Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles

Atropisomeric, bench-stable benzoazepine-fused isoindolesweresynthesized via oxidation from isoindoline precursors. Using the isoindoles 5d-f as models, the stereochemistry andconformational folding of the systems were examined. Chiral UHPLCwas used to analyze the rate of racemization and calculate the Gibbsfree energy of enantiomerization (& UDelta;G (& DDAG;) (Enant)). X-ray crystallography, H-1 NMR spectroscopy,and DFT calculations were used to elucidate the three axes of chiralityand clarify the structural factors contributing to & UDelta;G (& DDAG;) (Enant). Tandem rotation aroundthe axes of chirality precludes the formation of diastereomers, withrotational restriction of the C-aryl-N-sulfonamide bond determined as the moderator of atropisomeric stability in thesystem, affected primarily by steric hindrance as well as by & pi;-stackinginteractions facilitated by the folded conformation of the sulfonamideover the isoindole moiety.

Automated summary

In this study, bench-stable benzoazepine-fused isoindoles were synthesized via oxidation from isoindoline precursors. The stereochemistry and conformational folding were examined using isoindoles 5d-f as models. The factors contributing to the stability of atropisomers were elucidated using various techniques including chiral UHPLC, X-ray crystallography, H-1 NMR spectroscopy, and DFT calculations, revealing the role of steric hindrance and folded conformation in stabilizing the system.