Choi et al.
JOCArticle
was added to a slurry of palladium(II) chloride (40 mg, 0.23 mmol)
and copper(I) chloride (58 mg, 0.59 mmol) in DMF (3 mL)
and water (1 mL). Oxygen gas was bubbled through the solution
for 2 h. The reaction mixture was filtered through silica, and
the residue was washed with ethyl acetate (100 mL) and hexane
(50 mL). The volatile solvents were removed in vacuo, and
the DMF was removed under high vacuum at 40 °C. The residue
was purified by flash chromatography using dichloromethane/
methanol (50:1) as eluent to give the title compound as an oil
(92 mg, 0.36 mmol, 86%); TLC (dichloromethane/methanol
50:1) Rf = 0.35; [R]19D -9.1 (c 0.44, CH2Cl2); νmax (neat)/cm-1
2929, 2848, 1749, 1601, 1334, 1212, 1200, 1158, 1026, 839, 731,
699; δH (300 MHz; CDCl3) 2.97 (2 H, m, CH2) 3.85 (3 H, s,
OCH3), 3.91 (3 H, s, OCH3), 5.74 (1 H, t, J = 6.0, CH), 6.40
(1 H, d, J = 3.0, 5-H), 6.44 (1 H, d, J = 3.0, 7-H), 9.81 (1 H, t,
J = 3.0, CHO); δC (75 MHz; CDCl3) 48.2 (CH2, C-20), 55.9
(CH3, OCH3), 56.0 (CH3, OCH3), 74.1 (CH, C-1), 97.8 (CH,
C-5), 99.1 (CH, C-7), 106.2 (C, C-3a), 153.8 (C, C-7a), 159.7 (C,
C-4), 167.0 (C, C-6), 167.5 (C, C-3), 198.0 (C, CdO); m/z (EI)
259 (18%, Mþ þ Na), 237 (2), 193 (9), 172 (7), 135 (2); HRMS (EI,
130 (4); HRMS (EI, MHþ) found 267.0858, calcd for C13H15O6
267.0863.
(S)-Methyl 2-(4,6-Dihydroxy-3-oxo-1,3-dihydroisobenzofur-
an-1-yl)acetate (12) and (S)-2-(4,6-Dihydroxy-3-oxo-1,3-dihydro-
isobenzofuran-1-yl)acetic Acid (Herbaric Acid; 1). To a solution
of (S)-methyl-2-(4,6-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-
1-yl)acetate 11 (11 mg, 0.04 mmol) in dichloromethane (3 mL)
was added BBr3 (0.04 mL, 0.41 mmol) at 0 °C. The solution
was stirred at 0 °C for 2 h, then at rt for 72 h. The reaction
mixture was slowly quenched with 1 M HCl (3 ꢀ 5 mL) and
extracted with ethyl acetate (3 ꢀ 10 mL). The organic layer was
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by flash chromatography
using dichloromethane/methanol (5:1) as eluent to give the title
compounds 12 as a colorless solid followed by 1 as a colorless
solid.
Data for (S)-methyl 2-(4,6-dihydroxy-3-oxo-1,3-dihydroiso-
benzofuran-1-yl)acetate (12): (1 mg, 0.005 mmol, 12%); mp =
164-166 °C; TLC (dichloromethane/methanol 5:1) Rf = 0.31;
[R]19D -10.5 (c 0.19, MeOH); νmax (neat)/cm-1 3265, 1720, 1614,
1477, 1440, 1336, 1216, 1163, 1071, 1016, 850, 692, 656; δH (400
MHz; MeOH) 2.75 (1 H, dd, J = 8.0, 16.5, 20-HR), 2.97 (1 H, dd,
J 3.8, 16.4, 20-Hβ), 3.71 (3 H, s, COOCH3), 5.68 (1 H, t, J = 8.0,
CH), 6.29 (1 H, s, 5-H), 6.39 (1 H, s, 7-H); δC (100 MHz; CDCl3)
40.3 (CH2, C-20), 52.5 (CH3, OCH3), 78.0 (CH, C-1), 101.7 (CH,
C-5), 103.8 (CH, C-7), 104.5 (C, C-3a), 154.5 (C, C-7a), 159.8 (C,
C-6), 167.1 (C, C-4), 171.4 (C, C-3), 171.7 (C, CdO); m/z (EI)
239 (100%, MHþ), 225 (10), 207 (2), 179 (7), 165 (35), 149 (4);
HRMS (EI, MHþ) found 239.0544, calcd for C11H11O6 239.0550.
Data for (S)-2-(4,6-dihydroxy-3-oxo-1,3-dihydroisobenzofur-
an-1-yl)acetic acid (Herbaric Acid, 1): (6 mg, 0.027 mmol, 65%);
mp = 190 °C; TLC (dichloromethane/methanol 5:1) Rf = 0.09;
M
þ þ Na) found 259.0581, calcd for C12H12NaO5 259.0577.
(S)-2-(4,6-Dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-
acetic Acid (10). To a solution of (S)-2-(4,6-dimethoxy-3-oxo-
1,3-dihydroisobenzofuran-1-yl)acetaldehyde 2 (100 mg, 0.42 mmol)
in DMF (5 mL) was added Oxone (260 mg, 0.42 mmol), and the
reaction mixture was stirred at rt for 6 h. The reaction mixture
was diluted with 1 M HCl (15 mL) and extracted with ethyl
acetate (3 ꢀ 20 mL). The combined organic layers were dried
over magnesium sulfate and concentrated under reduced pres-
sure. The residue was purified by flash chromatography using
dichloromethane/methanol (10:1) as eluent to give the title com-
pound as a colorless solid (95 mg, 0.38 mmol, 89%); mp =
201 °C; TLC (dichloromethane/methanol 5:1) Rf = 0.32; [R]19
[R]19 -21.7 (c 0.18, MeOH); νmax (neat)/cm-1 3201, 2959,
D
D
-14.3 (c 0.21, EtOH); νmax (neat)/cm-1 3171, 2983, 1738, 1711,
1601, 1330, 1225, 1204, 1164, 1060, 1009, 836, 694; δH (400
MHz; d6-DMSO) 2.57 (1 H, dd, J = 8.4, 16.8, 20-HR), 3.07
(1 H, dd, J = 3.6, 16.8, 20-Hβ), 3.84 (3 H, s, OCH3), 3.85 (3 H, s,
OCH3), 5.61 (1 H, q, J = 4.0, CH), 6.57 (1 H, d, J = 1.6, 5-H),
6.78 (1 H, t, J = 1.2, 7-H); δC (100 MHz; d6-DMSO) 39.5 (CH2,
C-20), 56.3 (CH3, OCH3), 56.5 (CH3, OCH3), 76.2 (CH, C-1),
99.2 (CH, C-5), 99.3 (CH, C-7), 106.1 (C, C-3a), 154.5 (C, C-7a),
159.4 (C, C-4), 166.8 (C, C-6), 167.3 (C, C-3), 171.3 (C, CdO);
m/z (EI) 253 (41%, MHþ), 235 (5), 227 (2), 193 (10); HRMS (EI,
MHþ) found 253.0708, calcd for C12H13O6 253.0707.
1707, 1612, 1474, 1399, 1366, 1336, 1251, 1216, 1160, 1076, 1012,
823, 737, 693; δH (400 MHz; d6-DMSO) 2.65 (1 H, br s, CH2),
2.73 (1 H, br s, CH2), 5.55 (1 H, br s, CH), 6.30 (1 H, br s, 5-H),
6.44 (1 H, br s, 7-H); δC (100 MHz; d6-DMSO) 77.0 (CH, C-1),
101.0 (C, C-3a), 103.0 (CH, C-5), 103.2 (CH, C-7), 154.6 (C,
C-7a), 158.6 (C, C-6), 165.3 (C, C-4), 168.2 (C, C-3), 172.1 (C,
CdO), 1 x CH2 obscured by d6-DMSO; m/z (EI) 225 (86%,
MHþ), 207 (3), 165 (56), 149 (12); HRMS (EI, MHþ) found
225.0400, calcd for C10H9O6 225.0394.
(S)-2-(4,6-Dihydroxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-
acetic Acid (Herbaric Acid; 1). A solution of (S)-methyl-2-(4,6-
dihydroxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)acetate 12 (5 mg,
0.021 mmol) in 2 M NaOH (3 mL) was stirred at rt for 2 h. The
reaction mixture was acidifed to pH = 2-3 with 1 M HCl
(10 mL) and extracted with ethyl acetate (3 ꢀ 10 mL). The
organic layer was dried over magnesium sulfate and concen-
trated under reduced pressure. The residue was purified by flash
chromatography using dichloromethane/methanol (5:1) as eluent
to give the title compound as a colorless solid (4 mg, 0.018 mmol,
85%); spectroscopic data as described previously.
(S)-Methyl 2-(4,6-Dimethoxy-3-oxo-1,3-dihydroisobenzofur-
an-1-yl)acetate (11). To a solution of (S)-2-(4,6-dimethoxy-3-
oxo-1,3-dihydroisobenzofuran-1-yl)acetic acid 10 (200 mg, 0.79
mmol) in methanol (10 mL) was added concentrated H2SO4
(1 mL). The reaction mixture was stirred at rt for 12 h and
concentrated under reduced pressure. The residue was purified
by flash chromatography using dichloromethane/methanol
(20:1) as eluent to give the title compound as a colorless solid
(173 mg, 0.65 mmol, 82%); mp = 145 °C; TLC (dichloromethane/
methanol 10:1) Rf = 0.55; [R]19 -13.0 (c 0.23, EtOH); νmax
D
(neat)/cm-1 2952, 2848, 1736, 1601, 1434, 1336, 1200, 1156, 1054,
1012, 838, 733, 689; δH (400 MHz; CDCl3) 2.83 (2 H, m, CH2)
3.74 (3 H, s, COOCH3) 3.86 (3 H, s, OCH3), 3.93 (3 H, s, OCH3),
5.69 (1 H, t, J = 6.8, CH), 6.42 (1 H, d, J = 2.0, 5-H), 6.46 (1 H, t,
J = 0.8, 7-H); δC (100 MHz; CDCl3) 39.6 (CH2, C-20), 52.1
(CH3, OCH3), 55.9 (CH3, OCH3), 56.0 (CH3, OCH3), 75.5 (CH,
C-1), 97.8 (CH, C-5), 99.1 (CH, C-7), 106.5 (C, C-3a), 153.7
(C, C-7a), 159.7 (C, C-4), 166.9 (C, C-6), 167.6 (C, C-3), 169.8
(C, CdO); m/z (EI) 267 (70%, MHþ), 226 (5), 193 (18), 149 (2),
Acknowledgment. The authors thank the Royal Society of
New Zealand Marsden fund for financial support. Professor
€
Peter Proksch (University of Dusseldorf) is thanked for
helpful discussions.
Supporting Information Available: 1H and 13C NMR spec-
tra and HPLC traces. This material is available free of charge via
7392 J. Org. Chem. Vol. 75, No. 21, 2010