High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones: Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine

摘要

A total of 21 amino acid based ligands including hydroxy amide, thioamide, and hydroxamic acid functionalities, respectively, were combined with [Ru(p-cymene)Cl2]2 and [RhCp*Cl2]2, and used as catalysts for the asymmetric transfer hydrogenation of four different heteroaromatic ketones in 2-propanol. The reactions were performed on a Chemspeed automated high-throughput screening robotic platform. Optimal catalysts were identified for the individual heterocyclic substrate classes. Based on these results, the formal syntheses of the antidepressant drugs (R)-fluoxetine and (S)-duloxetine were conducted by using the found catalysts in the key reaction step, which results in high isolated yields (94?%) and excellent product enantioselectivities (>99?% ee) of the formed 1,3-amino alcohols.