Yohko Sakamoto

Physicochemical properties of amorphous salt of cimetidine and diflunisal system.

The purpose of this study was to prepare amorphous precipitates of the binary system of cimetidine (CIM) and diflunisal (DIF) and to investigate the physicochemical properties of the precipitates. To achieve this, the interaction between CIM and DIF molecules was studied by means of nuclear magnetic resonance (NMR) and Fourier-transform infrared (FTIR) measurements. The binary system of CIM and DIF was found to become amorphous upon precipitation from ethanol solution, without heating or melting. In the thermal analysis by TG-DTA equipped with a mass spectrometer, decarboxylation of DIF was found to occur below its melting temperature. In NMR studies, the chemical shifts of a proton in the imidazole ring of CIM and the carbon to which the DIF carboxyl group is bound were found to change depending on the composition of the binary system. The change in NMR chemical shifts suggested that a salt was formed between CIM and DIF. The precipitates had higher solubility than intact drugs due to this salt formation. The results suggest that CIM may be useful as an amorphous carrier, without requiring heating or melting, due to the formation of a salt with acidic drugs.

An N–Ar axially chiral mimetic. A new approach to ligand design for asymmetric catalysis

Abstract A new-type chiral ligand, ( S )- N -[2-(diphenylphosphino)naphthyl]-2-(pyrrolidinylmethyl)piperidine mimicking N–Ar axial chirality, has been developed. This chiral ligand was found to exhibit 99% ee with the use of ( E )-1,3-diphenyl-2-propenyl acetate as the standard substrate, and achieved slightly better results than the Pfaltz and Trost ligands with the use of ( E )-1-phenyl-3-trimethylsilyl-2-propenyl acetate as the substrate, in the palladium-catalyzed asymmetric allylic substitution.

Conformational analysis of enalapril (MK-421) in solution by 1H and 13C NMR

Abstract The conformations of enalapril (MK-421, (−)-( N -(( S )-1-ethoxycarbonyl-3-phenylpropyl)- l -alanyl- l -proline), in CD 3 OD, were investigated in order to account for their biological activity as inhibitors of angiotensin converting enzyme (ACE). The ratio of trans to cis conformation around the amide bond is 3:2. The preferred optimum structures of the trans and cis forms are postulated. With reference to the proline ring the N -type trans isomer was more prevalent than the S -Type trans isomer.

Synthesis of Hexabenzo[a,cd,f,j,lm,o]perylene

Hexabenzo[a,cd,f,j,lm,o]perylene (HBP), an undecacyclic condensed polycyclic aromatic hydrocarbon with two severely crowded fjord regions, was synthesized by Clars method; the starting material 8H-benzo[fg]-naphthacene-8-one was newly prepared by the glycerol condensation of 5,12-dihydro-naphthacene-5,12-dione. 1H and 13C NMR spectra of HBP were measured and the chemical shifts were completely assigned. Absorption and fluorescence spectra of HBP were also measured and the effects of nonplanarity on its spectroscopic properties was discussed.

Conformational studies by 1H and 13C NMR of lisinopril

Abstract Lisinopril, N-N -[( s -1-carboxy-3-phenylpropyl]- l -lysyl- l -proline) (MK-521), is an inhibitor of angiotensin-converting enzyme and a new drug for the treatment of hypertension. 1H and 13 C NMR studies have shown that the s -cis equilibrium about the amide bond is strongly dependent on the configuration of the chiral centres. Vicinal coupling constants of stereochemical significance were obtained in deuterated solvent using NMR techniques. Comparison with values calculated for lisinopril using potential energy calculations and NMR show that lisinopril exists in preferred optimum conformation in solution.

Mechanism for the direct synthesis of tryptophan from indole and serine: a useful NMR technique for the detection of a reactive intermediate in the reaction mixture

The reaction mechanism for the biomimetic synthesis of tryptophan from indole and serine in the presence of Ac2O in AcOH was investigated. Although the time‐course 1H‐NMR spectra of the reaction of 5‐methoxyindole with N‐acetylserine were measured in the presence of (CD3CO)2O in CD3CO2D, the reactive intermediate could not be detected. This reaction was conducted without 5‐methoxyindole in order to elucidate the reactive intermediate, but the intermediate could not be isolated from the reaction mixture. Since the intermediate would be expected to have a very short life time, and therefore be very difficult to detect by conventional analytical methods, the structure of the intermediate was elucidated using a 2D‐NMR technique, diffusion‐ordered spectroscopy (DOSY). Two intermediates were detected and confirmed to be 2‐methyl‐4‐methyleneoxazol‐5(4H)‐one and 2‐methyl‐4‐hydroxymethyloxazol‐5(4H)‐one. The present results demonstrated that DOSY is a powerful tool for the detection of unstable intermediates. Copyright

Development of NEural network simulator for structure-activity COrrelation of molecules: Neco(2). The structure-activity relationship between 13C-NMR chemical shifts and the carcinogenicity of polycyclic aromatic hydrocarbons(PAH).

構造活性相関解析のためのニューラルネットワークシミュレータ (Neco) を用いて多環式芳香族炭化水素 (PAH) の 13C-NMRケミカルシフトとその発癌性における特徴抽出を行ない、発癌性に関係のあるパラメータの選択を行なった。用いたニューラルネットワークの構造は入力層・中間層・出力層の3層からなる階層型ニューラルネットワークである。入力データは、11種類の多環式芳香族炭化水素の共通する構造の10個の炭素原子の 13C-NMRケミカルシフト値である。学習法に青山らの再構築学習法を用いて入力データの特徴抽出を行ない、発癌性に関係のあるパラメータの抽出を行なった結果、過去の研究を統括するような結果が得られた。

Effect of solvent and internal rotation on 1JCH coupling in methylamine and methanol

Abstract Dependence of 1 J CH coupling on dielectric constant (ϵ ) has been studied in methylamine and methanol by 13 C NMR measurement and by calculation with the FPT—INDO—Solvaton method. In methylamine the observed 1 J CH coupling decreases with increasing ϵ, but in methanol the observed 1 J Ch coupling increases with increasing ϵ. This result is reproduced in calculation. This is related to the fact that the calculated excitation energy of the former increases with increasing ϵ, but that of the latter decreases. Also, the effect of internal rotation on 1 j ch coupling is studied. It is found that when a lone pair of nitrogen or oxygen atom trans -orients against a C-H bond in a methyl group, the electrons are shifted to the C-H bond, resulting in a decrease of s character of the bond and the corresponding decrease in 1 j ch coupling.

CONFORMATIONAL ANALYSIS OF 2-(DIPHENYLPHOSPHANYL)-N, N-DIMETHYL-1-BENZ AMIDE AND 2-(DIPHENYLPHOSPHANYL)-PHENYL-PYRROLIDIN-1-YL-METHANONE BY NMR SPECTROSCOPY

We have synthesized 2-(Diphenylphosphanyl)-N, N-dimethyl-1-benzamide (1) and 2-(Diphenylphosphanyl)- phenyl-pyrrolidin-1-yl-methanone (2), and examined their conformations on the basis of NMR spectral data. Conformational analysis of the compounds is useful in deducing the structure in which they are active as a catalyst. In the present NMR measurements, 1H-X fg-JHMBC (field gradient J-Resolved Hetero-nuclear Multiple-Bond Correlation) spectroscopy was implemented as a tool for the determination of hetero-nuclear three bond, phosphorus and protons and carbon-protons coupling constants. By fitting a sine curve to the experimental data by the method of 3D J-resolved HMBC NMR measurements, accurate n J HX coupling constants were obtained. From the coupling constants, the corresponding dihedral angles, H3-C2-C3-P, H12-C12-C11-P, H16-C16-C11-P, H18-C18-C17-P, and H22-C22-C17-P, of compounds (1) and (2) were determined. The optimized structures of the compounds were obtained by molecular orbital calculations in which the dihedral angles experimentally determined were used.

CONDENSATION PRODUCTS OF 7H-BENZO[DE]NAPHTHACENE-7-ONE

Condensation reaction of 7H-benzo[de]naphthacene-7-one (1) was conducted in fused salt using zinc dust at 275°C for 2 h. The reaction products were isolated by column chromatography and then purified by recrystallization, yielding crystals of orange-yellow needles as the main product. This compound with an absorption maximum at 450 nm was identified as trinaphtho[2,3-c; 2′,1′,8′-fgh; 2″,1″,8″-uva]-pentaphene by one-dimensional and two-dimensional 1H NMR spectroscopy, which was one of expected condensation products. We are now trying to isolate the other expected condensation products, benzo[vwx]dinaphtho[2,1-a; 8′,1′,2′-cde]hexaphene and benzo[cd]naphtho[2,3-f]anthra[3,2,1-lm]perylene, from the byproducts.