HETEROCYCLES

■ Contents

■ Eudistomin U, Isoeudistomin U, and Related Indole Compounds: Synthesis and Biological Activity

Alexandra A. Kolodina and Olga V. Serdyuk*

*Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, Nikolaus-Fiebiger-Str. 10, Erlangen 91058, Germany

Abstract

Eudistomin U and isoeudistomin U are important derivatives of β-carboline, tryptophan-derived metabolites. These natural products and related 2-substituted 1,2,3,4-tetrahydroeudistomins U demonstrate antibacterial, antimalarial, and anticancer activities, as well as a DNA-binding ability and strong KSP inhibition, that makes them very attractive targets for synthetic chemists. This manuscript highlights advances in the synthesis of eudistomin U, isoeudistomin U, their derivatives, and related compounds bearing an indole unit. A detailed discussion of biological activities, including structure-activity relationships, and future prospects, are also presented.

■ Synthesis of an Analog of Amphidinol 3 Corresponding to the C31–C67 Section

Tomoyuki Koge, Yuma Wakamiya, Makoto Ebine, and Tohru Oishi*

*Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan

Abstract

An artificial analog corresponding to the C31–C67 section of amphidinol 3 (AM3) was designed as a part of the structure–activity relationship studies to elucidate structure requirements for eliciting antifungal activity. To reduce the number of synthetic steps, the 43-deoxy-51-epi derivative containing common tetrahydropyran ring system was designed and synthesized from a pivotal intermediate in 17 steps. The analog elicited no antifungal activity, suggesting that not only the two tetrahydropyran rings, but also polyol section of AM3 are necessary to elicit antifungal activity.

■ Deprotonation of 4-Ethynylpyrazolium Salts

Nils Lennart Ahlburg, Olivia Doppleb, Kai Hillrichs, Jan C. Namyslo, Eike G. Hübner, and Andreas Schmidt*

*Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany

Abstract

4-Ethynyl-1,2-dimethylpyrazolium salts were prepared by methylation of the corresponding 4-ethynyl-1-methylpyrazoles with trimethyloxonium tetrafluoroborate and were deprotonated to give the corresponding pyrazolium-4-acetylenides, which are mesomeric betaines. These can be represented as alkynyl- or mesoionic allenylidene-type resonance forms. Calculations and spectroscopic investigations were performed to determine the contribution of each canonical form to the overall structure. Ylides and N-heterocyclic carbenes are tautomers of the betaines. Their relative stabilities have been compared.

■ Construction of PQQ-Enzyme Multi-Immobilized Electrodes for Electrocatalytic Reduction of Carbonyl Compounds

Yoshitomo Kashiwagi,* Tetsuya Ono, Kentaro Yoshida, Toshinori Ito, and Nobuki Sakurai*

*School of Pharmaceutical Sciences, Ohu University, 31-1 Misumido, Tomita-machi, Koriyama, Fukushima 963-8611, Japan

Abstract

A thin poly(arylamine) (PAA) and poly(acrylic acid) (PAAc) layers-coated graphite felt (GF) electrode immobilizing all mediation components of pyrroloquinolinequinone (PQQ), diaphorase (Dp), oxidized nicotinamide adenine dinucleotide (NAD+) and alcohol dehydrogenase (ADH) to construct a complete bioelectrochemical reactor was prepared and applied to electrocatalytic reduction of carbonyl compounds in a phosphate buffer at constant potential of –0.65 V vs. Ag/AgCl. The carbonyl compounds were reduced to the corresponding alcohols with high current efficiency (97.2 – 100%) and high yield (97.4 – 100%), respectively.

■ Silver-Mediated 2-Arylation/Alkylation/Acylation of Benzothiazoles with Aldehydes in Water

Min Hua, Chunqin Wang, Qixing Liu,* Danyi Chen, Hao Fu, and Haifeng Zhou*

*Research Center of Green Pharmaceutical Technology and Process, Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China

Abstract

An efficient and environmentally benign method was developed for the facile synthesis of various 2-aryl and 2-alkyl substituted benzothiazoles in moderate to good yields, using a silver-mediated redox condensation of benzothiazoles and aldehydes in water. Furthermore, this method is also applicable to prepare 2-acyl benzothiazoles.

■ Synthesis of Bicyclo[2.2.2]octadiene-Fused Sapphyrins and Their Thermal Conversion

Tetsuo Okujima,* Toshiki Abe, Shigeki Mori, Takahiro Nakae, and Hidemitsu Uno

*Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan

Abstract

A series of sapphyrins fused with bicyclo[2.2.2]octadiene were successfully synthesized via [3+1+1] porphyrinoid synthesis. The retro Diels–Alder thermal conversion afforded the corresponding di-, tri-, tetra-, and pentabenzosapphyrins.

■ Synthesis of 5-Hydroxythieno[2,3-d]pyrimidin-6(5H)-one Derivatives by the Reaction of 2-(4-Chloropyrimidin-5-yl)-2-hydroxyalkanoate with Sodium Hydrogensulfide

Kazuhiro Kobayashi,* Ikuma Murayama, Ryoga Ono, Daiki Fujiwara, Hidetaka Hiyoshi, and Kazuto Umezu

*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 convenient sequence for the preparation of 5-hydroxythieno[2,3-d]pyrimidin-6(5H)-one derivatives from 4,6-dichloro-2-(methylsulfanyl)pyrimidine (DCSMP) has been developed. Thus, 4,6-dichloro-5-lithio-2-(methylsulfanyl)pyrimidine, generated by the reaction of DCSMP with lithium diisopropylamide (LDA), was allowed to react with α-keto esters to afford 2-(4,6-dichloropyrimidin-5-yl)-2-hydroxyalkanoate derivatives. These underwent cyclization on treatment with sodium hydrogensulfide to give the corresponding 4-chloro-5-hydroxythieno[2,3-d]pyrimidin-6(5H)-one derivatives. After displacement of one of the two chloro groups of 2-(4,6-dichloropyrimidin-5-yl)-2-hydroxyalkanoate derivatives with methoxy, dialkylamino, or ethyl(or phenyl)sulfanyl groups, the resulting 2-(4-chloropyrimidin-5-yl)-2-hydroxyalkanoates were similarly treated with sodium hydrogensulfide to afford the corresponding desired products.

■ Synthesis and Electrochemical Properties of 2,2’-Biguaiazulene-Based 1,2-Dithiin and Thiophene

Ohki Sato* and Ryuto Sakai

*Department of Chemistry, Graduate School of Science and Engineering, Saitama University, Shimo-okubo 255, Sakura-ku, Saitama 338-8570, Japan

Abstract

The synthesis of diguaiazuleno[3,2-c:2’,3’-e][1,2]dithiin was achieved by the reaction of 2,2’-biguaiazulene with disulfur dichloride/imidazole as a sulfuration reagent. Thermolysis of the dithiin afforded the corresponding desulfurized compound, diguaiazuleno[3,2-b:2’,3’-d]thiophene. Cyclic voltammetry of the S-heterocycles showed one reversible wave at the reduction region, respectively.

■ Water Assisted and Choline Chloride-Dimethylurea Deep Eutectic Salts as Catalyst towards the Attractive Reaction of Indole, Benzaldehyde, and Malononitrile

Hongli Ruan, Yue Lv, Shijun Yu, Chengwei Lv,* and Yue An*

*School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, China

Abstract

The condensation of indole, benzaldehyde, and malononitrile was relatively rigorous compared with other Yonemitsu type reaction. We described a strategy using catalytic amount of choline chloride-dimethylurea deep eutectic salts as cheap and safe accelerator. We also found that introducing right amount of water in reaction system was crucial. This method tolerates variations in all three components to get desired 3-substituted indoles in satisfactory yields.

■ Synthesis of (E)-N-Substituted 1,2-Benzothiazol-3(2H)-imine 1,1-Dioxide Derivatives from Secondary Benzenesulfonamides and 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

A new and simple method for the preparation of (E)-N-substituted 1,2-benzothiazol-3(2H)-imine 1,1-dioxide derivatives has been developed. 2,N-Dilithiobenzenesulfonamides, generated by the treatment of secondary benzenesulfonamides with two equivalents of butyllithium, react with isothiocyanates to afford the corresponding 2-(aminosulfonyl)benzothioamides, which undergo ring closure with a formal elimination of hydrogen sulfide on treatment with thionyl chloride in the presence of two equivalents of pyridine to provide the desired products. Acid hydrolysis of some of these products leads to the formation of N-substituted saccharins.

■ Synthesis and DNA Cleavage Activity of Novel Spiro Pyrazol-3-ones Containing Isoxazoline Moiety

Eiichi Masumoto, Emi Shirouzu, Nobuhiro Kashige, Fumi Okabe-Nakahara, Fumio Miake, Kenji Yamagata, and Hiroshi Maruoka*

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

Abstract

An approach to the synthesis of novel spiro pyrazol-3-ones containing isoxazoline moiety is described. A plausible mechanism for the conversion is proposed. The spiro compounds were formed via potassium carbonate-assisted intramolecular cyclocondensation reaction of β-hydroxy ketoximes, which were prepared from pyrazol-3-ones containing β-hydroxy ketone moiety through an oximation. On the other hand, treatment of the β-hydroxy ketoximes with [hydroxy(tosyloxy)iodo]benzene (HTIB) caused an oxidative N–O coupling reaction to give the spiro pyrazol-3-ones containing isoxazoline N-oxide moiety. All the synthesized compounds were characterized by spectroscopic analysis and were tested for their DNA cleavage activity.