<i>N</i>‑Benzoyl-1,5-benzothiazepine and Its <i>S</i>‑Oxide as Vasopressin Receptor Ligands: Insight into the Active Stereochemistry around the Seven-Membered Ring

The stereochemistry of <i>N</i>-benzoyl-1,5-benzothiazepine and its <i>S</i>-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 (<i>cis</i>,a<i>S</i>) for 1,5-benzothiazepine (<b>5</b>–<b>7</b>)-<b>II</b> and (<i>cis</i>,1<i>S,</i>a<i>S</i>) (<i>syn</i>) for its <i>S</i>-oxide (<b>8</b>–<b>10</b>)-<b>II</b>. The C9-methyl derivative of 1,5-benzothiazepine <i>S</i>-oxide (<b>10</b>-<b>II</b>) was designed and synthesized, achieving the putative active <i>syn</i>-isomer

<i>N</i>‑Benzoyl- and <i>N</i>‑Sulfonyl-1,5-benzodiazepines: Comparison of Their Atropisomeric and Conformational Properties

The atropisomeric and conformational properties of 1,5-benzodiazepines with an <i>N</i>-sulfonyl (<i>p</i>-tosyl/mesyl) group (<b>IIa</b>/<b>b</b>) were investigated by comparison with those of the <i>N</i>-benzoyl congeners (<b>I</b>). Similar to <b>I</b>, when the Ar–N­(SO₂) axis was frozen by a C9-substitution in the molecules, <b>IIa</b>/<b>b</b> were separated into the (a<i>R</i>)- and (a<i>S</i>)-atropisomers. The conformation of <b>IIa</b>/<b>b</b> revealed that the substituent (<i>p</i>-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., (+)-(a<i>R</i>)-<i>N</i>-<i>p</i>-tosyl<b>-</b>1,5-benzodiazepin-2-one (<b>IIa-2</b>)], whereas that of <b>I</b> is <i>anti</i> to the diazepine ring [e.g., (−)-(a<i>R</i>)-<i>N</i>-benzoyl<b>-</b>1,5-benzodiazepin-2-one (<b>I-2</b>)], which was further supported by a computational study. The stereochemical stability also differed between the two congeners (e.g., Δ<i>G</i>^⧧: 104 kJ/mol for <b>I-2</b> and 132 kJ/mol for <b>IIa-2</b>)

Stereochemistry of <i>N</i>‑Benzoyl-5-substituted-1-benzazepines Revisited: Synthesis of the Conformationally Biased Derivatives and Revision of the Reported Structure

The <i>syn</i> (a<i>R</i>*,5<i>R*</i>) and <i>anti</i> (a<i>S</i>*,5<i>R*</i>) diastereomers of <i>N</i>-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 <i>N</i>-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

A Complete Gear System in <i>N</i>‑Benzoyl-Carbazole Derivatives

2′,6′-Disubstituted <i>N</i>-benzoylated carbazole derivatives were found to exhibit atropisomerism. The bulky substituents restricted rotation about the N–C7′ and C7′–C1′ bonds to separate four atropisomers, in which rotation about the C7′–C1′ bond was in perfect concert with rotation about the N–C7′ bond. Complete geared rotation without slippage at 37 °C for 7 days was observed for the first time. Conformational analysis clarified the preference for the gear system over other internal conversion pathways