Direct Catalytic Asymmetric Conjugate Addition of Benzofuran-3(2H)-Ones to α,β-Unsaturated Thioamides: Stereodivergent Synthesis of Rocaglaol

Abstract

Rocaglaol, a representative flavagline, has attracted significant attention because of its unique chemical structure and biological activities. This paper reports a mild and scalable copper-catalyzed enantioselective conjugate addition of benzofuran-3(2H)-ones to α,β-unsaturated thioamides. This method allows for the concise synthesis of all possible stereoisomers of a key intermediate of rocaglaol and its derivatives in a highly diastereo- and enantioselective manner using different chiral phosphine ligands. Theoretical insights into the reaction mechanism and the origin of ligand-dependent diastereodivergence were obtained using density functional theory calculations.

Keywords: asymmetric catalysis; conjugate addition; natural products; thioamide; total synthesis.