Synthesis of Isoxazolidinyl Triazoles - Promising Drug Candidates

Isoxazolidinyl triazoles represent an important group of heterocyclic compounds which have been found to be promising drug candidates in pharmacological research.^1,2 Some of them were evaluated for their antiproliferative activity and were able to inhibit cell proliferation of follicular (FTC-133) and anaplastic (8305C) human tumor cells at concentration varied from 3.87 to 8.76 μM.²

It is possible that such compounds could act as nucleoside analogues consisting of three key elements: i) the hydroxymethyl group, which is needed for activation through phosphorylation by kinases, ii) the triazole scaffold as modified heterocyclic base, which is needed for the recognition by the enzymes, and iii) the isoxazolidine ring as the spacer (the furanose ring in natural compounds), which present the two former groups in the adequate disposition.³

Recently, we have achieved the first entry into the synthesis of novel types of isoxazolidinyl triazoles with the isoxazolidine ring hydroxylated at C-4 carbon atom.⁴ In this presentation, we report a new synthetic approach towards such modified triazoles, bearing biologically important hydroxymethyl group.

The key intermediate, 4-hydroxy-5-azidoisoxazolidine, has been prepared according to the procedure based on the dihydroxylation reaction of the 2,3-dihydroisoxazole followed by Lewis acid-catalysed nucleophilic substitution of the corresponding benzoylated isoxazolidine-4,5-diol with trimethylsilyl azide. Finally, triazole scaffold has been synthesized applying the 1,3-dipolar cycloaddition of azidoisoxazolidine with phenylacetylene.