HETEROCYCLES

■ Contents

■ Applications of Sulfated Tin Oxide (STO) in Organic Synthesis - from 2016 to 2021

Narsimhaswamy Dubasi and Ravi Varala*

*Scrips Pharma, Mallapur-500076, Hyderabad, Telangana, India

Abstract

In this mini-review, authors have briefed about the applications of sulfated tin oxide (STO) as bifunctional catalyst in various C-C, C-hetero bond formations. Synthesis of biologically relevant pyranoquinolines, benzimidazoles, benzodiazepines, fully substituted pyridines, dihydropyridines and isoxazoles were performed by heterogeneous recyclable and reusable solid acid catalyst, STO. In addition, methodologies such as N-Boc protection of amines, production of renewable less viscous, high-density fuel molecules from α-pinene, selective production of MeCl from CH4, esterification, tert-butylation and conversion of glucose into value added 5-hydroxymethylfurfural, were established by using STO as catalyst.

■ Synthesis, Biological Evaluation, and In Silico Studies of New Heterocycles Incorporating 4,5,6,7-Tetrabromophthalimide Moiety as Potential Antibacterial and Anticancer Agents

Magda H. Abdellattif,* Hossam Nada, and Ahmed Elkamhawy

*Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia

Abstract

Cancer and infectious illnesses are currently the most significant public health issues in the globe. Phthalimide derivatives, including thalidomide (multi-target drug), have anti-inflammatory, analgesic, anticancer, antibacterial, and anticonvulsant biological activities. A new series of heterocyclic compounds incorporating 4,5,6,7-tetrabromophthalimide moiety were synthesized and biologically evaluated for potential antimicrobial and anticancer activities. While compounds 4a‒c and 11a‒c were the most active antimicrobial activities upon evaluation over Aspergillus favus, E. coli, Staphylococcus, and Fusarium moniliform, derivatives 4a and 4cb showed the most potent values over cervical and ovarian cancer (6.933‒11.46 µg/mL). Further in silico studies, including a molecular docking investigation over HSP90 protein, were carried out to investigate the potential binding mode and toxicity profile(s) of the newly synthesized compounds.

■ Theoretical Investigation on the Mechanism and Selectivity of Catalyst-Free Annulation of Ynediones and (Iso)quinoline N-Oxides

Nan Lu,* Hui Liang, Chengxia Miao, and Xiaozheng Lan

*College of Chemistry and Material Science, Shandong Agricultural University, No.61 Daizong Street, Taian 271018, China

Abstract

The mechanism is investigated for tandem annulation of ynedione and (iso)quinoline N-oxide without catalyst using M06-2X functional. The [3 + 2] cycloaddition generates active isoxazolo[3,2-α]isoquinoline in stage 1, which undergoes ring-opening delivering tautomerization intermediates. A series of imine-enamine and keto-enol tautomerism takes place in stage 2. Four competitive paths exist in stage 3. The pure N-nucleophilic addition and one concerted path involving asynchronous hydrogen transfer generate pyrrolo[2,1-α]isoquinoline and pyrrolo[1,2-α]quinoline. The by-product (isoquinolin-1-yl)-2,5-diphenylfuran is difficult to obtain owing to the unavailability of starting intermediate of O-nucleophilic addition. The high regioselectivity is controlled both by thermodynamics and kinetics in stage 3. The energy barriers of most steps are decreased in THF solution verifying an advantageous solvation effect. The competitive N- and O-nucleophilic additions are supported by Multiwfn analysis on Frontier Molecular Orbital and Mayer bond order of vital transition states.

■ Synthesis of Hexahydroquinoline-3-carboxamide Derivatives and Their HIV-1 Antiviral Activity

Reagan Lehlogonolo Mohlala, Elena Mabel Coyanis,* Muhammad Qasim Fish, and Moira Leanne Bode*

*Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO Wits, Johannesburg, 2050, South Africa

Abstract

Computational modelling was used to identify scaffolds with the potential to disrupt the interaction between HIV-1 integrase and lens epithelium-derived growth factor (HIV-1-IN-LEDGF/p75). Virtual screening of commercial library collections led to the identification of N-(4-chlorophenyl)-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide as a promising candidate. The synthesis of this compound and its derivatives involved the reaction of the corresponding carboxylic acid derivatives with aniline in the presence of coupling agent carbonyldiimidazole (CDI). This gave rise to N-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamides in yields of 71-85%. These compounds were found to be non-toxic in an MT4 cell line at 100 μM and were subsequently evaluated for antiviral activity in infected MT4 cells at a single dose concentration of 100 μM.

■ Characterization and Antitumor Activity of Furazano[3,4-g]pteridine-2,4(1H,3H)-dione

Yoshimasa Makita,* Shin-ichi Kawaguchi, and Shin-ichi Fujiwara

*Department of Chemistry, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata, Osaka, Japan, Japan

Abstract

Alloxazine derivatives exhibit a wide variety of properties imparted by their tautomerization to isoalloxazine and the presence of similar H-bonding to uracil. Herein, we characterized the structure and properties of furazano[3,4-g]pteridine-2,4(1H,3H)-dione (1) by X-ray crystal structure analysis and evaluated its antitumor activity. The IC50 value of 1 was 172 μM, as determined using HeLa cells.

■ Inhibition of Amyloid β Aggregation by p-Terphenyl Derivatives Isolated from Boletopsis leucomelas

Akihisa Kobori, Kentaro Hosaka, and Hideyuki Shigemori*

*Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan

Abstract

The number of patients with Alzheimer's disease (AD) is increasing rapidly. Amyloid polypeptides are thought to be involved in the pathogenesis of the disease. Amyloid-β (Aβ), which aggregates in the brain, is cytotoxic and is considered the cause of AD. Therefore, inhibiting the aggregation of amyloid polypeptides and degrading existing amyloid aggregates is a promising approach for the treatment and prevention of the disease. In the present study, we report the inhibition of Aβ42 aggregation by p-terphenyl derivatives 1–4 isolated from Boletopsis leucomelas and the hydrolysis derivative 5 and acetyl derivative 6 of compound 3. p-Terphenyl derivatives exhibited aggregation-inhibiting activity in a dose-dependent manner. All of the p-terphenyl derivatives used in this study demonstrated activity, suggesting that daily consumption of foods containing p-terphenyl derivatives may be effective for the prevention and treatment of AD.

■ L-Cysteine Catalyzed One-Pot Synthesis of Bicyclic δ-Lactones under Ball-Milling Conditions

Ling Jiang, Qingqing Lu, Qianqian Tang, Yue Cheng, and Xiaohe Chu*

*Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou 310014, PR China

Abstract

A series of bicyclic δ-lactones 4a-4t were synthesized in moderate to good yields via a simple one-pot reaction. The facile method depended on one-pot three-component reaction of aromatic aldehyde, Meldrum's acid and β-diketone in the presence of L-cysteine as a catalyst under ball-milling conditions. The reactions were completed in mere 30 min in 50-87% yields. The synthesized compounds were characterized by 1H NMR, 13C NMR and ESI-MS. Environmental acceptability, wide substrate scope, low cost and operational simplicity are the key features of this method.

■ A New Monoterpenoid Indole Alkaloid from Uncaria rhynchophylla

Guiyang Wang, Xiao Yu, Linlin Zhu, Yan Liang, Mengnan Zhou, Bin Liu,* and Wei Zhang*

*School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People’s Republic of China

Abstract

A new alkaloid, uncanidine A (1) and 14 known alkaloids (2-15) were isolated from the hook-bearing branches of Uncaria rhynchophylla. Their structures were elucidated by spectroscopic analyses, including 1D-, 2D-NMR, HR-ESI-MS, ECD, as well as comparison with the data reported in the literature. Noteworthily, uncanidine A (1) was a novel Uncaria alkaloid which possessed a 6/5/6/6/6/5 hexacyclic ring system. In addition, uncanidine A (1) was found to inhibit the generation of NO from RAW 264.7 cells stimulated by LPS.

■ Iodine-Promoted Cyclization of Alkylidene Barbiturates in Water: Facile Synthesis of Dihydrofuryl Spirobarbiturates

Zeng-Yang He, Hui Xu,* Wen-Bin Wang, Hua-Jun Xu, and Peng Zou*

*School of Chemical and Environmental Engineering, Anhui Polytechnic University, Wuhu, Anhui 241000, China

Abstract

An efficient and environmentally benign method via iodine-promoted bimolecular annulation of alkylidene barbiturates in water has been developed, affording a variety of significant spirobarbiturate derivatives in good to excellent yields. All products were directly obtained by filtration and following recrystallization. The present protocol exhibits its advantages in terms of simple operation, high efficiency, good functional group tolerance and feasibility for large-scale synthesis.

■ Middle-Scale IsoChichibabin Desmosine Synthesis

Takahiro Suzuki, Nao Tanaka, Hiroaki Tanaka, and Toyonobu Usuki*

*Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan

Abstract

Desmosine is a 1,3,4,5-tetrasubstituted pyridinium amino acid that crosslinks elastin, and is considered to be a useful biomarker for elastin-degraded diseases such as chronic obstructive pulmonary disease (COPD). In this work, starting from the corresponding aldehyde and amine, the isoChichibabin pyridinium synthesis of protected desmosine was achieved on a middle-scale in H2O/CH2Cl2 (1/6) with Pr(OTf)3. A shorter route for the synthesis of the aldehyde was also developed.

■ Triflic Acid Adsorbed on Silica Gel as an Efficient Catalyst for O-Isopropylidenation of Sugar Derivatives

Lisha Wu, Shuying Li, Wei Guo, and Shiqiang Yan*

*Weihai Ocean Vocational College, Weihai, 264300, China

Abstract

Triflic acid immobilized on silica gel has been identified as an excellent catalyst for the chemoselective O-isopropylidenation of free sugars and functionalized carbohydrates with acetone. This method is simple and economic for large-scale synthesis together with good to excellent yield, low catalyst loading and non-aqueous workup procedure.

■ Synthesis of Covalent Boroxine Frameworks by Polycondensation of Tetrahydroxydiboron

Haruka Yamauchi, Atsushi Asano, and Shotaro Hayashi*

*School of Environmental Science and Engineering, Kochi University of Technology, 185 Miyanokuchi, Tosayamada, Kami, Kochi, Japan

Abstract

We have demonstrated synthesis of boroxine networks by condensation of tetrahydroxydiboron. The network material was obtained in quantitative yield by microwave-assisted heating of N,N-dimethylacetamide. The material had a crystalline structure and good stability. In addition, the material could be easily decomposed to the monomer by water addition.