Highly efficient synthesis of enantioenriched β-hydroxy α-amino acid derivatives via Ir-catalyzed dynamic kinetic asymmetric hydrogenation

Abstract

Asymmetric hydrogenation of aryl α-dibenzylamino β-ketoesters and α-dibenzylamino aromatic ketone catalyzed by the Ir/f-phamidol catalytic system through dynamic kinetic resolution was achieved. Asymmetric reduction of aryl α-dibenzylamino β-ketoesters proceeded smoothly to provide the corresponding chiral aryl β-hydroxy α-amino derivatives with excellent diastereo- and enantioselectivities (>99/1 dr, up to >99% ee). The dibenzyl protecting group was easily removed by performing a 10% Pd(OH)₂-catalyzed hydrogenation under 5 atm of H₂ at room temperature to furnish the syn-aryl β-hydroxy α-amino acid, which is an important drug candidate. A gram-scale experiment demonstrated the synthetic utility of this approach. In addition, the α-dibenzylamino aromatic ketone was hydrogenated to the amino alcohol product with excellent enantioselectivity and a high turnover number (S/C up to 10 000). After deprotection of the dibenzyl group, the chiral amino alcohol can serve as a useful scaffold for chiral ligands or auxiliaries in the field of asymmetric synthesis.