Catalysis

Enantioselective synthesis

Engineering

Gossypol

Coupling (piping)

Receptor

Biochemistry

Tetra

Stereochemistry

Mechanical engineering

Medicinal chemistry

Combinatorial chemistry

Ligand (biochemistry)

Organic chemistry

Axial symmetry

Structural engineering

Chemistry

Steric effects

Chiral ligand

Journal of the American Chemical Society

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.

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