 mL) was added at 0 °C,
and the mixture was extracted with EtOAc (2 ꢁ 30 mL). The combined
organics were washed with water and brine, then dried (MgSO4),
filtered, and concentrated in vacuo. Purification by flash column
chromatography (hexane to hexane/EtOAc 4:1) afforded compound
38 as a white powder (260 mg, 79%), mp 167ꢀ169 °C. δH 0.79 (3H, s),
1.21 (3H, t, J 7.4), 1.27ꢀ1.61 (6H, m), 1.74ꢀ1.97 (3H, m), 2.20ꢀ2.48
(5H, m), 2.59 (2H, q, J 7.4), 2.77ꢀ2.83 (2H, m), 4.03ꢀ4.12 (2H, m),
4.49 (1H, s), 5.26ꢀ5.37 (1H, m), 6.48 (1H, s), 7.06 (1H, s). HRMS
(ESþ): m/z found 349.2129; C22H30O2Naþ (MþþNa) requires
349.2138. Anal. (C22H30O2) C, H.
(E)-2-Ethyl-3-O-sulfamoyl-17-(2-methoxyethylidene)estra-
1,3,5(10)-triene 42. Compound 41 (170 mg, 0.5 mmol) was treated
withsulfamoylchloride(1.0 mmol) inDMA (1.0 mL) asdescribed for the
synthesis of compound 16. Purification by flash column chromatography
(hexane/EtOAc 10:1 to 5:1) afforded compound 42 as a white powder
(142 mg, 68%), mp 126ꢀ127 °C. δH 0.79 (3H, s), 1.20 (3H, t, J 7.4),
1.22ꢀ1.67 (6H, m), 1.78ꢀ1.98 (3H, m), 2.17ꢀ2.47 (4H, m), 2.68 (2H,
q, J 7.4), 2.82ꢀ2.88 (2H, m), 3.32 (3H, s), 3.87ꢀ3.93 (2H, m), 5.14
(2H, s), 5.18ꢀ5.24 (1H, m), 7.06 (1H, s), 7.19 (1H, s). HRMS (ESþ):
m/z found420.2188; C23H34O4NSþ (Mþ þ H) requires 420.2203. Anal.
(C23H33O4NS) C, H, N
(Z)-2-Ethyl-3-hydroxy-17- (2-hydroxyethylidene)estra-1,3,
5(10)-triene 39. Compound 35 (180 mg, 0.49 mmol) was treated with
DIBAL-H (1 M in THF, 1.0 mL, 1.0 mmol) in THF (5 mL) as described
for the synthesis of 38. Purification by flash column chromatography
(hexane to hexane/EtOAc 4:1) afforded compound 39 as a white powder
(90 mg, 56%), mp 149ꢀ151 °C. δH 0.93 (3H, s), 1.23 (3H, t, J 7.4),
1.28ꢀ1.61 (6H, m), 1.72ꢀ1.82 (2H, m), 1.87ꢀ1.92 (1H, m), 2.19ꢀ2.40
(4H, m), 2.47ꢀ2.54 (1H, m), 2.60 (2H, q, J 7.4), 2.74ꢀ2.83 (2H, m),
(E)-2-Ethyl-3-O-sulfamoyl-17-(2-hydroxyethylidene)estra-1,
3,5(10)-triene 43. Compound 36 (110 mg, 0.25 mmol) was treated
with DIBAL-H in (1 M in THF, 0.5 mL, 0.5 mmol) in THF (5 mL)
4874
dx.doi.org/10.1021/jm200483x |J. Med. Chem. 2011, 54, 4863–4879