When the lower-barrier pathway yields the minor enantiomer: reversibility and intermediate stability in pyrroloindoline synthesis
- 1Departamento de Química Fundamental
- 2Instituto de Química, Universidade de São Paulo
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.
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BibTeX
@misc{cardoso2026when,
title = {{When the lower-barrier pathway yields the minor enantiomer: reversibility and intermediate stability in pyrroloindoline synthesis}},
author = {Felipe Schoma Cardoso and Bruno Matos Paz and Ataualpa A. C. Braga},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009131/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009131/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - When the lower-barrier pathway yields the minor enantiomer: reversibility and intermediate stability in pyrroloindoline synthesis
AU - Felipe Schoma Cardoso
AU - Bruno Matos Paz
AU - Ataualpa A. C. Braga
PY - 2026
DA - 2026/09/21
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009131/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009131/v1
AB - 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.
ER -