Discovery of an Ir-ate Catalyst for Ultra-efficient Asymmetric Hydrogenation of Ketones with 3S Character (Stable, Speed and Selectivity)

Abstract Reduction of organocarbonyl compounds occupies a large space in organic synthesis and mass production of fuels, chemicals and materials. 1-9 Instead of using stoichiometric reduction agents, the development of ultra-efficient homogeneous hydrogenation catalysts using green dihydrogen is one of the foremost challenges in the transition from chiral resolution toward selective production of chiral entities, as evidenced from the growing capacity and quantity of production plants. 10,11 However, despite useful enantioselectivities (>98% ee) are often obtained in asymmetric hydrogenation (AH) of ketones, the celebrated Noyori-type catalysts are currently limited in few million turnover numbers (TONs) and a hundred turnover frequencies (TOFs). 12-24 Challenges especially remain for nitrogen-containing ketones that are relevant to construction of high-value bioactive compounds where at most 10,000 TONs are reported. Here, by integration of the concepts of multidentate ligation and ate-type complex, we report the first ultra-efficient Ir-ate catalyst for highly selective construction of chiral alcohols via AH of ketones with remarkable, biocatalysis-like 3S capacity of >99% ee (enantiomeric excess) selectivity, 13,425,000 turnover number (TON) and 253 s-1 turnover frequency (TOF). With this Ir-ate catalyst a selective industrial route to chiral nicotine at 500 kg batch scale has been established, already providing 40 tons of product. Mechanistic studies reveal a novel ONa/MH bifunctional mechanism of the Ir-ate catalyst. Such concept is yet to be explored and may have a major impact in applied homogeneous catalysis.