2026/07/09 by Yuee Ke, Songlin Bai, Gen Li +3 · 1 voice
Chemistry · #Radical Photochemical Reactions #Catalytic C–H Functionalization Methods #Catalytic Cross-Coupling Reactions
paper · pdf · doi:10.26434/chemrxiv.15005912/v1
openalex publication_date 2026/07/09 · openalex created_date 2026/07/11 · openalex updated_date 2026/07/15
Enantioselective radical–radical cross-coupling represents a powerful yet largely unsolved strategy for constructing stereogenic C(sp 3 ) centers, because simultaneously controlling cross-selectivity and absolute stereochemistry between two distinct, transient alkyl radicals is exceptionally challenging. Here, we report a nickel-catalyzed C(sp 3 )–C(sp 3 ) cross-coupling that overcomes this limitation by using alkylzirconocenes, readily generated in situ from unactivated alkenes, and α‑halo amides. The reaction proceeds under mild, blue‑light‑driven conditions and provides direct access to chiral α‑aliphatic amides with outstanding efficiency (up to 98% yield) and enantioselectivity (up to 99:1 e.r.). The method exhibits remarkably broad substrate scope: a wide range of functional groups are tolerated on both coupling partners, and the protocol is successfully applied to the late‑stage diversification of complex natural products, including derivatives of cholesterol, estrone, and vitamin E. Furthermore, the reaction is extended to the highly enantioselective construction of quaternary carbon stereocenters, underscoring its practical synthetic value. Critical to this success was the development of a new pyridine–imidazoline (Pyim) ligand through over 140 iterative experimental cycles and deep learning framework for ligand optimization. This systematic screening campaign not only delivered a superior ligand, but also generated a rich, high‑quality dataset that precisely maps ligand structure to catalytic performance.