Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles

• Published in: Journal of organic chemistry 2023-07, Vol.88 (13), p.8738-8750
• Main Authors: de Ceuninck van Capelle, Lillian A., Wales, Steven M., Macdonald, James M., Kruger, Megan, Richardson, Christopher, Gardiner, Michael G., Hyland, Christopher J. T.
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.3c00607

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.