Rapid access to epothilone analogs via semisynthetic degradation and reconstruction of epothilone D

A facile and efficient route to epothilone analogs has been developed from the natural product epothilone D (1). Degradation of 1 via an oxidative cleavage sequence provides acid intermediate 4 rapidly in six steps. From 4, a variety of epothilone analogs have been prepared utilizing ring-closing metathesis to reconstruct the trisubstituted-12,13-double bond. Using this approach, we report a number of epothilone analogs with varying C-15 aromatic side chains and C-14 allylic substitutions and their biological activities.