Ru-Catalyzed Asymmetric Hydrogenation of γ-Amino Ketones

A RuPHOX-Ru-catalyzed asymmetric hydrogenation of γ-amino ketones via an inner-sphere pathway has been developed for synthesizing chiral (R)-4-amino-1-arylbutan-1-ols under mild reaction conditions, affording up to 99% yield and >99% ee. Comprehensive mechanistic studies, involving control experiments and DFT calculations, provided several key insights: the reaction exhibits a dormant period attributed to the in situ formation of the catalytically active [Ru–H] species, which is integral to the catalytic cycle; 31P NMR control experiments adequately revealed that the ancillary ligand PPh3 remains coordinated to the Ru center throughout the catalytic cycle and acts cooperatively with the chiral RuPHOX ligand to modulate both reactivity and enantioselectivity; molecular hydrogen serves as the sole hydrogen source and participates in both the rate- and stereodetermining steps; and notably, an inner-sphere mechanism facilitated by weak noncovalent interactions between the substrate and the catalyst was identified as a key factor enhancing catalyst efficiency. The reaction proceeds on a gram scale with low catalyst loading (up to 10,000 S/C), and the resulting products can be readily transformed into valuable chiral building blocks, including a key intermediate for the synthesis of (S)-Nicotine.