When the lower-barrier pathway yields the minor enantiomer: reversibility and intermediate stability in pyrroloindoline synthesis
Year: 2026
Type: preprint
Abstract: In this work, we present a computational study that provides evidence for the origins of selectivity in the enantioselective synthesis of pyrroloindolines catalyzed by iminium ions. Through a conformational search combined with DFT calculations, we obtained the catalytic energy profile, which shows that the enantioselectivity is not determined by the barriers of the enantiodetermining C–C bond-forming step. A microkinetic model built on this profile reproduces the experimental enantiomeric excess and identifies the origin of the selectivity: under conditions in which the steps preceding product release are reversible, the catalyst-bound intermediate I9 accumulates preferentially along the S pathway, where it is markedly more stable than its R counterpart. The selectivity therefore reflects a thermodynamic contribution operating at the level of the diastereomeric on-cycle intermediates rather than a difference in activation barriers. We stress that this outcome is not accessible from the free energy profile alone: a simple inspection of the activation barriers predicts the opposite sense of induction, and only the explicit kinetic treatment reproduces the experimental results. Previous studies have suggested that control of the E/Z ratio of the iminium ion intermediate was related to catalytic selectivity; here we show that the stereoinduction originates from the predominance of the E isomer of the iminium ion. Furthermore, for the C–C bond-forming step, we identify the regions of the system involved in the noncovalent interactions that govern selectivity. Finally, by introducing substituents on the substrate, we observe a decrease in the activation barrier associated with the iminium ion–substrate interaction when electron-donating groups are present in the nucleophile.
Source: ChemRxiv
Institution: Universidade de São Paulo
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7213950846