Synthesis of isoxazole conjugates of sugars via 1,3-dipolar cycloaddition Vipraja V. Vaidya, Karuna S. Wankhede, Manikrao M. Salunkhe, and Girish K. Trivedi Abstract: Isoxazole conjugates of sugar have been synthesized by the aid of 1,3-dipolar cycloaddition in a click chem- istry approach. The sugar-derived propargyl ethers underwent 1,3-dipolar cycloadditions smoothly with in situ generated nitrile oxides from aromatic oximes in good yields. The reaction exhibited a high degree of regioselectivity. Key words: isoxazole conjugates, 1,3-dipolar cycloadditions, nitrile oxides. Résumé : Faisant appel à une cycloaddition 1,3-dipolaire et une approche chimique qui marche très bien, on a réalisé la synthèse d’isoxazoles conjugués à un sucre. Les éthers propargyliques dérivés du sucre donnent lieu en douceur et avec de bons rendements à des réactions de cycloaddition 1,3-dipolaire avec les oxydes de nitrile générés in situ à par- tir d’oximes aromatiques. La réaction présente un degré élevé de régiosélectivité. Mots–clés : produits conjugués de l’isoxazole, cycloadditions 1,3-dipolaires, oxydes de nitrile. [Traduit par la Rédaction] Vaidya et al. 141 Introduction Several compounds of natural and non-natural origin com- prised of the isoxazole moiety possess a broad spectrum of biological properties viz., fungicidal, antibacterial, anti- inflammatory, anti-allergic, anti-tumor, herbicidal, etc. The isoxazole class of compounds are also synthetically impor- tant as 1,3-dicarbonyl equivalents (1). Among the plethora of protocols reported for the synthesis of the isoxazole skel- eton, two major routes are the 1,3-dipolar cycloadditon of alkenes and alkynes with nitrile oxides and the reaction of hydroxylamine with a three-carbon atom component, such as 1,3-diketone or an α, β-unsaturated ketone. 1,3-Dipolar cycloaddition has proven particularly valuable for the con- struction of complex five-membered conformationally rigid heterocycles (2). Isoxazoles, also among the five-membered heterocycles, can be accessed by 1,3-dipolar cycloaddition reaction. In particular, nitrile oxides undergo cycloaddition with alkynes resulting in good yields of isoxazoles (3). A similar class of compounds, i.e., triazoles, have been synthe- sized via 1,3-dipolar cycloaddition of azides and alkynes. This reaction has been considered as the prototype of click chemistry (4). There are several excellent contributions from various groups in the domain of click chemistry, wherein 1,3–dipolar cycloadditions are employed as a tool to conju- gate molecules of structural diversity (5). Such linkage may result in altogether new attributes and (or) an ensemble of attributes. The continuing interest in this field and the im- portance of the isoxazole moiety has encouraged us to report our results. Results and discussion We herein report regioselective syntheses of sugar conju- gates of isoxazoles (1–10) via 1,3-dipolar cycloaddition of carbohydrate derived alkynes and in situ generated nitrile oxides from oximes (Scheme 1). D-Glucose was utilized as a precursor to prepare all dipolarophiles i.e., sugar alkynes. The dipolarophiles (1a–5a) were synthesized following stan- dard procedures. The dipoles, i.e., nitrile oxides, were gener- ated in situ from the biphasic oxidation of the oximes with NaOCl in dichloromethane-triethyl amine (6). These dipoles underwent cycloaddition with dipolarophiles to afford cycloadducts, i.e., new isoxazole conjugates of sugars in good yields. D-Glucose was utilized to synthesize 1,2:5,6 diisopropyli- dene- α-D-glucofuranose, which was subsequently subjected to etherification using propargyl bromide to yield the dipolarophile 1a. The dipolarophile 1a upon treatment with benzonitrile oxide, 4-methoxy benzonitrile oxide, and 3,4- dimethoxy benzonitrile oxide afforded cycloadducts (1–3) in 75%–80% yields. The dipolarophile 2a was also treated with the three previ- ously mentioned nitrile oxides separately to generate corre- sponding cycloadducts (4–6) in 69%–75% yields. The dipolarophile 3a was treated with benzonitrile oxide to yield cycloadduct 7 in 74% yield. The dipolarophile 4a was ac- cessed by Ferrier O-glycosylation of 3,4,6-tri-O-acetyl-D- glucal with propargyl alcohol. It was further subjected to 1,3-dipolar cycloaddition with benzonitrile oxide to yield cycloadduct 8 in 67% yield. Our next objective was to synthesize bis-isoxazole deriva- tives, and in that direction we carried out the propargylation of the cycloadduct 7 to have one more site for cycloaddition Can. J. Chem. 86: 138–141 (2008) doi:10.1139/V07-145 © 2008 NRC Canada 138 Received 22 October 2007. Accepted 23 November 2007. Published on the NRC Research Press Web site at canjchem.nrc.ca on 17 January 2008. V.V. Vaidya, K.S. Wankhede, M.M. Salunkhe, 1 and G.K. Trivedi. Department of Chemistry, The Institute of Science, 15-Madam Cama Road, Mumbai 400 032, India. 1 Corresponding author (e-mail: mmsalunkhe@hotmail.com).