Enantioselective Nickel‐Catalyzed Reductive Decarboxylative C(sp ³ )‐C(sp ² ) Cross‐Coupling of Malonic Acid Derivatives ^†

Comprehensive Summary This study establishes a highly enantioselective nickel‐catalyzed reductive cross‐coupling strategy that directly converts ubiquitous malonic acid derivatives into valuable chiral α‐aryl and α‐alkenyl esters. The protocol employs stable redox‐active esters (RAEs) as practical alkyl radical precursors, which undergo decarboxylative coupling with a wide array of (hetero)aryl and alkenyl halides under mild reductive conditions. A central achievement is the identification of a tailored chiral bis‐imidazoline (BiIM) ligand, which is critical for achieving exceptional stereocontrol over the prochiral, electrophilic radical intermediate generated in situ —a longstanding challenge in asymmetric synthesis. The reaction demonstrates remarkable generality with respect to both coupling partners. A broad spectrum of malonic acid‐derived RAEs bearing diverse α‐substituents, including linear and branched primary alkyl groups, benzyl groups, heterocycles, and sterically hindered secondary alkyl groups, are all compatible substrates. The electrophile scope is equally comprehensive, successfully incorporating aryl bromides and iodides with either electron‐withdrawing or electron‐donating substituents, various pharmaceutically relevant heteroaryl halides, and alkenyl bromides. Products are consistently obtained in good yields and with excellent enantioselectivity. The synthetic utility of this method is underscored by its operational simplicity, excellent functional group tolerance, and successful application in the late‐stage functionalization of complex drug‐like molecules, enabling the efficient synthesis of enantioenriched hybrids. Mechanistic investigations, including radical trapping and clock experiments, support a reaction pathway involving a key alkyl radical intermediate. Collectively, this work provides a powerful, modular, and practical platform for the direct construction of enantioenriched C(sp 3 )–C(sp 2 ) linkages from simple and inexpensive feedstocks, with significant potential for accelerating discovery in medicinal chemistry and asymmetric synthesis.