A high-yielding, two-step stereoselective synthesis of the anticancer drug
(Z)-combretastatin A-4 (1) has been devised. The method uses the Perkin con
densation of 3,4,5-trimethoxyphenylacetic acid and 3-hydroxy-4-methoxybenza
ldehyde followed by decarboxylation of the cinnamic acid intermediate using
copper and quinoline. The iodine-catalyzed isomerization of the Z isomer 1
results in complete conversion to the E isomer. The Suzuki cross-coupling
of an aryl boronic acid and vinyl bromide has also been successfully employ
ed to produce both Z and E isomers of combretastatin A-4 stereoselectively.
Both methods are far superior to the current five-step Wittig synthesis in
which both isomers are produced nonstereoselectively.