Enantioselective α‐Benzylation of Acyclic Esters Using π‐Extended Electrophiles

The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1‐ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX‐9065a. Cooperate to benzylate: Cooperative catalysis enables the direct enantioselective α‐benzylation of aryl‐ and alkenylacetic acid esters using π‐extended benzylic electrophiles. Critical to the successful development of this method was the identification of diphenylphosphate as a uniquely effective nucleofuge, which permits oxidative addition of palladium(0).