The Olefin Metathesis Approach to Epothilone A and Its Analogues

The olefin metathesis approach to epothilone A (1) and several analogues (39−41, 42−44, 51−57, 58−60, 64−65, and 67−69) is described. Key building blocks 6−8 were constructed in optically active form and were coupled and elaborated to olefin metathesis precursor 4 via an aldol reaction and an esterification coupling. Olefin metathesis of compound 4, under the catalytic influence of RuCl2(CHPh)(PCy3)2, furnished cis- and trans-cyclic olefins 3 and 48. Epoxidation of 49 gave epothilone A (1) and several analogues, whereas epoxidation of 50 resulted in additional epothilones. Similar elaboration of isomeric as well as simpler intermediates resulted in yet another series of epothilone analogues and model systems.