Carboxyl Group-Directed Iridium-Catalyzed Enantioselective Hydrogenation of Aliphatic γ-Ketoacids

Although the transition metal-catalyzed asymmetric hydrogenation of aromatic ketones has been extensively explored, the enantioselective hydrogenation of aliphatic ketones remains a challenge because chiral catalysts cannot readily discriminate between the re and si faces of these ketones. Herein, we report a carboxyl-directing strategy for the asymmetric hydrogenation of aliphatic gamma-ketoacids. With catalysis by iridium complexes bearing chiral spiro phosphino-oxazoline ligands, hydrogenation of aliphatic gamma-ketoacids afforded chiral gamma-hydroxylacids with high enantioselectivity (up to 99% ee). Mechanistic studies revealed that the carboxyl group of the substrate directs hydrogen transfer and ensures high enantioselectivity. Density functional theory calculations suggested the occurrence of chiral induction involving a hydrogen-hydrogen interaction between a hydride on the iridium atom and the substituent on the oxazoline ring of the ligand, and on the basis of the calculations, we proposed a catalytic cycle involving only Ir(III), which differs from the Ir(III)/Ir(V) catalytic cycle that operates in the hydrogenation of alpha,beta-unsaturated carboxylic acids.