Novel syntheses of cis and trans isomers of combretastatin A-4.
Gaukroger, Keira Hadfield, John A Hepworth, Lucy A Lawrence, Nicholas J McGown, Alan T
Gaukroger, Keira
Hadfield, John A
Hepworth, Lucy A
Lawrence, Nicholas J
McGown, Alan T
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Abstract
A high-yielding, two-step stereoselective synthesis of the anticancer drug (Z)-combretastatin A-4 (1) has been devised. The method uses the Perkin condensation of 3,4,5-trimethoxyphenylacetic acid and 3-hydroxy-4-methoxybenzaldehyde 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 employed 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.
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2001-11-30
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Novel syntheses of cis and trans isomers of combretastatin A-4. 2001, 66 (24):8135-8 J. Org. Chem.