Overcoming Copper Reduction\nLimitation in Asymmetric\nSubstitution: Aryl-Radical-Enabled Enantioconvergent Cyanation of\nAlkyl Iodides

Cu-catalyzed enantioconvergent cross-coupling\nof alkyl\nhalides\nhas emerged as a powerful strategy for synthesizing enantioenriched\nmolecules. However, this approach is intrinsically limited by the\nweak reducing power of copper(I) species, which restricts the scope\nof compatible nucleophiles and necessitates extensive ligand optimization\nor the use of complex chiral scaffolds. To overcome these challenges,\nwe introduce an aryl-radical-enabled strategy that decouples the alkyl\nhalide activation step from the chiral Cu center. We demonstrate that\nmerging aryl-radical-enabled iodine abstraction with Cu-catalyzed\nasymmetric radical functionalization enables the conversion of racemic\nα-iodoamides to enantioenriched alkyl nitrile products with\ngood yield and enantioselectivity. The rational design of chiral ligands\nidentified a new class of carboxamide-containing BOX ligands. Mechanistic\nstudies support an aryl-radical-enabled pathway and the unique hydrogen-bonding\nability in the newly designed BOX ligands. This aryl-radical-enabled\nasymmetric substitution reaction has the potential to significantly\nexpand the scope of Cu-catalyzed enantioconvergent cross-coupling\nreactions.