Catalytic Enantioselective Nucleophilic Amination of α-Halo Carbonyl Compounds with Free Amines

J Am Chem Soc. 2024 Dec 26. doi: 10.1021/jacs.4c12069. Online ahead of print.

Abstract

Catalytic enantioselective substitution of the readily available racemic α-halo carbonyl compounds by nitrogen nucleophiles represents one of the most convenient and direct approaches to access enantioenriched α-amino carbonyl compounds. Distinct from the two available strategies involving radicals and enolate ions, herein we have developed a new protocol featuring an electronically opposite way to weaken/cleave the carbon-halogen bond. A suitable chiral anion-based catalyst enables effective asymmetric control over the key positively charged intermediates. This protocol not only allows free amines to serve as nucleophiles but also permits different types of carbonyl compounds (ketones, esters, and amides) to participate in the enantioselective C-N bond formation, thereby providing a valuable complement to the known strategies that are limited to certain carbonyl substrates and/or nitrogen nucleophiles. Preliminary studies indicated that an SN2 pathway is operational and kinetic resolution is involved.