Mechanistic Study of the -Quaternized Pyridoxal-Catalyzed Biomimetic Asymmetric Mannich Reaction: Insights into the Origins of Enantioselectivity and Diastereoselectivity.

Density functional theory calculations have been performed to gain insights into the catalytic mechanism of the -quaternized pyridoxal (i.e., )-mediated biomimetic asymmetric Mannich reaction of -butyl glycinate with -diphenylphosphinyl imine to give the diamino acid ester in high yield with excellent enantiomeric and diastereomeric selectivity ( , , 1438). The study reveals that the whole catalysis can be characterized via three stages: (i) the catalyst reacts with the -butyl glycinate to generate the active carbanion complex . (ii) then reacts with the -diphenylphosphinyl imine giving the imine intermediate . (iii) undergoes hydrolysis to give the final product anti- and regenerate the catalyst for the next catalytic cycle. Each stage is kinetically and thermodynamically feasible for experimental realization. The hydrolysis step in the stage III is predicted to be the rate-determining step during the whole catalytic cycle. Furthermore, the origins of the enantioselectivity and diastereoselectivity for the target reaction, as well as the deactivation of the catalyst , are also discussed.