3840 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Miller et al.
48.00, 43.74, 38.36, 37.53, 34.94, 31.13, 27.66, 26.32, 23.49,
11.71. Anal. (C19H24O2) C, H.
described in general procedure C (crystalline needles, Rf )
0.23, mp 219-221 °C, 77%): 1H NMR 8c (CDCl3) δ 7.233 (s,
1H), 6.99 (d, J ) 10.8 Hz, 1H), 6.69 (d, J ) 10.4 Hz, 1H), 3.91
(s, 3H), 3.73 (t, J ) 8.47 Hz, 1H), 2.83 (m, 1H), 2.61 (m, 1H),
2.3-1.2 (complex, 14H), 0.768 (s, 3H). Anal. (C20H26O3‚1/2H2O)
C, H.
Gen er a l P r oced u r e A: P yr id in e-In d u ced Rin g Exp a n -
sion . The requisite dihalocarbene monoadduct (1 g) was
dissolved in pyridine (10 mL), and reflux was initiated and
held for 5 h. After cooling, the mixture was filtered through
silica gel with ethyl ether and the filtrate concentrated under
reduced pressure. The resultant gum was taken up in dichlo-
romethane and flash chromatographed eluting with 30% ethyl
ether/petroleum ether to afford the corresponding triene.
Gen er a l P r oced u r e B: Ep oxid a tion w ith Dim eth yl-
d ioxir a n e. The requisite halomethoxy triene (0.25 g) was
dissolved in 80% aqueous acetone (20 mL) and cooled to 0 °C
in an open vessel. After portionwise addition of a freshly
prepared solution of dimethyldioxirane17 in acetone (0.1 M, 2.2
equiv), the mixture was allowed to warm to room temperature
and monitored by TLC. Upon completion, solvents were
removed under reduced pressure. Flash chromatography of
the residue eluting with 50% ethyl ether/petroleum ether
provided the requisite R-hydroxy dienone. Alternatively, flash
chromatography (SiO2 acid impregnated with acidic bromo-
form) of the residue eluting with 15% acetone in chloroform
provided the requisite halotropone. Crystalline solids were
obtained by recrystallization from ethyl acetate.
Gen er a l P r oced u r e C: P d (P P h 3)4-Med ia ted Alk oxyla -
tion . The requisite halotropone (10 mg) was dissolved in THF/
alcohol (1:1, 5 mL), and Pd(PPh3)4 (2 equiv) was added under
Ar(g). Initiation of reflux was followed by the addition of K2-
CO3 (2 equiv) in four equal portions over 1 h. After an
additional hour at reflux, the mixture was diluted with 30%
methanolic chloroform and filtered through silica gel and the
filtrate concentrated under reduced pressure. Radial chro-
matography of the residue eluting with 30% acetone in
chloroform afforded the corresponding R-alkoxytropone. Crys-
talline solids were obtained by recrystallization from ethyl
acetate.
3-B r o m o -4-m e t h o x y -A-h o m o -2,4,5(10)-e s t r a t r ie n -
17â-ol (7a ) a n d 3-Ch lor o-4-m eth oxy-A-h om o-2,4,5(10)-
estr a tr ien -17â-ol (7b). The title compounds 7a (white foam,
65% yield, Rf ) 0.26 with 50% ethyl ether/petroleum ether)
and 7b (oil, Rf ) 0.27 with 50% ethyl ether/petroleum ether,
67% yield) were prepared from 2a and 2b, respectively, as
described in general procedure A: 1H NMR 7a (CDCl3) δ 5.84
(t, J ) 8.09 Hz, 1H), 5.78 (s, 1H), 3.56 (s, 3H), 3.52 (t, J ) 8.1
Hz, 1H), 2.665 (d, J ) 12.7 Hz, 1H), 2.615 (d, J ) 12.3 Hz,
1H), 2.2-0.95 (complex, 16H), 0.631 (s, 3H); 13C NMR 7a
(CDCl3) δ 153.97, 129.95, 128.75, 126.27, 114.43, 110.64, 81.21,
55.46, 49.95, 47.42, 44.04, 40.26, 37.77, 31.11, 30.78, 30.71,
28.80, 27.06, 23.27, 11.59; 1H NMR 7b (CDCl3) δ 5.78 (s, 1H),
5.66 (t, J ) 8.08 Hz, 1H), 3.57 (s, 3H), 3.52 (t, J ) 7.3 Hz, 1H),
2.648 (d, J ) 12.7 Hz, 1H), 2.620 (d, J ) 13.09 Hz, 1H), 2.4-
0.95 (complex, 16H), 0.634 (s, 3H).
3-Br om o-4-oxo-A-h om o-1(10),2,4a -estr a tr ien -17â-ol (8a )
a n d 3-Ch lor o-4-oxo-A-h om o-1(10),2,4a -estr a tr ien -17â-ol
(8b). The title compounds 8a (crystalline needles, Rf ) 0.64
with 30% acetone in chloroform, mp 132-143 °C dec, 53%)
and 8b (crystalline needles, Rf ) 0.63 with 30% acetone in
chloroform, mp 125-220 °C dec, 46%) were prepared from 7a
and 7b, respectively, as described in general procedure B: 1H
NMR 8a (CDCl3) δ 7.98 (d, J ) 10.01 Hz, 1H), 7.149 (s, 1H),
6.72 (d, J ) 10.01 Hz, 1H), 3.69 (t, J ) 8.08 Hz, 1H), 2.77 (dt,
J ) 15 Hz, J ) 8.2 Hz, 1H), 2.55 (dd, J ) 15 Hz, J ) 5.0 Hz,
1H), 2.25-1.95 (m, 4H), 1.9-1.25 (complex, 10H), 0.754 (s, 3H);
13C NMR 8a (CDCl3) δ 180.39, 152.90, 150.49, 139.78, 139.15,
136.36, 125.79, 81.82, 52.30, 44.92, 43.68, 36.50, 36.05, 33.54,
30.93, 25.54, 25.38, 23.79, 11.48. Anal. 8a (C19H23BrO2) C,
H. 1H NMR 8b (CDCl3) δ 7.64 (d, J ) 11.24 Hz, 1H), 7.130 (s,
1H), 6.78 (d, J ) 11.24 Hz, 1H), 3.678 (t, J ) 9.26 Hz, 1H),
2.73 (dt, J ) 14 Hz, J ) 8.0 Hz, 1H), 2.51 (ddd, J ) 15 Hz, J
) 6.94 Hz, J ) 4 Hz,1H), 2.24-1.90 (m, 4H), 1.8-1.15
(complex, 10H), 0.710 (s, 3H); 13C NMR 8b (CDCl3) δ 179.32,
152.06, 150.35, 145.03, 136.89, 134.99, 120.00, 81.2, 51.78,
44.34, 43.61, 35.00, 35.57, 33.12, 30.38, 25.06, 24.80, 23.26,
10.95. Anal. 8b (C19H23ClO2) C, H.
4-B r o m o -3-m e t h o x y -A-h o m o -2,4,5(10)-e s t r a t r ie n -
17â-ol (9a ) a n d 4-Ch lor o-3-m eth oxy-A-h om o-2,4,5(10)-
estr a tr ien -17â-ol (9b). Title compounds 9a (foam, Rf ) 0.23
with 50% ethyl ether/petroleum ether, 68%) and 9b (foam, Rf
) 0.22 with 50% ethyl ether/petroleum ether, 60% yield) were
prepared from 5a and 5b, respectively, as described in general
procedure A: 1H NMR 9a (CDCl3) δ 6.89 (s, 1H), 4.70 (t, J )
8.1 Hz, 1H), 3.57 (t, J ) 8.1 Hz, 1H), 3.56 (s, 3H), 2.5-1.0
1
(complex, 18H), 0.861 (s, 3H); H NMR 9b (CDCl3) δ 6.58 (s,
1H), 4.79 (t, J ) 8.1 Hz, 1H), 3.53 (t, J ) 7.7 Hz, 1H), 3.47 (s,
3H), 2.6-0.95 (complex, 18H), 0.634 (s, 3H).
4-Br om o-3-oxo-A-h om o-4,5(10)-estr adien -2,17â-diol (10a)
a n d 4-Ch lor o-3-oxo-A-h om o-4,5(10)-estr a d ien -2,17â-d iol
(10b). The title compounds 10a (clear oil, Rf ) 0.5 with ethyl
ether, 62%) and 10b (white foam, Rf ) 0.57 with ethyl ether,
45%) were prepared from 9a and 9b, respectively, as described
in general procedure B: 1H NMR 10a (CDCl3) δ 7.35 (s, 1H),
4.02 (d, J ) 13.9 Hz, 1H), 3.71 (t, J ) 8.08 Hz, 1H), 2.65 (d, J
) 15 Hz, 1H), 2.43 (t, J ) 14 Hz, 1H), 2.3-1.05 (complex, 17H),
0.807 (s, 3H); 13C NMR 10a (CDCl3) δ 195.0, 149.4, 147.8,
131.9, 120.7, 82.1, 77.7, 74.5, 50.2, 48.3, 43.9, 39.3, 37.6, 32.6,
31.2, 27.3, 26.8, 23.4, 11.8; 1H NMR 10b (CDCl3) δ 7.08 (s,
1H), 4.60 (dd, J ) 8.5 Hz, J ) 2.3 Hz, 1H), 3.66 (t, J ) 8.47
Hz, 1H), 2.86 (dd, J ) 14.3 Hz, J ) 8.9 Hz, 2H), 2.2-0.95
(complex, 17H), 0.802 (s, 3H).
4-Br om o-3-oxo-A-h om o-1,4,5(10)-estr a tr ien -17â-ol (11a )
a n d 4-Ch lor o-3-oxo-A-h om o-1,4,5(10)-est r a t r ien -17â-ol
(11b). The title compounds 11a (oil, Rf ) 0.40, 54% yield) and
11b (needles, mp 140-240+ °C dec, Rf ) 0.48, 57% yield) were
prepared from 9a and 9b, respectively, as described in general
procedure B: 1H NMR 11a (CDCl3) δ 7.95 (s, 1H), 7.30 (d, J )
13 Hz, 1H), 7.01 (d, J ) 13 Hz, 1H), 3.74 (t, J ) 8.86 Hz, 1H),
2.85-2.70 (m, 2H), 2.25 (dq, J ) 13 Hz, J ) 3.5 Hz, 1H), 2.19-
2.09 (m, 2H), 1.98 (dt, J ) 12.3 Hz, J ) 3.1 Hz, 1H), 1.9-1.8
(m, 1H), 1.7 (dq, J ) 10 Hz, J ) 2 Hz, 1H), 1.6-1.15 (complex,
8H), 0.794 (s, 3H). Anal. 11a (C19H23BrO2) C, H. 1H NMR
11b (CDCl3) δ 7.64 (s, 1H), 7.34 (d, J ) 13.2 Hz, 1H), 7.04 (d,
J ) 13 Hz, 1H), 3.74 (t, J ) 8.10 Hz, 1H), 2.9-2.7 (m, 2H),
1.6-1.15 (complex, 14H), 0.789 (s, 3H). Anal. 11b (C19H23
ClO2) C, H.
-
4-Met h oxy-3-oxo-A-h om o-1,4,5(10)-est r a t r ien -17â-ol
(11c) a n d 4-Eth oxy-3-oxo-A-h om o-1,4,5(10)-estr a tr ien -
17â-ol (11d ). The title compounds 11c (crystalline needles,
mp 173-175 °C, Rf ) 0.23, 77% yield) and 11d (crystalline
needles, mp 177-179 °C, Rf ) 0.25, 71% yield) were prepared
from 11a as described in general procedure C: 1H NMR 11c
(CDCl3) δ 7.233 (s, 1H), 6.99 (d, J ) 10.8 Hz, 1H), 6.69 (d, J )
10.4 Hz, 1H), 3.91 (s, 3H), 3.73 (t, J ) 8.47 Hz, 1H), 2.83 (m,
1H), 2.61 (m, 1H), 2.3-1.2 (complex, 14H), 0.768 (s, 3H). Anal.
11c (C20H26O3) C, H. 1H NMR 11d (CDCl3) δ 7.223 (s, 1H),
6.92 (d, J ) 10.8 Hz, 1H), 6.69 (d, J ) 10.8 Hz, 1H), 4.12 (q, J
) 6.93 Hz, 2H), 3.73 (t, J ) 8.5 Hz, 1H), 2.9-2.5 (m, 2H), 2.3-
1.2 (complex, 17H), 0.772 (s, 3H). Anal. 11d (C21H28O3) C,
H.
3-Met h oxy-2-oxo-A-h om o-1(10),3,4a -est r a t r ien -17â-ol
(12) a n d 2-Meth oxy-3-oxo-A-h om o-1,4,5(10)-estr a tr ien -
17â-ol (13). Hydroxy dienone 10a (20 mg, 0.05 mmol) was
dissolved in acetone (1 mL), and water (10 mL) was added,
followed by the addition of silver nitrate (42 mg, 0.25 mmol).
Reflux was initiated and held for 5 h. After cooling, the
mixture was concentrated, diluted with 15% acetone in
chloroform, chromatographically filtered, and concentrated to
5 mL. The resultant mixture was treated with TMSCHN2
(0.25 mmol, 2 M in hexane), and after 20 min it was
concentrated. Flash chromatography of the residue eluting
with 30% acetone in chloroform yielded 12 (white solid, mp
145-168 °C dec, Rf ) 0.20, 42%) and 13 (white solid, mp 99-
104 °C dec, Rf ) 0.17, 44%): 1H NMR 12 (CDCl3) δ 7.05 (m,
2H), 6.95 (s, 1H), 3.92 (s, 3H), 3.76 (t, J ) 8.8 Hz, 1H), 2.90-
2.65 (m, 2H), 2.33-2.1 (m, 2H), 2.01 (dt, J ) 12.3 Hz, J ) 3.5
3-Met h oxy-4-oxo-A-h om o-1(10),2,4a -est r a t r ien -17â-ol
(8c). The title compound 8c was prepared from 8a as