Artificial Intelligence-Driven Development of Nickel-Catalyzed Enantioselective Cross-Coupling Reactions

The conventional approach to developing asymmetric synthetic methods relies heavily on empirical optimization. However, the integration of artificial intelligence (AI) and high-throughput experimentation (HTE) technology presents a paradigm shift with immense potential to revolutionize the discovery and optimization of asymmetric reactions. In this study, we present an efficient workflow for the development of a series of nickel-catalyzed asymmetric cross-coupling reactions, leveraging AI and HTE technology. Many nickel-catalyzed enantioselective cross-coupling reactions share a common Ni(III) intermediate, which dictates the enantioselectivity. To harness this mechanistic insight, we embarked on developing a predictive model for nickel-catalyzed enantioselective coupling reactions, elucidating the general rules governing enantioselectivity. Through the application of data science tools and HTE technology, we curated a data set to construct an AI-based model. This model was subsequently utilized to facilitate the discovery of efficient nickel hydride-catalyzed enantioselective and regioselective cross-coupling reactions. Employing AI-assisted virtual ligand screening and HTE-enabled condition optimization, we successfully identified optimal ligands for eight coupling reactions. Consequently, a series of chiral sp3 C–C bonds were synthesized with high yield and enantioselectivity.