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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.

This paper deals with the application of a Monte-Carlo (MC)-based conformational analysis carried out in water on a set of known β3-adrenergic ligands. On the basis of their conformation at the global minimum, the molecules under study can be grouped into two clusters: the ‘extended’ and the ‘folded’ cluster. Each cluster is identified by well-defined values of torsion angles and distances between the pharmacophoric groups. It is worth noting that a ligand included in the cluster characterized by an extended conformation invariably shows a higher affinity for the human β3-adrenoreceptor with respect to the corresponding rodent receptor.

Regioisomeric 3-hydroxyisoxazolinyl prolines [HIP-A (±)- 6 and HIP-B (±)- 7 ], which represent a restricted conformation of NMDA, AMPA, and kainic acid, potent and selective agonists at ionotropic glutamate receptors, have been prepared through two different strategies. In the first approach bromonitrile oxide was added to N -BOC- Δ 3 -pyrroline or N -BOC- Δ 3 -pyrrolin-2-one and the carboxylic group was subsequently appended. The alternative strategy is based on the cycloaddition of the same 1,3-dipole to N -BOC-3,4-didehydroproline methyl ester.

The cycloaddition of bromonitrile oxide to monosubstituted olefins has a high regioselectivity yielding 3-bromo-5-substituted isoxazolines contaminated by minor amounts (4-9%) of the 4-substituted isomer. The adducts of bromonitrile oxide to allyl a3lcohol and N-protected allylamine were employed as key intermediates in the preparation of racemic dihydromuscimol (DHM). The synthesis of (R)-(-)- and (S)-(+)-DHM was accomplished by using the two diastereomers obtained by the cycloaddition of bromonitrile oxide to (S)-(+)-isopropylidene-3-buten-1,2-diol. The enantiomeric excesses of (R)-(-)- and (S)-(+)-DHM, determined by capillary GLC on the appropriate precursors, were 98.8 and >99.0 %. A spectroscopic survey of the tautomerism of 3-hydroxyisoxazolines indicates the predominant or exclusive occurrence of the NH form

The reduction of a series of isoxazolino-3-carboxylate esters with sodium borohydride gave 3-(hydroxymethyl)isoxazolines in 34–98% yield. Reduction with DIBAH gave isoxazoline-3-carboxaldehydes in 63 and 85% yields for the two reactions studied. Isoxazoline-3-carboxaldehydes could also be prepared by Swern oxidation of the corresponding 3-(hydroxymethyl)isoxazolines. The hydroxyl group of 3-(hydroxymethyl)isoxazoline 11b was silylated and the endocyclic double bond was cleaved by ozonolysis to produce a monosilylated triol.