ABSTRACT: A concise and enantioselective total synthesis of the Veratrum alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 15-step longest linear sequence (LLS) was enabled by a de novo synthesis of the trans-6,5 hetero-bicycle 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.