HETEROCYCLES

■ Contents

■ Syntheses of Heterocycles via Alkyne Cycloadditions Catalyzed by Cyclopentadienylruthenium-Type Complexes

Yoshihiko Yamamoto*

*Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan

Abstract

Transition-metal catalysis not only simplifies molecular assemblies by reducing the synthetic steps but also decreases waste production, thus accomplishing an efficient and environmentally benign synthesis of heterocycles. Ruthenium catalysis has made significant progress in the past decades, and its application to heterocycle synthesis has become one of the major research topics. In particular, organoruthenium complexes with a cyclopentadienyl-type ligand have been successfully utilized in various carbon-carbon and carbon-heteroatom bond formations. This review extensively surveys the synthetic methods of five- and six-membered heterocycles via the ruthenium-catalyzed cycloadditions of alkynes with other unsaturated compounds. The applications of the ruthenium-catalyzed heterocycle synthesis are also briefly outlined.

■ SYNTHESIS OF CIS OR TRANS 4-HETEROAROMATIC SUBSTITUTEd FURANO AND PYRANO[3,2-C]TETRAHYDROQUINOLINES BY ONE-POT IMINO DIELS-ALDER REACTIONS

Rui Zhou, Wei Huang, Wen Ren, Li Guo,* Shi Zeng, Pan Liu, Liang Ouyang, Xiangrong Song, Cheng Peng, and Gu He*

*West China Hospital, Sichuan University, No.17 3rd section, People's Road South 610041, China

Abstract

A mild and an efficient method for the synthesis of substitute furano and pyrano[3,2-c]tetrahydroquinoline derivatives was described, using the imino Diels-Alder reaction between 2-(4-aminophenyl)benzofuran, aromatic aldehyde, and cyclic enol ethers. Furthermore, 2-hydroxyalkyl-4-heteroaromatic substituted tetrahydrofurano[3,2-c]quinoline was synthesized with good yields through the same imino Diels-Alder reaction in the absence of aldehydes. The advantages of this procedure are mild reaction conditions, and good yields with high diastereoselectivity.

■ DIOSPENTENOLS A AND B, TWO NEW CYCLOPENTAPYRANS ISOLATED FROM ABANDONED MINE BACTERIUM STREPTOMYCES SP. KMA-001

Jin-Soo Park, Jin Wook Cha, Seong-Hwan Kim, Dong-Chan Oh, and Hak Cheol Kwon*

*Natural Medicine Center, Korea Institute of Science and Technology, 679 Saimdang-ro, 210-340, Korea

Abstract

Two new cyclopentapyrans, diospentenols A and B were isolated from the Streptomyces sp. KMA-001 which was isolated from a heat-treated soil sample collected at the abandoned zinc mine. Spectroscopic analyses including extensive 2D NMR spectra, mass spectrometry, and chemical modification revealed structures of diospentenols consisted of 7,7a-dihydro-2H- cyclepenta[b]pyran-6-one core with a hydroxyl group and allyl side chain. This carbon skeleton is rare in natural products reported in the literature. Diosphenol, previously isolated from marine sponge and ascidian, is one of a few known natural products that possess this structural core. Each diospentenol was verified as a racemate using the modified Mosher method and chiral HPLC analysis.

■ SYNTHESIS AND BIOLOGICAL EVALUATIONS OF A SERIES OF NOVEL AZOLYL, AZINYL, PYRANYL, CHROMONYL AND AZEPINYL PHOSPHONATES

Tarik E. Ali,* Salah A. Abdel-Aziz, Somaya M. El-Edfawy, El-Hossain A. Mohamed, and Somaia M. Abdel-Kariem

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt

Abstract

facile synthetic methodology of novel azolyl, azinyl and azepinyl phosphonates as cyclic α-aminophosphonates was described. Chromonyl α-aminophosphonates, γ-pyranyl and γ-pyridinyl phosphonates were also prepared. The methodology depends on reaction of 6-methyl-3-formylchromone, nitrogen and carbon nucleophiles in the presence of diethyl phosphite in one-pot three component under solvent-free conditions. The products were evaluated for their antimicrobial activities and antioxidant properties.

■ 4-Trifluoroacetyl-2-phenyloxazol-5-one: Versatile Template for Synthesis of Trifluoromethyl-Substituted Heterocycles

Ryosuke Saijo, Ken-ichi Kurihara, and Masami Kawase*

*Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan

Abstract

4-Trifluoroacetyl-2-phenyloxazol-5-one (1) is a versatile template for the synthesis of various trifluoromethyl-substituted heterocycles. Cyclocondesation of 1 with hydroxylamine and hydrazine afforded isoxazole and pyrazole, respectively. Another key protocol involves nucleophilic ring opening of 1 with H2O or MeOH to give α-amido trifluoromethylketones which are transformed into trifluoromethyl-substituted thiazoles, oxazoles, imidazoles, pyrazoles, and pyrimidines.

■ Synthesis of Nigricanin via Intramolecular Biaryl Coupling Reaction of Functionalized Phenol Benzoate

Takuya Matsukihira, Tatsuya Kida, Kei Hidaka, Shumpei Saga, Mami Takemura, Atsuro Yonoki, Tsuyoshi Nishimori, Yoshikazu Horino, Takashi Harayama, Yasuo Takeuchi, and Hitoshi Abe*

*Department of Environmental Applied Chemistry, Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

A tetracyclic natural product, nigricanin (1), was synthesized through an intramolecular biaryl coupling reaction of the phenyl benzoate derivative which was derived from the corresponding phenol and benzoic acid.

■ Iminophosphoranes in Heterocyclic Synthesis: Synthesis of Pyrazolo[1,5-a]pyrimidine, Imidazo[1,2-b]pyrazole and Pyrazolo[1,5-b][1,2,4]triazine Derivatives via Intermolecular Aza-Wittig Reactions

Mohamed Abdelmonem Raslan, Mohamedaly Aly Khalil, and Samia Mohamed Sayed*

*Department of Chemistry, Faculty of Science, Aswan University, Aswan 81528, Egypt

Abstract

Series of pyrazolo[1,5-a]pyrimidine derivatives, imidazo[1,2-b]pyrazole derivative and pyrazolo[1,5-b][1,2,4]triazine derivatives were obtained by the initial reaction of 5-(triphenylphosphoranylideneamino)-1H-pyrazole derivative with carbonyl compounds and hydrazonyl halides. The newly synthesized compounds were confirmed by spectral and analytical data.

■ A Convenient Synthesis of 9H-Thioxanthen-9-ones and Their Aza-Analogues

Kazuhiro Kobayashi,* Toshihide Komatsu, Kazuhiro Nakagawa, Erika Hara, and Shohei Yuba

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

Abstract

An efficient method for the preparation of 9H-thioxanthen-9-ones and their three aza-analogues has been developed. The reaction of (2-fluorophenyl)(2-halophenyl)methanones, derived from 1-bromo-2-fluorobenzens and 2-halobenzaldehydes by an easy two-step sequence, with Na2S·9H2O in DMF at 60 °C gives 9H-thioxanthen-9-ones. This procedure can be applied to the synthesis of 5H-[1]benzothiopyrano[2,3-b](or [2,3-c])pyridin-5-ones or 10H-[1]benzothiopyrano[3,2-c]pyridin-10-ones starting from 2-, 3- or 4-chloropyridines, respectively.

■ Synthetic Exploitation of Halogenated Alkenes Containing Electron-Withdrawing Group (EWG): Access to Valuable 2,4-Dinitrothiophenes via Ring-Closing and Ring-Opening/Ring-Closing Protocols

Amac Fatih Tuyun*

*Department of Chemical Engineering, Engineering and Architecture Faculty, Beykent University, 34396, Turkey

Abstract

With the goal of their exploitation for the synthesis of highly functionalized 2,4-dinitrothiophenes, 2-(2,3-dichloro-1,3-dinitroallylidene)-1,3-dithiolane (2a), derived from the initial ring-closing of polyhalogenated nitrobutadienic building blocks with 1,2-ethanedithiol, were reacted with secondary amines. After protic work up, highly functionalized 2,4-dinitrothiophenes have been accomplished via ring-opening/ring-closing protocols.

■ A MILD AND CONVENIENT ONE-POT SYNTHESIS OF 4,6-DIARYL-3-AMINOISOXAZOLO[3,4-B]PYRIDINES

Chun-Bao Miao,* Yan-Hong Wang, Chun-Ping Dong, Hai-Tao Yang, Qi Meng, and Xiao-Qiang Sun

*School of Petrochemical Engineering, Changzhou University, Gehu Road 1#, Wujin Area, Changzhou City, China

Abstract

We developed a convenient method for the synthesis of a series of new 4,6-diaryl-3-aminoisoxazolo[3,4-b]pyridines through one-pot reaction starting from the easily available chalcones, malontrile, and hydroxylamine. This class of compounds might have potential pharmacological activities in medicinal chemistry.

■ Design, Synthesis, and Biological Evaluation of 7H-Thiazolo[3,2-b]-1,2,4-triazin-7-one Derivatives as Dual Binding Site Acetylcholinesterase Inhibitors

Si-Jie Liu, Li-Bo Cui, Hiu-Lan Xu, Tie-Ying Wang, Chun Hu,* Shuo Li, Huang-Quan Lin, and David Chicheong Wan

*Department of Organic Chemistry, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenhe District, Shenyang 110016, China

Abstract

A series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors. The target compounds exhibited promising inhibitory activity for AChE. The structure-activity relationships were discussed and their binding conformation and simultaneous interactions mode were further clarified by the molecular docking studies.

■ Iriomoteolides-4A and -5A, Hydrophilic Macrolides from Marine Dinoflagellate Amphidinium species

Keiko Kumagai,* Masashi Tsuda,* Eri Fukushi, and Jun Kawabata

*Science Research Center, Kochi University, Oko Kohasu, Nankoku, Kochi 783-8506, Japan

Abstract

Two new macrolides, iriomoteolides-4a (1) and 5a (2), have been isolated from a marine benthic dinoflagellate Amphidinium sp. (strain HYA024), and the structures was assigned by detailed analyses of 2D NMR data. Iriomotelide-4a (1) is a 16-membered macrolide with five hydroxyl groups on the lactone ring and an isoprenoid-like side chain, while iriomoteloide-5a (2) is a 20-membered macrolide with five hydroxyl groups and three vicinally-located C1 branches. Iriomoteolides-4a (1) and 5a (2) exhibited moderate cytotoxic activity against antitumor cells.

■ Cytotoxic Xanthones from Hypericum chinense

Yinke Li, Yong Xu, Jia Wu, Sujuan Wang, Yanlin Meng, Yanqing Ye, Haiyin Yang, Xuemei Gao, and Qiufen Hu*

*Key Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs Commission & Ministry of Education, School of Chemistry and Biotechnology, Yunnan University of Nationalities, Kunming, Jingming South Road, Chenggong New District, Kunming, Yunnan 650500, China

Abstract

Two new xanthones, 1-hydroxy-4-(2-hydroxyethyl)-3,8-dimethoxy-9H-xanthen-9-one (1) and (S)-1-hydroxy-4-(1-hydroxy-3-oxobutyl)-3,8-dimethoxy-9H-xanthen-9-one (2), together with three known xanthones (3-5) were isolated from the leaves and stems of Hypericum chinense. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1-5 were tested for their cytotoxicity against five human tumor cell lines (NB4, A549, SHSY5Y, PC3, and MCF7). The results revealed that compound 1 showed high cytotoxicity against A549 and PC3 cell with IC50 values of 2.8 and 3.4 μM, and 2 showed high cytotoxicity with IC50 valves of 2.8 μM, respectively.

■ A New Total Synthesis of (±)-α-Noscapine

Yongjun Mao, Shuai Song, Dongmei Zhao,* and Maosheng Cheng

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

Abstract

A new, convergent total synthesis of (±)-α-noscapine was developed on a grams scale through the condensation of 3-trimethylsilyl meconin derivative 9 and the iodized salt cotarnine derivative 20 as the key step. Staring from simple 2,3-dimethoxybenzoic acid, piperonal and 2,2-dimethoxyethanamine, through the traditional chemical processes to give the final product in 11.6% yield over 14 steps.

■ A Versatile Method for the Synthesis of Fluorine-Containing Chloroquine Analogues Starting from 7-Chloro-4-(N,N-dimethylamino)quinoline Using Nucleophilic N-N, N-S, and N-O Exchange Reactions

Norio Ota, Mizuki Hatakenaka, Takuro Ashida, and Etsuji Okada*

*Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

A new synthetic method was developed to access fluorine-containing chloroquine analogues which have unique potentials contributing to the discovery of novel anti-microorganisms. (7-Chloro-3-trifluoroacetylquinolin-4-yl)amines (7), thiols (8), and ethers (9) were easily synthesized in high yields by the trifluoroacetylation of 7-chloro-4-(N,N-dimethylamino)quinoline (6) with 1-trifluoroacetyl-4-dimethylaminopyridinium trifluoroacetate followed by the nucleophilic N-N, N-S, and N-O exchange reactions.

■ 3,4-Dihydro-2H,5H-pyrano[3,2-c]chromene and Benzophenone Derivatives from Cultured Lichen Mycobionts of Vietnamese Graphis sp.

Yukiko Takenaka,* Shota Taguchi, Duy Hoang Le, Nobuo Hamada, and Takao Tanahashi

*Organic chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan

Abstract

Spore-derived mycobionts of the lichen Graphis sp. collected in Vietnam were cultivated on a malt-yeast extract medium supplemented with 10% sucrose and their metabolites were investigated. Two new phenolic compounds 2 and 3 were isolated along with proserin A (1). Their structures were determined by spectroscopic methods.