Convergent Total Synthesis of (−)-Cyclopamine
Manolis Sofiadis, Dongmin Xu, Anthony J. Rodriguez, Benedikt Nissl, Sebastian Clementson, Nadia Nasser Petersen, Phil S. Baran
Abstract
A concise and enantioselective total synthesis of the Veratrum alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 16-step longest linear sequence (LLS) was enabled by a de novo synthesis of the trans -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.
Topics & Concepts
ChemistryTotal synthesisCyclopamineStereochemistryBiochemistrySignal transductionHedgehogChemical synthesis and alkaloidsAlkaloids: synthesis and pharmacologyAxial and Atropisomeric Chirality Synthesis