Palladium-Catalyzed Site– and Enantiodifferentiating Allylic C–H Alkylation of Internal Alkenes

The site- and enantioselective transformation of allylic C-H bonds in ubiquitous internal alkenes represents a significant challenge in asymmetric synthesis. Introducing an enzyme-like chiral environment is a crucial strategy to achieve pro-<i>R</i>/<i>S</i> and site-differentiation of allylic C-H bonds, thereby circumventing the formation of complex regio- and stereoisomeric mixtures. In this work, we report a highly site- and enantiodifferentiating allylic C-H alkylation of internal alkenes through pocket-like chiral phosphoramidite-Pd catalysis. This method is effective for a wide spectrum of cyclic and acyclic internal alkenes. Dispersion interactions are highlighted as playing a pivotal role in stabilizing the enantiodifferentiating transition states of allylic C-H bond cleavage. Within an open pocket delineated by the segments of bulky phosphoramidite ligand, electronically and sterically similar allylic C-H bonds are discriminated. This process culminates in the generation of chiral σ-allylpalladium intermediates that rapidly engage in S_N2'-allylation, installing the functional group precisely at the position of the initially cleaved prochiral hydrogen.