Full details of a catalytic asymmetric amination with a lanthanum/amide-based ligand catalyst system are described. A catalyst comprising La(NO(3))(3)*6H(2)O, (R)-3a and H-d-Val-O(t)Bu was identified to promote the catalytic asymmetric amination of nonprotected succinimide derivative 1 with as little as 1 mol % catalyst loading. Mechanistic studies by various spectroscopic analyses and several control and kinetic experiments suggested that the catalyst components were in equilibrium between the associated and dissociated forms, and that the reaction likely proceeded through a La(NO(3))(3)*6H(2)O/(R)-3a/H-d-Val-O(t)Bu ternary complex. This catalyst system was also effective for asymmetric amination of N-nonsubstituted alpha-alkoxycarbonyl amides 7, hitherto unprecedented substrates in asymmetric catalysis, probably due to their attenuated reactivity and difficult stereocontrol, affording the amination products in up to >99% yield and >99% ee. The high catalytic performance and enantiocontrol of the reaction with highly coordinative substrates were achieved by the activation/recognition of the substrates exerted by coordination to lanthanum and hydrogen bonding cooperatively in the transition state.

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A catalytic asymmetric amination with a lanthanum/amide complex was significantly improved. The use of lanthanum nitrate hydrate in place of lanthanum triisopropoxide made the process reproducible, scalable, and cost-effective. The development of a ternary catalytic system of La/ligand/amine was a key to high ee and catalytic turnover. A 100 g scale reaction was performed to showcase a practical synthesis of a key intermediate for AS-3201, a highly potent aldose reductase inhibitor.

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