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MHz, CDCl3): d = 6.75 (1 H, d, J = 8.4 Hz), 6.69 (1 H, d, J = 8.4
Hz), 6.66 (1 H, d, J = 11.7 Hz), 6.61 (1 H, d, J = 11.7 Hz), 6.32 (1
H, s), 6.19 (1 H, ddt, J = 17.1, 10.3, 6.0 Hz), 5.42 (1 H, dq, J = 17.1,
0.5 Hz), 5.25 (1 H, dd, J = 10.3, 1.5 Hz), 4.53 (2 H, d, J = 6.0 Hz),
3.90 (3 H, s), 3.85 (3 H, s), 3.81 (3 H, s), 3.40 (3 H, s). 13C NMR (75
MHz, CDCl3): d = 152.1 (C), 151.4 (C), 150.9 (C), 147.8 (C), 142.3
(C), 134.8 (CH), 134.6 (C), 134.0 (CH), 132.5 (C), 129.8 (CH),
126.1 (CH), 118.3 (CH2), 112.5 (CH), 110.7 (C), 109.8 (CH), 98.9
(C), 74.0 (CH2), 61.3 (CH3), 61.1 (CH3), 56.2 (CH3), 55.8 (CH3).
MS (ES+): m/z (%) = 585 (100) [M(81Br) + Na]+, 583 (88) [M(79Br)
+ Na]+.
References and Notes
(1) Combretastatin A-4 was isolated from the bark of the
African bush willow, Combretum caffrum. See: Pettit, G. R.;
Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt,
J. M.; Hogan, F. J. Med. Chem. 1995, 38, 1666.
(3) For previous syntheses of combretastatin A-4, see:
(a) Fürstner, A.; Nikolakis, K. Liebigs Ann. 1996, 2107.
(b) Orsini, F.; Pelizzoni, F.; Bellini, B.; Miglierini, G.
Carbohydr. Res. 1997, 301, 95. (c) Bedford, S. B.;
Quaterman, C. P.; Rathbone, D. L.; Slack, J. A. Bioorg. Med.
Chem. Lett. 1996, 6, 157. (d) Lawrence, N. J.; Ghani, F. A.;
Hepworth, L. A.; Hadfield, J. A.; McGown, A. T.; Pritchard,
R. G. Synthesis 1999, 1656. (e) Gaukroger, K.; Hadfield, J.
A.; Hepworth, L. A.; Lawrence, N. J.; McGown, A. J. J. Org.
Chem. 2001, 66, 8135.
(4) (a) Dunne, E. C.; Coyne, J.; Crowley, P. B.; Gilheany, D. G.
Tetrahedron Lett. 2002, 43, 2449. See also: (b) Hwang, J.-
J.; Lin, R.-L.; Shieh, R.-L.; Jwo, J.-J. J. Mol. Catal. A: Chem.
1999, 142, 125. (c) Harrowven, D. C.; Guy, I. L.; Nanson, L.
Angew. Chem. Int. Ed. 2006, 45, 2242.
(Z)-1-[2-(3-Hydroxy-2-iodo-4-methoxyphenyl)-1-ethenyl]-2-
bromo-3,4,5-trimethoxybenzene (8b)
To a solution of stilbene (Z)-8d (102 mg, 0.18 mmol) and Pd(PPh3)4
(10 mg, 5 mol%) at r.t. was added morpholine (0.32 mL, 3.64
mmol) slowly and the reaction was stirred at r.t. for 48 h. The reac-
tion mixture was concentrated in vacuo and the residue was redis-
solved in Et2O (15 mL). The organic phase was washed with 2 M
HCl (3 × 10 mL), dried (MgSO4), concentrated in vacuo and puri-
fied by column chromatography (SiO2, 20% EtOAc–PE) to yield
(Z)-8b (90 mg, 0.17 mmol, 95%) as a colorless oil. IR (neat): nmax
=
(5) Sinhababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48,
2356.
3550–3200 (br w), 3001 (w), 2937 (w), 2840 (w), 1595 (w), 1557
(w), 1479 s, 1388 (m), 1325 (m), 1272 (m), 1239 (m), 1197 (m),
1165 (m), 1102 (s), 1027 (s), 1006 (s), 923 (m) cm–1. 1H NMR (300
MHz, CDCl3): d = 6.68 (1 H, d, J = 11.8 Hz), 6.67–6.61 (2 H, m),
6.62 (1 H, d, J = 11.8 Hz), 6.35 (1 H, s), 6.17 (1 H, s, OH), 3.90 (3
H, s), 3.85 (6 H, s), 3.42 (3 H, s). 13C NMR (75 MHz, CDCl3): d =
152.1 (C), 150.9 (C), 145.8 (C), 144.8 (C), 142.4 (C), 134.6 (CH),
134.4 (C), 132.6 (C), 130.0 (CH), 121.9 (CH), 110.7 (C), 110.5
(CH), 109.8 (CH), 87.2 (C), 61.3 (CH3), 61.1 (CH3), 56.5 (CH3),
55.9 (CH3). MS (EI): m/z (%) = 522 (9) [M(81Br)]+, 520 (8)
[M(79Br)]+, 314 (26), 207 (65), 154 (61), 44 (100). MS: m/z calcd
for C18H18O579BrI: 519.9382; found [M+] 519.9386.
(6) Markovich, K. M.; Tantishaiyakul, V.; Hamada, A.; Miller,
D. D.; Romstedt, K. J.; Shams, G.; Shin, Y.; Fraundorfer, P.
F.; Doyle, K.; Feller, D. R. J. Med. Chem. 1992, 35, 466.
(7) Speicher, A.; Schoeneborn, R. Phytochemistry 1997, 45,
1613.
(8) It has been shown that o-methoxybenzylidenetriphenyl-
phosphoranes generally enhance E-selectivity in reactions
with benzaldehyde derivatives. See: (a) McEwen, W. E.;
Cooney, J. V. J. Org. Chem. 1983, 48, 983. Conversely,
o-methoxybenzaldehydes generally promote formation of
(Z)-stilbenes. See: (b) Yamataka, H.; Nagareda, K.; Ando,
K.; Hanafusa, T. J. Org. Chem. 1992, 52, 2865.
(c) Cushman, M.; Nagarathnam, D.; Gopal, D.; Chakraborti,
A. K.; Lin, C. M.; Hamel, E. J. Med. Chem. 1991, 34, 2579.
(9) Bhalla, K. N. Oncogene 2003, 22, 9075.
(10) Supplementary information providing characterization data
for each of the (Z)-stilbenes reported herein, together with
details of their preparation and the method of purification
employed, is available from the author.
Combretastatin A-4 (1)
To a cooled solution (–78 °C) of (Z)-8b (90 mg, 0.17 mmol) in THF
(5 mL) was added a 2.5 M hexane solution of n-BuLi (0.3 mL, 0.75
mmol) over 2 min. After 30 min at –78 °C the solution was allowed
to warm to r.t. then H2O (5 mL), sat. NH4Cl (5 mL) and EtOAc (10
mL) were added. The aqueous phase was separated and extracted
with EtOAc (5 × 10 mL). The combined organic phases were then
dried (MgSO4), concentrated in vacuo and purified by column chro-
matography (SiO2, 30% EtOAc–PE × 2) to give combretastatin A-
4 (Z)-1 (49 mg, 0.16 mmol, 90%) as a pale yellow solid.11
(11) All spectral and physical data were in close agreement with
literature values,1,3 except for the mp, (lit.1 116 °C).
Following recrystallization of our synthetic sample from
either EtOAc or EtOAc–hexane, it gave mp 83–84 °C
(recorded in duplicate on two separate apparatuses).
Acknowledgment
We thank EPSRC for a quota studentship (I.G.) and Cancer
Research UK for supporting the biological assessment of our
compounds.
Synlett 2006, No. 18, 2977–2980 © Thieme Stuttgart · New York