CALS News Fall 2011

Oxidation of 1,5-benzo­thiazepin-4-one (<b>5</b>-<b>A</b>) stereoselectively afforded the <i>S</i>-oxide <b>8I</b>-<b>A</b> (a<i>S</i>,1<i>S</i>) in preference to the diastereomer <b>8II</b>-<b>A</b> (a<i>S</i>,1<i>R</i>) affected by the remote stereogenic axis. All the enantiomers (<b>8I</b>-<b>A</b>/<b>8I</b>-<b>B</b> and <b>8II</b>-<b>A</b>/<b>8II</b>-<b>B</b>) were separated and isolated, and the interconversion between <b>8I</b> and <b>8II</b> (equilibrium ratio ≈5:1) was unequivocally verified to be caused by the rotation around the axis

Tolvaptan-Type Vasopressin Receptor Ligands: Important Role of Axial Chirality in the Active Form

The <i>anti</i> and <i>syn</i> isomers of tolvaptan-type compounds, <i>N</i>-benzoyl-5-hydroxy-1-benzazepines (<b>5a</b>–<b>c</b>), were prepared in a stereocontrolled manner by biasing the conformation with a methyl group at C9 and C6, respectively, and the enantiomeric forms were separated. Examination of the affinity at the human vasopressin receptors revealed that the axial chirality (a<i>S</i>) plays a more important role than the central chirality at C5 in receptor recognition, and the most preferable form was shown to be (<i>E</i>,a<i>S</i>,5<i>S</i>)

Tolvaptan-Type Vasopressin Receptor Ligands: Important Role of Axial Chirality in the Active Form

The <i>anti</i> and <i>syn</i> isomers of tolvaptan-type compounds, <i>N</i>-benzoyl-5-hydroxy-1-benzazepines (<b>5a</b>–<b>c</b>), were prepared in a stereocontrolled manner by biasing the conformation with a methyl group at C9 and C6, respectively, and the enantiomeric forms were separated. Examination of the affinity at the human vasopressin receptors revealed that the axial chirality (a<i>S</i>) plays a more important role than the central chirality at C5 in receptor recognition, and the most preferable form was shown to be (<i>E</i>,a<i>S</i>,5<i>S</i>)

<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

Elucidation of the <i>E-</i>Amide Preference of <i>N</i>‑Acyl Azoles

The conformational properties of <i>N</i>-acyl azoles (imidazole, pyrazole, and triazole) were examined. The <i>N</i>-2′,4′,6′-trichlorobenzoyl azoles were stable in methanol at room temperature, and no hydrolyzed products were observed over 7 days in the presence of 5% trifluoroacetic acid or 5% triethylamine in CDCl₃. The high stability may be explained by the double-bond amide character caused by the steric hindrance due to the <i>ortho</i>-substituents in the benzoyl group. While specific <i>E</i>-amide preferences were observed in <i>N</i>-acyl pyrazoles/triazoles, the amides of the imidazoles gave a mixture of <i>E</i> and <i>Z</i>. One of the conceivable ideas to rationalize this conformational preference may be repulsive interaction between two sets of lone-pair electrons on the pyrazole 2-nitrogen (n_N) and the carbonyl oxygen atoms (n_O) in the <i>Z</i>-conformation of <i>N</i>-acyl pyrazoles/triazoles. However, analysis of orbital interactions suggested that in the case of the <i>E</i>-conformation of <i>N</i>-acyl pyrazoles, such electron repulsion is small because of distance. The interbond energy calculations suggested that the <i>Z</i>-conformer is involved in strong vicinal σ–σ repulsion along the amide linkage between the σ_N1N2 and σ_C1C2 orbitals in the <i>anti</i>-periplanar arrangement and between the σ_N1C5 and σ_C1C2 orbitals in the <i>syn</i>-periplanar arrangement, which lead to the overwhelming <i>E</i>-preference in <i>N</i>-acyl pyrazoles/triazoles. In the case of <i>N</i>-acyl imidazoles, similar vicinal σ–σ repulsions were counterbalanced, leading to a weak preference for the <i>E</i>-conformer over the <i>Z</i>-conformer. The chemically stable and <i>E</i>-preferring <i>N</i>-acyl azoles may be utilized as scaffolds in future drug design