HETEROCYCLES

■ Contents

■ Sixteen-Membered Macrolides: Chemical Modifications and Future Applications

Keiichi Ajito,* Tomoaki Miura, Takeshi Furuuchi, and Atsushi Tamura

*Intellectual Property Department, Meiji Seika Pharma Co., Ltd., 2-4-16, Kyobashi, Chuo-ku, Tokyo 104-8002, Japan

Abstract

To produce a novel macrolide antibiotic, which is biologically stable and effective against erythromycin-resistant Streptococcus pneumoniae constitutively expressing the erm gene, we designed and synthesized a variety of novel macrolides starting from 16-membered macrolides. Initially, metabolically stable 16-membered macrolides were produced by constructing a 4-O-alkylated cladinose moiety as a stable neutral sugar. Then, an arylalkyl group was introduced to the lactone ring to improve the antibacterial activities against resistant S. pneumoniae. Although the novel analogues, which possess an arylalkyl group at the C-3 position or the western hemisphere improved antibacterial activities against inducible resistant and efflux type S. pneumoniae, they did not have sufficient activities against constitutive erm-resistant S. pneumoniae. Further, exploration of a novel macrolactone led to identification of a unique 11-azalide framework. We systematically synthesized 14- to 16-membered azalides and azalactams, and a 16-membered azalide (azalactone) was selected as a template for further medicinal chemistry. Finally, we optimized the connecting position of an arylalkyl group, structure of an arylalkyl moiety, and a neutral sugar moiety, and we synthesized a novel 15-β-substituted 16-membered 11-azalide, which was biologically stable and effective against constitutive erm-resistant S. pneumoniae.

■ Synthetic Studies of Yessotoxin: Iterative Synthesis of the AB Ring System via Pd(II)-Catalyzed Cyclization of Alcohol

Hajime Yokoyama,* Yasuhiro Kusumoto, Koshiro Sumiyoshi, Masahiro Miyazawa, and Yoshiro Hirai*

*Department of Chemistry, Graduate School of Science and Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

We report an iterative synthesis of the AB ring system of yessotoxin by using our Pd(II)-catalyzed cyclization reaction, as an approach towards a total synthesis.

■ Synthesis and Photochemical Properties of 2,4,6-Triaryl-4H-1,4-oxazines

Hongbo Tan, Hongxing Xin, and Hong Yan*

*College of Life Sciences & Bioengineering, Beijing University of Technology, Pingleyuan 100, Chaoyang District, Beijing 100124, China

Abstract

A series of 2,4,6-triaryl-4H-1,4-oxazines was synthesized, and their photochemical properties were studied. The 2,4,6-triaryl-4H-1,4-oxazines underwent photoreaction to N-(1-methoxy-2-oxo-2-arylethyl)-N-arylformamides determined by 1H NMR, 13C NMR, MS, and single crystal X-ray diffraction analyses.

■ Simple Synthesis of New 3-Substituted 4-(3-Chloro-4-fluorophenyl)-1H-pyrrole Derivatives and Their Anticancer Activity in Vitro

Lan Lan, Xiaoping Zhan, Weixi Qin, Zenglu Liu, and Zhenmin Mao*

*School of Pharmacy, Shanghai Jiaotong University , No.800 Dongchuan Road, Minhang District, Shanghai 200240, China

Abstract

The preparation of the new 3-substituted 4-(3-chloro-4-fluorophenyl)-1H-pyrrole derivatives was based on the Van Leusen pyrrole synthesis. In this article, eighteen compounds were readily synthesized in satisfactory to good yields and their cell proliferation inhibiting activities against 2 normal cell lines and 16 cancer cell lines were evaluated. It was particularly important that the new pyrroles displayed barely cytotoxicity against the tested normal cell, which meant these pyrrole analogues might show excellent selectivity towards cancer cell and normal cell. Cell cycle analysis by flow cytometry (FCM) showed that the G0/G1 phase decreased a lot and S phase arrested, in between a minor and transient G2/M block was observed. Cell death induced by 3-cyano-4-(3-chloro-4-fluorophenyl)-1H-pyrrole (2r) was also verified by multiple methods.

■ Synthesis of 2-Deoxy-L-ribose via Palladium(II)-Catalyzed Cyclization

Masahiro Miyazawa,* Erika Akita, Kazusi Onda, Magsarjav Narantsetseg, Haruna Minabe, Hajime Yokoyama, and Yoshiro Hirai*

*Department of Chemistry, Graduate School of Science and Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

We present a total synthesis of 2-deoxy-L-ribose through intramolecular palladium(II)-catalyzed cyclization of aldehyde via an unstable hemiacetal intermediate as the key step.

■ Studies on the Chemical Transformations of Simple Condensates Derived from 3-Formylchromone under Nucleophilic Conditions

Magdy A. Ibrahim* and Nasser M. El-Gohary

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

Abstract

The chemical reactivity of the simple condensates 1 and 2, derived from 3-formylchromone, was studied towards some nucleophilic reactions. Reactions of compounds 1 and 2 with some nucleophilic reagents mainly proceed via nucleophilic addition at the exocyclic vinyl bond followed by either elimination or cyclization during the course of reactions. A variety of products were obtained depending on the substrate and the nucleophile used.

■ The First Total Synthesis of the Antiplasmodial Alkaloid (±)-Cassiarin C Based on a Microwave-Assisted Thermal Azaelectrocyclic Reaction

Yoshinari Tazaki, Yuhta Tsuchiya, Tominari Choshi,* Takashi Nishiyama, Noriyuki Hatae, Hideo Nemoto, and Satoshi Hibino*

*Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

A first total synthesis of the antiplasmodial alkaloid (±)-cassiarin C is described. The key step was a microwave-assisted thermal azaelectrocyclic reaction for the construction of the tricyclic pyrano[2,3,4-ij]isoquinoline core.

■ Synthesis of Quinolizidinone and Indolizidinone Using N-Acyliminium Ion Cyclization and a One-Pot Procedure for Preparation of Benzoquinolizidinone

Punlop Kuntiyong,* Nuanpan Piboonsrinakara, Pijitra Bunrod, Duangkamol Namborisut, Sunisa Akkarasamiyo, Poramate Songthammawat, Chitlada Hemmara, Artid Buaphan, and Boonsong Kongkathip

*Department of Chemistry, Faculty of Science, Silpakorn University, 6 Rajamanka Nai Rd, Muang Nakhon Pathom 73000, Thailand

Abstract

Quinolizidinone, and indolizidinone systems were synthesized in a non-racemic form using cyclization of chiral N-acyliminium ions. The key reactive intermediates were prepared from the corresponding 2-arylethylamine or 3-butenylamine and L-glutamic acid or L-aspartic acid. The stereocenter bearing a dibenzylamino group was used for stereocontrol and resulted in diastereomeric products. A one-pot procedure for synthesis of benzoquinolizidinone was also developed. The dibenzylamino moiety was subsequently converted via Cope elimination to the corresponding cyclic enamide which is suitable as a synthetic precursor for a variety of quinolizidine alkaloids in enantiomerically pure form.

■ Identification, Synthesis and Photo-Protection Evaluation of Arylthiazole Derivatives as a Novel Series of Sunscreens

Guoliang Li, Yundong He, Wenbo Zhou, Peng Wang, Yong Zhang, Weiguang Tong, Haigang Wu, Mingyao Liu, Xiyun Ye,* and Yihua Chen*

*Institute of Biomedical Sciences and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, 500 Dongchuan Rd., Minhang, Shanghai 200241, China

Abstract

A novel series of aryl thiazole derivatives have been designed, synthesized and evaluated in preventing keratinocyte cell (HaCaT) from UVB exposure induced cellar damage. The structure-activity relationship (SAR) was discussed from chemical modification of amide, aryl-thiazole rings and the linker. Preliminary data suggested that four compounds (5a, 11a, 13c and 17) effectively protected Keratinocytes cell from UVB induced cell death compare with positive control polydatin. More importantly, compound 5a significantly protected the dorsal skin of BALB/c-nu mice against UVB-induced decrustation in vivo. The in vitro and in vivo data for these aryl thiazole derivatives suggest further studies for their potential use as photo-protection agents as well as sunscreen candidates.

■ Two New Linear Furanocoumarins from Angelica apaensis

Yong Li, Min Zhang, Min Luo, Xue Wu, Qiuli Xiao, Juan Hua, and Xian Li*

*School of Pharmacy, Kunming Medical University, 1168 West Chun Rong Road, Cheng Gong, Kunming, Yunnan 650500, China

Abstract

Two new linear furanocoumarins, together with 13 known analogues, were isolated from the roots of Angelica apaensis. The structures of new compounds were elucidated by spectroscopic methods including extensive 1D and 2D NMR experiments, as well as high-resolution EI mass analysis. All furanocoumarins obtained were assayed for their cytotoxic ability against K562 and SMMC-7721 human tumor cell lines.

■ Reaction of Fenchone Hydrazone with Diselenium Dibromide: Novel Formation of Bicyclic Diselenide

Kentaro Okuma,* Kazunori Munakata, Hiroyuki Matsui, Noriyoshi Nagahora, and Kosei Shioji

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

Abstract

Bicyclic diselenane containing a norbornane skeleton was synthesized by the reaction of fenchone hydrazone with Se2Br2. Initially formed selenofenchone further reacted with another molar amount of Se2Br2 to afford Wagner-Meerwein rearranged diselenane. Camphor hydrazone also reacted with Se2Br2 to afford the corresponding diselenane, whereas no rearranged product was formed.

■ Anthraquinones from Cassia fistula and Their Anti-Tobacco Mosaic Virus Activity

Yin-Ke Li, Yu-Chun Yang, Ying Qin, Yanlin Meng, Yan-Qing Ye, Hai-Ying Yang, Xue-Mei Gao,* and Qiu-Fen 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 anthraquinones, 9,11-dihydroxy-2-(hydroxymethyl)-5-methyl-4H-naphtho[2,3-h]chromene-4,7,12-trione (1) and 9,11-dihydroxy-2,5-dimethyl-4H-naphtho[2,3-h]chromene-4,7,12-trione (2), together with five known anthraquinones (3-7) were isolated from the stems of Cassia fistula. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1-7 were tested for their anti-tobacco mosaic virus activity. The results showed that compound 7 exhibited high anti-TMV activity with inhibition rate of 35.2%. The inhibition rate is high than that of positive control. The other compounds also showed potential anti-TMV activities with inhibition rates in the range of 15.2 –24.8%, respectively.

■ Facile Synthesis of Glycidates via Oxidation of Acrylates with Aqueous Solution of NaOCl in the Presence of Ammonium Salts

Bungo Ochiai* and Taiki Hirano

*Faculty of Engineering, Department of Chemistry and Chemical Enginnering, Yamagata University, 3-16 Jonan 4-Chome, Yonezawa 992-8510, Japan

Abstract

Various glycidates were obtained in high yields via green oxidation of acrylates with aqueous solution of NaOCl in the presence of ammonium salts. The appropriate choice of ammonium salts fitting to the polarity of the substrates and the reaction under slightly basic conditions were essential for efficient reactions.

■ Synthesis of 6-Aryl-6,7-dihydro-8H-thiopyrano[2,3-b]pyrazin-8-ones by the Reaction of 3-Aryl-1-(3-chloropyrazin-2-yl)prop-2-en-1-ones with Sodium Hydrogensulfide

Kazuhiro Kobayashi* and Ayumi Imaoka

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

Abstract

A convenient process for the preparation of 6-aryl-6,7-dihydro-8H-thiopyrano[2,3-b]pyrazin-8-ones has been developed, which employs the reaction of 3-aryl-1-(3-chloropyrazin-2-yl)prop-2-en-1-ones, derived from 2- chloropyrazine and 3-arylprop-2-enals, with NaSH in DMF at –20 °C.

■ An Improved Synthesis of Di-Nitro-Functionalized trans-A2B2-Tetraphenylporphyrins

Zheng-Lin Zhang, Yuan-Bin She,* Hai-Yan Fu,* Xu-Feng Song, and Zhi-Cheng Sun

*Department of Chemistry & Chemical Engineering, Institute of Green Chemistry & Fine Chemicals, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang District, Beijing 100124, China

Abstract

An improved Macdonald-type 2+2 condensation was used to synthesize a series of di-nitro-functionalized trans-A2B2-tetraphenylporphyrins, and all the structures were characterized by melting point analysis, electronic absorption spectroscopy, infrared spectroscopy, 1H NMR spectroscopy, high-resolution mass spectroscopy, and elemental analysis. The synthesis process was systematically investigated, and several important factors were examined to increase the product yield. The optimum reaction conditions were then established, and the method was found to have the advantages of high reactant concentration, no quinone as oxidant, and good yields of 5,15-bis(p-nitrophenyl)-10,20-bis(p-R-phenyl)porphyrins (R = H, F, Cl, Br, CH3, and CH3O). Moreover, side reactions, such as scrambling, could be suppressed easily by regulating reaction condition.

■ Stereocontrolled Synthesis of the C1-C7 Fragment of Enigmazole A

Takayuki Kishi, Yuka Fujisawa, Hiroyoshi Takamura, and Isao Kadota*

*Graduate School of Natural Sciences and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

An enantio- and stereoselective synthesis of the C1-C7 fragment of enigmazole A is described. The three asymmetric centers of the molecule were constructed efficiently by using Evans chiral auxiliary protocol.