Novel syntheses of cis and trans isomers of combretastatin A-4.
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.
Gaukroger
K
K
CRC Drug Development Group and CRC Radiochemical Targeting and Imaging Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, M20 4BX, U.K.
Hadfield
J A
JA
Hepworth
L A
LA
Lawrence
N J
NJ
McGown
A T
AT
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; C058728:fosbretabulin