Enantioselective Total Synthesis of Clavirolide C. Applications of Cu-Catalyzed Asymmetric Conjugate Additions and Ru-Catalyzed Ring-Closing Metathesis

Abstract

The first enantioselective total synthesis of clavirolide C, a member of the dolabellane family of diterpenes isolated from Pacific soft coral Clavularia viridis, is disclosed. The total synthesis features the application of chiral amino acid based ligands in Cu-catalyzed asymmetric conjugate addition (ACA) reactions and a relatively rare application of catalytic ring-closing metathesis to access an 11-membered ring structure. The total synthesis effort has spawned the development of a new protocol for NHC.Cu-catalyzed ACA of alkylaluminum reagents to beta-substituted cycloalkenones. The enantioselective clavirolide C synthesis requires 17 steps (longest linear sequence), affords the target molecule in 3.5% overall yield, and confirms the stereochemical assignment for the natural product.