The stereochemistry of N-benzoyl-1,5-benzothiazepine and its S-oxide derivatives as vasopressin receptor ligands was examined in detail by freezing the conformation with a methyl group at the C6 or C9 of 1,5-benzothiazepine. It was revealed that the active forms recognized by the receptors are (cis,aS) for 1,5-benzothiazepine (5-7)-II and (cis,1S,aS) (syn) for its S-oxide (8-10)-II. The C9-methyl derivative of 1,5-benzothiazepine S-oxide (10-II) was designed and synthesized, achieving the putative active syn-isomer.
The atropisomeric and conformational properties of 1,5-benzodiazepines with an N-sulfonyl (p-tosyl/mesyl) group (IIa/b) were investigated by comparison with those of the N-benzoyl congeners (I). Similar to I, when the Ar-N(SO2) axis was frozen by a C9-substitution in the molecules, IIa/b were separated into the (aR)- and (aS)-atropisomers. The conformation of IIa/b revealed that the substituent (p-tolyl/methyl group) in the sulfonyl moiety occupies the position over the diazepine ring (folded form) in both the solid and solution states [e.g., (+)-(aR)-N-p-tosyl-1,5-benzodiazepin-2-one (IIa-2)], whereas that of I is anti to the diazepine ring [e.g., (-)-(aR)-N-benzoyl-1,5-benzodiazepin-2-one (I-2)], which was further supported by a computational study. The stereochemical stability also differed between the two congeners (e.g., ΔG(‡): 104 kJ/mol for I-2 and 132 kJ/mol for IIa-2).
The syn (aR*,5R*) and anti (aS*,5R*) diastereomers of N-benzoyl-C5-substituted-1-benzazepines originating in the chiralities at C5 and the Ar-N(C═O) axis were first stereoselectively synthesized by biasing the conformation with a substituent at C6 and C9, respectively. Detailed examination of the stereochemistry (i.e., conformation and configuration) of these N-benzoyl-1-benzazepines by X-ray crystallographic analysis, VT NMR, and DFT calculations revealed new physicochemical aspects of these heterocycles including revision of the stereochemistry previously reported.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.