Stereoselective Synthesis of 4-Amino-3-hydroxy-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-4-carboxylic Acid, a Conformationally Constrained Analogue of Aspartic Acid

Paola Conti; Andrea Pinto; Gabriella Roda; Lucia Tamborini; Dario Arosio; Carlo De Micheli

doi:10.1055/s-2007-983750

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Stereoselective Synthesis of 4-Amino-3-hydroxy-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-4-carboxylic Acid, a Conformationally Constrained Analogue of Aspartic Acid

Paola Conti, Andrea Pinto, Gabriella Roda, Lucia Tamborini, Dario Arosio, Carlo De Micheli*
Istituto di Chimica Farmaceutica e Tossicologica ‘Pietro Pratesi’, Università di Milano, via Mangiagalli 25, 20133 Milan, Italy
Fax: +39(2)50317565; e-Mail: carlo.demicheli@unimi.it;

Abstract

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Abstract

An alternative synthesis of 4-amino-3-hydroxy-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-4-carboxylic acid, a conformationally constrained analogue of aspartic acid, is described. The synthetic strategy is based on a regioselective 1,3-dipolar cycloaddition to give the cyclopenta[d]isoxazoline framework; subsequent condensation of this 4-oxocyclopenta[d]isoxazoline with 4-methoxybenzylamine gives a 4-imino derivative, which undergoes a highly stereoselective nucleophilic attack by the cyanide ion. This gives a 4-(methoxybenzylamino)-4-cyano derivative, which is oxidized to the corresponding 4-amino-4-cyano derivative, which itself is transformed into the target 4-carboxylic acid. This amino acid is obtained in 27% overall yield in five steps, whereas the previously described synthetic strategy gave the target derivative in only 0.5% overall yield over 15 steps.

Key words

aspartate analogues - heterocycles - 1,3-dipolar cycloaddition - stereoselective synthesis - glutamate transporters

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