Convergent Total Synthesis of (−)-Cyclopamine

Abstract

A concise and enantioselective total synthesis of the <i>Veratrum</i> alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 16-step longest linear sequence (LLS) was enabled by a <i>de novo</i> synthesis of the <i>trans</i>-6,5-heterobicycle via a strain-inducing halocyclization process, a key Tsuji-Trost cyclization to construct the fully substituted, spirocyclic THF motif with exquisite diastereocontrol, and a late-stage ring-closing metathesis (RCM) reaction to forge the central tetrasubstituted olefin.