TOTAL SYNTHESIS OF OXAZOLE-CONTAINING AND CYCLOPROPANE-CONTAINING EPOTHILONE-B ANALOGS BY THE MACROLACTONIZATION APPROACH

In order to probe structure-activity relationships in the epothilone a rea, two series of epothilone B analogues have been designed and synth esized. The first series containing an oxazole moiety in place of a th iazole on the side chain was constructed by utilizing key intermediate s 7-9 or 10, 12, and 13 (Scheme 1), whereas the second series containi ng an ethano group instead of the gem-dimethyl group at position 4 was synthesized from fragments 42 and 43. A Yamaguchi-type macrolactoniza tion reaction was used to construct the macrocycle from a seco-acid, w hich was assembled, in both cases, by means of a) an aldol reaction, b ) an Enders alkylation, and c) a Wittig-type reaction. This convergent strategy provided access to oxazole analogues 2, 4, 29-32 and 4,4-eth ano derivatives 3, 40, 60-63 for biological studies.