key: cord-0812075-h6d76dmw authors: Shanmugasundaram, Muthian; Senthilvelan, Annamalai; Kore, Anilkumar R. title: Highly regioselective 1,3-dipolar cycloaddition of 3′-O-propargyl guanosine with nitrile oxide: an efficient method for the synthesis of guanosine containing isoxazole moiety date: 2020-09-19 journal: Tetrahedron Lett DOI: 10.1016/j.tetlet.2020.152464 sha: 708aa4fe7f6c4bd6d65ea1e19ded5383dd00b807 doc_id: 812075 cord_uid: h6d76dmw The 1,3-dipolar cycloaddition reaction of 3′-O-propargyl guanosine with various in-situ generated nitrile oxides in the presence of DMF as a solvent is described. It is noteworthy that the reaction is highly regioselective that affords biologically important guanosine containing isoxazole moiety in good yields with high purities. The 1,3-dipolar cycloaddition reaction of 3′-O-propargyl guanosine with various in-situ generated nitrile oxides in the presence of DMF as a solvent is described. It is noteworthy that the reaction is highly regioselective that affords biologically important guanosine containing isoxazole moiety in good yields with high purities. Keywords: Guanosine; Nitrile oxide; Regioselective; 1,3-Dipolar cycloaddition The nucleic acid chemistry has been the subject of immense interest in the area of medicinal chemistry as the nucleotides serve as a versatile building blocks for both DNA and RNA synthesis as well as involve in numerous critical biological process. 1, 2 It has been well documented in the literature that there are several approved drugs on the market containing nucleoside/nucleotide analogs have been used for the treatment of cancers, parasites, bacterial, viral and fungal infections. 3, 4 Notably, these analogs represent the unique class of antiviral drugs for various viruses such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), influenza virus, respiratory syncytial virus (RSV), hepatitis B virus (HBV), human papillomavirus (HPV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV). 5 It is believed that nucleoside analog acts as a prodrug which converts into the corresponding triphosphorylated analog in the presence of kinase. The active form of the drug is the triphosphorylated analog that acts as an inhibitor for intracellular enzymes and helps to inhibit the viral replication. The chemical modifications in the sugar moiety has had a great impact in terms of biological activity as well as degree of selective toxicity. Given the global pandemic due to the outbreak of the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) and also the emerging infectious diseases worldwide from several other viruses, 6,7 the development of novel antiviral drugs containing nucleoside/nucleotide analogs with a broad spectrum activity against different virus genotypes or viral stains has been warranted. The 1,3-dipolar cycloaddition provides a powerful method for the construction of novel heterocyclic compounds. 8 In particular, the 1,3-dipolar cycloaddition of alkynes with nitrile oxide results in the formation of biologically important isoxazole derivatives. 9 It is to be noted that several approved drugs with isoxazole derivatives display several therapeutic activities such as antibacterial, antifungal, antitubercular, antipsychotic, antitumor, antidepressant, antirheumatic, anticonvulsant, and bronchodilatory agent. 10 While the 1,3-dipolarcycloaddition reaction with nitrile oxide involving pyrimidine nucleosides have been studied, [11] [12] [13] [14] [15] to the best of our knowledge, no example of 1,3dipolarcycloaddition reaction with nitrile oxide involving guanosine nucleoside has been reported in the literature. It has been reported that several 2′-deoxyuridine containing isoxazole derivatives display antiviral activity against HSV and several RNA viruses. 13 In addition, these analogs exhibit activities against several types of human cancer cell lines. 14 Furthermore, Guo et. al. reported that several 5-isoxazol-3-yl-pyrimidine nucleosides exhibited significant in vitro antileishmanial activity. 15 We envisaged that the design of new guanosine containing isoxazole moiety may possess potentially interesting biological activity for various therapeutical applications such as antiviral, anticancer, and antileishmanial agents. Our continuous interest in the area of nucleic acid chemistry, 16 prompted us to synthesize guanosine containing isoxazole moiety and study its biolgical evaluation. Herein, we report the first example of the 1,3-dipolar cycloaddition of 3′-O-propargyl guanosine with nitrile oxides, leading to the formation of guanosine containing isoxazole moiety in good yields with high purities. Similarly, the addition is also insensitive to steric substituent. The reaction of 4 with 9anthraldehyde oxime (1e) under similar conditions afforded the corresponding product 5e in 72% yield (entry 5). Furthermore, the cycloaddition was successfully extended to heterocyclic oximes. Under similar conditions, the cycloaddition reaction of 4 with 3pyridinealdoxime (1f), 4-bromo-2-thiophenecarbaldehyde oxime (1g), and 1H-indole-3carboxaldehyde oxime (1h) afforded the corresponding products 5f-h in 77%, 71%, and 79% yields, respectively (entries 6-8). There are several interesting features that merit comments for the present 1,3dipolar cycloaddition reaction. First, unlike conventional 1,3-dipolar cycloaddition reaction, 8  The present reaction is highly regioselective  An efficient synthesis of biologically important guanosine containing isoxazole moiety is described  It is likely that these analogs are potential lead candidate for the treatment of cancer and viral infections 20. The chemistry of C-nucleosides Ed. 1,3-Dipolar cycladdition chemistry Intermolecular 1,3-Dipolar cycloaddition After 15 h, triethylamine (2.0 mmol) and 3′-Opropargyl guanosine (1.0 mmol) were added to the reaction mixture and stirred for the time specified in Table 1. The reaction mixture was evaporated under rotary evaporator to give crude reaction mixture. The crude reaction mixture was purified by silica gel column chromatography using Biotage instrument 10 (s, 1H) ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work