2536 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Pettit et al.
was collected and recrystallized from ethanol in a colorless
solid (22.8 g, 92%): mp 275 °C (lit.12c mp 266-268 °C).
4′-(t er t -Bu t yld im e t h ylsilyloxy)-3,5-d im e t h oxyst il-
ben e (14a ,b). Phosphonium bromide 13 (6.9 g) in anhydrous
tetrahydrofuran (40 mL) at -78 °C was treated with n-
butyllithium (2.5 M, 5.6 mL) and aldehyde 5b (3.3 g) in
tetrahydrofuran (10 mL) according to the general Wittig
procedure (see above). Data for (Z)-isomer 14a : EIMS m/z 370
(M+), 355, 313, 298, 157; IR (KBr, cm-1) νmax 2932, 2857, 1591,
1508, 1262, 1155, 914; 1H NMR δ 7.14 (2H, d, J ) 8.5 Hz),
6.70 (2H, d, J ) 8.5 Hz), 6.51 (1H, d, J ) 12.0 Hz), 6.43 (1H,
d, J ) 12.0 Hz), 6.42 (2H, d, J ) 2.0 Hz), 6.31 (1H, t, J ) 2.0
Hz), 3.65 (6H, s, OCH3 × 2), 0.96 (9H, s, C(CH3)3), 0.17 (6H, s,
Si(CH3)2); 13C NMR (75.5 MHz) δ 160.5, 154.9, 139.4, 130.3,
130.2, 128.8, 119.8, 106.6, 99.8, 55.2, 25.7, 18.2, -4.45. Data
for (E)-isomer 14b: EIMS m/z 370 (M+), 355, 313, 255, 165,
73; IR (KBr, cm-1) νmax 2955, 2859, 1595, 1508, 1263, 1154,
914, 839; 1H NMR δ 7.40 (2H, d, J ) 8.5 Hz). 7.05 (1H, d, J )
16.0 Hz), 6.92 (1H, d, J ) 16.0 Hz), 6.85 (2H, d, J ) 8.5 Hz),
6.66 (2H, d, J ) 2.5 Hz), 6.39 (1H, t, J ) 2.5 Hz), 3.84 (6H, s,
OCH3 × 2), 1.01 (9H, s, C(CH3)3), 0.23 (6H, s, Si(CH3)2); 13C
NMR (75.5 MHz) δ 160.9, 155.7, 139.7, 130.5, 128.8, 127.7,
126.7, 120.3, 104.3, 99.6, 55.3, 25.7, 18.2, -4.4.
yielding a colorless oil (0.6 g, 79%): EIMS m/z 266 (M+), 209,
181, 166, 89, 58, IR (KBr, cm-1) νmax 2932, 2859, 1703, 1593,
1468, 1337, 1059, 839; 1H NMR δ 9.86 (1H, s, CHO), 7.00 (1H,
d, J ) 2.0 Hz), 6.92 (1H, d, J ) 2.0 Hz), 6.63 (1H, t, J ) 2.0
Hz), 3.81 (3H, s, OCH3), 0.97 (9H, s, C(CH3)3), 0.21 (6H, Si-
(CH3)2); 13C NMR (75.5 MHz) δ 191.8, 161.2, 157.3, 138.4,
114.5, 113.0, 106.6, 55.5, 25.6, 18.2, -4.5.
3-(t er t -Bu t yld im e t h ylsilyloxy)-4′,5-d im e t h oxyst il-
ben e (14e,f). Reaction of phosphonium bromide 3 (1.71 g) with
aldehyde 9c (1.0 g) led to stilbenes 14e,f (0.75 g, 55% total
yield). Data for (Z)-isomer 14e: EIMS m/z 370 (M+), 313, 298,
156, 89; IR (KBr, cm-1) νmax 2955, 2859, 1588, 1510, 1433, 1252,
1159, 1034, 839, 679; 1H NMR δ 7.21 (2H, d, J ) 9.0 Hz), 6.77
(2H, d, J ) 9.0 Hz), 6.52 (1H, d, J ) 12.0 Hz), 6.45 (1H, s)
6.43 (1H, d, J ) 12.0 Hz), 6.36 (1H, d, J ) 2.1 Hz), 6.27 (1H,
t, J ) 2.1 Hz), 3.78 (3H, s, OCH3), 3.67 (3H, s, OCH3), 0.95
(9H, s, C(CH3)3), 0.11 (6H, s, Si(CH3)2); 13C NMR (75.5 MHz)
δ 160.6, 158.8, 156.7, 139.4, 130.3, 128.8, 127.5, 126.3, 113.6,
110.9, 105.4, 55.2, 25.3, 14.1, -4.5. Anal.: C, 71.36; H, 8.08.
Data for (E)-isomer 14f: EIMS m/z 370 (M+), 313, 298, 156,
89; IR (KBr, cm-1) νmax 2955, 2859, 1588, 1510, 1433, 1252,
1159, 1034, 941, 839; 1H NMR δ 7.45 (2H, d, J ) 8.7 Hz), 7.01
(1H, d, J ) 15.9 Hz), 6.90 (2H, d, J ) 8.7 Hz), 6.87 (1H, d, J
) 15.9 Hz), 6.66 (1H, s), 6.58 (1H, s), 6.31 (1H, t, J ) 2.1 Hz),
3.83 (3H, s, OCH3), 3.81 (3H, s, OCH3), 1.00 (9H, s, C(CH3)3),
0.23 (6H, s, Si(CH3)2); 13C NMR (75.5 MHz) δ 160.8, 159.4,
156.9, 139.6, 130.0, 128.5, 127.8, 126.6, 114.1, 110.9, 104.8,
55.3, 25.7, 14.1, -4.4.
(Z)- a n d (E)-3,5-Dim eth oxy-4′-h yd r oxystilben e (14c,d )
a n d Gen er a l Silyloxy Dep r otection P r oced u r e. To a
solution of the silyloxy-protected (Z)-stilbene 14a (1.2 g) in
anhydrous tetrahydrofuran (20 mL) was added tetrabutylam-
monium fluoride (1 M, 3.4 mL). The pale yellow solution was
stirred for 45 min, poured into water, and extracted with
dichloromethane, from which phase removal of the solvent in
vacuo provided a tan oil. The oil was separated by gravity
column chromatography (4:1 hexane/ethyl acetate) to afford
cis-stilbene 14c as a yellow oil (88%): IR (neat, cm-1) νmax 3385,
3005, 2940, 2837, 1591, 1512, 1456, 1152, 1065, 679; 1H NMR
δ 8.01 (1H, s, OH), 7.15 (2H, d, J ) 8.7 Hz), 6.71 (2H, d, J )
8.7 Hz), 6.51 (1H, d, J ) 12.6 Hz), 6.43 (2H, d, J ) 2.5 Hz),
6.42 (1H, d, J ) 12.6 Hz), 6.31 (2H, d, J ) 2.5 Hz), 3.66 (6H s,
OCH3 × 2).
3-Hyd r oxy-4′,5-d im eth oxystilben e (14g,h ). The preced-
ing stilbene (0.75 g) isomeric mixture was deprotected, and
the products were separated by gravity column chromatogra-
phy (9:1 hexane/ethyl acetate). As usual the cis-stilbene (0.25
g) eluted first followed by the trans isomer (0.26 g, 99% total
yield). Data for (Z)-isomer 14g: EIMS m/z 256 (M+), 225, 181,
152, 115; IR (KBr, cm-1) νmax 3407, 3005, 2938, 2837, 1607,
1
1511, 1456, 1300, 1254, 1154, 1057; H NMR δ 7.20 (2H, d, J
) 9.0 Hz), 6.77 (2H, d, J ) 9.0 Hz), 6.52 (1H, d, J ) 12.0 Hz),
6.42 (1H, s), 6.40 (1H d, J ) 12.0 Hz), 6.33 (1H, d, J ) 2.1
Hz), 6.27 (1H, t, J ) 2.1 Hz), 3.79 (3H, s, OCH3), 3.67 (3H, s,
OCH3). Data for (E)-isomer 14h : EIMS m/z 256 (M+), 225, 181,
152, 115; IR (KBr, cm-1) νmax 3405, 2936, 2837, 1593, 1510,
(E)-3,5-Dim eth oxy-4′-h yd r oxystilben e (14d ) was simi-
larly prepared from stilbene 14b (0.5 g) and tetrabutylammo-
nium fluoride (1M, 1.3 mL) in anhydrous tetrahydrofuran (10
mL), to yield 0.8 g of yellow oil (90%): IR (neat, cm-1) νmax
3385, 3005, 2940, 2837, 1591, 1512, 1456, 1152, 1065, 961; 1H
NMR δ 8.01 (1H, s, OH), 7.44 (2H, d, J ) 8.7 Hz), 7.18 (1H, d,
J ) 16.5 Hz), 6.98 (1H, d, J ) 16.5 Hz), 6.85 (2H, d, J ) 8.7
Hz), 6.73 (2H, d, J ) 2.1 Hz), 6.38 (1H, t, J ) 2.1 Hz), 5.25
(1H, br s, OH), 3.81 (6H, s, OCH3 × 2).
1
1456, 1252, 1150, 1057; H NMR δ 7.44 (2H, d, J ) 8.7 Hz),
7.02 (1H, d, J ) 15.9 Hz), 6.90 (2H, d, J ) 8.7 Hz), 6.86 (1H,
d, J ) 15.9 Hz), 6.63 (1H, t, J ) 2.1 Hz), 6.58 (1H, t, J ) 2.1
Hz), 6.31 (1H, t, J ) 2.1 Hz), 3.83 (3H, s, OCH3) 3.82 (3H, s,
OCH3).
3,5-Di(t er t -Bu t yld im e t h ylsilyloxy)-4′-m e t h oxyst il-
ben e (14i,j). Intermediate 9a and 3 served as starting
materials for preparing stilbenes 14i (1.73 g) and 14j (0.19 g).
Data for (Z)-isomer 14i: EIMS m/z 470 (M+), 455, 413, 147,
73; IR (KBr, cm-1) νmax 2955, 2859, 1582, 1510, 1437, 1331,
1254, 1165, 1031, 678; 1H NMR δ 7.17 (2H, d, J ) 8.1 Hz),
6.75 (2H, d, J ) 8.1 Hz), 6.49 (1H, d, J ) 12.0 Hz), 6.39 (1H,
d, J ) 12.0 Hz), 6.35 (2H, d, J ) 2.4 Hz), 6.19 (1H, t, J ) 2.4
Hz), 3.77 (3H, s, OCH3), 0.93 (18H, s, C(CH3)3 × 2), 0.10 (12H,
s, Si(CH3)2 × 2). Data for (E)-isomer 14j: EIMS m/z 470 (M+),
455, 413, 147, 73; IR (KBr, cm-1) νmax 2955, 2859, 1582, 1510,
1437, 1331, 1254, 1165, 1031, 980; 1H NMR δ 7.44 (2H, d, J )
8.1 Hz), 6.97 (1H, d, J ) 16.2 Hz), 6.89 (2H, d, J ) 8.1 Hz),
6.83 (1H, d, J ) 16.2 Hz), 6.59 (2H, d, J ) 2.1 Hz), 6.24 (1H,
t, J ) 2.1 Hz), 3.83 (3H, s, OCH3), 1.00 (18H, s, C(CH3)3 × 2),
0.22 (12H, s, Si(CH3)3 × 2).
Unless otherwise noted, the following intermediates and
stilbene objectives were prepared by the preceding general
methods for silyloxy protection, Wittig reaction, and depro-
tection.
3-(t er t -Bu t yld im e t h ylsilyloxy)-5-h yd r oxyb e n za ld e -
h yd e (9b). 3,5-Dihydroxybenzaldehyde (1.1 g) in dimethyl-
formamide (10 mL) was monosilylated using DIEA (1.9 mL,
1.4 equiv) and the silyl chloride (1.2 g) with stirring for 3 h.
The oily product was separated by flash column chromatog-
raphy (9:1 hexane/ethyl acetate) to afford some disilylated
product (0.7 g) and the desired monosilylated product as a
colorless oil (0.8 g, 38.5%) that crystallized from ethanol: mp
79.6-80 °C; EIMS m/z 252 (M+), 195, 167, 58, 45; IR (KBr,
1
cm-1) νmax 3211, 2930, 2859, 1672, 1591, 1332, 841; H NMR
δ 9.84 (1H, s, CHO), 6.99 (1H, dd, J ) 2.0, 1.0 Hz), 6.91 (1H,
dd, J ) 2.0, 1.0 Hz), 6.64 (1H, t, J ) 2.0 Hz), 6.00 (1H, br s,
OH), 0.97 (9H, s, C(CH3)3), 0.21 (6H, s, Si(CH3)2); 13C NMR
(75.5 MHz) δ 192.4, 157.6, 157.4, 138.3, 114.4, 114.0, 109.1,
25.6, 18.2, -4.47.
3,5-Dih yd r oxy-4′-m eth oxystilben e (14k ,l). The preceding
silyloxy-protected stilbene isomers 14i,j were deprotected to
yield 0.60 and 0.05 g, respectively. Data for (Z)-isomer 14k :
EIMS m/z 242 (M+), 226, 211, 194, 181, 152, 137; IR (KBr,
cm-1) νmax 3356, 3009, 2971, 2837, 1605, 1510, 1254, 1154,
3-(t er t -Bu t yld im e t h ylsilyloxy)-5-m e t h oxyb e n za ld e -
h yd e (9c). To a solution of phenol 9b (0.7 g) in dichlo-
romethane (10 mL) was added molecular sieves (4 Å, 0.8 g),
proton sponge (1.6 g, 2.5 equiv), and trimethyloxonium tet-
rafluoroborate (1.1 g, 2.5 equiv), and the solution was stirred
for 15 h. The solution was filtered, the sieves were rinsed with
ethyl acetate, and the solvent was removed from the combined
filtrate in vacuo to yield a yellow oil. The oil was purified by
flash column chromatography (10:1 hexane/ethyl acetate),
1
1005, 677; H NMR δ 7.20 (2H, d, J ) 8.7), 6.77 (2H, d, J )
8.7 Hz), 6.50 (1H, d, J ) 12.0 Hz) 6.36 (1H, d, J ) 12.0 Hz),
6.32 (2H, d, J ) 2.1 Hz), 6.22 (1H, t, J ) 2.1 Hz), 4.89 (2H, br
s, OH × 2), 3.77 (3H, s, OCH3). Data for (E)-isomer 14l: EIMS
m/z 242 (M+), 226, 211, 194, 181, 152, 137; IR (KBr, cm-1) νmax
3356, 3009, 2971, 2837, 1605, 1510, 1254, 1154, 1005, 974; 1H
NMR δ 7.43 (2H, d, J ) 8.1 Hz), 7.01, (1H, d, J ) 15.9 Hz),