HETEROCYCLES

■ Contents

■ Rhodanine as a Scaffold: A Short Review on Its Synthesis and Anti-Diabetic Activities

Shaikha S. Alneyadi*

*Department of Chemistry, College of Science, UAE University, Al-Ain, UAE

Abstract

Heterocyclic compounds play an important role in biological processes and synthetic medicinal chemistry, and comprise approximately half of the over 6 million compounds recorded to date in Chemical Abstracts. Owing to their high degree of structural variety, heterocycles have proven to be widely useful therapeutic agents and lead candidates in drug design. In this review, I outline recent studies on the synthesis of the rhodanine core, an important heterocyclic, and the anti-diabetic activities of its derivatives reported between 2007 and 2017.

■ Solvent-Free Microwave Accelerated Synthesis and Structural Characterization of Phthalide-Fused Indolines

Wong Sheryn, Fatimatul Akma Awang Ngah, Jalifah Latip, Nurul Izzaty Hassan, and Siti Aishah Hasbullah*

*School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia

Abstract

The 3-substituted phthalides (3a–3d) were synthesized by coupling reaction of methylenindoline derivatives (1) with 2-formylbenzoic acid derivatives (2), under solvent-free microwave irradiation. The reaction rate enhancement resulted from irradiation has proven to be higher and more efficient compared to the conventional method with an excellent yield of 80–98%. The structures of the phthalides were deduced by their analytical and spectral data (FTIR, UV-Vis, 1H NMR, 13C NMR, LC-MS) and confirmed by chemical crystallography. Compounds 3a and 3b were successfully crystallized in monoclinic system with space group P21/c and C2/c, respectively. The molecular structure consists of fused 1 and 2 groups connected by the enamine carbon.

■ A Novel Tetraphenylethene-Based Fluorescence Probe Based on the Hg2+-Promoted Deprotection of Thioacetal

Jie Ma,* Luliang Yan, Bingkun Chen, and Mengya Sun

*School of Science, University of Shanghai for Science and Technology, Shanghai 200093, China

Abstract

A novel tetraphenylethene-based fluorescence probe compound 1 bearing 1,2-ethanedithiol units linked with tetraphenylethene moiety is synthesized efficiently. Compound 1 exhibit sensitively and selectively to Hg2+ over other metal ions in DMF/H2O solution based on aggregation induced emission (AIE) mechanism. The results show that compound 1 demonstrates an Hg2+-specific bathochromic shift and fluorescent enhancement with a 1:2 reacting stoichiometry. The detection limit of compound 1 for Hg2+ is 2×10-6 mol·L-1.

■ Design, Synthesis, and Biological Evaluation of Novel 8-Methoxyquinolones Bearing Fused Pyrrolidinyl Moieties at the C-7 Position with Potent Antibacterial Activity Against Respiratory Pathogens

Takashi Odagiri,* Hiroaki Inagaki, Masatoshi Nagamochi, Takahiro Kitamura, Satoshi Komoriya, and Hisashi Takahashi

*R&D Division, Daiichi Sankyo CO., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

Abstract

Novel 8-methoxyquinolones bearing fused pyrrolidinyl moieties at the C-7 position were designed, synthesized, and evaluated for their potent antibacterial activity for the treatment of respiratory tract infections. Compound 5, possessing a trans-fused octahydroisoindole ring at the C-7 position of the quinolone scaffold, exhibited potent in vitro antibacterial activity against nosocomial respiratory pathogens including levofloxacin-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus strains. Furthermore, compound 5 showed a favorable pharmacokinetic profile after a single oral administration in rats.

■ A Formal Synthesis of (–)-Kainic Acid by Means of SmI2-Mediated Radical Cyclization

Kazunori Takahashi,* Takumi Ito, Wataru Yamada, Masayoshi Tsubuki, and Toshio Honda

*Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

A formal synthesis of (–)-kainic acid (1) starting from the known D-serine derivative 9 has been established in 14 steps. Construction of all the stereogenic centers on the pyrrolidine core of 1 was successfully achieved by application of SmI2-mediated radical cyclization to the α,β-unsaturated ester having an alkyne moiety, followed by hydroxy group directed diastereoselective hydrogenation over Wilkinson’s catalyst.

■ Preparation of Chiral β-Enamino Esters from Methyl Propiolate: Synthesis of Chiral Methyl 1-Substituted 6-Oxo-1,4,5,6-tetrahydropyridine-3-carboxylates

Hugo Pilotzi, Dino Gnecco,* María L. Orea,* Jorge R. Juárez, David M. Aparicio, and Joel L. Terán

*Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Edif. IC9, Complejo de Ciencias, C. U. 72570 Puebla, Pue., Mexico

Abstract

An efficient procedure to prepare chiral β-enamino esters by reaction of methyl propiolate with chiral amines is described. Aza-annulation of these chiral β-enamino esters with acryloyl chloride afforded the corresponding chiral methyl 1-substituted 6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylates in good yield.

■ One-Pot Synthesis of 2-Substituted 1H-Isoindole-1,3(2H)-dithiones from Secondary Benzothioamides and Isothiocyanates

Kazuhiro Kobayashi,* Daiki Fujiwara, and Miyuki Tanmatsu

*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

The reaction of 2,N-dilithiobenzothioamides, generated from readily available secondary benzothioamides and two equivalents of butyllithium, with isothiocyanates, followed by aqueous workup, gives the corresponding N1,N2-disubstituted benzene-1,2-dicarbothioamides, which undergo intramolecular attack of one of the thioamide nitrogen on the adjacent thiocarbonyl moiety with loss of primary amines to provide 2-substituted 1H-isoindole-1,3(2H)-dithiones.

■ Synthesis of 3-Aroylindoles as Intermediates of Cannabimimetics and Elucidation of Their Physicochemical Properties

Koji Araki, Kosho Makino, Hidetsugu Tabata, Hiroshi Nakayama, Kei Zaitsu, Tetsuta Oshitari, Hideaki Natsugari, and Hideyo Takahashi*

*Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

Abstract

In order to synthesize the intermediates of cannabimimetics, the benzoylation of indoles with 2'/3'/4'-substituted benzoyl chloride in the presence of Et2AlCl was examined. Among the products, we found that the 1H NMR spectra of 3-(2'-substituted)-benzoyl-2-methylindoles had interesting features. We investigated their physicochemical properties based on VT-NMR, and it was revealed that conformer A (s-trans) is present in preference to conformer B in these compounds.

■ Two New Steroidal Alkaloids from the Bulbs of Fritillaria thunbergii

Won Se Suh, Seung Young Lee, Jong Eel Park, Dong Hyun Kim, Sun Yeou Kim, and Kang Ro Lee*

*Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-Ro, Jangan-ku, Suwon, Gyeonggi-do, Korea

Abstract

In the quest for biologically active compounds from natural medicinal sources in Korea, the bulbs of Fritillaria thunbergii were investigated. Phytochemical analysis of the MeOH extracts resulted in the isolation and identification of ten steroidal alkaloids (1–10) including two new compounds, named frithunbol A and B (1 and 2). The structures of these new compounds were elucidated based on 1D, 2D NMR analyses and HR-FAB-MS. All the isolated compounds (1–10) were evaluated for their effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV-2 cells and the neuroprotective effect was determined via induction of nerve growth factor (NGF) in C6 glioma cells. Compounds 2, 3, and 10 significantly inhibited NO levels with IC50 values of 16.35 μM, 11.45 μM and 18.02 μM, respectively. Also, compound 9 was a potent stimulant of NGF release, and enhanced the levels of NGF by 134.81 ± 3.66%.

■ A New Phenolic Compound from Salix glandulosa

Chung Sub Kim, Lalita Subedi, Joonseok Oh, Sun Yeou Kim, Sang Un Choi, and Kang Ro Lee*

*Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea

Abstract

A new phenolic compound, saliglandol (1), was isolated from Salix glandulosa along with 22 known ones. Their chemical structures were established through analyzing spectroscopic data. Comparison of calculated and experimental ECD spectra of 1 resulted in assignment of its absolute configuration. All isolated compounds (1–23) were evaluated for their cytotoxic activities against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, an BT549), anti-inflammatory effects measuring nitric oxide (NO) levels in lipopolysaccharide (LPS)-stimulated murine microglia BV2 cells, and potential neuroprotective effects through induction of nerve growth factor (NGF) in C6 glioma cells.

■ Acid Promoted Metal Free Synthesis of Triazole-Fused Heterocycles via Intramolecular [3+2] Cycloaddition

Youlai Zhang, Mengdi Wang, Junru Li, Qingtong Di, Ziye Tian, Baoquan Chen, 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, China

Abstract

A practical and efficient protocol for the synthesis of triazole-fused heterocycles through intramolecular metal free [3+2] azide-alkyne cycloaddition reaction is described. Range of acids was selected to demonstrate the reaction conditions. Organic azides and propargyl cations generated by acids gave fused triazoles including multivariate rings and heterocycles. Various fused triazoles and bistriazoles were obtained in good yields under mild reaction conditions.