HETEROCYCLES

■ Contents

■ Direct Routes to 2H-Tetrazoles by Cyclization and Ring Transformation

Dietrich Moderhack*

*Institute of Medicinal and Pharmaceutical Chemistry, Technical University, Braunschweig, Beethovenstrasse 55, Germany

Abstract

This review summarizes the known routes to the title compounds that were formed from cyclization of open-chain precursors and ring transformation of non-tetrazolic heterocycles, i.e. procedures that are not based on ring substitution of the corresponding N-unsubstituted tetrazoles.

■ Synthesis of Alkaloids Using Radical Cyclizations

Tsuyoshi Taniguchi and Hiroyuki Ishibashi*

*School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

This review focuses on radical cyclizations for the synthesis of a variety of alkaloids. Emphasis has been placed on radical cascades that afford synthesis of (−)-cephalotaxine and (±)-stemonamide.

■ Novel Synthesis of Thioalkoxy-Substituted Oxa[9]helicenes by the Reaction of Helical Quinones with Thiols

Mohammad Salim, Takao Kimura, and Michinori Karikomi*

*Department of Material and Environmental Chemistry, Faculty of Engineering, Utsunomiya University, 7-1-2, Yoto, Utsunomiya, Tochigi 321-8585, Japan

Abstract

The reaction of helical quinone with thiols in the presence of Brønsted acid such as HCl, para-toluene sulfonic acid (pTSA), Yb(OTf)3·3H2O or BF3·OEt2 to form resulted in the formation of thioalkoxy-substituted oxa[9]helicenes in moderate to good yields.

■ Synthesis and Biological Activity of Novel Heterocyclic Ring Systems: Imidazo[4’,5’:3,4]pyrido[2,1-a]isoquinolines and Imidazo[4,5-f][3]benzazecines

Robert Otto, Christoph Enzensperger, and Jochen Lehmann*

*Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany

Abstract

Derivatives of two novel heterocyclic ring systems were synthesized and their affinities for dopamine receptors were measured. The compounds were obtained by reacting histamine with 2-(2-bromoethyl)benzaldehyde including an atypical Pictet-Spengler condensation, which afforded basic and not the usual neutral or acidic conditions. The resulting imidazo[4',5':3,4]pyrido[2,1-a]-isoquinoline derivative 4 was Boc protected at the most basic imidazole nitrogen, the isoquinoline nitrogen then quaternized by using methyl iodide and the tetracyclic isoquinolinium salt was both deprotected and cleaved under Birch conditions in one step to give a tricyclic imidazo[4,5-f][3]benzazecine derivative (3) by opening two 6-membered heterocycles towards one 10-membered. Radioligand binding studies showed a significant affinity of the moderately constrained 3 but not of 4 for dopamine receptors. Similar to the analogous indolo-benzazecine LE300, a preference of 3 for the D1 receptor family was observed, but with some loss of affinity over all.

■ One-Pot Synthesis of 2H-Indazolo[2,1-b]phthalazinetrione Catalyzed by Magnetic Room Temperature Dicationic Ionic Liquid under Solvent-Free Conditions

Bijan Mombani Godajdar,* Ali Reza Kiasat, and Mohammad Mahmoodi Hashemi

*Department of Chemistry, Science and Research Branch, Islamic Azad University, P.O. Box 19395-1775 Tehran, Iran

Abstract

The efficient one-pot condensation of aldehyde, dimedone, and phthalhydrazide has been achieved in the presence of a catalytic amount of Fe(III)-based dicationic ionic liquid, [C4(mim)2](FeCl4)2, as a novel environmentally benign magnetic catalyst under solvent-free conditions. The catalyst was easily separated after completion of the reaction and was recycled four times without affecting the catalytic property.

■ A Convenient Methodology for the in situ Oxidation of 4-Substituted Urazoles. Setting Up a One-Pot Procedure for the Efficient Protection of Dienes

María A. Fernández-Herrera, Jesús Sandoval-Ramírez,* Sara Montiel-Smith, and Socorro Meza-Reyes

*Organic Chemistry, Facultad de Ciencias Químicas, Benemerita Universidad Autonoma de Puebla, Blv 14 Sur y Av. San Claudio CU, 72570, Mexico

Abstract

The oxidation of 4-substituted urazoles to the corresponding 1,2,4-triazoline-3,5-diones can be performed selectively in the presence of dienic systems by the action of the nitrosonium ion, formed in situ by stoichiometric amounts of sodium nitrite and acetic acid. This convenient methodology is mild, fast, and allows the efficient protection of dienic systems in a one-pot procedure. The dienes were not affected whatsoever by the nitrosonium ion, and react extremely fast with triazolinediones; promptly forming the corresponding Diels-Alder cycloadducts in good to excellent yields. The reaction medium did not affect steroids having an extra double bond at the side chain or an acid-labile spiroketal moiety.

■ Aurones and Isoaurones from the Flowers of Rosa damascena and Their Biological Activities

Xue-Mei Gao, Li-Ying Yang, Xiang-Zhong Huang, Li-Dan Shu, Yan-Qiong Shen, Qiu-Fen Hu,* and Zhang-Yu Chen*

*Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, School of Chemistry and Biotechnology, Yunnan University of Nationalities, Kunming 650031, China

Abstract

One new aurone, one new isoaurone, damaurones A and B (1 and 2), and five known compounds (3-7) were isolated from the flowers of Rosa damascena. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D- NMR techniques. Compound 1 is the first naturally occurring aurone derivatives bearing an acetyl group. Compounds 1-7 were tested for their anti-HIV-1 activities and cytotoxicities. The results showed that compound 1 has significant potential anti-HIV-1 activity with therapeutic index (TI) values above 80, and showed high cytotoxicities against NB4 and MCF7 cell with IC50 values of 3.4 and 2.6 μM, respectively.

■ Synthetic and Theoretical Approach towards Spirothiazolidinone Systems

Johnson George, Saurabh Singh, Rahul Joshi, Pushpa Pardasani, and Ramchand T. Pardasani*

*Department of Chemistry, Central University of Rajasthan, Bandarsindri, Distt. Ajmer-305802, India

Abstract

A convenient synthesis of spirothiazolidinones by nucleophilic cyclocondensation of intermediate imine with mercaptoacetic acid is described. Computational studies have been performed to substantiate the proposed mechanism as well as to ascertain transition state of the system.

■ Phosphonated Bicycles Bearing a N-N Junction

Elise Villemin, Marie-France Herent, and Jacqueline Marchand-Brynaert*

*Institute of Condensed Matter and Nanosciences (IMCN), Université Catholique de Louvain, Bâtiment Lavoisier, place Louis Pasteur 1, B-1348 Louvain-la-Neuve , Belgium

Abstract

The Diels-Alder reaction between diethyl 1-phosphono-1,3-butadiene and cyclic azo dienophiles, such as 4-phenyl- and 4-methyl-1,2,4-triazoline-3,5-diones and phthalazine-1,4-dione gave access to phosphonated bicyclic cycloadducts with a nitrogen-nitrogen junction. Various fonctionalizations (dihydroxylation, hydrogenation and phosphonic ester deprotection) have been performed with success. The selective N-N cleavage was not possible for the preparation of large heterocycles. The coordination properties of selected bicycles were tested by ESI-HRMS.

■ Synthesis of Tetracyclic Indoline and Indolenine Derivatives Having β-Lactam Using Amphiphilic Reactivity of 2-Methylindolenine

Atsuo Nakazaki, Yukari Hara, Shigeo Kajii, and Toshio Nishikawa*

*Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, Aichi 464-8601, Japan

Abstract

Novel tetracyclic indoline and indolenine β-lactam derivatives were synthesized from 2-methylindolenine β-lactams using the amphiphilic nature of 2-methylindolenine.

■ Further Bisindole Alkaloids from Catharanthus roseus and Their Cytotoxicity

Wei-Ku Zhang, Jie-Kun Xu, Hai-Yan Tian, Lei Wang, Xiao-Qi Zhang, Xu-Zhi Xiao, Ping Li,* and Wen-Cai Ye*

*Department of Pharmacology, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No.2 Ying Hua Dong Lu, ChaoYang District, Beijing, China

Abstract

Two novel bisindole alkaloids, cyclovinblastine A-B (1-2), together with ten known alkaloids 4-deacetoxycyclovinblastine (3), cycloleurosine (4), leurosine (5), vinblastine (6), leurosidine (7), vinblastine N'b-oxide (8), isoleurosine (9), 4'-deoxyleurosidine (10), 4'-deoxyleurosidine N'b-oxide (11) and 4-desacetoxyvinblastine (12) were isolated from the leaves of Catharanthus roseus. The structures of 1 and 2 were established by analysis of their NMR and HR-ESI-MS spectroscopic data. All alkaloids (1-12) were evaluated for their cytotoxic activities against the human hepatocellular carcinoma (HepG2) cell line, human colorectal carcinoma (Lovo) cell line, and human breast carcinoma (MCF-7) cell line by the MTT method in vitro, respectively. The results indicated that cytotoxic activities of alkaloids 9, 10 and 12 were much more potent than those of the positive control vinblastine (6). In addition, the structure-activity relationships (SAR) were conducted on the basis of the cytotoxicity of these isolated alkaloids.

■ Isolation and Structure Elucidation of Alkaloids from Pinellia ternata

Zhihao Zhang, Wenjie Li, Ruichao Lin,* Zhong Dai,* and Xiaofeng Li

*Faculty of Chinese Medicine, Macau University of Science and Technolog, Avenida Wai Long, Taipa, Macau 999078, China

Abstract

A new compound, 3-(6,7-dimethoxyisoquinolin-1-yl)-4,7-dimethoxy-3-methylisobenzofuran-1(3H)-one (1) named alkterlactone was isolated from Pinellia ternata, together with four known compounds N-trans-feruloyloctopamine (2), 2'-O-methyladenosine (3), 5'-S-methyl-5'-thioadenosine (4) and 2'-deoxy-thymidine (5). Compounds 2–5 were isolated for the first time from Pinellia ternata. The structures of these compounds were elucidated and characterized on the basis of 1D NMR, 2D NMR and MS data.

■ Asperelines G and H, Two New Peptaibols from the Marine-Derived Fungus Trichoderma asperellum

Li Chen,* Ping Zhong, Jian-Ru Pan, Kang-Jing Zhou, Kai Huang, Zhe-Xiang Fang, and Qi-Qing Zhang*

*Institute of Biomedical and Pharmaceutical Technology & College of Chemistry and Chemical Engineering, Fuzhou University, NO. 523, Gongye Road, Fuzhou City, 350002, China

Abstract

Two new peptaibols, asperelines G (1) and H (2), together with five known compounds, asperelines A (3), C (4), D (5), E (6), and F (7) were isolated from the marine-derived fungus Trichoderma asperellum. The structures of these compounds were determined through spectroscopic methods, X-ray diffraction analysis, and chemical derivatization. This study is the first report on asperelines with an acetylated C-terminus and a crystal structure.

■ Synthesis of Pyrazoles through Copper-Catalyzed Three-Component Coupling of Aldehydes, Alkynes, and p-Toluenesulfonylhydrazide

Feng Wu, Lu Hao, and Zhuang-ping Zhan*

*College of Chemistry and Chemical Engineering, Department of Chemistry, Xiamen University, 422 Siming Nanlu, Xiamen, Fujian 361005, China

Abstract

A convenient one-pot synthesis of 3,5-disubstitued 1H-pyrazoles through copper-catalyzed three-component of aldehydes, alkynes, and para-tolylsulfonohydrazide has been developed. This method provides a flexible and rapid route to 3,5-disubstituted 1H-pyrazoles.

■ Synthesis, Chemical Properties, and Biological Evaluations of Some Twin-Drug Type C2-Symmetrical Derivatives

Fumiko Fujisaki, Haruka Usami, Saya Nakashima, Sho Nishida, Toshihiro Fujioka, Nobuhiro Kashige, Fumio Miake, and Kunihiro Sumoto*

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

Abstract

We describe the synthesis and chemical properties of newly designed C2-symmetrical twin-drug type aminoguanidines or 4-aminomethyloxazolidinone derivatives (4-7) in which a long chain alkyl group [-(CH2)10-] was used as a linker. Synthesis of some triplet-drug type symmetrical oxazolidinones (8) is also described. Among the tested compounds, the aminoguanidine derivative 4a showed the highest α-glucosidase inhibition activity (IC50 = 76.3 μmol/L).