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436 J ournal of Natural Products, 2002, Vol. 65, No. 4
Verotta et al.
added an excess of 3,5-dinitrobenzoyl chloride (3.87 g, 16.8
mmol, 15 molar equiv). After stirring 30 min at room temper-
ature, the reaction was worked up by dilution with water and
extraction with EtOAc (3 × 10 mL), and the organic phase
was washed sequentially with 2 N HCl, saturated NaHCO3,
and brine. After drying and removal of the solvent, the residue
was purified by column chromatography (petrol/EtOAc, 9:1)
and then by recrystallization from hexane, affording 365 mg
of 2b (45%). The mother liquors were further purified by
column chromatography (hexane/ether, 9:1) to afford an ad-
ditional 102 mg of 2b (overall yield 58%). The acetyl- and
trimethoxycinnamoyl derivatives (2a , 2c) were prepared in a
similar way, in overall yields of 65% and 81%, respectively.
H-17), 1.68 (3H, s, H-19), 1.63 (3H, s, H-20), 2.19 (1H, m, H-21),
1.82 (1H, m, H-21′), 5.11 (1H, m, H-22), 1.75 (3H, s, H-24),
1.63 (3H, s, H-25), 3.14 (1H, dd, J ) 14.9, 7.1 Hz, H-26), 2.92
(1H, dd, J ) 14.1, 7.0 Hz, H-26′), 5.09 (1H, m, H-27), 1.59 (3H,
s, H-29), 1.57 (3H, s, H-30), 2.61 (1H, dd, J ) 15.3, 6.5 Hz,
H-31), 2.34 (1H, dd, J ) 15.3, 6.0 Hz, H-31′), 5.09 (1H, m,
H-32), 1.57 (3H, s, H-34), 1.59 (3H, s, H-35), 7.36 (2H, s, Ar),
3.95 (6H, s, OCH3), 3.98 (3H, s, OCH3); 13C NMR (125 MHz,
CDCl3) δ 206.5 (s, C-1), 84.7 (s, C-2), 50.2 (s, C-3), 42.2 (d, C-4),
38.5 (t, C-5), 57.7 (s, C-6), 162.3 (s, C-7), 134.7 (s, C-8), 193.7
(s, C-9), 208.6 (s, C-10), 43.2 (d, C-11), 20.6 (q, C-12), 21.4 (q,
C-13), 13.9 (q, C-14), 36.7 (t, C-15), 25.2 (t, C-16), 125.0 (d,
C-17), 131.6 (s, C-18), 25.9 (q, C-19), 17.9 (q, C-20), 27.3 (t,
C-21), 123.1 (d, C-22), 133.0 (s, C-23), 26.0 (q, C-24), 17.9 (q,
C-25), 24.2 (t, C-26), 120.2 (d, C-27), 133.9 (s, C-28), 25.8 (q,
C-29), 18.2 (q, C-30), 30.5 (t, C-31), 119.7 (d, C-32), 134.1 (s,
C-33), 25.8 (q, C-34), 18.4 (q, C-35); CIMS, m/z 731 [M]+ + 1.
Meth yla tion of Hyp er for in (1) w ith Dia zom eth a n e. To
a solution of hyperforin (1) (300 mg; 0.560 mmol) in ether (2
mL) was added dropwise ethereal CH2N2, until evolution of
nitrogen ceased. Silica gel was then added to quench the excess
diazomethane, and the solution was filtered and evaporated
to give 291 mg of 3 (94%) as a colorless gum.
Hyp er for in a ceta te (2a ): colorless oil; [R]25 +54° (c 0.9,
D
CH2Cl2); IR (KBr) νmax 1741, 1640, 1597, 1430, 1381, 1246,
1081, 844 cm-1 1H NMR (500 MHz, CDCl3) δ 1.78 (1H, m,
;
H-4), 1.97 (1H, brdd, J ) 13, 4 Hz, H-5), 1.36 (1H, dd, J ) 13,
13 Hz, H-5′), 1.94 (1H, qq, J ) 6.5, 6.5 Hz, H-11), 1.08 (3H, d,
J ) 6.5 Hz, H-12), 0.97 (3H, d, J ) 6.5 Hz, H-13), 0.98 (3H, s,
H-14), 1.86 (1H, m, H-15), 1.39 (1H, m, H-15′), 2.07 (1H, m,
H-16), 1.86 (1H, m, H-16′), 5.02 (1H, m, H-17), 1.63 (3H, brs,
H-19), 1.57 (3H, brs, H-20), 2.09 (1H, brd, J ) 15 Hz, H-21),
1.75 (1H, m, H-21′), 4.98 (1H, m, H-22), 1.67 (3H, brs, H-24),
1.52 (3H, s, H-25), 3.02 (1H, brdd, J ) 15, 6.5 Hz, H-26), 2.83
(1H, dd, J ) 15, 6.5 Hz, H-26′), 4.98 (1H, brdd, J ) 6.5, 6.5
Hz, H-27), 1.63 (3H, brs, H-29), 1.63 (3H, brs, H-30), 2.47 (1H,
brdd, J ) 15.5, 5 Hz, H-31), 2.31 (1H, brdd, J ) 15.5, 6.0 Hz,
H-31′), 5.02 (1H, m, H-32), 1.67 (3H, s, H-34), 1.65 (3H, brs,
H-35), 2.21 (3H, s, CH3CO); 13C NMR (125 MHz, CDCl3) δ
206.2 (s, C-1), 84.3 (s, C-2), 49.8 (s, C-3), 42.2 (d, C-4), 38.0 (t,
C-5), 57.0 (s, C-6), 162.7 (s, C-7), 133.7 (s, C-8), 193.4 (s, C-9),
208.4 (s, C-10), 42.8 (d, C-11), 20.3 (q, C-12), 21.1 (q, C-13),
13.8 (q, C-14), 36.4 (t, C-15), 24.9 (t, C-16), 124.7 (d, C-17),
131.0 (s, C-18), 25.7 (q, C-19), 17.6 (q, C-20), 27.0 (t, C-21),
122.4 (d, C-22), 133.8 (s, C-23), 25.8 (q, C-24), 17.9 (q, C-25),
23.9 (t, C-26), 119.8 (d, C-27), 134.0 (s, C-28), 25.6 (q, C-29),
17.7 (q, C-30), 30.0 (t, C-31), 119.1 (d, C-32), 133.9 (s, C-33),
25.6 (q, C-34), 18.1 (q, C-35); HREIMS m/z 578.8211 [M]+ (8)
(calcd for C37H54O5, 578.8217).
O-Meth ylh yp er for in (3): 1H NMR (500 MHz, CDCl3) δ
1.10 (3H, d, J ) 6.5 Hz H-12), 1.01 (3H, d, J ) 6.5 Hz, H-13),
0.98 (3H, s, H-14), 1.85 (1H, m, H-15), 1.39 (1H, m, H-15′),
2.07 (1H, m, H-16), 1.87 (1H, m, H-16′), 5.03 (1H, t, J ) 7.0
H-17), 1.67 (3H, s, H-19), 1.63 (3H, s, H-20), 2.10 (1H, m, H-21),
1.73 (1H, m, H-21′), 4.94 (1H, t, J ) 7.1 Hz, H-22), 1.67 (3H,
s, H-24), 1.63 (3H, s, H-25), 3.17 (1H, d, J ) 6.5 Hz, H-26),
5.05 (1H, t, J ) 7.0, Hz H-27), 1.58 (3H, s, H-29), 1.67 (3H, s,
H-30), 2.49 (1H, dd, J ) 15.0, 6.0 Hz, H-31), 2.40 (1H, dd, J )
15.0, 7.5 Hz, H-31′), 4.99 (1H, t, J ) 7.0 Hz, 32), 1.67 (3H, s,
H-34), 1.55 (3H, s, H-35), 3.91 (3H, s, OCH3); 13C NMR (125
MHz, CDCl3) δ 207.1 (s, C-1), 84.1 (s, C-2), 49.2 (s, C-3), 43.2
(d, C-4), 38.8 (t, C-5), 58.6 (s, C-6), 173.9 (s, C-7), 133.3 (s, C-8),
193.9 (s, C-9), 209.1 (s, C-10), 42.6 (d, C-11), 20.4 (q, C-12),
21.3 (q, C-13), 13.6 (q, C-14), 36.5 (t, C-15), 24.9 (t, C-16), 124.7
(d, C-17), 131.0 (s, C-18), 25.9 (q, C-19), 17.9 (q, C-20), 27.1 (t,
C-21), 122.5 (d, C-22), 132.9 (s, C-23), 25.8 (q, C-24), 17.6 (q,
C-25), 23.4 (t, C-26), 121.7 (d, C-27), 127.4 (s, C-28), 25.7 (q,
C-29), 18.0 (q, C-30), 30.1 (t, C-31), 119.7 (d, C-32), 133.8 (s,
C-33), 25.6 (q, C-34), 17.9 (q, C-35); HREIMS m/z 550.8119
[M]+ (6) (calcd for C36H54O4, 550.8116).
Mitsu n obu Eth er ifica tion of Hyp er for in (1). To a cooled
(0 °C) solution of methanol (80 mg, 2.5 mmol, 2.5 molar equiv)
and hyperforin (1) (551 mg, 1 mmol) in THF (8 mL) were added
triphenylphosphine (655 mg, 2.5 mmol, 2.5 molar equiv) and
DEAD (393 µL, 435 mg, 2.5 equiv, 2.5 molar equiv). The
reaction was stirred for 2 h, then left to warm to room
temperature over 5 h, and eventually worked up by evapora-
tion. The residue was purified by column chromatography
(petrol; petrol/diethyl ether, 99:1; and petrol/EtOAc, 95:5) to
afford 3 (97 mg, 18%) as a colorless oil.
Hyp er for in 3,5-d in itr oben zoa te (2b): colorless leaflets;
mp 108-110 °C; [R]25D +59° (c 0.3, CH2Cl2); IR (KBr) νmax 1751,
1736, 1721, 1661, 1551, 1461, 1341, 1250, 1136, 1076 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.96 (1H, m, H-4), 2.17 (1H, brdd,
J ) 13, 4 Hz, H-5), 1.49 (1H, dd, J ) 13, 13 Hz, H-5′), 2.05
(1H, qq, J ) 6.5, 6.5 Hz, H-11), 1.14 (3H, d, J ) 6.5, Hz H-12),
1.04 (3H, d, J ) 6.5 Hz, H-13), 1.08 (3H, s, H-14), 1.93 (1H,
m, H-15), 1.55 (1H, m, H-15′), 2.16 (1H, m, H-16), 1.63 (1H,
m, H-16′), 5.08 (1H, m, H-17), 1.68 (3H, brs, H-19), 1.63 (3H,
brs, H-20), 2.22 (1H, brd, J ) 15 Hz, H-21), 1.81 (1H, m, H-21′),
5.13 (1H, m, H-22), 1.77 (3H, brs, H-24), 1.60 (3H, s, H-25),
3.17 (1H, brdd, J ) 15, 6.5 Hz, H-26), 2.95 (1H, dd, J ) 15,
6.5 Hz, H-26′), 5.01 (1H, brdd, J ) 6.5, 6.5 Hz H-27), 1.54 (3H,
brs, H-29), 1.51 (3H, brs, H-30), 2.65 (1H, brdd, J ) 15.5, 5
Hz, H-31), 2.30 (1H, brdd, J ) 15.5, 6.0 Hz, H-31′), 5.08 (1H,
m, H-32), 1.67 (3H, s, H-34), 1.52 (3H, brs, H-35), 9.28 (1H, t,
J ) 2 Hz, OR), 9.11 (2H, d, J ) 2 Hz, OR); 13C NMR (125
MHz, CDCl3) δ 205.1 (s, C-1), 80.6 (s, C-2), 50.8 (s, C-3), 42.6
(d, C-4), 38.8 (t, C-5), 57.4 (s, C-6), 162.3 (s, C-7), 134.3 (s, C-8),
193.1 (s, C-9), 207.4 (s, C-10), 43.1 (d, C-11), 20.3 (q, C-12),
21.0 (q, C-13), 13.8 (q, C-14), 36.8 (t, C-15), 25.0 (t, C-16), 124.8
(d, C-17), 131.2 (s, C-18), 25.6 (q, C-19), 17.6 (q, C-20), 27.3 (t,
C-21), 122.5 (d, C-22), 133.2 (s, C-23), 25.7 (q, C-24), 17.9 (q,
C-25), 24.1 (t, C-26), 119.7 (d, C-27), 134.8 (s, C-28), 25.4 (q,
C-29), 17.7 (q, C-30), 30.5 (t, C-31), 119.2 (d, C-32), 134.4 (s,
C-33), 25.5 (q, C-34), 18.0 (q, C-35), 159.1 (s, OR), 132.3 (s,
OR), 129.6 (d, OR), 149.3 (s, OR), 123.2 (d, OR); HREIMS m/z
730.8872 [M]+ (2) (calcd for C42H54N2O9, 730.8862).
Meth yla tion of Hyp er for in (1) w ith Na H-DMSO/MeI.
To a solution of hyperforin (1) (1.2 g, 2.2 mmol) in dry DMSO
(12 mL) were added NaH (352 mg of a 60% dispersion in
mineral oil, 8.8 mmol, 4 molar equiv) and MeI (0.55 mL, 1.25
g, 8.8 mmol; 4 molar equiv). After stirring 4 h at room
temperature, the reaction was worked up by removal under
vacuum of the excess MeI, dilution with aqueous NH4Cl, and
extraction with petroleum ether/ether, 3:1 (3 × 30 mL). The
organic phase was washed with brine, dried, and evaporated.
A yellowish residue was obtained, then purified by column
chromatography (petrol/EtOAc, 99:1, and next petrol/EtOAc,
95:5, as eluant) to give 892 mg of 4 (72%).
C-Meth ylh yp er for in (4): colorless oil, [R]25 +21° (c 0,64,
D
Hyp er for in tr im eth oxyben zoa te (2c): white powder; mp
CH2Cl2); IR (KBr) νmax 2972, 2876, 1728, 1705, 1449, 1377,
1246, 1086, 735 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.55 (1H,
m, H-4), 2.19 (1H, m, H-5), 1.62 (1H, m, H-5′), 2.21 (1H, qq, J
) 6.5 Hz, H-11), 1.17 (3H, d, J ) 6.5 Hz, H-12), 1.00 (3H, d, J
) 6.5 Hz, H-13), 1.00 (3H, s, H-14), 1.98 (1H, m, H-15), 2.14
(1H, m, H-16), 1.87 (1H, m, H-16′), 5.01 (1H, t, J ) 7 Hz, H-17),
1.69 (3H, s, H-19), 1.62 (3H, s, H-20), 2.02 (1H, m, H-21), 1.65
(1H, m, H-21′), 4.79 (1H, brt, J ) 7 Hz, H-22), 1.65 (3H, s,
82 °C; [R]20 +36° (c 0.5, CHCl3); IR (KBr) νmax 3424, 1736,
D
1721, 1655, 1636, 1595, 1505, 1464, 1418, 1331, 1233, 1132
cm-1 1H NMR (500 MHz, CDCl3) δ 1.95 (1H, m, H-4), 2.12
;
(1H, dd, J ) 13.5, 3.7 Hz, H-5), 1.43 (1H, m, H-5′), 2.02 (1H,
m, H-11), 1.15 (3H, d, J ) 6.6 Hz, H-12), 1.04 (3H, d, J ) 6.6
Hz, H-13), 1.06 (3H, s, H-14), 1.93 (1H, m, H-15), 1.49 (1H, m,
H-15′), 2.15 (1H, m, H-16), 1.93 (1H, m, H-16′), 5.09 (1H, m,