π-π Interactions-Directed Asymmetric Hydrogenation of Sterically Unbiased Aromatic Ketones

Abstract

Transition metal-catalyzed asymmetric hydrogenation of ketones has been well established; however, the asymmetric hydrogenation of sterically unbiased ketones remains a formidable challenge, due to the difficulty in control of enantioselectivity. Herein, we have developed a highly practical and efficient protocol for the asymmetric hydrogenation of sterically unbiased aromatic ketones, and a series of chiral cyclic diaryl alcohols, including the key intermediate of Baloxavir (super Tamiflu), with up to 99% yield and up to 99% ee. Mechanistic investigations indicate that iridium precursor [Ir(COD)Cl]2 could undergo an intramolecular oxidative C-H activation with the oxa-spirocyclic ligand to produce a highly rigid butterfly-shaped complex which is responsible for achieving high enantioselectivity, and X-ray diffraction analysis indicate that the ligand behaves as a tetradentate PNNC ligand, which could inhibit the toxicity of the sulfur-containing substrate to the catalyst. Preliminary DFT calculations and NCI analysis demonstrated that π-π interactions between the substrate and catalyst played a key role in the control of enantioselectivity. Furthermore, the synthetic potential of our catalytic system was verified by the gram-scale asymmetric hydrogenation, and Baloxavir intermediate was obtained with retention of enantioselectivity.