Highly Efficient Preparation of Chiral β ‐ or γ ‐Amino Alcohols and Pharmaceutical Intermediates by Ir/f‐Amphbinol‐Catalyzed Enantioselective Hydrogenation

ABSTRACT The iridium complexes of PNO‐type ligands containing phenolic hydroxyl groups have been successfully applied to the asymmetric hydrogenation of various amino ketones bearing strong coordinating N atoms. A series of chiral β ‐ or γ ‐amino alcohols were obtained with up to > 99% yields and > 99% ee. The gram‐scale experiments have been conducted with S/C = 10,000, and the resulting products (93%–96% yields and 97%–98% ee) could be further applied in the treatment of hypotension caused by shock or anesthesia ( R )‐Phenylephrine, antidepressant drugs, or potential analgesic agents ( S )‐duloxetine, ( R )‐fluoxetine, and ( R )‐atomoxetine. Additionally, based on the previous reports, control experiments, and DFT calculations, we proposed a possible transition state model for enantioselective hydrogenation involving alkali metal cations. The alkali cation (Li + , Na + , and K + ) can polarize the carbonyl of the ketone, which promotes the carbonyl carbon hydrogenation. This catalytic system exhibits high catalytic efficiency and excellent tolerance of substrates (up to 58 examples). Moreover, the solvent EtOH and the base NaOH used are both inexpensive and suitable for industrial applications. This protocol verified the practicality of the Ir‐f‐Amphbinol in the asymmetric hydrogenation of various α ‐ or β ‐amino ketones. The mechanism research provides certain theoretical guidance for the design and synthesis of novel and highly efficient catalysts for asymmetric hydrogenation.