HETEROCYCLES

■ Contents

■ Bridged Nucleic Acids: Development, Synthesis and Properties

Satoshi Obika,* S. M. Abdur Rahman, Aki Fujisaka, Yuji Kawada, Takeshi Baba, and Takeshi Imanishi*

*Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 560-0871, Japan

Abstract

Restricting the sugar moiety of a nucleic acid to a single conformation can be accomplished by forming a bridge in the sugar. A large number of bridged nucleic acids with variable bridged structures and conformations have been developed. The synthesis and properties of these artificial nucleic acid analogues are discussed. Such conformational restriction of the sugar moiety significantly improved the properties of the nucleic acid.

■ Synthesis and Chemistry of 4-Amino-1,2,4-triazin-5-ones

Magdy A. Ibrahim*

*Department of Chemistry, Faculty of Education, Ain Shams University, El-Maqreezy St, Roxy, Heliopolis, Cairo 11711, Egypt

Abstract

This review summarizes research results concerning the synthesis and chemical reactivity of 4-amino-1,2,4-triazin-5-ones and their related compounds.

■ Synthesis and Anti-Hepatitis C Virus Activity of Morpholino Triazine Derivatives

Takashi Misawa, Mohammed T. A. Salim, Mika Okamoto, Masanori Baba,* Hiroshi Aoyama, Yuichi Hashimoto, and Kazuyuki Sugita*

*Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Abstract

A series of morpholino triazines was synthesized and evaluated for anti-hepatitis C virus (HCV) activity. Incorporation of OMe, CN and F into the phenyl moiety afforded analogues with moderate potency and good selectivity, as assessed with the subgenomic HCV RNA replicon assay.

■ A New Synthesis of Novel Tricyclic 2(5H)-Furanone Heterocycles from 3,4,5-Trichloro-2(5H)-furanone

Jian Ren, Dan-Dan Ma, Yu Sha, Feng Li, and Mao-Sheng Cheng*

*The Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

Abstract

A novel class of five-six-six tricyclic 2(5H)-furanone heterocycles was synthesized from 3,4,5-trichloro-2(5H)-furanone and bifunctional o-nucleophiles in a single step. In addition, 2-(chloromethyl)quinoxaline was obtained through this method, and the distinctive formation mechanism of this compound is discussed.

■ Determination of the Structure and Its Absolute Configuration of 2”-Hydroxynicotianamine, an Inhibitor against Angiotensin-I Converting Enzyme in Buckwheat, through the Total Synthesis

Keisuke Yoshikawa,* Hidenori Watanabe, Yasuo Aoyagi, and Takeshi Kitahara

*Technical Research Institute, T. Hasegawa Co., Ltd., Kariyado, Nakahara-ku, Kawasaki city, Japan

Abstract

Nicotianamine is known as an inhibitor against Angiotensin-I Converting Enzyme (ACE). We synthesized a new nicotianamine derivative with an additional hydroxy group isolated from buckwheat (Fagopyrum esculentum Moench) powder and determined its regio and stereochemistry unambiguously by the enantioselective synthesis of diastereomers.

■ Rod-Like Conjugated Molecules with Ethynylene Linkage and Pyridazines Moieties: Synthesis and Light Emitting Properties

Caroline Hadad, Catherine Fiol-Petit, Anne-Sophie Cornec, Georges Dupas, Yvan Ramondenc, and Nelly Plé*

*Department of Heterocyclic Chemistry (LCOFH), UMR 6014 CNRS, INSA and University of Rouen, 8 rue Tenière, 76131 Mont-Saint-Aignan Cedex, France

Abstract

In this paper, we describe the synthesis of various rod-like conjugated molecules with ethynyl and vinylpyridazines units. The key steps involve Sonogashira cross-coupling and condensation reactions. The light-emitting properties of some molecules are investigated in terms of absorption and emission spectra.

■ Convenient Synthesis of 1,3-Dihydroisobenzofurans by Hydriodic Acid-Catalyzed Cyclization of 2-Vinylbenzyl Alcohols

Kazuhiro Kobayashi,* Kazuaki Shikata, Yuri Fujii, Shuhei Fukamachi, Miyuki Tanmatsu, and Hisatoshi Konishi

*Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A new and short process has been developed for the preparation of 1,1,3-tri- and 1,1,3,3-tetra-substituted 1,3-dihydroisobenzofurans (phthalanes) from α-substituted 2-bromostyrenes. The method involves addition of α-substituted 2-lithiostyrenes, generated by the bromine-lithium exchange between α-substituted 2-bromostyrenes and butyllithium, to aliphatic aldehydes or ketones, followed by hydriodic acid catalyzed cyclization of the resulting 2-vinylbenzyl alcohols.

■ Synthesis of Dihydroindoles and Tetrahydroquinolines by the Intramolecular Diels-Alder Reaction of N-Alkenylated 2-Acylamino-3-furancarbonitriles

Hiroshi Maruoka,* Fumi Okabe, Yoshimichi Koutake, Eiichi Masumoto, Toshihiro Fujioka, and Kenji Yamagata

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

An approach to dihydroindoles and tetrahydroquinolines from N-alkenylated 2-acylamino-3-furancarbonitriles via a [4 + 2] cycloaddition reaction is described. Thermal treatment of N-alkenylated 2-acylamino-3- furancarbonitriles 5a−d, 6a−d, 9a−d, and 10a−d, which were prepared from 2-acylamino-3-furancarbonitriles 3a−d and/or 4a−d and 4-bromo-1-butene and/or 5-bromo-1-pentene, caused an intramolecular Diels-Alder reaction to give the corresponding dihydroindole and tetrahydroquinoline derivatives 7a−d, 8a−d, 11a−d, and 12a−d. This method has the advantage of easier work-up procedure.

■ A Synthesis of β-Allyl Substituted Isotetronic Acid Derivatives via Thermal Claisen Rearrangement

Xiaping Ma, Zhiming Li, and Quanrui Wang*

*Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China

Abstract

Isotetronic acids are of great interest in agricultural and pharmacological research and occur in a number of natural products. This paper describes the first Claisen rearrangement of the O-allyl substituted isotetronic acids 2 under thermal conditions furnishing the β-allyl substituted isotetronic acid derivatives 3 in high yields.

■ Pyrrolizidine Alkaloids from the Roots of Paris verticillata

Ki Hyun Kim, Kyu Ha Lee, Sang Un Choi, Kyung Ran Kim, and Kang Ro Lee*

*Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, 300 Chunchun-dong, Jangan-ku, Suwon 440-746, Korea

Abstract

Three new pyrrolizidine alkaloids, verticillatins A (1), B (2), and C (3), together with seven known pyrrolizidine alkaloids (4-10), were isolated from the roots of Paris verticillata (Liliaceae). Their structures were determined by spectroscopic data and chemical evidences. Verticillatin A (1), verticillatin B (2), verticillatin C (3), heliovinine N-oxide (4), and indicine N-oxide (5) showed cytotoxicity against the HCT15 cell line, with IC50 values of 67.6, 92.4, 35.7, 36.2, and 74.7 μM, respectively.

■ Novel and Practical Synthesis of Candesartan Cilexetil

Yongjun Mao, Ruisheng Xiong, Zheng Liu, Haihong Li, Jingkang Shen, and Jingshan Shen*

*Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai, 201203, China

Abstract

A novel and convergent synthetic route of candesartan cilexetil (API of Atacand), an effective angiotensin II receptor blocker, is described. Cleavage of the N-Boc and N-trityl protective group are implemented simultaneously and formation of the benzimidazole ring is conducted at the last step of this route, which gives candesartan cilexetil in 55% yield over six steps with 99.1% purity (HPLC).

■ Synthesis of 4-Aryl-1H-pyrazoles by Suzuki-Miyaura Cross Coupling Reaction between 4-Bromo-1H-1-tritylpyrazole and Arylboronic Acids

Hayato Ichikawa, Miho Nishioka, Masao Arimoto, and Yoshihide Usami*

*Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan

Abstract

A general procedure for the synthesis of 4-aryl-1H-pyrazoles by the Suzuki-Miyaura cross coupling reaction between 4-bromo-1H-1-tritylpyrazole and commercially available arylboronic acids was developed. Using this procedure, a direct synthesis of 4-aryl-1H-pyrazoles possessing functional groups, such as hydroxyl, nitro, and amino groups, on the aryl ring was realized. Those molecules could not be prepared by our previous synthesis of 4-aryl-1H-pyrazoles via the Kumada cross coupling reaction.