Li et al.
103.2, 72.9 (CH2), 70.9 (CH2); MS [C20H18O3], m/z (M+) calcd
306, found 306.
mmol), PdI2 (72 mg, 0.2 mmol), thiourea (15 mg, 0.2 mmol),
CBr4 (4.56 g, 14 mmol), and Cs2CO3 (4.65 g, 14 mmol), and
the reaction mixture was first degassed with CO and then
stirred at 50 °C for 2 h under a balloon pressure of CO. The
reaction was quenched by addition of a saturated solution of
NH4Cl (20 mL) and extracted with ethyl acetate (3 × 50 mL).
The combined extracts was dried (Na2SO4) and concentrated,
and the residue was purified by flash chromatography on silica
gel (elution with 1:6 EA/PE) to give compound 23 (1.23 g, 87%)
as a white solid. Mp 141-142 °C; Rf 0.7 (2:3 EA/PE); IR v 1709
(CdO); 1H NMR (300 MHz, CDCl3) δ 7.64-7.11 (m, 22 H), 6.20
(s, 2 H), 5.22 (s, 2 H), 5.18 (s, 2 H), 5.02 (s, 4 H), 3.73 (s, 3 H),
3.68 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 164.2, 162.7, 159.0,
155.7, 149.43, 147.8, 146.7, 137.4, 136.9, 136.7, 128.4, 128.3,
128.2, 127.7, 127.7, 127.5, 127.2, 127.1, 126.5, 119.5, 111.9,
107.3, 102.8, 98.2, 92.7, 72.1, 71.5, 70.4, 55.2, 50.9; MS
[C45H38O8], m/z (M+) calcd 706, found 706.
Syn th esis of Com p ou n d 9: To a solution of compound 23
(1.0 g, 1.4 mmol) in distilled ethyl acetate (25 mL) was added
Pd-C (10% on charcoal, 100 mg), and the mixture was stirred
under a balloon pressure of H2 at 25 °C for 24 h. The mixture
was filtered and concentrated to give compound 9 (450 mg,
93%) as a white solid (NMR study indicated the product is
pure). Mp150 °C dec; Rf )0.3 (4:1 CH2Cl2/CH3OH); IR v 1695
(CdO); 1H NMR (300 MHz, acetone-d6) δ 7.44 (s, 1 H), 7.00 (s,
1 H), 6.11 (s, 2 H), 3.76, 3.74 (s, 6 H); 13C NMR (75 MHz,
acetone-d6) δ 163.0, 160.9, 156.5, 153.9, 147.3, 142.6, 141.3,
117.1, 110.2, 104.4, 98.4, 96.0, 91.6, 53.1, 49.1; MS [C17H14O8],
m/z (M+ - 1) calcd 345, found 345.
Syn th esis of w ed elola cton e: To a solution of compound
9 (300 mg, 0.867 mmol) was added AcOH (4.0 mL), followed
by addition of 40% H2SO4 (2.0 mL), and the reaction mixture
was stirred at 50 °C for 1 h. The reaction was quenched with
NH4OAc (2.0 g) at 25 °C, and the mixture was first diluted
with ethyl acetate (25 mL), then filtered through a silica gel
pad and eluted with 20:1 EA/MeOH. The filtrate was concen-
trated, and the residue was purified by flash chromatography
on silica gel (elution with 20:1 EA) to give wedelolactone 8
(253 mg, 93%) as a gray solid. Mp 300 °C dec; Rf 0.35 (4:1
CH2Cl2/CH3OH); IR v 1700 (CdO); 1H NMR (300 MHz,
acetone-d6) δ 7.42 (s, 1 H), 7.22 (s, 1 H), 6.58 (d, J ) 2.1 Hz, 1
H), 6.55 (d, J ) 2.4 Hz, 1 H), 3.89 (s, 3 H); 13C NMR (75 MHz,
acetone-d6) δ 162.3, 158.9, 157.6, 155.2, 154.3, 149.0, 144.6,
143.4, 113.9, 104.1, 101.6, 97.8, 97.6, 96.4, 92.7, 54.7; 1H NMR
(300 MHz, DMSO-d6) δ 7.23 (s, 1 H), 7.15 (s, 1 H), 6.55 (d, J
) 1.8 Hz, 1 H), 6.40 (d, J ) 2.1 Hz, 1 H), 3.77 (s, 3 H); 13C
NMR (75 MHz, DMSO-d6) δ 162.2, 158.9, 157.8, 155.3, 154.8,
148.9, 145.4, 144.3, 113.8, 104.6, 101.7, 98.9, 98.1, 96.7, 93.2,
55.7; MS [C16H10O7] m/z (M+ - 1) calcd 313, found 313.
Syn th esis of com p ou n d 20a : To a solution of phenol 20
(9.0 g, 29 mmol) in dried THF (100 mL) were added Et3N (5.6
g, 55 mmol) and AcCl (4.0 g, 51 mmol), and the mixture was
stirred at 25 °C for 2 h. The reaction was then quenched with
a saturated solution of NaCl (30 mL), and the mixture was
extracted with ethyl acetate (3 × 50 mL). The combined
extracts were dried (Na2SO4) and concentrated, and the
residue was purified by flash chromatography on silica gel
(elution with 1:3 EA/PE) to afford compound 20a (10.0 g (28.7
g, 99%) as a white solid. Mp 96-97 °C; Rf 0.35 (1:4 EA/PE);
IR v 1764 (CdO); 1H NMR (300 MHz, CDCl3) δ 7.42-7.30 (m,
10 H), 6.91 (d, J ) 8.7 Hz, 1 H), 6.72 (d, J ) 2.7 Hz, 1 H), 6.61
(dd, J 1 ) 8.7 Hz, J 2 ) 2.7 Hz, 1 H), 5.13 (s, 4 H), 2.26 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 169.6, 149.5, 146.7, 144.8, 137.1,
136.7, 128.4, 128.4, 127.8, 127.8, 127.3, 115.4, 113.7, 108.7,
71.8 (CH2), 71.2 (CH2), 20.9 (CH3); MS [C22H20O4], m/z (M+)
calcd 348, found 348.
Syn th esis of com p ou n d 12: To a solution of 20a (8.8 g,
25.6 mmol) in CH3CN (120 mL) was added dropwise a solution
of NIS (6.24 g, 28 mmol) and CF3COOH (0.91 g, 8 mmol) in
CH3CN (50 mL) at 40 °C for 2 h. After addition, the mixture
was stirred at 40 °C for an additional 10 h. After removal of
CH3CN, the residue was dissolved in ether (200 mL), washed
sequentially with aqueous NaHSO3 (2 × 10 mL), water (2 ×
10 mL), and brine (10 mL), and dried over Na2SO4. The
extracts were filtered and concentrated and the residue was
purified by flash chromatography on silica gel (elution with
1:9 EA/PE) to give compound 12 (11.4 g, 94%) as a gray solid.
Mp 90-91 °C dec, Rf 0.55 (1:4 EA/PE); IR v 1761 (CdO), 474
(C-I); 1H NMR (300 MHz, CDCl3) δ 7.41-7.30 (m, 10 H), 6.73
(s, 1 H), 5.09 (s, 2 H), 5.08 (s, 2 H), 2.32 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 168.9, 149.8, 147.6, 145.5, 136.5, 136.3, 128.5,
128.0, 127.4, 127.3, 124.2, 109.4, 78.5, 71.9, 71.2, 21.2; MS
[C22H19IO4], m/z (M+) calcd 474, found 474.
Syn th esis of com p ou n d 21: To a N2-degassed solution of
CH3CN (50 mL) and Et3N (3.1 mL) were added compounds 11
(2.6 g, 7.5 mmol), 12 (3.5 g, 7.4 mmol), PdCl2 (PPh3)2 (61.6 mg,
0.088 mmol), and CuI (16.8 mg, 0.088 mmol), and the mixture
was stirred at 25 °C for 12 h. After removal of the solvent, the
residue was filtered, concentrated, and purified by flash
chromatography on silica gel (elution with 1:10 EA/PE) to give
compound 19 (4.58 g, 90%) as a white solid. Mp 131-132 °C
dec; Rf 0.25 (1:3 EA/PE); IR v 2360 (CtC), 1757 (CdO); 1H
NMR (300 MHz, CDCl3) δ 7.55-7.25 (m, 20 H), 7.03 (s, 1 H),
6.70 (s, 1 H), 6.16 (s, 2 H), 5.15 (s, 4 H), 5.11 (s, 2 H), 4.97 (s,
2 H), 3.74 (s, 3 H), 1.96 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
169.5, 161.2, 149.3, 146.5, 145.4, 136.9, 136.8, 136.5, 128.5,
128.4, 127.9, 127.8, 127.4, 127.3, 127.1, 118.0, 110.7, 108.9,
96.2, 92.8, 91.5, 85.9, 71.6, 71.1, 70.6, 55.3, 20.4; MS [C45H38O7],
m/z (M+) calcd 690, found 690.
Syn th esis of com p ou n d 22: To a solution of 19 (2.07 g, 3
mmol) in THF (50 mL) was added hydrazine monohydrate
(1.25 g, 25 mmol), and the mixture was stirred at 25 °C for 2
h. The reaction mixture was first diluted with PE (100 mL),
then filtered through a silica gel pad and eluted with 1:3
EtOAc/PE. The elute was concentrated and the residue was
purified by flash chromatography on silica gel (elution with
1:1 EA/PE) to give compound 22 (1.91 g, 98%) as a white solid.
Mp 149-150 °C; Rf 0.35 (1:1 CH2Cl2/PE); IR v 2360 (CtC),
1313 (C-O); 1H NMR (300 MHz, CDCl3) δ 7.46-7.27 (m, 2
OH), 6.94 (s, 1 H), 6.56 (s, 1 H), 6.35 (s, 1 H), 6.13 (s, 2 H),
5.16 (s, 4 H), 5.0 9 (s, 2 H), 5.01 (s, 2 H), 3.67 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 161.1, 160.2, 152.8, 150.9, 141.9,
137.4, 136.7, 136.4, 128.6, 128.5, 128.4, 127.9, 127.8, 127.7,
127.5, 127.2, 127.1, 117.1, 101.9, 101.3, 95.6, 92.6, 91.2, 89.1,
72.6, 70.7, 70.7, 55.3; MS [C43H36O6], m/z (M+) calcd 648, found
648.
Ack n ow led gm en t. We thank Dr. Maryann Dono-
van for her assistance in editing this manuscript. The
most preliminary investigation was conducted at ICCB,
and we thank Professor Stuart L. Schreiber, Timothy
J . Mitchison, and Rebecca Ward for their encourage-
ment during the course of the research at ICCB. We also
thank Professor J .-Y. Yuan, who initiated this exciting
program and inspire us to pursue this total synthesis.
Financial support from the NIH (Grant 1PO1 CA78048,
Merck & Co.; Grant MCI97MITC804) and the sponsored
research program of VivoQuest, Inc. and NSFC (Grant
Nos. 20142004 and 20242002) are gratefully acknowl-
edged.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for all the new compounds. This material is
Syn th esis of Com p ou n d 23: To a solution of MeOH (40
mL) and THF (20 mL) were added compound 22 (1.3 g, 2
J O030228F
8504 J . Org. Chem., Vol. 68, No. 22, 2003