Issue 16, 2022

The chiral pyridoxal-catalyzed biomimetic Mannich reaction: the mechanism and origin of stereoselectivity

Abstract

A biomimetic organocatalyst with a pyridoxal-like structure is one of the most successful examples of catalyzing organic reactions under mild conditions in an asymmetric synthesis field. However, the origin of stereoselectivity for these kinds of reactions remains less studied in theory. Herein, we performed density functional theory (DFT) calculations to explore the detailed mechanism of the biomimetic chiral pyridoxal-catalyzed Mannich reaction between glycine and aryl N-diphenylphosphinyl imine to obtain a chiral amine product. The calculated results indicate that the reaction occurs through two stages, including condensation and asymmetric addition, and asymmetric addition has been identified as the stereoselectivity-determining process. Furthermore, atoms-in-molecules (AIM) analysis demonstrated that the N–H⋯O and O–H⋯N hydrogen bond interactions between the axially chiral biaryl pyridoxal catalyst and the imine were responsible for the energetic favorability of the RR-configurational pathway, which was in agreement with the experimental observations. By constructing and comparing the transition states with different groups on the substitute, 2D contour maps indicated that steric hindrance should be another key factor for switchable stereoselectivity. Furthermore, we have additionally investigated the possible structural models of the different catalyst species to explore their actual roles.

Graphical abstract: The chiral pyridoxal-catalyzed biomimetic Mannich reaction: the mechanism and origin of stereoselectivity

Supplementary files

Article information

Article type
Research Article
Submitted
03 May 2022
Accepted
26 Jun 2022
First published
27 Jun 2022

Org. Chem. Front., 2022,9, 4401-4410

The chiral pyridoxal-catalyzed biomimetic Mannich reaction: the mechanism and origin of stereoselectivity

L. Han, Q. Zhang, X. Li, Y. Qiao, Y. Lan and D. Wei, Org. Chem. Front., 2022, 9, 4401 DOI: 10.1039/D2QO00705C

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