Data-Driven Phosphine Ligand Design of Ni-Catalyzed Enantioselective Suzuki–Miyaura Cross-Coupling Reaction for the Synthesis of Biaryl Atropisomers: standing on the shoulder of Pd catalysis giants

Abstract

The Suzuki-Miyaura cross-coupling reaction is a cornerstone in organic synthesis, enabling the formation of carbon–carbon bonds with high efficiency and selectivity. This study represents a groundbreaking advancement in the field by pioneering the first enantioselective Ni-catalyzed Suzuki–Miyaura cross-coupling reactions for the synthesis of biaryl atropisomers. Employing a data-driven approach, we have crafted a novel N-protected Xiao-Phos ligand, which, in conjunction with commercially available Ni(COD)2, delivered unparalleled enantioselectivity and reactivity under mild conditions. The ligand design was meticulously guided by an extensive examination of the existing literature on Pd-catalyzed asymmetric Suzuki–Miyaura cross-coupling reactions, directing the virtual screening and subsequent experimental verification of the synthesized ligands in a single iteration. The innovative ligand N-Bn-Xiao-Phos exhibited impressive enantioselectivities coupled with exceptional yields, showcasing versatility with a diverse array of functional groups and aryl boronic acids, and accomplishing successful gram-scale synthesis. DFT computational studies provided profound insights into the reaction mechanism and the roots of enantioselectivity, elucidating the dynamic coordination modes of the chiral ligand and the steric induction. This breakthrough not only broadens the horizons of Ni-catalyzed cross-coupling reactions but also highlights the immense potential of machine learning in the judicious design of chiral ligands for asymmetric synthesis.