Epothilone A-D and their thiazole-modified analogs as novel anticancer agents

Starting from epothilone A-D (1a-2b) obtained by large scale fermentation of the myxobacterium Sorangium cellulosum the thiazole side-chain was extensively modified by substitution, oxidation and replacement. Metallation afforded the C-19 carbanion 4 which was quenched by Various carbon and heteroatom electrophiles to give C-19 substituted epothilones 5. Thiazole N-oxides 9 were obtained by treatment of 2a and 2b with m-chloroperbenzoic acid and rearranged by acetic anhydride to 21-acetoxy epothilones 10. Cleavage of epothilones A and B with ozone gave methyl ketones 11 from which carbonyl derivatives 12, 13, 14, and aldol condensation products 16 were prepared. Similarly vinyl boronic acid 17 was obtained and transformed by Suzuki coupling or iodination/Stille coupling to aryl and heteroaryl analogs 15.