Stereoretentive Radical-Radical Cross-Coupling

The construction of stereogenic C(sp³)-C(sp³) bonds through cross-coupling remains a formidable challenge in organic synthesis due to inherent limitations in traditional cross-coupling methods, including β-hydride elimination, homo vs. heterocoupling selectivity, and poor stereocontrol in radical pathways. Herein, we report the first stereoretentive radical-radical cross-coupling (RRCC) of two distinct unstabilized alkyl radicals-derived from enantioenriched sulfonylhydrazides and achiral primary and secondary alkyl halides-achieved without chiral catalysts, directing groups, or exogenous redox. This substrate-controlled approach leverages a nickel-catalyzed, redox-neutral manifold, enabling precise kinetic matching of diazene-mediated radical generation and halogen atom transfer. Optimization via highthroughput experimentation yields products with excellent enantiospecificity (typically 80-96% e.s.) and synthetically useful yields (40-90%) across diverse piperidine and pyrrolidine scaffolds with remarkable chemoselectivity, tolerating ethers, free amines, aryl halides, heterocycles, olefins, and other sensitive motifs. Mechanistic studies, including radical clock experiments and DFT computations, reveal a caged radical rebound at Ni to preserve chirality, followed by Ni(I)/Ni(III)-mediated radical capture and reductive elimination. The reaction is scalable and can be used to control diastereoselectivity and override innate substrate bias. Synthetic utility is demonstrated through streamlined access to medicinally relevant intermediates and natural products like (S,S)-stenusine, outperforming prior multi-step routes. This paradigm shifts asymmetric synthesis by embedding stereochemistry in radical precursors, opening new retrosynthetic avenues for complex chiral molecules.