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.