Enantioselective Synthesis of Axial Chiral Aryl Isoquinolines via N‐Directed 3d Metal Catalysts: A Perspective

Abstract

Axially chiral N‐heterobiaryls are important structural motifs in asymmetric catalysis, medicinal chemistry, and chiral functional materials. Their enantioselective synthesis has traditionally relied on noble‐metal catalysis or resolution‐based strategies, which often suffer from high cost, limited modularity, and restricted coupling‐partner scope. Recent advances in nitrogen‐directed 3d metal catalysis have enabled the enantioconvergent functionalization of racemic N‐heterobiaryl electrophiles. In these reactions, coordination of the heteroaryl nitrogen to cobalt or nickel promotes the formation of configurationally labile five‐membered metallacyclic intermediates, allowing chiral ligands to control axial epimerization and subsequent bond formation through kinetic resolution or dynamic kinetic asymmetric transformation. This perspective summarizes representative cobalt‐ and nickel‐catalyzed strategies, including radical coupling, reductive conjugate addition, Grignard‐type addition, Nozaki–Hiyama–Kishi‐type addition, carbon–methoxy bond activation, carboxylation with carbon dioxide, carbon–phosphorus coupling, carbon–oxygen/carbon–sulfur coupling, and nucleophilic chlorination. Emphasis is placed on nitrogen‐assisted axial epimerization, the complementary reactivity of cobalt and nickel, and future challenges in substrate generality, mechanism‐guided catalyst design, scalability, and application‐oriented synthesis.