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The erythro- and threo-amino-(3′-hydroxy-4′,5′-dihydro-isoxazol-5′-yl)-acetic acids, stereoisomers of tricholomic acid, were synthesized along with the corresponding higher homologues erythro- and threo-amino-(3′-carboxy-4′,5′-dihydro-isoxazol-5′-yl)-acetic acids. The target compounds were prepared via the 1,3-dipolar cycloaddition of a suitable nitrile oxide to (±)-2-tert-butoxycarbonylamino-3-buten-1-ol. Such a strategy allowed the synthesis of the two stereoisomeric amino acids in comparable amounts. The pharmacological activity of these compounds was investigated at ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs) by means of receptor binding assays to rat cortical membranes, electrophysiological tests and second messenger assays at cloned receptors expressed in CHO cells. Their pharmacological profiles were compared to those of l -glutamate and of the previously described selective NMDA receptor antagonists 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acids in order to highlight the effect of increasing/reducing the distance between the amino acid moiety and the distal acid group, which represent the two pharmacophoric entities.

Stereomeric 3-carboxy-Δ 2 -isoxazoline–cyclopentane amino acids, which represent restricted conformations of glutamic acid, have been prepared through a strategy based on the 1,3-dipolar cycloaddition of ethoxycarbonylformonitrile oxide to a suitably protected 1-amino-cyclopent-2-enecarboxylic acid. These amino acids, assayed at iGluRs and mGluRs, proved to be inactive. The biological data have been accounted for through the comparison of their conformational profile with that of a 3-carboxy-Δ 2 -isoxazolinyl proline (CIP-A) and (±)-1-aminocyclopentane-1,3-dicarboxylic acid.

2,3-Dihydropyrazolo[3,2-b]oxazoles were used as intermediates in a new method for preparation of N1-methyl-3-hydroxypyrazoles. Synthesis of this bicyclic system was achieved either by alkylation of 3-hydroxypyrazole with 1,2-dibromoethane or, with better yields, by cyclization of 1-tosyl-2-(2-hydroxyethyl)pyrazol-3-ones via a nitrogen to oxygen transfer of the tosyl group. Alkylation with methyl trifluoromethanesulfonate followed by dihydrooxazole ring-opening with sodium iodide, led to the 1-methyl-2-(2-iodoethyl)pyrazoles. Removal of the iodoethyl chain on N2 to give the target 3-hydroxypyrazoles was achieved either via a cyanation and then a decyanoethylation reaction or via an elimination of hydrogen iodide, followed by an iodine-based oxidation of the resulting vinylic derivative. Using the latter method, 1-methyl-3-hydroxypyrazoles were obtained in 58–73% yields from the corresponding 2,3-dihydropyrazolo[3,2-b]oxazoles.