Ni/Cu Cocatalyzed Asymmetric Hydrogenation of Amino Ketones with Water as a Hydrogen Source

Abstract

While the asymmetric hydrogenation of protected amino ketones provides straightforward access to chiral amino alcohols, a significant gap exists in developing asymmetric transfer hydrogenation with cost-effective, nonprecious metal catalysts that ensure safety and sustainability. Herein, we present a Ni/Cu cocatalyzed asymmetric reduction of amino ketones employing water as the hydrogen source. This cocatalytic system efficiently converts a broad range of α- and β-amino ketones into their corresponding chiral amino alcohols with high yields and enantioselectivities. The method’s scalability was demonstrated by a successful gram-scale reaction alongside versatile derivatizations leading to eight pharmaceuticals, underscoring the method’s synthetic utility. This approach offers a safe, cost-effective, and easy-handling route to enantioenriched chiral amino alcohols, providing a valuable platform for synthesizing chiral pharmaceuticals and ligands. Additionally, mechanistic insights provided by an in-depth DFT study revealed that the high enantioselectivity and catalytic activity are primarily driven by steric effects within the Ni/Cu catalytic system.