HETEROCYCLES

■ Contents

■ Selenium-Containing Bicyclic β-Lactams

Dinesh R. Garud, Masayuki Ninomiya, and Mamoru Koketsu*

*Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan

Abstract

The first β-lactam ring system was synthesized by H. Staudinger in 1907, but β-lactams as a class of compounds became attractive only after it was established that penicillin contained a β-lactam unit as the structural feature. Over the years, countless numbers of penicillin derivatives and a variety of new β-lactam ring systems have been prepared, tested, and introduced. As a class of β-lactam derivatives, selenium-containing bicyclic β-lactams have received only a limited attention. In this review the advances in the development of synthesis methods for selenium-containing bicyclic β-lactams are presented and discussed.

■ Design and Synthesis of Novel Retinoid Synergists Having a Dibenzodiazepine Skeleton

Kiminori Ohta, Emiko Kawachi, Koichi Shudo, and Hiroyuki Kagechika*

*Graduate School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10, Surugadai, Kanda, Chiyoda-ku 101-0062, Japan

Abstract

Based on the structures of potent RXR agonists 2 and 3, novel dibenzodiazepine derivatives 4 – 6, containing two diphenylamine substructures, were designed as RXR modulator candidates and synthesized by utilizing Pd-catalyzed and Cu-promoted diphenylamine-generating reactions as key reactions. These compounds showed retinoid-synergistic activity, enhancing the HL-60 cell differentiation-inducing ability of the RAR agonist Am80.

■ Novel Application of Electrooxidative Method for the Cyclization of N-Benzyl-2-(hydroxymethyl)- and N-Benzyl-2-(2-hydroxyethyl)piperidines

Mitsuhiro Okimoto,* Takashi Yoshida, Masayuki Hoshi, and Kousuke Ohashi

*Department of Biotechnology and Environmental Chemistry, Kitami Institute of Technology, Koen-cho 165, Kitami, Hokkaido 090-8507, Japan

Abstract

Several novel 1,3-oxazinane and oxazolidine derivatives were obtained from the corresponding N-benzyl-2-(2-hydroxyethyl)- and N-benzyl-2-(hydroxymethyl)piperidines via electrochemical oxidation. The reactions were carried out in methanol under basic conditions. The yields of the cyclic products were significantly improved using catalytic amounts of iodide ions, which presumably act as effective electron carriers in the two-electron oxidation process.

■ Computational Study on the Cyclopropanation Reaction of Ylides Generated from α-Pyridiniumacetates

Shuji Matsumura,* Ryukichi Takagi, Satoshi Kojima, Katsuo Ohkata, and Manabu Abe

*First Institute of New Drug Discovery Medicinal Chemistry Group, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192,

Abstract

Ab initio MO calculations were performed on the cyclopropanation reaction of methylidenemalononitriles with the ylide generated from α-pyridiniumacetates. The calculations indicated that the rate-determining step was the final cyclopropane forming step for the gas phase reaction, whereas solvent effect approximations implied that it was the initial Michael addition leading to the cis intermediate for reaction in water. It was also revealed that the plausible [3+2] cycloaddition reaction to give bicyclic products is more likely to be a stepwise and not an asynchronous concerted process in DFT calculations at the B3LYP/6-31G(d) level of theory.

■ UNIQUE PHENYL ETHER TYPE BIFLAVONOIDS, ZIZYFLAVOSIDES A AND B WITH BIOMIMETIC SYNTHESIS FOR ZIZYFLAVOSIDE A

Mahmoud Mostafa,* Fumihide Takano, and Tomihisa Ohta*

*Department of Pharmacognosy and Chemistry of Natural Products, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

During our investigation of Zizyphus spina-christi (L.) Willd. leaves for anti-inflammatory activity, eight compounds were characterized. Two are new phenyl ether type biflavonoids, which were assigned as zizyflavosides A (1) and B (2). The structures of 1 and 2 were determined by spectroscopic analyses including 1D, 2D NMR and MS spectroscopic and chemical data. The other isolated compounds were known flavonoids kaempferol-3-O-rutinoside (5), quercetin-3-O-rutinoside (6), 3',5'-di-C-β-D-glucosylphloretine (7), quercetin-3-O-[β-D-xylosyl-(1→2)-α-L-rhamnoside]-4'-O-α-L-rhamnoside (8), epiafzelechin (9) and quercetin-3-O-[β-D-xylosyl-(1→2)-α-L-rhamnoside] (10). Zizyflavoside A was synthesized from quercetin-3-O-rutinoside and kaempferol-3-O-rutinoside using laccase as an enzyme and this biomimetic synthesis could be indication to its biosynthetic pathway.

■ Alkylations of 10H-2,7-Diazaphenothiazine to Alkyl-2,7-diazaphenothiazinium Salts and 7-Alkyl-2,7-diazaphenothiazines

Beata Morak-Młodawska, Krystian Pluta,* Kinga Suwińska, and Małgorzata Jeleń

*Department of Organic Chemistry, The Medical University of Silesia, Jagielloñska Str. 4, 41-200 Sosnowiec, Poland

Abstract

Alkylations of 10H-2,7-diazaphenothiazine (1) with alkyl halides led to different products depending on the reaction conditions: 10-methyl derivative (2), 2,10-dimethyl-2,7-diazaphenothiazinium and 7,10-dimethyl-2,7-diazapheno-thiazinium iodides (3-4), 2,7-dialkyl-2,7-diazaphenothiazidiinium dihalides (5-8) and 7-alkyl-2,7-diazaphenothiazines (9-12). The last compounds were the isomers of recently published 10-alkyl-2,7-diazaphenothiazines. 2,7-Dialkyl-2,7-diazaphe-nothiazidiinium dihalides (5) and (8) were transformed into 7-alkyl-2,7-diazaphe-nothiazines (9) and (12) in basic conditions. The structures of the products were determined on the basis of physical properties, 1H NMR (ROESY, COSY) and MS spectra, and were confirmed by X-ray analysis of compounds (3-5).

■ Formal Total Synthesis of Enantiopure Tricyclic (S)-Myrmicarin Alkaloids 217, 215A and 215B

Marco Santarem, Corinne Vanucci-Bacqué,* and Gérard Lhommet*

*Department of Chemistry, IPCM, University of Paris VI, 4, Place Jussieu, F-75252 Paris Cedex 05, France

Abstract

We described herein a formal synthesis of the enantiopure tricyclic (4aS)-myrmicarin alkaloids 217, 215A and 215B owing to the obtention of a common pyrroloindolizidine intermediate, starting from a chiral cis-(2S,5R)-disubstituted pyrrolidine. An intramolecular one-pot aldolization-crotonization-aromatization process of a diketo indolizidine constitutes the key step for the formation of the pyrrole ring of the target compound.

■ Mild Oxidation of Alcohols Using Soluble Polymer-Supported TEMPO in Combination with Oxone: Effect of a Basic Matrix of TEMPO Derivatives

Kazutsugu Matsumoto,* Toshiaki Iwata, Masahiro Suenaga, Masayuki Okudomi, Masaki Nogawa, Mariko Nakano, Ai Sugahara, Yuta Bannai, and Kenji Baba

*Department of Chemistry, Meisei University, Hodokubo 2-1-1, Hino, Tokyo 191-8506, Japan

Abstract

The highly efficient and mild oxidation of alcohols using new soluble polymer-supported TEMPO derivatives in combination with Oxone is disclosed. Two types of the PEG-supported TEMPO derivative were easily synthesized by a simple esterification or Click Chemistry. The oxidation of primary alcohols with the precatalysts, TBAB, and Oxone in CH2Cl2 or BTF proceeded to afford the corresponding oxidized products. As a result of the reactions using several TEMPO derivatives including the nonpolymer-supported and insoluble polymer-supported compounds under the same reaction conditions, the synthesized PEG-supported TEMPO bearing a succinate spacer between the PEG and TEMPO parts was chosen as the best due to its high reactivity and product selectivity. This reaction was also applicable for the oxidation of secondary alcohols. In this system, the isolation of the products was achieved by simple filtration. The PEG-supported TEMPO bearing a succinate spacer was easily recovered and reused at least 10 times without a purification process.

■ Synthesis of 1-Azaxanthones and 1-Azathioxanthones by Yb(OTf)3/TfOH Co-Catalyzed Intramolecular Friedel-Crafts Reaction

Jie Li, Can Jin, and Weike Su*

*Key Laboratory of Pharmaceutical Engineering of Ministry of Educations, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China

Abstract

Intramolecular Friedel-Crafts cyclization of phenoxypyridine acids (1a-1j) and phenythiopyridine acids (3a-3i) to form 1-azaxanthones (2a-2j) and 1-azathioxanthones (4a-4i), respectively, was efficiently promoted by Yb(OTf)3/TfOH as co-catalysts. And a number of substrates could be cyclized in moderate to good yields.

■ Convertible Formation of Different Glycoside Using Molecular Iodine

Rungnapha Saeeng,* Uthaiwan Sirion, Yada Sirichan, Thanida Trakulsujaritchok, and Poolsak Sahakitpichan

*Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand

Abstract

The observation of convertible formation between 2-deoxy-2-iodo-O-glycosides and 2,3-unsaturated glycoside was described. The selective formation of 2-deoxy-2-iodo-O-glycosides was found from the reaction of D-glucal with iodine in the excess alcohol acceptor or the addition of ceric ammonium nitrate as additive while the addition of a stoichiometric amount of alcohol in solvent favored 2,3-unsaturated glycosides formation.

■ Total Synthesis of (S)-(-)-Stepholidine Using (S)-tert-Butanesulfinylimine

Jianjun Cheng, Liqiang Fu, Chenyu Ling, and Yushe Yang*

*State Key Laboratory of Drug Research, Shanghai Institute of Material Medica, Chinese Academy of Sciences, 555, Zuchongzhi Road, Zhangjiang High-Tech Park, Shanghai 201209, China

Abstract

A new synthetic strategy of (S)-(−)-stepholidine, a promising antipsychotic drug candidate, is described. Nucleophilic addition of a laterally lithiated nitrile to a (S)-tert-butanesulfinylimine was used as the key step, which was complished in 94 % de and the main isomer was isolated in 52% yield. (S)-(−)-Stepholidine was prepared after another 5 steps, with an overall yield of 18.3% and > 98% ee.

■ Total Synthesis of (±)-Scuteflorin A

Fang Tan, Liu-Lan Shen, Young-Shin Kwak,* and Jin-Hyun Jeong*

*Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Dongdaemoon-Ku, Heoki-Dong, #1, Seoul 130-701, Korea

Abstract

A highly efficient synthesis was developed for the first total synthesis of scuteflorin A. © 2010 Elsevier Science. All rights reserved.

■ Synthesis of Readily Accessible BODIPY-Based Fluorescence Derivatization Reagents for Amines

Ryota Saito* and Eri Ito

*Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan

Abstract

Two BODIPY-based fluorescence derivatization reagents (FDRs) for amines were synthesized in a simple manner with practically acceptable yields via five steps. Both FDRs showed prompt reactivity, even against sterically hindered amines, to afford the corresponding FDR-labeled products in good yields. The solvent effect upon the fluorescence intensity of the derivatized amine was also investigated in a methanol-water binary solvent system to demonstrate that the strong fluorescence intensity was maintained in the solvent with a 0-60% water ratio. The detection limits of the new FDRs were estimated to be 20 fmol, which makes it much more sensitive than commercially available FDRs.

■ Regioselectivity in Direct Arylation of Benzanilide Possessing Oxygen Substituents in the Benzoyl Part Using Palladium without Phosphine Ligand

Takashi Harayama,* Chie Nagura, Taeko Miyagoe, Yuko Kawata, Hitoshi Abe, and Yasuo Takeuchi

*Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki City, Kagawa 769-2193, Japan

Abstract

The direct arylation of benzanilide (1) possessing ether oxygen(s) in benzoyl part was examined under phosphine ligand-free conditions, which afforded ortho-product (2) and para-product (3) in very similar ratio to presence of P(o-Tol)3 conditions. This results suggest that bulkiness of palladium under phosphine-free conditions would be comparable to that of P(o-Tol)3 conditions.

■ Synthesis of 5,7-Dibromotropono[c]pyrazole Derivatives

Yang Li and Wentao Gao*

*Institute of Superfine Chemicals, School of Chemistry and Chemical Engineering, Bohai University, 19 Keji Road, Jinzhou 121000, China

Abstract

A facile synthesis of some novel 5,7-dibromotropono[c]pyrazole derivatives via the condensation reaction of 3-acetyl-5,7-dibromotropolone with aromatic hydrazines is described. All the synthesized compounds were obtained in good yields of 67-88% and their structures were characterized by IR, 1H NMR, MS, and elemental analysis.

■ The Reaction of [(1-Azaazulen-2-yl)imino]phosphorane with Arylaldehydes: Formation of Bis[(1-azaazulen-2-yl)amino]arylmethanes

Hiroyuki Fujii, Kentaro Nagamatsu, Takahiro Gunji, Toshihiro Murafuji, and Noritaka Abe*

*Department of Industrial Chemistry, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

Reaction of [(3-ethoxycarbonyl-1-azaazulen-2-yl)imino]triphenylphosphorane with arylaldehydes gave bis[(3-ethoxycarbonyl-1-azaazulen-2-yl)amino]arylmethanes via corresponding azaazulenylimine intermediacy.

■ Synthesis and Evaluation of Phosphodiesterase IV Inhibitory Potency of Isocarbostyril Derivatives of Naturally Occurring Isocoumarins, Scoparines A and B

Kumiko Taguchi, Koichi Kobayashi, Keiko Ishida, Katsuo Kamata, and Toshio Honda*

*Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Eight isocarbostyril derivatives bearing n-propyl substituent at the 3-position were prepared from the naturally occurring isocoumarins, scoparines A and B. Their phosphodiesterase IV (PD-4) inhibitory potency were evaluated by the vascular relaxation response in the mesenteric artery. Eight derivatives showed vascular relaxation response, probably relating with PD-4 inhibitory. However, these responses were weaker than the known PD-4 inhibitor (Ro201724).