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 alpha-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 eta(3)-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.

Automated summary

The first asymmetric Ni/Cu cocatalyzed benzylation of aldimine esters is reported, allowing the synthesis of benzyl-substituted alpha-quaternary amino acids in high yield and with high enantioselectivity. The strong electrophilicity of the eta(3)-benzylnickel intermediate was found to be crucial for the high reactivity, enabling the reaction under base-free conditions.