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

Enantioselective hydrogenation of beta-amino ketones is a powerful tool to produce bioactive molecules, but their asymmetric transformation is synthetically challenging. Here, an iridium-catalysed system with tridentate ferrocene-based phosphine ligands bearing unsymmetrical vicinal diamine scaffolds is developed for the efficient asymmetric synthesis of diverse gamma tertiary-amino and gamma-secondary-amino alcohols, including intermediates of (S)-duloxetine, (R)-fluoxetine and (R)-atomoxetine. Chiral gamma-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of beta-amino ketones provides a straightforward and powerful tool for the synthesis of chiral gamma-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 beta-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse beta-tertiary-amino ketones and beta-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral gamma-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.

Automated summary

A novel iridium-catalyzed system was developed for the efficient asymmetric synthesis of diverse chiral γ-amino alcohols, including intermediates for certain drugs. The system exhibited high catalytic activity and high enantioselectivity towards the substrates.