Isoxazolidines play a very important role in organic chemistry as constituents of biologically interesting compounds or as valuable intermediates in many synthetic routes.[1] Among them, isoxazolidinyl 1,2,3-triazoles represent an important group of heterocyclic compounds, which have been found to be promising drug candidates in pharmacological research.[2],[3]

Recently, we have achieved the first entry into the synthesis of novel types of isoxazolidinyl 1,2,3-triazoles with an isoxazolidine ring hydroxylated at C-4 carbon atom.[4] In this presentation, we wish to report a new synthetic approach towards such modified triazoles bearing the biologically important hydroxymethyl group attached at C-3.

The synthesis is based on a well-known method of multicomponent Knoevenagel-aza-Michael cyclocondensation (KaMC) reaction between aldehydes, Meldrum's acid, and N-carbamate hydroxylamines leading to isoxazolidin-5-ones.[5]

The key intermediates, 4,5-unsubstituted 2,3-dihydroisoxazoles, have been prepared according to the procedure based on the elimination reaction of the 5-hydroxyisoxazolidines readily synthesized by reduction of the corresponding isoxazolidin-5-ones with Super-Hydride. Epoxidation reactions of 2,3-dihydroisoxazoles with 3,3-dimethyldioxirane (DMDO) yielded novel isoxazolidinyl epoxides, which were subjected to regiospecific epoxide ring opening reactions with thionyl bromide and lithium chloride providing 5-haloisoxazolidin-4-ols, respectively. Model 5-chloroisoxazolidine was subsequently used in nucleophilic substitution reaction with sodium azide to obtain the corresponding 5-azidoisoxazolidine. Finally, the triazole scaffold was prepared applying the 1,3-dipolar cycloaddition of 5-azidoisoxazolidine with phenylacetylene.

We would like to gratefully thank the Slovak Grant Agencies (VEGA, project no. 1/0552/18 and ASFEU, ITMS project nos. 26240120001, 26240120025).

[1] Chiacchio, M. A.; Giofrè, S. V.; Romeo, R.; Romeo, G.; Chiacchio, U. Curr. Org. Synth. 2016, 13, 726-749.
[2] Piotrowska, D. G.; Balzarini, J.; Głowacka, I. E. Eur. J. Med. Chem. 2012, 47, 501-509.
[3] Romeo, R.; Giofrè, S. V.; Carnovale, C.; Campisi, C.; Parenti, R.; Bandini, L.; Chiacchio, M. A. Bioorg. Med. Chem. 2013, 21, 7929-7937.
[4] Záborský, O.; Štadániová, R.; Doháňošová, J.; Moncol, J.; Fischer, R. Synthesis 2017, 49, 4942-4954.
[5] Berini, C.; Sebban, M.; Oulyadi, H.; Sanselme, M.; Levacher, V.; Brière, J.-F. Org. Lett. 2015, 17, 5408-5411.