Cu-Controlled Enantiodivergence in Pd-Catalyzed Stille Cross-Coupling Reactions

We report enantiodivergent Pd-catalyzed cross-coupling reactions between enantioenriched alkylcarbastannatrane nucleophiles and aryl electrophiles in which the stereochemical course of the reaction is dictated by the inclusion or omission of a Cu(I) additive. Using a new electron-deficient biarylphosphine ligand (MaPhos), a previously unknown stereoinvertive pathway for the transmetalation of unactivated and benzylic secondary alkylstannanes to Pd has been uncovered. When a Cu(I) salt is included in the reaction, the stereochemical course of the reaction changes from stereoinvertive to stereoretentive. Thus, both enantiomers of the cross-coupling product can be accessed in high enantiopurity using a single achiral ligand. Mechanistic investigations suggest that net-stereoretentive alkyl transfer, in the presence of Cu(I), results from consecutive stereoretentive transmetalations from tin to copper and copper to palladium. In contrast, direct alkyl transmetalation from tin to palladium proceeds primarily via a stereoinvertive pathway that is facilitated by the presence of electron-deficient ligands. Both experiment and DFT computations agree that ligand electronic properties play an important role in dictating the stereochemical course of direct (copper-free) alkyl transmetalation from tin to palladium. DFT results additionally reveal the governing structural features and interactions that promote the stereoinvertive transmetalation pathway in the copper-free reaction using MaPhos.