Enantioselective Coupling of Unactivated Alkenes with α-Imino Esters via Alkylzirconium Radical Intermediates

Abstract

Abstract Converting simple hydrocarbon feedstocks into stereochemically complex molecules remains a central goal of synthetic chemistry. α-Tetrasubstituted amino acids, which feature densely substituted stereogenic centers and important applications in chemical biology and medicinal chemistry, are particularly challenging to access through direct catalytic methods. Here, we report a photoinduced nickel-catalyzed asymmetric alkylation of α-imino esters using alkylzirconium intermediates generated directly from unactivated alkenes. By merging hydrozirconation chemistry with asymmetric radical coupling, the method enables precise control over transient alkyl radicals and their stereoselective incorporation into imine electrophiles. The transformation provides rapid access to diverse α-tetrasubstituted amino acid derivatives from abundant alkene feedstocks, including challenging internal, cyclic, and gaseous alkenes, while accommodating minimally differentiated alkyl substituents. In addition, a copper-catalyzed asymmetric coupling of alkylzirconium reagents with isatin imines was developed. Together, these transformations establish alkene-derived alkylzirconium chemistry as a versatile platform for the asymmetric synthesis of structurally diverse, enantioenriched nitrogen-containing compounds from simple hydrocarbon feedstocks.