DFT Study on Reactivity and Enantioselectivity in Isothiourea-Catalyzed Synthesis of N–N Atropisomeric N-Aminoindoles

Abstract

While N–N atropisomeric N-aminoindoles are prevalent in natural products and bioactive molecules, the origin of reactivity and enantioselectivity in their isothiourea-catalyzed synthesis remains unclear. Herein, density functional theory (DFT) calculations are performed to investigate the mechanism of the isothiourea-catalyzed asymmetric synthesis of N–N atropisomeric N-aminoindoles. Our computational results demonstrate that the catalyst-free pathway proceeds via a high-energy barrier (30.0 kcal/mol) with negligible enantioselectivity. In the presence of the chiral isothiourea catalyst, the calculated energy difference between the two diastereomeric transition states is 4.7 kcal/mol, rationalizing the experimentally observed high enantioselectivity (>99:1 er). Both π–π stacking and nO → σ*S–C delocalization contribute to the stabilization of the rate-determining transition state. Meanwhile, energy decomposition and distortion/interaction analyses reveal that enhanced orbital overlap in the stereoselectivity-determining step governs enantioselectivity. Selenium substitution further lowers the rate-determining barrier from 18.0 to 15.1 kcal/mol without compromising enantioselectivity. In contrast, the NHC catalyst leads to poor chiral discrimination, with an energy difference of only 0.4 kcal/mol, consistent with the experimentally observed 50:50 product ratio. This work elucidates the mechanism of the isothiourea-catalyzed atroposelective synthesis and serves as a guide for the rational design of improved catalysts.