Axial chirality originating in amide and sulfonamide structures: Flexible stereochemistry of benzo-fused seven-membered-ring heterocycles

The benzo-fused seven-membered-ring nitrogen heterocycles (e.g., 1-benzazepine, 1,5-benzodiazepine, and 1,5-benzothiazepine), which have been used as important core structures of various biologically active molecules, possess a flexible stereochemical (conformational) nature. When exerting biological activity, the receptors and enzymes should recognize the specific conformation of the heterocycles. Conformational change may cause chirality due to the axis. This article describes such axial chirality originating in amide and sulfonamide structures in relation to biological activity Conformation of the benzo-fused seven-membered-ring was frozen by introducing a methyl group at the peri-position of the benzene ring to enable separation of the (aS)/(aR)-axial isomers originating in the sp²-sp² axis of the Ar-N(CO) and Ar-N(SO₂) moieties. Thus, the conformational and atropisomeric properties of 1N-benzoyl-1,5-benzodiazepine (A), 1,5-benzothiazepin-4-one and its S-oxide (B), N-benzoyl-1,5-benzothiazepine and its S-oxide (C), and 1 N-sulfonyl-1,5-benzodiazepine (D) were clarified. In addition, A and C were evaluated as vasopressin receptor ligands to identify the active conformation recognized by the receptor.