Hidetsugu Tabata

Atropisomeric properties of the dibenzo[b,d]azepin-6-one nucleus.

Dibenzo[b,d]azepin-6-ones (2a,b) were separated by chiral HPLC into the aR- and aS-atropisomers with high stereochemical stability, and methylation at C7 of 2a stereoselectively gave the (aR*,7R*) isomer (4a), which converted to the thermodynamically stable (aS*,7R*) atropisomer (5a) after heating.

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

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.

Stereochemistry of 1,5-Benzothiazepin-4-one S-Oxide: Insight into the Stereogenic Elements at the Sulfur Atom and Axis

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

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

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.

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

The anti and syn isomers of tolvaptan-type compounds, N-benzoyl-5-hydroxy-1-benzazepines (5a-c), 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 (aS) plays a more important role than the central chirality at C5 in receptor recognition, and the most preferable form was shown to be (E,aS,5S).

N-benzoyl- and N-sulfonyl-1,5-benzodiazepines: comparison of their atropisomeric and conformational properties.

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).

Comprehensive Quantitation Using Two Stable Isotopically Labeled Species and Direct Detection of N-Acyl Moiety of Sphingomyelin

Sphingomyelin (ceramide-phosphocholine, CerPCho) is a common sphingolipid in mammalian cells and is composed of phosphorylcholine and ceramide as polar and hydrophobic components, respectively. In this study, a qualitative liquid chromatography-electrospray ionization tandem mass spectrometry (LC–ESI–MS/MS/MS) analysis is proposed in which CerPCho structures were assigned based on product ion spectra corresponding to sphingosylphosphorylcholine and N-acyl moieties. From MS/MS/MS analysis of CerPCho, we observed product ion spectra of the N-acyl fatty acids as [RCO2]− ions as well as sphingosylphosphorylcholine. A calibration curve for CerPCho was constructed using two stable isotopically labeled CerPCho species and then used to quantify the CerPCho species in HeLa cells as a proof-of-principle study. The present study proposes an accurate method for quantifying and assigning structures to each CerPCho species in crude biologic samples by LC–ESI–MS/MS/MS analysis.

[Development of a therapeutic agent for Menkes disease: solubilization of a copper-disulfiram complex].

Menkes disease (MD) is a neurodegenerative disorder characterized by copper deficiency. It is caused by defective intestinal absorption of copper resulting from a deficiency of a copper-transporting ATPase, ATP7A. We investigated the effects of combination therapy with copper and disulfiram, a known lipophilic chelator. We synthesized a copper-disulfiram complex (Cu-DSF) and determined its crystal structure by X-ray crystallographic analysis. Unfortunately, Cu-DSF was not orally bioavailable due to its lipophilicity. We therefore planned to use cyclodextrin as a solubilizing agent to increase the water solubility of Cu-DSF. After comparisons of the effects of cyclodextrins (α, β, γ), it was found that addition of β-cyclodextrin (β-CyD) increased the solubility of Cu-DSF. Moreover, the modified β-CyD, hydroxypropyl-β-cyclodextrin, was yet more effective as a solubilizing agent. For the development of a convenient method to determine the concentration of Cu-DSF included by β-cyclodextrins, a standard curve based on UV-visible(VIS) absorption was derived.