Ni-Catalyzed Asymmetric Alkyl–Alkyl Cross-Coupling: Reaction Mode Development and Applications

ConspectusStereogenic carbon centers with an alkyl-alkyl (C(sp³)-C(sp³)) bond constitute a fundamental structural motif in organic molecules, where precise stereocontrol is critical for the development of pharmaceuticals, agrochemicals, and functional materials. Although transition-metal-catalyzed cross-coupling has revolutionized bond formation, enantioselective alkyl-alkyl coupling to access stereogenic carbon centers remains less developed, mainly due to challenges in selectivity control and the inherent instability and side reactions associated with alkyl metallic intermediates. Nickel-catalyzed asymmetric carbon-carbon cross-coupling has emerged as a powerful strategy for building stereogenic carbon centers via asymmetric C(sp²)-C(sp³) cross-coupling. Traditional Ni-catalyzed asymmetric alkyl-alkyl cross-coupling heavily relies on the use of stoichiometric alkyl electrophiles and stoichiometric alkyl metallic reagents as nucleophiles. Recently, Ni-catalyzed asymmetric hydroalkylation of alkenes provides a new solution for the construction of stereogenic carbon centers with an alkyl-alkyl bond, thereby avoiding the use of stoichiometric organometallic species as alkyl nucleophiles. However, significant challenges remain in Ni-catalyzed alkyl-alkyl cross-coupling reactions. To address these challenges, our group has focused on developing asymmetric Ni-catalyzed alkyl-alkyl bond-forming reactions. This Account outlines the development of reaction modes in Ni-catalyzed asymmetric alkyl-alkyl cross-coupling and presents three strategies from our laboratory: Ni-catalyzed asymmetric hydroalkylation of alkenes, Ni-catalyzed reductive asymmetric alkyl-alkyl cross-coupling, and Ni-catalyzed reductive-oxidative asymmetric alkene-alkene cross-coupling. First, we focused on developing Ni-catalyzed asymmetric hydroalkylation of alkenes, which enables direct and enantioselective alkyl-alkyl bond formation from electron-rich, electron-neutral, and electron-deficient alkenes and alkyl electrophiles. Next, we developed a reductive asymmetric alkyl-alkyl cross-coupling that directly couples two alkyl electrophiles. This strategy eliminates the need for preformed organometallic reagents and achieves high chemoselectivity and enantioselectivity in alkyl-alkyl cross-coupling by using alkyl electrophiles as the sole coupling partner. Most recently, we introduced a reductive-oxidative asymmetric alkene-alkene cross-coupling, a distinctive strategy that unites two alkenes through a redox event. Two alkenes act as surrogates for different alkyl metallic nucleophiles in the presence of hydride. This reaction mode enables alkyl-alkyl cross-coupling without the use of stoichiometric alkyl nucleophiles or alkyl electrophiles, allowing for control of the chemoselectivity, regioselectivity, and enantioselectivity. We hope that the strategies and concepts discussed herein will inspire the further development of new nickel-catalyzed methodologies for stereoselective alkyl-alkyl cross-couplings, thereby providing synthetic tools for organic chemistry and related fields.