Evolution of a Total Synthesis of (−)-Kendomycin Exploiting a Petasis−Ferrier Rearrangement/Ring-Closing Olefin Metathesis Strategy

Abstract

A convergent stereocontrolled total synthesis of (-)-kendomycin (1) has been achieved. The synthesis proceeds with a longest linear sequence of 21 steps, beginning with commercially available 2,4-dimethoxy-3-methylbenzaldehyde (12). Highlights of the synthesis include an effective Petasis-Ferrier union/rearrangement tactic to construct the sterically encumbered tetrahydropyran ring, a ring-closing metathesis to generate the C(4a-13-20a) macrocycle, an effective epoxidation/deoxygenation sequence to isomerize the C(13,14) olefin, and a biomimetic quinone-methide-lactol assembly to complete the synthesis.