Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles

Lillian A de Ceuninck van Capelle; Steven Wales; James M Macdonald; Megan Kruger; Christopher Richardson; Michael G Gardiner; Christopher J. T Hyland

doi:10.1021/acs.joc.3c00607

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Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles

Journal article

Peer reviewed

Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles

Lillian A de Ceuninck van Capelle, Steven Wales, James M Macdonald, Megan Kruger, Christopher Richardson, Michael G Gardiner and Christopher J. T Hyland

Journal of Organic Chemistry, Vol.88(13), pp.8738-8750

2023

DOI: https://doi.org/10.1021/acs.joc.3c00607

PMID: 37326851

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Abstract

chirality

conformation

crystal structure

stability

sulfones

Atropisomeric, bench-stable benzoazepine-fused isoindoles were synthesized via oxidation from isoindoline precursors. Using the isoindoles 5d–f as models, the stereochemistry and conformational folding of the systems were examined. Chiral UHPLC was used to analyze the rate of racemization and calculate the Gibbs free energy of enantiomerization (ΔG ‡ Enant). X-ray crystallography, 1H NMR spectroscopy, and DFT calculations were used to elucidate the three axes of chirality and clarify the structural factors contributing to ΔG ‡ Enant. Tandem rotation around the axes of chirality precludes the formation of diastereomers, with rotational restriction of the Caryl–Nsulfonamide bond determined as the moderator of atropisomeric stability in the system, affected primarily by steric hindrance as well as by π-stacking interactions facilitated by the folded conformation of the sulfonamide over the isoindole moiety.

Details

Title: Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles
Authors: Lillian A de Ceuninck van Capelle (Author) - University of Wollongong
Steven Wales (Author) - University of Wollongong
James M Macdonald (Author) - CSIRO Manufacturing
Megan Kruger (Author) - CSIRO Manufacturing
Christopher Richardson (Author) - University of Wollongong
Michael G Gardiner (Author) - University of Tasmania
Christopher J. T Hyland (Corresponding Author) - University of Wollongong
Publication details: Journal of Organic Chemistry, Vol.88(13), pp.8738-8750
Publisher: American Chemical Society
DOI: 10.1021/acs.joc.3c00607
ISSN: 1520-6904
PMID: 37326851
Organisation Unit: School of Science, Technology and Engineering; Student Services and Engagement
Language: English
Record Identifier: 99741895002621
Output Type: Journal article

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Web Of Science research areas: Chemistry, Organic

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