6754 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23
Chan et al.
δ 56.3, 61.6, 67.4, 69.4, 70.2, 70.6, 70.7, 72.4, 94.2, 95.9, 98.6,
107.4, 110.0, 114.8, 123.8, 126.5, 127.5, 127.5, 128.4, 136.3, 159.3,
159.5, 160.7, 161.1, 161.2, 177.3.
mg), and DMF (10 mL) by the general procedure for synthesis of
flavonoid dimers. After flash column chromatography (4% MeOH
in CH2Cl2) on silica gel (15 g), the title compound (160 mg, 54%)
was obtained as a white foam: 1H NMR (CDCl3) δ 3.44 (s, 6H),
3.61-3.69 (m, 20H), 3.82 (t, J ) 4.2 Hz, 4H), 4.12 (t, J ) 4.2 Hz,
4H), 5.17 (s, 4H), 5.18 (s, 4H), 6.44 (d, J ) 1.6 Hz, 2H), 6.51 (s,
2H), 6.69 (d, J ) 1.6 Hz, 2H), 6.94 (d, J ) 8.6 Hz, 4H), 7.25 (t,
J ) 6.8 Hz, 2H), 7.36 (dd, J ) 6.8, 7.0 Hz, 4H), 7.60 (d, J ) 7.0
Hz, 4H), 7.34 (d, J ) 8.6 Hz, 4H); 13C NMR (CDCl3) δ 56.4,
67.5, 69.5, 70.5, 70.5, 70.8, 94.3, 95.9, 98.6, 107.4, 110.1, 114.8,
123.7, 126.6, 127.5, 128.5, 128.7, 136.4, 159.3, 159.5, 160.6, 161.2,
177.3; LRMS (ESI) m/z 1099 (M+ + H, 7), 1121 (M+ + Na, 31);
HRMS (ESI) calcd for C62H66O18Na (M+ + Na) 1121.4147, found
1121.4132.
1,25-Bis[4′-((5-benzyloxy-7-methoxymethoxy)-4H-chromen-
4-on-2-yl)phenyl]-1,4,7,10,13,16,19,22,25-nonaoxapentacosane
(21h). This compound was prepared from 12a (250 mg, 0.62 mmol),
octaethylene glycol dimesylate (200 mg, 0.38 mmol), K2CO3 (420
mg), and DMF (10 mL) by the general procedure for synthesis of
flavonoid dimers. After flash column chromatography (4% MeOH
in CH2Cl2) on silica gel (15 g), the title compound (170 mg, 48%)
was obtained as a white foam: 1H NMR (CDCl3) δ 3.43 (s, 6H),
3.59-3.67 (m, 24 H), 3.80 (t, J ) 4.8 Hz, 4H), 4.10 (t, J ) 4.8
Hz, 4H), 5.15 (s, 4H), 5.16 (s, 4H), 6.43 (d, J ) 2.0 Hz, 2H), 6.50
(s, 2H), 6.68 (d, J ) 2.0 Hz, 2H), 6.92 (d, J ) 9.2 Hz, 4H), 7.25
(t, J ) 7.6 Hz, 2H), 7.34 (dd, J ) 7.6, 7.2 Hz, 4H), 7.59 (d, J )
7.2 Hz, 4H), 7.72 (d, J ) 9.2 Hz, 4H); 13C NMR (CDCl3) δ 56.4,
67.5, 69.4, 70.5, 70.5, 70.8, 94.3, 95.9, 98.6, 107.4, 110.1, 114.8,
123.7, 126.5, 127.5, 128.5, 136.4, 159.3, 159.5, 160.6, 161.2, 161.2,
177.2; LRMS (ESI) m/z 1144 (M+ + H, 3), 1166 (M+ + Na, 21);
HRMS (ESI) calcd for C64H70O19Na (M+ + Na) 1165.4409, found
1165.4424.
1,13-Bis[4′-((5-benzyloxy-7-methoxymethoxy)-4H-chromen-
4-on-2-yl)phenyl]-1,4,7,10,13-pentaoxatridecane (21d) and 12-
[4′-((5-Benzyloxy-7-methoxymethoxy)-4H-chromen-4-on-2-yl)-
phenyl]-3,6,9,12-tetraoxadodecan-1-ol (23b). These compounds
were prepared from 12a (1.33 g, 3.3 mmol), tetraethylene glycol
dimesylate (0.72 g, 2.1 mmol), K2CO3 (2.27 g), and DMF (30 mL)
by the general procedure for synthesis of flavonoid dimers. After
flash column chromatography (2% MeOH in CH2Cl2) on silica gel
(40 g), the titled compound 21d (0.93 g, 58%) was obtained as a
white foam: 1H NMR (CDCl3) δ 3.44 (s, 6H), 3.67 (t, J ) 1.6 Hz,
4H), 3.69 (t, J ) 1.6 Hz, 4H), 3.83 (t, J ) 4.4 Hz, 4H), 4.09 (t, J
) 4.0 Hz, 4H), 5.15 (s, 8H), 6.42 (d, J ) 1.8 Hz, 2H), 6.49 (s,
2H), 6.67 (d, J ) 1.8 Hz, 2H), 6.92 (d, J ) 8.8 Hz, 4H), 7.25 (t,
J ) 7.2 Hz, 2H), 7.36 (dd, J ) 7.2, 7.6 Hz, 4H), 7.60 (d, J ) 7.6
Hz, 4H), 7.71 (d, J ) 8.8 Hz, 4H); 13C NMR (CDCl3) δ 56.4,
67.5, 69.5, 70.6, 70.6, 70.8, 94.3, 95.9, 98.6, 107.4, 110.0, 114.8,
123.7, 126.6, 127.5, 127.5, 128.5, 136.5, 159.3, 159.5, 160.6, 161.2,
177.2; LRMS (ESI) m/z 967 (M+ + H, 18), 989 (M+ + H, 100);
HRMS (ESI) calcd for C56H55O15 (M+ + H) 967.3541, found
967.3568. The title compound 23b (0.27 g, 14%) was obtained as
a pale yellow oil: 1H NMR (CDCl3) δ 3.00 (br s, 1H), 3.44 (s,
3H), 3.56 (t, J ) 4.2 Hz, 2H), 3.62-3.69 (m, 10H), 3.82 (t, J )
4.5 Hz, 2H), 4.13 (t, J ) 4.5 Hz, 2H), 5.17 (s, 2H), 5.18 (s, 2H),
6.44 (d, J ) 1.8 Hz, 1H), 6.53 (s, 1H), 6.70 (d, J ) 1.8 Hz, 1H),
6.94 (d, J ) 8.8 Hz, 2H), 7.25 (t, J ) 7.4 Hz, 1H), 7.35 (dd, J )
7.4, 7.6 Hz, 2H), 7.59 (d, J ) 7.6 Hz, 2H), 7.74 (d, J ) 8.8 Hz,
2H); 13C NMR (CDCl3) δ 56.2, 61.4, 67.3, 69.3, 70.0, 70.3, 70.4,
70.4, 70.6, 72.4, 94.1, 95.8, 98.5, 107.2, 109.9, 114.7, 123.6, 126.4,
127.4, 128.3, 136.2, 159.2, 159.3, 160.6, 161.0, 161.1, 177.2.
1,16-Bis[4′-((5-benzyloxy-7-methoxymethoxy)-4H-chromen-
4-on-2-yl)phenyl]-1,4,7,10,13,16-hexaoxahexadecane (21e). This
compound was prepared from 12a (300 mg, 0.74 mmol), penta-
ethylene glycol dimesylate (170 mg, 0.43 mmol), K2CO3 (480 mg),
and DMF (10 mL) by the general procedure for synthesis of
flavonoid dimers. After flash column chromatography (2% MeOH
in CH2Cl2) on silica gel (15 g), the title compound (160 mg, 43%)
was obtained as a white foam: 1H NMR (CDCl3) δ 3.44 (s, 6H),
3.63-3.68 (m, 12H), 3.81 (t, J ) 4.2 Hz, 4H), 4.09 (t, J ) 4.2 Hz,
4H), 5.15 (s, 8H), 6.42 (d, J ) 1.6 Hz, 2H), 6.49 (s, 2H), 6.67 (d,
J ) 1.6 Hz, 2H), 6.93 (d, J ) 8.6 Hz, 4H), 7.26 (t, J ) 6.8 Hz,
2H), 7.36 (dd, J ) 6.8, 7.4 Hz, 4H), 7.59 (d, J ) 7.4 Hz, 4H), 7.71
(d, J ) 8.6 Hz, 4H); 13C NMR (CDCl3) δ 56.4, 67.5, 69.5, 70.5,
70.8, 94.3, 95.9, 98.6, 107.4, 110.0, 114.8, 123.7, 126.6, 127.5,
127.5, 128.5, 128.6, 136.4, 159.3, 159.5, 160.6, 161.2, 177.3; LRMS
(ESI) m/z 1011 (M+ + H, 4), 1033 (M+ + Na, 26); HRMS (ESI)
calcd for C58H59O16 (M+ + H) 1011.3803, found 1011.3793.
1,19-Bis[4′-((5-benzyloxy-7-methoxymethoxy)-4H-chromen-
4-on-2-yl)phenyl]-1,4,7,10,13,16,19-heptaoxanonadecane (21f).
This compound was prepared from 12a (230 mg, 0.57 mmol),
hexaethylene glycol dimesylate (160 mg, 0.37 mmol), K2CO3 (400
mg), and DMF (10 mL) by the general procedure for synthesis of
flavonoid dimers. After flash column chromatography (2% MeOH
in CH2Cl2) on silica gel (15 g), the title compound (160 mg, 53%)
was obtained as a white foam: 1H NMR (CDCl3) δ 3.47 (s, 6H),
3.64-3.71 (m, 16H), 3.85 (t, J ) 4.4 Hz, 4H), 4.15 (t, J ) 4.4 Hz,
4H), 5.19 (s, 4H), 5.21 (s, 4H), 6.47 (d, J ) 2.0 Hz, 2H), 6.54 (s,
2H), 6.72 (d, J ) 2.0 Hz, 2H), 6.97 (d, J ) 8.8 Hz, 4H), 7.27 (t,
J ) 7.2 Hz, 2H), 7.38 (dd, J ) 7.2, 7.6 Hz, 4H), 7.61 (d, J ) 7.6
Hz, 4H), 7.76 (d, J ) 8.8 Hz, 4H); 13C NMR (CDCl3) δ 56.4,
67.5, 69.5, 70.5, 70.6, 70.6, 70.8, 94.3, 95.9, 98.7, 107.5, 110.1,
114.9, 123.8, 126.6, 127.5, 128.5, 136.4, 159.4, 159.5, 160.6, 161.2,
177.3; LRMS (ESI) m/z 1055 (M+ + H, 11), 1077 (M+ + Na,
47); HRMS (ESI) calcd for C60H62O17Na (M+ + Na) 1077.3885,
found 1077.3883.
1,28-Bis[4′-((5-benzyloxy-7-methoxymethoxy)-4H-chromen-
4-on-2-yl)phenyl]-1,4,7,10,13,16,19,22,25,28-decaoxaocta-
cosane (21i). This compound was prepared from 12a (240 mg, 0.59
mmol), nonaethylene glycol dimesylate (210 mg, 0.37 mmol), K2-
CO3 (410 mg), and DMF (10 mL) by the general procedure for
synthesis of flavonoid dimers. After flash column chromatography
(4% MeOH in CH2Cl2) on silica gel (15 g), the title compound
(180 mg, 51%) was obtained as a white foam: 1H NMR (CDCl3)
δ 3.42 (s, 6H), 3.58-3.66 (m, 28H), 3.80 (t, J ) 4.6 Hz, 4H), 4.10
(t, J ) 4.6 Hz, 4H), 5.14 (s, 4H), 5.15 (s, 4H), 6.42 (d, J ) 2.0 Hz,
2H), 6.48 (s, 2H), 6.67 (d, J ) 2.0 Hz, 2H), 6.91 (d, J ) 8.8 Hz,
4H), 7.23 (t, J ) 7.6 Hz, 2H), 7.33 (t, J ) 7.6 Hz, 4H), 7.59 (d, J
) 7.6 Hz, 4H), 7.71 (d, J ) 8.8 Hz, 4H); 13C NMR (CDCl3) δ
56.3, 67.5, 69.4, 70.5, 70.5, 70.8, 94.2, 95.9, 98.6, 107.4, 110.1,
114.8, 123.7, 126.5, 127.5, 128.5, 136.4, 159.3, 159.5, 160.6, 161.2,
161.2, 177.2; LRMS (ESI) m/z 1188 (M+ + H, 3), 1210 (M+
+
Na, 23); HRMS (ESI) calcd for C66H75O20 (M+ + H) 1187.4852,
found 1187.4825.
General Procedure for Hydrogenolysis of Compounds 21a-i
and 23a,b. A round-bottom flask was charged with compound 21
or 23, a catalytic amount of 10% Pd on activated charcoal, and
chloroform. The reaction mixture was stirred vigorously under
hydrogen atmosphere at balloon pressure and room temperature
for 12 h. When TLC indicated complete consumption of the starting
material, the charcoal was removed by suction filtration. The pale
yellow filtrate was purified by passage through a short pad of silica
gel to furnish the deprotected products.
1,4-Bis[4′-((5-hydroxy-7-methoxymethoxy)-4H-chromen-4-on-
2-yl)phenyl]-1,4-dioxabutane (22a). This compound was prepared
from 21a (64 mg, 0.08 mmol), 10% Pd on charcoal (15 mg), and
chloroform (10 mL) by the general procedure for hydrogenolysis
described above. The title compound (43 mg, 86%) was obtained
1
as a white solid: mp 206-207 °C; H NMR (CDCl3) δ 3.51 (s,
6H), 4.44 (s, 4H), 5.24 (s, 4H), 6.47 (d, J ) 2.0 Hz, 2H), 6.59 (s,
2H), 6.66 (d, J ) 2.0 Hz, 2H), 7.07 (d, J ) 8.8 Hz, 4H), 7.86 (d,
J ) 8.8 Hz, 4H), 12.73 (s, 2H); 13C NMR (CDCl3) δ 56.4, 66.5,
94.2, 94.3, 100.1, 104.5, 106.2, 115.1, 124.0, 128.1, 157.5, 161.5,
162.0, 162.9, 163.9, 182.5; LRMS (ESI) m/z 655 (M+ + H, 14),
1,22-Bis[4′-((5-benzyloxy-7-methoxymethoxy)-4H-chromen-
4-on-2-yl)phenyl]-1,4,7,10,13,16,19,22-octaoxadocosane (21g),
This compound was prepared from 12a (220 mg, 0.54 mmol),
heptaethylene glycol dimesylate (160 mg, 0.33 mmol), K2CO3 (370