8648
S. Shrestha et al. / Bioorg. Med. Chem. 16 (2008) 8643–8652
and concentrated by rotary evaporator to obtain brown oil. Column
chromatographic purification (hexane/EtOAc 4:1, Rf = 0.3) afforded
12d (38 mg): yield (33%), yellow oil, 1H NMR (CDCl3, 200 MHz): d
10.79 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.84
(d, J = 8.4 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 16.4 Hz, 2H),
7.11–7.01 (m, 3H), 6.55 (m, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.85 (s,
3H).
1H), 7.19 (m, 2H), 7.07 (d, J = 8.8 Hz, 1H); 13C NMR (DMSO-d6): d
171.74, 171.68 (CO2H), 161.44, 161.12, 144.55, 133.46, 130.68,
130.45, 129.16, 127.98, 125.63, 117.75, 117.23, 114.29, 113.20,
111.35.
4.1.2.14. 4-[(E)-2-(5-Bromo-3-carboxy-4-hydroxyphenyl)vinyl]-
2-hydroxybenzoic acid (5b).
Yield 343 mg (91%), light yellow
solid, m.p. 297–300 °C (dec); 1H NMR (DMSO-d6, 200 MHz): d
11.33 (br s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H),
7.83 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 16.4 Hz, 1H), 7.31 (d,
J = 15.4 Hz, 1H), 7.19 (s, 2H); 13C NMR (DMSO-d6): d 171.78,
171.51 (CO2H), 161.44, 157.67, 144.32, 135.84, 130.52, 129.45,
129.05, 128.51, 126.82, 117.36, 114.61, 114.47, 111.59, 111.05.
4.1.2.8. Methyl 5-[(E)-2-(3-Methoxycarbonyl-4-methoxyphenyl)-
vinyl]-2-methoxybiphenyl-3-carboxylate (8).
Yield 271 mg
(27%), brown oil, 1H NMR (CDCl3, 200 MHz): d 7.97 (d, J = 2.2 Hz,
1H), 7.88 (d, J = 2.4 Hz, 1H), 7.62–7.57 (m, 4H), 7.48–7.38 (m,
3H), 7.00 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 13 Hz, 2H), 3.97 (s, 3H),
3.93 (s, 3H), 3.92 (s, 3H), 3.49 (s, 3H).
4.1.2.15. 5-[(E)-2-(4-Carboxy-5-hydroxyphenyl)vinyl]-3-(furan-
4.1.2.9. General procedure for the deprotection of hydroxyl and
2-yl)-2-methoxybenzoic acid (5c).
Yield 98%, yellow solid,
carboxyl groups to obtain 4a–c, 5a–c, and 6.
BBr3 (1.0 M in
m.p. 224–226 °C (dec); 1H NMR (DMSO-d6, 200 MHz): d 13.17 (br
s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.87 (d, J =
1.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 16.6 Hz, 1H), 7.34
(s, 1H), 7.23 (s, 1H), 7.17 (d, J = 18 Hz, 1H), 7.05 (d, J = 3.4 Hz,
1H), 6.70 (m, 1H), 3.79 (s, 3H); 13C NMR (DMSO-d6): d 171.79
(CO2H), 167.26, 161.50, 154.53, 148.39, 144.14, 142.95, 132.48,
130.52, 130.15, 127.89, 127.66, 127.60, 126.98, 125.05, 117.45,
114.75, 112.48, 111.93, 110.76, 61.17.
CH2Cl2, 2.1 mmol) was added to a stirred solution of stilbene deriv-
atives (1 mmol) in dry CH2Cl2 (10 ml) under a N2 over a period of
5 min while cooling the reaction mixture at À70 °C. The reaction
mixture was allowed to stir at room temperature for 1–8 h. Then
the reaction mixture was cooled in ice-water bath and quenched
with 1.0 M HCl (4 ml). The precipitate formed was dissolved in
EtOAc (30 mL), and the combined organic layer was washed with
water (20 mL Â 2), brine (20 mL), and dried (Na2SO4). After evapo-
ration of the solvent under reduced pressure, the brownish solid
was dissolved in 95% EtOH (20 mL), and KOH (9.2 mmol) was
added in solid form. The reaction mixture was heated to reflux
for 2 h. The cooled mixture was acidified with 1.0 M HCl (16 mL).
The white precipitate was dissolved in EtOAc (20 mL) and the
aqueous layer was extracted with EtOAc (20 mL). The combined
organics were washed with water (2 Â 15 mL) and brine (15 mL)
successively, dried (Na2SO4), and concentrated to obtain a yellow-
ish white solid.
4.1.2.16. 5-[(E)-2-(3-Carboxy-4-hydroxyphenyl)vinyl]-2-hydrox
ybiphenyl-3-carboxylic acid (6).
Yield 131 mg (35%), brown-
ish yellow solid, m.p. >300 °C (dec); 1H NMR (DMSO-d6, 400 MHz):
d 11.96 (br s, 1H), 11.29 (br s, 1H), 8.01 (d, J = 2 Hz, 1H), 7.99 (d,
J = 2 Hz, 1H), 7.87 (d, J = 2 Hz, 1H), 7.81 (dd, J = 1.6, 8.8 Hz, 1H),
7.62 (d, J = 7.6 Hz, 1H), 7.48–7.36 (m, 4H), 7.26 (d, J = 16.4 Hz,
1H), 7.19 (d, J = 16.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H); 13C NMR
(DMSO-d6): d 172.58, 171.86 (CO2H), 160.49, 158.02, 136.85,
133.56, 132.97, 129.83, 129.29, 128.73, 128.52, 128.38, 128.10,
127.59, 127.35, 126.14, 125.61, 117.59, 113.16, 113.06.
4.1.2.10. 5-[(E)-2-Phenylvinyl]-2-hydroxybenzoic
acid
(4a). Yield 181 mg (72%), yellowish white solid, m.p.
4.1.3. Synthesis of 15a–e
216 °C; 1H NMR (DMSO-d6, 200 MHz): d 8.03 (d, J = 2.2 Hz, 1H),
7.89–7.83 (dd, J = 2.2, 8.4 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.44–
7.28 (m, 3H); 7.25 (d, J = 16.6 Hz, 1H), 7.20 (d, J = 16.6 Hz, 1H),
7.05 (d, J = 8.6 Hz, 1H); 13C NMR (DMSO-d6): d 171.76 (CO2H),
160.64, 137.14, 133.09, 128.64, 128.49, 128.47, 128.35, 127.35,
127.26, 126.86, 126.29, 117.64, 113.11.
4.1.3.1. General procedure for Wittig reaction.
For the gen-
eration of 15a, 15b, and 15d, the reaction conditions were similar
to those of 4a–c, 5a–c, and 6, described above. Diphosphonium
salts were treated with 3 equivalents of lithium diisopropylamine
and then with 2 equivalents of the corresponding aldehydes. To
prepare 15c and 15e, Stille coupling was performed with 15b
(0.11 mmol) and 15d (0.23 mmol), respectively.30,31
4.1.2.11. 5-[(E)-2-Phenylvinyl]-3-bromo-2-hydroxybenzoic acid
(4b).
Yield 238 mg (75%), brownish white solid, m.p. 212–215 °C
4.1.3.2. Methyl
methoxyphenyl)vinyl]phenyl}vinyl)-2-methoxybenzoate
(15a).
Yield 384 mg (35%), yellow solid, m.p. 231–234 °C; 1H
NMR (CDCl3, 200 MHz): d 7.98 (d, J = 2.2 Hz, 2H), 7.64–7.59 (dd,
J = 2.2, 8.8 Hz, 2H), 7.48 (s, 4H), 7.05 (d, J = 17 Hz, 4H), 6.96 (d,
J = 8.8 Hz, 2H), 3.93 (s, 12H).
5-((E)-2-{4-[(E)-2-(3-Methoxycarbonyl-4-
(dec); 1H NMR (DMSO-d6, 200 MHz): d 8.18 (d, J = 2.2 Hz, 1H), 8.02 (d,
J = 1.8 Hz, 1H), 7.61 (m, 2H), 7.41 (d, J = 16.6 Hz, 1H), 7.29 (d,
J = 16.6 Hz, 1H), 7.41 (s, 3H); 13C NMR (DMSO-d6): d 171.52, (CO2H),
156.99, 136.91, 135.53, 129.69, 128.66, 128.13, 127.81, 127.61,
126.41, 125.97, 114.41, 110.89.
4.1.2.12. 5-[(E)-2-Phenylvinyl]-2-hydroxybiphenyl-3-carboxylic
acid (4c).
4.1.3.3. Methyl
5-((E)-2-{4-[(E)-2-(5-Bromo-3-methoxycar-
Yield 243 mg (76%), yellow solid, m.p. 216 °C; 1H
bonyl-4-methoxyphenyl)vinyl]phenyl}vinyl)-3-bromo-2-methoxy-
NMR (acetone-d6, 200 MHz): d 8.12 (d, J = 2.2 Hz, 1H), 7.89 (d,
J = 2.2 Hz, 1H), 7.67–7.59 (m, 4H), 7.49–7.36 (m, 6H), 7.32 (d,
J = 7.8 Hz, 1H), 7.24 (d, J = 8 Hz, 1H); 13C NMR (acetone-d6): d
173.66 (CO2H), 160.38, 139.02, 138.68, 135.56, 131.99, 130.82,
130.29, 130.12, 130.04, 129.44, 129.29, 129.01, 128.81, 128.73,
128.59, 128.00, 127.80, 114.14.
benzoate (15b).
Yield 158 mg (11%), yellow solid, m.p. 171-
172 °C; 1H NMR (CDCl3, 200 MHz): d 7.88 (s, 4H), 7.50 (s, 4H),
7.05 (d, J = 16.2 Hz, 2H), 7.04 (d, J = 16.2 Hz, 2H), 3.96 (s, 6H),
3.95 (s, 6H).
4.1.3.4. Methyl
carbonyl-4-methoxyphenyl)vinyl] phenyl}vinyl)-3-(furan-2-yl)-
2-methoxybenzoate (15c). To a suspension of Pd(PPh3)2Cl2
(5.0 mg, 7.0 mol) in anhydrous 1,4-dioxane (0.2 mL), 15b
5-((E)-2-{4-[(E)-2-(5-(Furan-2-yl)-3-methoxy-
4.1.2.13. 4-[(E)-2-(3-Carboxy-4-hydroxyphenyl)vinyl]-2-hydroxy-
benzoic acid (5a).
Yield 206 mg (68%), yellowish white solid,
l
m.p. >300 °C; 1H NMR (DMSO-d6, 200 MHz): d 11.35 (br s, 2H, OH),
8.07 (d, J = 2.2 Hz, 1H), 7.92–7.86 (dd, J = 2.2, 8.4 Hz, 1H), 7.82 (d,
J = 8.4 Hz, 1H), 7.49–7.41 (d, J = 16.6 Hz, 1H), 7.21 (d, J = 16.6 Hz,
(120 mg, 0.29 mmol) in 1,4 dioxane (2.0 mL) and 2-(tributylstan-
nyl)furan (0.11 mL, 0.34 mmol) was added successively by syringe.
After refluxing overnight, an additional 2-(tributylstannyl)furan