F. Wang et al. / Bioorg. Med. Chem. 17 (2009) 6380–6389
6387
starting materials and purified on silica gel chromatography using
CHCl3/EtOAc (50:1) as eluent. Yellow solid, yield: 0.63 g (45%); 1H
NMR (CDCl3, 400 MHz) d 11.19 (s, 1H, OH-5), 6.86–7.26 (m, 8H, Ar-
H), 6.06 (s, 1H, H-8), 5.99 (s, 1H, H-6), 4.99 (d, 1H, J = 12.0 Hz, H-2),
4.98 (d, 1H, J = 8.0 Hz, H-11), 4.52 (m, 2H, H-3, 23a), 4.37 (m, 1H, H-
10), 4.26 (m, 1H, H-23b), 3.91 (s, 3H, OCH3), 3.90 (s, 6H, OCH3), 3.83
(s, 3H, OCH3); ESI-MS m/z 675 [MꢀH]+; HRESI-MS m/z: 675.1725
[MꢀH]+ (calcd for C35H31O14: 675.1714).
J = 10.8 Hz, H-2), 4.90 (d, 1H, J = 7.6 Hz, H-11), 4.36 (m, 1H, H-
23a), 4.25 (q, 2H, J = 7.2 Hz, OCH2CH3), 4.22 (m, 2H, H-3, 10), 4.08
(m, 1H, H-23b), 3.76 (s, 3H, OCH3), 3.41 (s, 2H, COCH2CO), 1.28
(t, 3H, J = 7.2 Hz, OCH2CH3); ESI-MS m/z 595 [MꢀH]+; HRESI-MS
m/z: 595.1459 [MꢀH]+ (calcd for C30H27O13: 595.1452).
4.2.1.10. 3-Chlorobenzoic acid, mono[[2,3-dihydro-3-(4-hydr-
oxy-3-methoxyphenyl)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxo-
4H-1-benzopyran-2-yl)-1,4-benzodioxin-2-yl] methyl] ester
(1j). This compound was prepared by the general method with
silybin and 3-chlorobenzoic acid (0.62 g, 4.00 mmol) as starting
materials and purified on silica gel chromatography using CDCl3/
EtOAc (50:1) as eluent. Yield: 0.64 g (50%), yellow solid; 1H NMR
(CDCl3, 400 MHz) d 11.20 (s, 1H, OH-5), 6.87–7.87 (m, 10H, Ar-
H), 6.07 (s, 1H, H-8), 6.00 (s, 1H, H-6), 5.00 (d, 1H, J = 8.0 Hz, H-
11), 4.97 (d, 1H, J = 12.0 Hz, H-2), 4.53 (m, 2H, H-3, 23a), 4.38 (m,
1H, H-10), 4.26 (m, 1H, H-23b), 3.86 (s, 3H, OCH3); ESI-MS m/z
619 [MꢀH]+; HRESI-MS m/z: 619.1015 [MꢀH]+ (calcd for
C32H24ClO11: 619.1007).
4.2.1.6. 3-(4-Methylphenyl)-2-propenoic acid, mono[[2,3-dihy-
dro-3-(4-hydroxy-3-methoxyphenyl)-6-(2,3-dihydro-3,5,7-tri-
hydroxy-4-oxo-4H-1-benzopyran-2-yl)-1,4-benzodioxin-2-yl]
methyl] ester (1f). This compound was prepared by the general
method with silybin and 3-(4-methylphenyl)-2-propenoic acid
(0.65 g, 4.00 mmol) as starting materials and purified on silica gel
chromatography using petroleum ether/EtOAc (2:1) as eluent. Yel-
low solid, yield: 0.43 g (33%); 1H NMR (CDCl3, 400 MHz) d 11.20 (s,
1H, OH-5), 7.64 (d, 1H, J = 16.0 Hz, H-70), 6.87–7.44 (m, 10H, Ar-H),
6.40 (d, 1H, J = 16.0 Hz, H-80), 6.04 (s, 1H, H-8), 5.97 (s, 1H, H-6),
4.98 (d, 1H, J = 11.6 Hz, H-2), 4.93 (d, 1H, J = 8.0 Hz, H-11), 4.52
(dd, 1H, J = 11.6, 4.0 Hz, H-3), 4.38 (m, 1H, H-23a), 4.29 (m, 1H,
H-10), 4.12 (m, 1H, H-23b), 3.87 (s, 3H, OCH3), 2.38 (s, 3H, 40-
CH3); ESI-MS m/z 625 [MꢀH]+; HRESI-MS m/z: 625.1717 [MꢀH]+
(calcd for C35H29O11: 625.1710).
4.2.1.11. 3,4-Dimethoxybenzoic acid, mono[[2,3-dihydro-3-(4-
hydroxy-3-methoxy phenyl)-6-(2,3-dihydro-3,5,7-trihydroxy-4-
oxo-4H-1-benzopyran-2-yl)-1,4-benzodioxin-2-yl] methyl] ester
(1k). This compound was prepared by the general method with
silybin and 3,4-dimethoxybenzoic acid (0.73 g, 4.00 mmol) as
starting materials and purified on silica gel chromatography using
CDCl3/EtOAc (50:1) as eluent. Yield: 0.70 g (52%), yellow solid; 1H
NMR (CDCl3, 400 MHz) d 11.20 (s, 1H, OH-5), 6.86–7.65 (m, 9H,
Ar-H), 6.00 (s, 1H, H-8), 5.98 (s, 1H, H-6), 5.00 (d, 1H, J = 8.0 Hz,
H-11), 4.99 (d, 1H, J = 12.0 Hz, H-2), 4.55 (m, 2H, H-3, 23a), 4.36
(m, 1H, H-10), 4.25 (m, 1H, H-23b), 3.97 (s, 3H, OCH3), 3.93 (s,
3H, OCH3), 3.81 (s, 3H, OMe); ESI-MS m/z 645 [MꢀH]+; HRESI-MS
m/z: 645.1617 [MꢀH]+ (calcd for C34H29O13: 645.1608).
4.2.1.7. 3-(4-Chlorophenyl)-2-propenoic acid, mono[[2,3-dihy-
dro-3-(4-hydroxy-3-methoxyphenyl)-6-(2,3-dihydro-3,5,7-tri-
hydroxy-4-oxo-4H-1-benzopyran-2-yl)-1,4-benzodioxin-2-yl]
methyl] ester (1g). This compound was prepared by the general
method with silybin and 3-(4-chlorophenyl)-2-propenoic acid
(0.73 g, 4.00 mmol) as starting materials and purified on silica gel
chromatography using CHCl3/EtOAc (50:1) as eluent. Yellow solid,
yield: 0.40 g (30%); 1H NMR (CDCl3, 400 MHz) d 11.20 (s, 1H, OH-
5), 7.63 (d, 1H, J = 16.0 Hz, H-70), 6.87–7.20 (m, 10H, Ar-H), 6.42
(d, 1H, J = 16.0 Hz, H-80), 5.96 (s, 1H, H-8), 5.95 (s, 1H, H-6), 4.99
(d, 1H, J = 11.6 Hz, H-2), 4.93 (d, 1H, J = 8.0 Hz, H-11), 4.53 (dd,
1H, J = 11.6, 4.4 Hz, H-3), 4.40 (m, 1H, H-23a), 4.30 (m, 1H, H-10),
4.14 (m, 1H, H-23b), 3.89 (s, 3H, OCH3); ESI-MS m/z 645 [MꢀH]+;
4.2.1.12. 3,4-Methylene-dioxy-benzoic acid, mono[[2,3-dihydro-
3-(4-hydroxy-3-methoxyphenyl)-6-(2,3-dihydro-3,5,7-trihydroxy-
4-oxo-4H-1-benzopyran-2-yl)-1,4-benzodioxin-2-yl] methyl] ester
(1l). This compound was prepared by the general method with silybin
and 1,3-benzodioxole-5-carboxylic acid (0.66 g, 4.00 mmol) as starting
materials and purified on silica gel chromatography using CDCl3/EtOAc
(40:1) as eluent. Yield: 0.59 g (45%), yellow solid; 1H NMR (CDCl3,
400 MHz) d 11.20 (1H, s, OH-5), 6.84–7.67 (9H, m, Ar-H), 6.05 (2H, s,
OCH2O), 6.03 (s, 1H, H-8), 5.98 (s, 1H, H-6), 4.99 (d, 1H, J = 12.0 Hz, H-
2), 4.98 (d, 1H, J = 7.2 Hz, H-11), 4.54 (m, 2H, H-3, 23a), 4.33 (m, 1H,
H-10), 4.24 (m, 1H, H-23b), 3.83 (s, 3H, OCH3); ESI-MS m/z 629
HRESI-MS m/z: 645.1174 [MꢀH]+ (calcd for C34H26ClO11
:
645.1164).
4.2.1.8. 3-(4-Bromophenyl)-2-propenoic acid, mono[[2,3-dihy-
dro-3-(4-hydroxy-3-methoxyphenyl)-6-(2,3-dihydro-3,5,7-tri-
hydroxy-4-oxo-4H-1-benzopyran-2-yl)-1,4-benzodioxin-2-yl]
methyl] ester (1h). This compound was prepared by the general
method with silybin and 3-(4-bromophenyl)-2-propenoic acid
(0.91 g, 4.00 mmol) as starting materials and purified on silica gel
chromatography using CHCl3/EtOAc (50:1) as eluent. Yellow solid,
yield: 0.50 g (35%); 1H NMR (CDCl3, 400 MHz) d 11.20 (s, 1H, OH-
5), 7.59 (d, 1H, J = 16.0 Hz, H-70), 6.87–7.54 (m, 10H, Ar-H), 6.43
(d, 1H, J = 16.0 Hz, H-80), 5.98 (d, 1H, J = 0.8 Hz, H-8), 5.96 (d, 1H,
J = 0.8 Hz, H-6), 4.99 (d, 1H, J = 12.0 Hz, H-2), 4.93 (d, 1H,
J = 8.0 Hz, H-11), 4.54 (dd, 1H, J = 12.0, 4.8 Hz, H-3), 4.40 (m, 1H,
H-23a), 4.29 (m, 1H, H-10), 4.16 (m, 1H, H-23b), 3.87 (s, 3H,
OCH3); ESI-MS m/z 689 [MꢀH]+; HRESI-MS m/z: 689.0667
[MꢀH]+ (calcd for C34H26BrO11: 689.0658).
[MꢀH]+; HRESI-MS m/z: 629.1303 [MꢀH]+ (calcd for C33H25O13
:
629.1295).
4.2.2. General procedure for the synthesis of compounds 1m–n
A solution of 1b or 1d (1 mM) in EtOAc (10 mL) was subjected to
catalytic reduction over 10% Pd–C (2.00 g). After absorption of
hydrogen had ceased, the catalyst was filtered off and the filtrate
was evaporated under reduced pressure to give oil. The oil was
chromatographed on silica gel to afford 1m and 1n, respectively.
4.2.2.1. 4-Aminobenzoic acid, mono[[2,3-dihydro-3-(4-hydroxy-
3-methoxyphenyl)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxo-4H-
1-benzopyran-2-yl)-1,4-benzodioxin-2-yl] methyl] ester
(1m). This compound was prepared by the general method with
1b (0.63 g, 1.00 mmol) as a starting material, and purified on silica
gel chromatography using CHCl3/EtOAc (30:1) as eluent. Yellow so-
lid, yield: 0.51 g (85%); 1H NMR (CDCl3, 400 MHz) d 11.53 (s, 1H,
OH-5), 7.74 (d, 2H, J = 8.4 Hz, H-20, 60), 6.82–7.29 (m, 6H, Ar-H),
6.63 (d, 2H, J = 8.4 Hz, H-30, 50), 5.94 (s, 1H, H-8), 5.92 (s, 1H, H-
6), 5.04 (d, 1H, J = 7.6 Hz, H-11), 5.02 (d, 1H, J = 10.8 Hz, H-2),
4.56 (m, 1H, H-23a), 4.41 (m, 2H, H-3, 10), 4.12 (m, 1H, H-23b),
4.2.1.9. Propanedioic acid, mono[[2,3-dihydro-3-(4-hydroxy-3-
methoxyphenyl)-6-(2,3-dihydro-3,5,7-trihydroxy-4-oxo-4H-1-
benzopyran-2-yl)-1,4-benzodioxin-2-yl] methyl] ethyl ester
(1i). This compound was prepared by the general method with
silybin and propanedioic acid monoethyl ester (0.53 g, 4 mmol)
as starting materials and purified on silica gel chromatography
using CHCl3/EtOAc (50:1) as eluent. Yellow solid, yield: 0.45 g
(36%); 1H NMR (CDCl3, 400 MHz) d 11.19 (s, 1H, OH-5), 6.82–8.25
(m, 6H, Ar-H), 6.07 (s, 1H, H-8), 5.99 (s, 1H, H-6), 4.98 (d, 1H,