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Peer-reviewedCC BY 4.0ACS Omega

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

  • Jingjing Li1
  • Meichen Feng1
  • Dongju Zhang2
  1. 1Shanxi Agricultural University , , ,
  2. 2Shandong University , , ,
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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.

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Cite

BibTeXRIS
BibTeX
@article{li2026study,
  title = {{DFT Study on Reactivity and Enantioselectivity in Isothiourea-Catalyzed Synthesis of N–N Atropisomeric N-Aminoindoles}},
  author = {Jingjing Li and Meichen Feng and Dongju Zhang},
  journal = {ACS Omega},
  year = {2026},
  month = oct,
  doi = {10.1021/acsomega.6c09961},
  url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c09961/5454100/DFT-Study-on-Reactivity-and-Enantioselectivity-in},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - DFT Study on Reactivity and Enantioselectivity in Isothiourea-Catalyzed Synthesis of N–N Atropisomeric N-Aminoindoles
AU  - Jingjing Li
AU  - Meichen Feng
AU  - Dongju Zhang
PY  - 2026
DA  - 2026/10/20
JO  - ACS Omega
DO  - 10.1021/acsomega.6c09961
UR  - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c09961/5454100/DFT-Study-on-Reactivity-and-Enantioselectivity-in
AB  - 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.
SN  - 2470-1343
ER  -