![]() 1B, and Supplementary Tables 2, 3) comparable to biocatalysts. In this manuscript, we report a simple and easily fabricated tetradentate ligand f-phamidol-based anionic Ir-catalyst that provides unprecedented up to 13 million TONs, hundreds of TOFs per second at ultra-high selectivity (>99% ee, 13,425,000 TON and 224 s −1 TOF, Fig. Importantly, compared to traditional anionic catalysts, multidentate ligands should help to stabilize the metal center through coordinative saturated 18 electron complexes and form well-defined chiral environment for converting specific substrates and give rise to highly stable and selective catalysts. The characteristic anionic complexes bearing a formal negative charge can, in principle, enable high hydricity 36 and accordingly high catalytic reaction rates, as evidenced from the seminal anionic metal hydride catalysts for hydrogenation reaction of carbonyl compounds by Pez 37, 38, 39, Poli 40, and others 40. Inspired by highly reactive anionic reductants and multidentate Noyori-type hydrogenation catalysts, we proposed the integration of the concepts of anionic complexes and multidentate ligands for developing ultra-efficient asymmetric hydrogenation catalysts with high selectivity, stability, and reactivity preeminence (Fig. Given the increasing capital investments, operational costs and sustainability requirements, to obtain ultra-efficient catalysts achieving 10-million TONs and biocatalysis-like reaction turnover frequencies (TOFs), beyond the state-of-the-art NH/MH bifunction catalysts, is highly important and has been the holy grail of the homogeneous transition metal catalysis 33, 34, 35. Exceptionally, Zhou’s tridentate ligand of Ir-PNN-catalyst provides the record-high TONs of 4,550,000 at 98% ee (enantiomeric excess). 2, Supplementary Information 3.1 and Supplementary Table 2). Indeed, Noyori-type catalysts, i.e., Ru(bisphos)(diamine) system by Noyori 17, 18, 19, Ir-PNN-complex by Zhou 20, 21, 22, 23, and others 24, 25, 26, 27, 28, 29, 30, 31, 32 operating via NH/MH 19, 27 bifunction mechanism are effective ketone asymmetric reducing catalysts (Fig. 3).Ĭompared to the representative hydrogenation catalysts 6, 7, 8, 9, 10, 11, 12, 13, 14 with inner-sphere mechanism, catalysts 15, 16 of the outer-sphere mechanism can avoid the contact of substrates to the metal center, thus making it possible to design highly stable, enantioselective and coordination saturated hydrogenation catalysts (Fig. In particularly, well-documented catalysts for challenging nitrogen-containing ketones that are relevant to construction of high-value bioactive compounds show at most 10,000 TONs, far from practical utilization (Supplementary Table 3 and Supplementary Fig. The celebrated Noyori-type catalysts often give useful enantioselectivities (>98% ee) but show few million turnover numbers (TONs) and a hundred turnover frequencies (TOFs) for asymmetric hydrogenation of aryl alkyl ketones 5. ![]() >10,000 tons, development of practical catalysts with both excellent enantioselectivity and turnover numbers (TONs) for asymmetric hydrogenation is of great importance 1, 2, 3, 4. ![]() In the context of industrial production of chiral entities estimated ca. A selective industrial route to enantiopure nicotine has been established using this anionic Ir-catalyst for the key asymmetric hydrogenation step at 500 kg batch scale, providing 40 tons scale of product. The anionic Ir-catalyst showed a novel preferred ONa/MH instead of NNa/MH bifunctional mechanism. Up to 1,000,000 TON and 99% ee were achieved for challenging pyridyl alkyl ketone where at most 10,000 TONs are previously reported. ![]() Biocatalysis-like efficacy of up to 99% ee (enantiomeric excess), 13,425,000 TON (turnover number) and 224 s −1 TOF (turnover frequency) were documented for benchmark acetophenone. Herein, we report an ultra-efficient anionic Ir-catalyst integrated with the concept of multidentate ligation for asymmetric hydrogenation of ketones. Developing catalysts with both useful enantioselectivities and million turnover numbers (TONs) for asymmetric hydrogenation of ketones is attractive for industrial production of high-value bioactive chiral entities but remains a challenging. ![]()
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