Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine

Abstract

Chiral γ-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of β-amino ketones provides a straightforward and powerful tool for the synthesis of chiral γ-amino alcohols, but the asymmetric transformation is synthetically challenging. Here, a series of tridentate ferrocene-based phosphine ligands bearing modular and tunable unsymmetrical vicinal diamine scaffolds were designed, synthesized, and evaluated in the iridium-catalyzed asymmetric hydrogenation of β-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse β-tertiary-amino ketones and β-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral γ-amino alcohols with up to 99% yields, >99% ee values, and turnover number (TON) of 48,500. The gram-scale reactions with low catalyst loading showed the potential application in industrial synthesis of chiral drugs, such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.