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

Journal Article


Abstract


  • 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.

Publication Date


  • 2021

Citation


  • De Ceuninck Van Capelle, L. A., Macdonald, J. M., & Hyland, C. J. T. (2021). Stereogenic and conformational properties of medium-ring benzo-fused N-heterocycle atropisomers. Organic and Biomolecular Chemistry, 19(33), 7098-7115. doi:10.1039/d1ob00836f

Scopus Eid


  • 2-s2.0-85113676356

Start Page


  • 7098

End Page


  • 7115

Volume


  • 19

Issue


  • 33

Abstract


  • 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.

Publication Date


  • 2021

Citation


  • De Ceuninck Van Capelle, L. A., Macdonald, J. M., & Hyland, C. J. T. (2021). Stereogenic and conformational properties of medium-ring benzo-fused N-heterocycle atropisomers. Organic and Biomolecular Chemistry, 19(33), 7098-7115. doi:10.1039/d1ob00836f

Scopus Eid


  • 2-s2.0-85113676356

Start Page


  • 7098

End Page


  • 7115

Volume


  • 19

Issue


  • 33