Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles.

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.

Stereogenic and conformational properties of medium-ring benzo-fused N-heterocycle atropisomers.

Medium-ring (7-9-membered) benzo-fused N-heterocycles - a core structure in several important pharmaceuticals - have a diverse range of interesting conformational and stereochemical properties which arise from restricted bond rotation in the non-aromatic ring. The atropisomers of these pharmaceutically relevant N-heterocycles typically exhibit different biological activities, warranting the need to deeply understand the factors controlling the conformation and stereochemistry of the systems. Beginning with a brief introduction to atropisomer classification, this review will detail a number of medium-ring benzo-fused N-heterocycle systems from the recent literature to provide an overview of structural factors which can affect the atropisomeric nature of the systems by altering the overall conformation and rate of stereo-inversion. As well as general factors such as ring-size and sterics, the impact of additional stereocentres in these systems will be addressed. This includes the differences between sulfur, nitrogen and carbon stereocentres, and the consequences of stereocentre placement around the N-heterocycle ring. Further, conformational stabilisation via non-covalent intramolecular bonds will be explored. As such, this review represents a significant resource for aiding in the design, synthesis and study of new and potentially bioactive medium-ring benzo-fused N-heterocycles.