8 research outputs found
CALS News Fall 2011
Oxidation
of 1,5-benzoÂthiazepin-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–NÂ(SO<sub>2</sub>) 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><sup>⧧</sup>: 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–NÂ(Cî—»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 CDCl<sub>3</sub>. 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<sub>N</sub>) and the carbonyl oxygen atoms (n<sub>O</sub>) 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<sub>N1N2</sub> and σ<sub>C1C2</sub> orbitals in the <i>anti</i>-periplanar arrangement
and between the σ<sub>N1C5</sub> and σ<sub>C1C2</sub> 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