Synthesis and biological evaluation of 12,13-cyclopropyl and 12,13-cyclobutyl epothilones.

With some members in clinical trials, the epothilones command attention as potential anticancer agents of considerable promise. In addition to several naturally occurring substances, an impressive array of epothilone analogues has been constructed and biologically evaluated. 2] We have previously reported the apartialo construction of two 12,13-cyclopropyl epothilone A analogues. Their structures recently came under closer scrutiny by us and by a Bristol ± Myers Squibb (BMS) group, whose independent synthesis of one of these compounds led to a revision of its structure. Here we wish to report i) an unambiguous chemical synthesis of cis-(12S,13S)-cyclopropyl epothilone A (2) and its 15R epimer 3 ; ii) the correct structure of the previously synthesized cyclopropyl epothilones and a mechanistic rationale for their unexpected formation; iii) the chemical synthesis of cis-(12S,13S)-cyclobutyl epothilone A (4) and its 15R epimer 5 ; and iv) the molecular modeling and biological evaluation of the newly synthesized compounds. Remarkably, compounds 2 and 4 exhibit potencies comparable