Nickel/Copper‐Cocatalyzed Asymmetric Benzylation of Aldimine Esters for the Enantioselective Synthesis of α‐Quaternary Amino Acids

The first asymmetric Ni/Cu cocatalyzed benzylation of aldimine esters is reported. A series of benzyl‐substituted α‐quaternary amino acids could be synthesized in high yield and with high levels of enantioselectivity (up to 90 % yield and 99 % ee). The experimental and theoretical calculation results suggested that the strong electrophilicity of the η3‐benzylnickel intermediate is crucial for the high reactivity, enabling the reaction under base‐free conditions. Furthermore, this method has been applied to the synthesis of the cell adhesion inhibitor BIRT‐377 analogues, and the key intermediate of the NK1 receptor antagonist PD154075 and CCK‐B receptor antagonist CI‐988. The first Ni/Cu cocatalyzed asymmetric benzylation of aldimine esters has been developed. DFT calculations revealed that the strong electrophilicity of the η3‐benzylnickel intermediate enabled the reaction to proceed smoothly under base‐free conditions. The method was applied to the synthesis of BIRT‐377 analogues, the key intermediate of PD154075 and CI‐988.