JOURNAL OF CHEMICAL RESEARCH 2008 35
3-O-Methyl-7a-pentoxyestra-1,3,5(10)-trien-3-ol-17-one 17,17-
(2'-[5',5'-dimethyl-1',3'-dioxane]) (12c): To a solution of 11 (100 mg,
0.26 mmol) in dry THF (1.5 ml) was added NaH (208 mg, 60w%
in oil, 5.2 mmol) and thereafter iodopentane (515 mg, 2.6 mmol).
The resulting reaction mixture was stirred under reflux for 20 h.
Thereafter, the mixture was poured into cold water and extracted
with ether. The organic phase was dried over anhydrous MgSO4
and concentrated in vacuo. The residue was subjected to column
chromatography on silica gel 60N (hexane/ether/CHCl3 10:1:1) to
give 12c (118 mg, 99%) as a colourless oil; (Found: MH+, 457.3314.
C29H45O4 requires MH, 457.3318 [FAB]); nmax (neat)/cm-1 2967,
d, 2J = 12.4 Hz), 4.62 (1H, d, 2J = 12.4 Hz), 6.59 (1H, d, 4J = 2.4 Hz),
6.73 (1H, dd, 3J = 8.6 Hz, 4J = 2.4 Hz), 7.16 (2H, d, 3J = 8.4 Hz), 7.25
(1H, d, 3J = 8.6 Hz), 7.40 (2H, d, 3J = 8.4 Hz); dC (67.8 MHz, CDCl3)
13.8, 22.0, 22.5, 22.8, 26.2, 27.0, 29.3, 30.4, 34.2, 36.0, 42.7, 42.8, 47.3,
55.2, 69.9, 70.6, 72.6, 73.0, 108.5, 111.7, 114.3, 121.0, 126.6, 129.2,
131.1, 132.8, 134.9, 138.4, 157.5; MS (FAB, 3-nitrobenzyl alcohol) m/z
(%) = 557 (6.5) [81BrMH+], 555 (7.7) [79BrMH+], 385 (100).
3-O-Methyl
7a-methoxyestra-1,3,5(10)-trien-3-ol-17-one
(13a): A solution of 12a (49 mg, 0.12 mmol) and p-TsOH (10 mg,
0.052 mmol) in acetone (10 ml) was stirred at room temperature for 15
h. Then the reaction mixture was poured into aq. Na2CO3. The mixture
was extracted with ether. The organic phase was dried over anhydrous
MgSO4 and concentrated in vacuo. Column chromatography of
the residue on silica gel 60N (hexane/ether/CHCl3 4:1:1) gave 13a
(38 mg, quant) as a colourless solid; m.p. 169°C nmax (KBr)/cm-1
3002, 2976, 1737, 1261, 1241; (Found: M+, 314.1879. C20H26O3
requires M, 314.1882); dH (270 MHz, CDCl3) 0.89 (3H, s, CH3),
1.48–2.52 (10H, m), 2.69 (1H, m), 2.87 (1H, dd, 2J = 17.8 Hz,
1
1257, 1230, 805; H NMR (270 MHz, CDCl3) d 0.72 (3H, s, CH3),
0.80 (3H, s, CH3), 0.85 (3H, t, 3J = 6.7 Hz, CH3), 1.16 (3H, s, CH3),
1.23–2.42 (17H, m), 2.71 (1H, m), 2.82 (1H, dd, 2J = 18.6 Hz,
3J 4.1 Hz), 3.03 (1H, d, 2J = 18.6 Hz), 3.25–3.68 (7H, m), 3.76 (3H,
s, OCH3), 6.60 (1H, d, 4J = 2.7 Hz), 6.70 (1H, dd, 3J = 8.6 Hz, 4J 2.7
3
Hz), 7.23 (1H, d, J = 8.6 Hz); dC (67.8 MHz, CDCl3) 13.8, 14.1,
22.0, 22.5, 22.5, 23.0, 26.3, 27.1, 28.4, 29.4, 29.7, 30.4, 34.2, 35.9,
42.8, 42.9, 47.3, 55.2, 69.1, 70.6, 72.7, 73.2, 108.6, 111.5, 114.4,
126.5, 133.0, 135.4, 157.4; MS (FAB, 3-nitrobenzyl alcohol) m/z (%)
= 457 (1.9) [MH+], 385 (1.9), 369 (3.1), 345 (1.7).
2
3J = 3.2 Hz), 3.17 (1H, d, J = 17.8 Hz), 3.39 (3H, s, OCH3), 3.69
(1H, m), 3.78 (3H, s, OCH3), 6.65 (1H, d, 4J = 2.4 Hz), 6.74 (1H, d,
3J = 8.6 Hz), 7.23 (1H, dd, 3J = 8.6 Hz, 4J = 2.4 Hz); dC (67.8 MHz,
CDCl3) 13.6, 21.4, 26.0, 31.4, 32.9, 35.8, 36.3, 42.0, 45.8, 47.8, 55.2,
56.8, 74.2, 111.9, 114.5, 126.5, 131.6, 134.7, 157.7, 220.7 (CO); MS
(FAB, 3-nitrobenzyl alcohol) m/z (%) = 314 (41) [M+], 282 (74).
3-O-Methyl 7a-propoxyestra-1,3,5(10)-trien-3-ol-17-one (13b):
A solution of 12b (75 mg, 0.175 mmol) and p-TsOH (13 mg,
0.068 mmol) in acetone (13 ml) was stirred at room temperature for
15 h. Then the reaction mixture was poured into aq. Na2CO3. The
mixture was extracted with ether. The organic phase was dried over
anhydrous MgSO4 and concentrated in vacuo. Column chromatography
of the residue on silica gel 60N (hexane/ether/CHCl3 4:1:1) gave 13b
(60 mg, quant) as a colourless solid; (Found: M+, 342.2200; C22H30O3
requires M, 342.2195); nmax (KBr)/cm-1 2978, 1735, 1261, 1241;
3-O-Methyl-7a-hexoxyestra-1,3,5(10)-trien-3-ol-17-one
17,17-
(2'-[5',5'-dimethyl-1',3'-dioxane]) (12d): To a solution of 11 (100 mg,
0.26 mmol) in dry THF (1.5 ml) was added NaH (208 mg, 60w%
in oil, 5.2 mmol) and thereafter iodohexane (551 mg, 2.6 mmol).
The resulting reaction mixture was stirred under reflux for 20 h.
Then the mixture was poured into cold water and extracted with ether.
The organic phase was dried over anhydrous MgSO4 and concentrated
in vacuo. The residue was subjected to column chromatography on
silica gel 60N (hexane/ether/CHCl3 10:1:1) to give 12c (122 mg,
quant) as a colourless solid; (Found: MH+, 471.3481. C30H47O4
requires MH, 471.3474, FAB); nmax (KBr)/cm-1 2955, 1273, 1247; dH
(270 MHz, CDCl3) 0.73 (3H, s, CH3), 0.80 (3H, s, CH3), 0.91 (3H,
m), 1.16 (3H, s, CH3), 1.24–2.47 (18H, m), 2.72 (1H, m), 2.80 (1H,
dd, 2J = 18.1 Hz, 3J = 3.9 Hz), 3.04 (1H, d, 2J = 18.1 Hz), 3.35–3.63
3
dH (270 MHz, CDCl3) 0.86 (3H, t, J = 7.6 Hz, CH3), 0.88 (3H, s,
CH3), 1.47–2.23 (12H, m), 2.76 (1H, m), 2.87 (1H, dd, 2J = 17.8 Hz,
4
2
2
(7H, m), 3.76 (3H, s, CH3), 6.61 (1H, d, J = 2.7 Hz), 6.71 (1H, dd,
3J = 3.8 Hz), 3.13 (1H, d, J = 17.8 Hz), 3.27 (1H, dd, J = 8.9 Hz,
3J = 6.7 Hz), 3.62 (1H, dt, 2J = 8.9 Hz, 3J = 6.2 Hz), 3.76 (1H, m), 6.64
(1H, d, 4J = 2.7 Hz), 6.73 (1H, dd, 3J = 8.4 Hz, 4J = 2.7 Hz), 7.22 (1H,
4
3
3J = 8.6 Hz, J = 2.7 Hz), 7.23 (1H, d, J = 8.6 Hz); dC (67.8 MHz,
CDCl3) 13.8, 14.0, 14.1, 22.0, 22.5, 22.6, 22.7, 25.9, 26.3, 27.0,
29.3, 29.9, 30.4, 31.6, 34.2, 35.9, 42.9, 47.3, 55.2, 69.0, 70.6, 72.7,
73.1, 108.6, 111.5, 114.3, 126.5, 132.9, 135.4, 157.5; MS (FAB, 3-
nitrobenzyl alcohol) m/z (%) = 471 (13) [MH+], 385 (20), 369 (31).
3-O-Methyl-7a-benzyloxyestra-1,3,5(10)-trien-3-ol-17-one 17,17-
(2'-[5',5'-dimethyl-1',3'-dioxane]) (12e): To a solution of 11 (100
mg, 0.26 mmol) in dry THF (3.0 ml) was added NaH (208 mg,
60 w%, 5.2 mmol) and then benzyl bromide (445 mg, 2.6 mmol).
The resulting reaction mixture was stirred under reflux for 20 h.
Then the mixture was poured into cold water and extracted with ether.
The organic phase was dried over anhydrous MgSO4 and concentrated
in vacuo. The residue was subjected to column chromatography
on silica gel 60N (hexane/ether/CHCl3 10:1:1) to give 12e (124
mg, quant) as a colourless, slowly solidifying oil; (Found: M+ H+,
477.3000. C31H41O4 requires M, 477.3005); nmax (KBr)/cm-1 3012,
2967, 1277, 1240, 815, 760; dH (270 MHz, CDCl3) 0.72 (3H, s, CH3),
0.78 (3H, s, CH3), 1.16 (3H, s, CH3), 1.24–2.43 (10H, m), 2.80 (1H,
m), 2.85 (1H, dd, 2J = 17.0 Hz, 3J = 3.2 Hz), 3.10 (1H, d, 2J = 17.0 Hz),
3
d, J = 8.4 Hz); dC (67.8 MHz, CDCl3) 10.7, 13.5, 21.4, 23.2, 25.9,
31.4, 33.7, 35.8, 36.1, 42.1, 45.8, 47.8, 55.2, 70.7, 72.4, 111.6, 114.4,
126.3, 131.9, 135.1, 157.6, 220.9; MS (EI, 70 eV) m/z (%) = 342 (23)
[M+], 282 (100).
3-O-Methyl 7a-pentoxyestra-1,3,5(10)-trien-3-ol-17-one (13c):
A solution of 12c (27 mg, 0.059 mmol) and p-TsOH (4.5 mg, 0.024
mmol) in acetone (4.5 ml) was stirred at room temperature for 15 h.
Then the reaction mixture was poured into aq. Na2CO3. The mixture
was extracted with ether. The organic phase was dried over anhydrous
MgSO4 and concentrated in vacuo. Column chromatography of
the residue on silica gel 60N (hexane/ether/CHCl3 4:1:1) gave 13c
(21 mg, 96%) as a colourless solid; m.p. 88°C; (Found: M+, 370.2504.
C24H34O3 requires M, 370.2508); nmax (KBr)/cm-1 2978, 2860, 1735,
3
1240, 821; dH (270 MHz, CDCl3) 0.78 (3H, t, J = 6.5 Hz, CH3),
0.81 (3H, s, CH3), 1.17–2.48 (16H, m), 2.67 (1H, m), 2.80 (1H, dd,
2J = 17.8 Hz, 3J = 3.8 Hz), 3.05 (1H, d, 2J = 17.8 Hz), 3.24 (1H, dt,
2J = 8.9 Hz, 3J = 7.0 Hz), 3.58 (1H, dt, 2J = 8.9 Hz, 3J = 6.2 Hz), 3.69
(1H, m), 3.71 (3H, s, OCH3), 6.56 (1H, d, 4J = 2.7 Hz), 6.66 (1H, dd,
2
3.43 (3H, m), 3.65 (1H, d, J = 11.3 Hz), 3.75 (1H, m), 3.76 (3H,
2
2
4
3
s, OCH3), 4.44 (1H, d, J = 12.4 Hz), 4.67 (1H, d, J = 12.4 Hz),
3J = 8.6 Hz, J = 2.7 Hz), 7.15 (1H, d, J = 8.6 Hz); dC (67.8 MHz,
CDCl3) 13.6, 14.1, 21.5, 22.5, 25.9, 28.5, 29.7, 31.4, 33.7, 35.9,
36.2, 42.1, 45.8, 47.8, 55.2, 69.0, 72.4, 111.7, 114.5, 126.4, 131.9,
135.2, 157.6, 221.0 (CO); MS (EI, 70 eV) m/z (%) = 370 (22) [M+],
282 (100).
4
3
4
6.60 (1H, d, J = 2.4 Hz), 6.72 (1H, dd, J = 8.9 Hz, J = 2.4 Hz),
7.23–7.33 (6H, m); dC (67.8 MHz, CDCl3) 13.8, 22.0, 22.5, 22.7,
26.3, 27.1, 29.3, 30.3, 34.2, 36.0, 42.8 (2C), 47.3, 55.2, 70.5, 70.6,
72.4, 72.6, 108.6, 111.6, 114.4, 126.6, 127.2, 127.6 (2C), 128.1 (2C),
132.9, 135.1, 139.3, 157.5; MS (FAB, 3-nitrobenzyl alcohol) m/z (%)
= 477 (5.6) [MH+], 385 (25), 369 (8.4).
3-O-Methyl 7a-hexoxyestra-1,3,5(10)-trien-3-ol-17-one (13d):
A solution of 12d (115 mg, 0.24 mmol) and p-TsOH (18 mg, 0.097
mmol) in acetone (18 ml) was stirred at room temperature for 15 h.
Then the reaction mixture was poured into aq. Na2CO3. The mixture
was extracted with ether. The organic phase was dried over anhydrous
MgSO4 and concentrated in vacuo. Column chromatography of the
residue on silica gel 60N 8 hexane/ether/CHCl3 4:1:1) gave 13d as a
colourless solid; (75 mg, 80%); m.p. 119°C; (Found: M+, 384.2659.
C25H36O3 requires M, 384.2664); nmax (KBr/cm-1) 2926, 2855, 1739,
3-O-Methyl-7a-(4-bromobenzyloxy)estra-1,3,5(10)-trien-3-ol-17-
one 17,17-(2'-[5',5'-dimethyl-1',3'-dioxane]) (12f): To a solution of 11
(100 mg, 0.26 mmol) in dry THF (3.0 ml) was added NaH (208 mg,
60w% in oil, 5.2 mmol) and then a solution of 4-bromobenzyl
bromide (650 mg, 2.6 mmol) in dry THF (1.0 ml). The resulting
reaction mixture was stirred under reflux for 20 h. Then the mixture
was poured into cold water and extracted with ether. The organic
phase was dried over anhydrous MgSO4 and concentrated in vacuo.
The residue was subjected to column chromatography on silica gel
60N (hexane/ether/CHCl3 10:1:1) to give 12f (112 mg, 78%) as a
colourless solid; (Found: M+ H+, 555.2106. C31H40O479Br requires
M, 555.2110); nmax (KBr)/cm-1 3010, 2973, 2930, 1270, 1245, 807;
dH (270 MHz, CDCl3) 0.74 (3H, s, CH3), 0.79 (3H, s, CH3), 1.17
(3H, s, CH3), 1.22–1.43 (10H, m), 2.78 (1H, m), 2.86 (1H, dd,
2J = 18.1 Hz, 3J = 3.8 Hz), 3.07 (1H, d, 2J = 18.1 Hz), 3.35–3.49 (3H, m),
3.66 (1H, d, 2J = 11.3 Hz), 3.73 (1H, m), 3.77 (3H, s, OCH3), 4.39 (1H,
3
1212; dH (270 MHz, CDCl3) 0.85 (3H, t, J = 6.5 Hz), 0.88 (3H, s,
CH3), 1.24–2.49 (18H, m), 2.75 (1H, m), 2.87 (1H, dd, 2J = 17.8 Hz,
2
2
3J = 3.5 Hz), 3.13 (1H, d, J = 17.8 Hz), 3.31 (1H, dt, J = 9.2 Hz,
2
3
3J = 6.8 Hz), 3.65 (1H, dt, J = 9.2 Hz, J = 6.5 Hz), 3.77 (1H, m),
3.78 (3H, s, OCH3), 6.64 (1H, d, 4J = 2.7 Hz), 6.73 (1H, dd, 3J = 8.6
4
3
Hz, J = 2.7 Hz), 7.22 (1H, d, J = 8.6 Hz); dC (67.8 MHz, CDCl3)
13.6, 14.0, 21.4, 22.6, 25.9 (2C), 29.9, 31.4, 31.6, 33.6, 35.8, 36.1,
42.0, 45.8, 47.8, 55.2, 69.0, 72.3, 111.6, 114.4, 126.4, 131.9, 135.1,
157.7, 221.0; MS (EI, 70 eV) m/z (%) = 384 (12) (M+), 282 (100).
PAPER: 07/5046