Enantioselective Cross-Coupling for Axially Chiral Tetra-ortho-Substituted Biaryls and Asymmetric Synthesis of Gossypol

Abstract

The axially chiral tetra-ortho-substituted biaryl skeleton exists in numerous biologically important natural products, pharmaceutical molecules, chiral catalysts, and ligands. The efficient synthesis of chiral tetra-ortho-substituted biaryl structures remains a challenging but unsolved problem. Among various asymmetric synthetic protocols, enantioselective Suzuki-Miyaura cross-coupling represents one of the most straightforward and versatile approaches. Herein we describe a powerful Suzuki-Miyaura coupling enabled by a P-chiral monophosphorus ligand BaryPhos, providing a broad range of synthetically challenging chiral tetra-ortho-substituted biaryls in excellent enantioselectivities and yields. In addition to the enhanced reactivity for sterically hindered cross-coupling, the rational design of BaryPhos also enabled a new catalysis mode of asymmetric cross-coupling involving noncovalent interactions between the ligand and two coupling partners to effect efficient stereoinduction. This protocol is robust and practical, allowing for a concise enantioselective synthesis of therapeutically valuable male contraceptive and antitumor agent gossypol.