Synergistic Pd/Cu Catalysis for the Asymmetric Synthesis of Alkylidenecycloalkanes Bearing Axial and Central Chirality

Abstract Axially chiral alkylidenecycloalkanes constitute an underexplored class of nonbiaryl chiral frameworks, and catalytic methods for simultaneously constructing their axial chirality and a nonadjacent carbon stereocenter remain limited. Herein, we report a synergistic Pd/Cu-catalyzed asymmetric coupling of vinylcycloalkyl acetates with glycine-derived iminoesters that establishes 1,3-related axial and central chirality in a single transformation. Complementary activation of the electrophilic and nucleophilic partners enables stereoselective carbon–carbon bond formation, providing modular access to structurally diverse amino acid derivatives. The reaction accommodates substituted vinylcyclohexyl and vinylcyclobutyl acetates, as well as iminoesters incorporating complex, biologically relevant fragments. The synthetic utility of the products is demonstrated through their conversion into dipeptides, hydantoins, spirocycles, and urea derivatives. This approach expands access to nonbiaryl axially chiral scaffolds bearing an additional central stereogenic element.