HETEROCYCLES

■ Contents

■ Understanding the Diversity and Molecular Basis of Biosynthesis of Heterocyles in Natural Products Produced by Actinobacteria

Yohei Katsuyama*

*Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan

Abstract

Many of the natural products produced by actinomycetes have useful biological activities including antibiotic, antitumor and immunosuppressant activities, reflecting their structural diversity. In addition, many of them have heterocyclic rings in their structures, and these rings are considered to be important for their biological activities. Various chemical reactions and enzymes catalyzing them are used for their formation reactions. In this review, our recent examples of biosynthetic studies on the natural product with heterocycles in actinomycetes are summarized. These include indoline and tetrahydroquinoline ring formation using the nitrene-forming reaction found in the biosynthetic pathway of benzastatin, oxazoline ring formation in nonribosomal peptide synthetases and polyketide-derived piperidine alkaloid biosynthesis. These studies are expected to provide novel insights into enzyme chemistry as well as a new idea for synthetic organic chemists.

■ An Efficient Catalyst-Free Synthesis of Vinyl Sulfides in Aqueous-Phase

Jiewei Rong and Haiying Wang*

*School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, P. R. China

Abstract

An efficient catalyst-free synthesis of vinyl sulfides via the Michael addition of thiol compounds and tetrolic acid ester (or methyl propiolate) in water were carried out in good yields. The products were identified by IR, 1H NMR and HRMS techniques. The structures of 5b, 6b and 8a were confirmed by X-ray diffraction analysis further. This protocol has the advantages of shorter reaction time, mild conditions, easy work-up and environmental friendliness.

■ Ultrasound-Promoted Kabachnik–Fields Synthesis of Novel Chromonyl α-Aminophosphonate Derivatives Incorporating Nitrogen Heterocycles Using CdI2 Nanoparticles as an Efficient Catalyst: Evaluation of Their Antifungal Properties

Mohamed Hussien, Tarik E. Ali,* Ibrahim El-Tantawy El Sayed, Abdelaleem Hassan Abdelaleem, and H. M. Torkey

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

Abstract

Synthesis of some novel chromonyl α-aminophosphonate esters clubbed with nitrogen heterocycles, was achieved. The methodology based on one-pot three-components reaction of 4-oxo-4H-chromene-3-carboxaldehydes, N-aminoheterocycles and diethyl phosphite in the presence of CdI2 nanoparticles as an efficient catalyst under conventional heating at 80 oC or ultrasound (US) irradiation at 50 oC. The mild reaction conditions, operational simplicity and excellent yields are the essential advantages of this protocol. The antifungal properties of the products were evaluated. Most of them recorded inhibitory effects towards plant pathogenic fungi nearly to the standard control. The hybridization between diethyl α-aminophosphonate and 6-methylchromone moieties with antipyrine, morpholine or 1,2,4-triazine in one molecular frame led to promising antifungal agents against plant pathogenic fungi.

■ Synthesis and in vitro Triglyceride-Lowering Activity of 2,3-Disubstituted Berberine Derivatives

Hualin Zhang, Yue Wang, Weicong Zhang, Zhixiong Li, and Weina Han*

*Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China

Abstract

Twenty-six 2,3-disubstituted berberine derivatives were designed, synthesized, and evaluated for their triglyceride-lowering activities in vitro. The results showed that most 2,3-disubstituted berberine derivatives had triglyceride-lowering activities in HepG2 cells. Among these compounds, compound 3c had the highest triglyceride-lowering activity with an inhibition rate of 63%, much higher than berberine. Therefore, we believed that forming an octatomic ring at R1 and R2 in berberine might be beneficial for triglyceride-lowering activity, which will provide a new idea for the development of berberine-like lipid-lowering agents with new structures.

■ Visible-Light-Induced Formal [3+2] Cycloaddition of α,β-Unsaturated Imides or Amide with N,N,N',N'-Tetramethyldiaminomethane for the Synthesis of 4-Alkyl- and 4-Aryl-1-methyl-2-pyrrolidinones

Kennosuke Itoh,* Sho Ito, Shun-ichi Nagao, Ken Tokunaga, Takaaki Mizuguchi, Fumika Karaki, Shigeto Hirayama, Yoshio Shibagaki, Masashi Hashimoto, and Hideaki Fujii*

*Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Abstract

We present herein a photochemical reaction to synthesize 4-alkyl- and 4-aryl-1-methyl-2-pyrrolidinones through the formal [3+2] photocycloaddition of α,β-unsaturated imides or amide with N,N,N',N'-tetramethyldiaminomethane, where an iridium(III) complex acts as a photosensitizer. The reaction is driven by visible-light-induced single-electron transfer between a photoexcited iridium(III) complex and N,N,N',N'-tetramethyldiaminomethane to generate an α-aminoalkyl radical. The resulting α-aminoalkyl radical is added to α,β-unsaturated imides or amide in a 1,4-fashion to produce conjugate adducts, subsequently causing intramolecular acylation to furnish 4-alkyl- and 4-aryl-1-methyl-2-pyrrolidinones.

■ 4-Amino-3-formylcoumarin as Building Block for Construction of Novel Heteroannulated Coumarins: Synthesis, Characterization and Antimicrobial Evaluation

Najla A. Alshaye and Magdy A. Ibrahim*

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Heliopolis 11757, Cairo, Egypt

Abstract

The chemical reactivity of 4-amino-3-formylcoumarin (1) was examined towards a diversity of carbon nucleophilic reagents as well as isomeric cyclohexanediones. A variety of heterocyclic compounds namely chromeno[4,3-b]pyrazolo[4,3-e]pyridines, chromeno[4,3-b]benzo[1,6]naphthyridine, chromeno-[4,3-b]quinoline and bis[1]chromenophenanthrolines were efficiently synthesized. Chromeno[4,3-b]quinoline 6 upon Vilsmeier-Haack formylation afforded the novel β-chloroenaldehyde 10 which used as a key intermediate for buliding a diversity of polyfused systems conatining coumarin moiety. Antimicrobial evaluation of the tested compounds showed excellent efficiency especially compounds 2-5, 12 and 14. On the basis of spectral and analytical analysis, the structures of the new products were determined.

■ Mechanochemical Rapid Synthesis of Novel Thiazoles Linked to 2H-Chromen-2-one Moiety

Tamer S. Saleh,* Abdullah S. Al-Bogami, Faisel M. Aqlan, and Omar A. Almaghrabi

*Department of Chemistry, College of Science, University of Jeddah, Jeddah 21959, Saudi Arabia

Abstract

A green mechanochemistry synthesis protocol achieved a one-pot synthesis of novel thiazoles linked to 2H-chromen-2-one. Chemical transformations were performed in a ball mill without requiring bulk dissolution of reactants. Using a simple one-pot reaction, the compounds were synthesized with good yields and in a short reaction time. Under ball-milling conditions, thiosemicarbazide, 3-(bromoacetyl)-2H-chromen-2-one, and aromatic aldehyde were milled in a three-component one-pot reaction utilizing silica triflate (STF) as solid acid catalyst. The reactions were completed in 20 min in 90-98% yields. The catalyst STF show good sustainability in which reused for six runs.  1H NMR, 13C NMR, and mass spectroscopy were used to characterize the synthesized compounds.

■ One-Pot Synthesis of N-Substituted 2-Aminothiazole Derivatives and in vitro Antibacterial Activity

Nga Hang Thi Phan,* Van-Hieu Mai, and Xuan Minh Thi Nguyen

*The University of Danang, School of Medicine and Pharmacy, Danang 50000, Vietnam

Abstract

A facile one-pot procedure for the synthesis of N-substituted 2-aminothiazoles under either conventional heating or microwave irradiation conditions is described. This approach efficiently produces N-substituted 2-aminothiazoles from 2-amino-4-arylthiazoles and aryl aldehydes in moderate to excellent yields. In general, the microwave-assisted method results in better yields (40–94%) compared to the conventional heating method (42–83%). The synthesized compounds are tested in vitro for the evaluation of antibacterial activity. Four compounds (4g, 4h, 4i, and 4j) exhibit growth inhibitory activity against tested bacterial strains with minimum inhibitory concentration (MIC) values in the range of 1–44 μg/mL.

■ Synthesis and Characterization of 6-Chloro-N-(substituted benzylidene)benzothiazol-2-amine by Microwave Irradiation

Archana Ratnakar Baraskar and Ratnamala P. Sonawane*

*The Institute of Science, Mumbai-400032, Dr. Homi Bhabha State University, Mumbai, Maharashtra, India

Abstract

A series of 6-chloro-N-(substituted benzylidene)benzothiazol-2-amine (3a-e) have been synthesized under microwave irradiation and conventional heating for comparison. 2-Amino-6-chlorobenzothiazole (2) was condensed with substituted aromatic aldehyde in ethanol/DMF in the presence of glacial acetic acid as a catalyst under conventional heating and microwave irradiation to yield the Schiff base respectively (3a-e). 2-Amino-6-chlorobenzothiazole (2) was synthesized by the reaction of p-chloroaniline (1) and KSCN in glacial acetic acid in presence of Br2 as a catalyst. Further, these Schiff bases were purified by column chromatography over silica gel using hexane: ethyl acetate (7:3) as an eluent. The structures of synthesized compounds were confirmed by IR, 1H NMR, 13C NMR, and Mass Spectral data.

■ Three-Component Synthesis of Tetrahydrobenzo[b]pyrans Catalyzed by Sodium Cyclamate

Fatemeh Baghaie and Hamzeh Kiyani*

*School of Chemistry, Damghan University, 36719-41167 Damghan, Iran

Abstract

The one-pot three-component cyclocondensation for the synthesis of tetrahydrobenzo[b]pyran derivatives in the presence of sodium cyclamate has been investigated. The three-component reaction was carried out in water medium under refluxing condition. Screening the reaction conditions revealed that 20 mol% sodium cyclamate refluxing water afforded the best results. Under green conditions, different substituted tetrahydrobenzo[b]pyrans were obtained from simple available starting materials, including malononitrile, functionalized benzaldehydes, and dimedone, via using an established efficient and straightforward approach.