Synthesis of epothilone analogues by antibody-catalyzed resolution of thiazole aldol synthons on a multigram scale. Biological consequences of C-13 alkylation of epothilones

Three monoclonal aldolase antibodies (84G3, 85H6, and 93F3), generated agai nst a beta -diketone hapten (II) by the reactive immunization technique, ca talyzed highly enantioselective retroaldol reactions of the racemic thiazol e aldols 13-20. Antibody 84G3 (0.0004-0.005 mol%) was used to resolve (+/-) -13-(+/-)-18 to afford compounds 13-18 in multigram quantities. Multiple 13 -alkyl analogues of epothilone (7-12) and their trans isomers ((E)-7- (E)-1 2) were synthesized starting from thiazole aldols 13-18. Construction of th e trisubstituted olefin moiety in compounds 7-12 and (E)-7-(E)-12 was catal yzed by Grubbs' catalyst (X). Initial biological testing with compounds 7-1 0 and their trans isomers showed that compounds 9, 10, and (E)-10 have appr eciable tubulin polymerization and antiproliferative activities that approa ched those of epothilone C. The most active compound, (E)-9, even displayed potencies comparable to those observed for epothilones A and D. Interestin gly, all trans analogues were more potent than their corresponding cis isom ers. While Introduction of an alkyl group at C-13 in the cis series led to an overall reduction in biological activity (compared to epothilone C), app ropriate modification of the thiazole moiety (replacement of the 2-methyl s ubstituent by a 2-methylthio group) was able to compensate for this loss. T hese results are encouraging in view of the expectation that epoxidations o f these compounds should further increase their cellular activities. Thus, compounds 9, 10, and (E)-9 and (E)-10 represent highly promising candidates for further studies.