HETEROCYCLES

■ Contents

■ Development of a Glycosylation Reaction: A Key to Accessing Structurally Unique Nucleosides

Yuichi Yoshimura*

*Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

Nucleosides are potential drug candidates for antitumor and antiviral chemotherapies. Thus, the synthesis of structurally diverse nucleosides would contribute to the search for new antitumor and antiviral agents. The use of the glycosylation reaction to synthesize nucleoside derivatives would be a practical way to prepare nucleosides with unnatural sugar moieties. Therefore, we synthesized many nucleoside derivatives by using new glycosylation reactions categorized into three types: 1) a Pummerer-type glycosylation reaction used for constructing 4’-thionucleoside skeletons, 2) a sulfur-assisted Mitsunobu reaction used for isonucleoside syntheses, and 3) an oxidative coupling reaction catalyzed by hypervalent iodine for carbocyclic nucleosides and in the syntheses of dihydropyranonucleosides. In this review, we describe the development of the glycosylation reactions and their application to the synthesis of various structurally unique nucleoside derivatives.

■ Antiviral Activities of Some New 2,4,6-Trisubstituted 1,3,5-Triazines Having Alkoxy and/or Alkylamino Groups

Nobuko Mibu, Kazumi Yokomizo, Ai Yuzuriha, Marie Otsubo, Yuna Kawaguchi, Marina Sano, Izumi Sakai, Keita Nakayama, Jian-Rong Zhou, and Kunihiro Sumoto*

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

Abstract

We report the preparation of C3- and CS-symmetrical 2,4,6-trisubstituted 1,3,5-triazine derivatives having alkoxy and/or alkylamino groups and results of biological evaluation of their anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. New targeted symmetrical molecules were obtained by using a method starting with 2,4,6-trichloro-1,3,5-triazine (1). Among the synthesized compounds, CS-symmetrical tri-aliphatic alkylamino-substituted compound 6s showed high anti-HSV-1 activity (EC50 = 5.4 μM) and low cytotoxicity (CC50 > 200 μM). The results of an SAR study suggested that the presence of two hydrogen bond donor protons of sec-amine functionality in the molecule is an important structural factor for expression of potential anti-HSV-1 activities.

■ Synthesis of 2,3-Dihydrobenzo[b]thiophen-3-amine 1,1-Dioxide Derivatives via LDA-Mediated Cyclization of o-(Alkylsulfonyl)benzyl Azides with Denitrogenation

Kazuhiro Kobayashi,* Yuuki Chikazawa, and Takashi Nogi

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

Abstract

A new and efficient method for the synthesis of 2,3-dihydrobenzo[b]thiophen-3-amine 1,1-dioxide derivatives has been developed. Thus, treatment of o-(alkylsulfonyl)benzyl azides, which are readily obtainable from commercially available starting materials by easily operational sequences, with lithium diisopropylamide (LDA) in THF at –78 ˚C gives, after aqueous workup, 2,3-dihydrobenzo[b]thiophen-3-amine 1,1-dioxides. These products can be isolated in moderate to fair yields after N-protection with acylating agents.

■ Synthesis of Highly Substituted 5,6-Dihydrobenzo[j]phenanthridine Derivatives via Domino Reaction

Yuqin Wu, Lidong Li, Liangyun Yu, Zhang Qi, Feng Xue, and Xu Qi*

*School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Jianjun East Road No. 211, Yancheng 224051, China

Abstract

An atom-economical method for diynes with aryl halides under palladium-catalyzed conditions has been developed. Using unactivated simple diynes with aryl halides in the presence of palladium catalytic system afforded various 7,12-diphenyl-5-tosyl-5,6-dihydrobenzo[j]phenanthridine derivatives through C–C coupling and C–H bond activation in one step. This cascade reaction was initiated by an intermolecular [2 + 2 + 2] cycloaddition.

■ An Efficient Synthesis of 1-Arylbenzo[c]thiophenes via the Reaction of 2-(Chloromethyl)phenyllithiums with Aromatic Aldehydes

Kazuhiro Kobayashi,* Yuuya Honda, and Yuuho Shigemura

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

Abstract

A simple and efficient sequence for the preparation of 1-arylbenzo[c]thiophenes has been developed. Thus, 2-(chloromethyl)phenyllithiums, generated by treating 2-(chloromethyl)phenyl bromides with butyllithium, are allowed to react with aromatic aldehydes to afford the corresponding diarylmethanol derivatives. These alcohols are oxidized with pyridinium chlorochromate (PCC) to give aryl[(2-chloromethyl)phenyl]methanones, of which treatment with sodium hydrogensulfide gives 1-aryl-1,3-dihydrobenzo[c]thiophen-1-ols. Dehydration of these crude alcohols to the desired products can be accomplished by the treatment with a catalytic amount of p-toluenesulfonic acid.

■ A New Fluorescence Chemosensor for Hg2+ Based on Carbazole and Thiourea

Fang-fang Yin, Wei-ju Zhu, Min Fang, Zhen-yu Wu, Ying Xu, Hai-lun Wang, Yao Wang, and Cun Li*

*School of Chemistry and Chemical Engineering & Anhui Province Key Laboratory of Environmental-friendly Polymer Materials, Anhui University, Hefei 230601, China

Abstract

A new thiourea-based Schiff-base (L) as a fluorescent chemosensor has been designed and synthesized, which exhibits selectivity toward Hg2+ by forming a 1:2 compound based on the method of Job’s plot. The detection limit was calculated to be 6.5×10-6 mol/L. The prominent recognizable changes of L could be observed by the naked eyes and fluorescence sensing conditions. The color of the L solution changed instantly from colorless to yellow after adding Hg2+ and returned to colorless by adding I–. The coordination reaction was reversible.

■ A Cytotoxic Pyranonaphthoquinone from Cultured Lichen Mycobionts of Haematomma sp.

Yukiko Takenaka, Yoshiyuki Mizushina, Nobuo Hamada, and Takao Tanahashi*

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

Abstract

Spore-derived mycobionts of the lichen Haematomma sp. were cultivated on malt-yeast extract medium supplemented with 10% sucrose to produce a new pyranonaphthoquinone, 4, as well as two known compounds (-)-usnic acid (2) and 5-deoxy-7-methylbostrycoidin (3). The structure of 4 was determined by spectroscopic methods. The inhibitory activities of 3, 4, and 6–8 against mammalian DNA polymerases (pols) and cytotoxic effects against a HeLa human cervical cancer cell line were also evaluated. Compound 4 showed the strongest mammalian pol inhibitory activity and cytotoxicity (ID50 = 6.7 μM) among the tested compounds.

■ Catalyst-Free Multicomponent Formation of Novel Acylpyrrole-Containing 6-Iminohexahydro-1H-pyrido[1,2-a]pyrimidine Derivatives

Xiaohua Wu, Zheng Zhao, Yuwei Song, and Cheng Guo*

*College of Chemistry and Molecular Engineering, Nanjing Tech University, 30 Puzhu South Road, Jiangsu, Nanjing, 211816, China

Abstract

A simple and green synthesis of acylpyrrole-containing 6-iminohexahydro-1H-pyrido[1,2-a]pyrimidine derivatives were successfully prepared via four-component reaction of 1,1-bis(methylthio)-2-nitroethene, propane-1,3-diamine, 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanenitrile and aromatic aldehydes in ethanol under microwave irradiation. This method offers several significant advantages, including green solvent, avoidance of catalysts, high-speed reaction, outstanding selectivity, tremendous substrate diversity and no column chromatographic purification.

■ Novel C2-Symmetrical Phenylboronic Acid Pinacol Esters with a Few Types of Linkers and Their Biological Activities

Makoto Furutachi, Toshiaki Gondo, Saho Goto, Saho Fuchigami, Kenta Ako, Yuki Oowada, Kazumi Yokomizo, Jian-Rong Zhou, Tomohiro Ishizaki, Takahiro Koga, 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 report the preparation of new C2-symmetrical cyclic phenylboronic acid derivatives and their biological activities. New targeted C2-symmetrical molecules (1) were obtained in good to excellent yields by a primitive amide bond formation reaction using the reported method starting with amino-substituted phenylboronic acid pinacol esters 2. A few C2-symmetrical phenylboronic acid ester analogues such as 5 and 7 that have two urea groups in the linker junction were also prepared in order to evaluate antibacterial and antiviral activities. The results of a structure-activity relationship study are also described.

■ One-Pot Synthesis of 2-Substututed 3-Thioxo-2,3-dihydro-1H-isoindol-1-ones by the Reaction of N-Substituted 2,N-Dilithiobenzamides with Isothiocyanates

Kazuhiro Kobayashi* and Daiki Fujiwara

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

Abstract

This paper describes an efficient one-pot method for the preparation of 2-substituted 3-thioxo-1H-isoindol-1-ones (3-thioxoisoindolinones) by the reaction of N-substituted 2,N-dilithiobenzamides, generated by treating N-substituted benzamides with two equivalents of butyllithium, with the respective isothiocyanates followed by ring closure of the resulting N-alkyl(or aryl)-2-(alkyl(or aryl)thiocarbamoyl)benzamide derivatives with loss of alkyl(or aryl)amines.

■ Secalonic Acids H and I, Two New Secondary Metabolites from the Marine-Derived Fungus Penicillium oxalicum

Li Chen, Yan-Xue Bi, Ya-Ping Li, Xin-Xin Li, Qin-Ying Liu, Min-Gang Ying, Qiu-Hong Zheng, Lin Du,* and Qi-Qing Zhang*

*Institute for Natural Products Applications and Research Technologies, Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States

Abstract

Two new secalonic acid derivatives, secalonic acids H and I (1 and 2), and one known compound, secalonic acid D (3), were isolated from the marine-derived fungus Penicillum oxalicum. The planar structures and relative configurations of the new compounds were elucidated by the analyses of their 1D and 2D NMR and high-resolution mass spectrometric data. The absolute configurations were established by comparison of their experimental and calculated electronic circular dichroism spectra. The in vitro cytotoxic activities of compounds 1 and 2 were evaluated against selected human cell lines.

■ Synthesis of Fused 1,2,3-Triazoles through Carbocation-Mediated Intramolecular [3+2] Cycloaddition of Azido-propargyl Alcohols

Youlai Zhang, Junru Li, Mengdi Wang, Huan Zhang,* Hiroki Tanimoto, Tsumoru Morimoto, and Kiyomi Kakiuchi

*Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion, School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, P.R. China

Abstract

A practical and efficient intramolecular cyclization reaction with azido-propargyl cations is described. Range of acids and activating reagents were selected to demonstrate the reaction conditions. Organic azides and propargyl cations generated by toluenesulfonic acid gave fused 1,2,3-triazoles undergo metal-free intramolecular azide–alkyne [3+2] cycloaddition reactions. Various fused triazoles were obtained within 30 min in good yields under mild reaction conditions.