Density functional theory study of the mechanism of a dipeptide-catalyzed intermolecular aldol reaction—the effects of steric repulsion interactions on stereoselectivity

Abstract

The mechanism of the dipeptide (S)-pro-(S)-asp catalyzed intermolecular aldol reaction with acetone as the donor and three aromatic aldehydes (benzaldehyde, p-methyl benzaldehyde and p-nitrobenzaldehyde) as the acceptors was studied by means of density functional theory (DFT) at the level of B3LYP/6-31G(d,p). The calculated results showed that there were four steps in the reaction path: (i) the nucleophilic attack of an amino group on carbonyl for the formation of intermediate A, which was the rate-determining step due to it having the largest energy barrier of 44.33 kcal mol⁻¹; (ii) the dehydration process to form an s-cis- or s-trans-enamine through an imine-generating step; (iii) the electrophilic addition of aldehyde, which decided the stereoselectivity of the product because of the steric repulsion interactions between the enamine and aldehyde; (iv) the removal of the dipeptide to generate the final products. According to the results analysis, it was found that the dipeptide-catalyzed aldol reaction via an s-trans-enamine was more energetically favorable to obtain the R-product (with an ee value > 99%). The energy variations in the reaction path were verified using CAM-B3LYP and M06-2X methods in the same basis set. The solvation effects were explored based on B3LYP/6-31G(d,p) combined with a polarizable continuum model (PCM), the substituent effects of aromatic aldehydes were also considered. The computed results provided a reference for experiments that DMSO and H₂O as the solvents could decrease the energy barriers in the reaction path and the impact of substituent effects might be small. The feasibility of the dipeptide provided a possibility for proteins to act as catalysts which are green and nontoxic.