Dynamic Ligand Exchange and Supramolecular Microenvironment Enable Asymmetric C–N Coupling of Electron-Deficient Azaarenes

Asymmetric C–N coupling of electron-deficient azaarenes presents significant challenges due to competitive ligand coordination, spatial separation of stereochemical information, and dynamic ligand exchange processes. We report a tripartite synergistic strategy integrating Pearson's HSAB principle-guided ligand design, non-covalent interaction-mediated dynamic ligand exchange, and chiral supramolecular microenvironments to overcome these limitations. Softness-optimized phosphine ligands with hydrogen-bond donors were rationally designed to enhance Pd–ligand affinity while enabling substrate activation through complementary non-covalent networks. This approach achieves remarkable stereocontrol (d.r. >20:1, up to 99% e.e.) in constructing dual chiral N-heterocycles via cascade C–N coupling and copper acetylide interception. Systematic mechanistic studies revealed critical hydrogen-bonding interactions that stabilize stereodefining transition states (3.5 kcal/mol energy difference via DFT) and accelerate supramolecular ligand exchange (³¹P NMR quantification). The methodology demonstrates broad substrate scope (32 examples), excellent functional group tolerance, and configurational stability under post-functionalization conditions. This work establishes a general paradigm for enantiocontrol in multi-coordination systems while expanding synthetic access to structurally complex chiral amines.