Heterocyclic GABA agonists. Synthesis and crystal structure of (RS)-5-(N-t-butyloxycarbonylaminomethyl)-3-oxoisoxazolidine-2-carboxamide, a derivative of dihydromuscimol

Abstract

Reaction of the O- and N-protected (RS)-3-hydroxy-4-aminobutyric acid ester (4) with hydroxyurea under basic conditions unexpectedly yielded (RS)-5-(N-t-butyloxycarbonylaminomethyl)-3-oxoisoxazolidine-2-carboxamide (8), the structure of which has been confirmed by an X-ray analysis. Elimination of the cyanate ion, which could be trapped with dimethylamine, converted (8) into the corresponding 2-isoxazolin-3-ol derivative (7). Attempts to prepare the individual enantiomers of (8) were unsuccessful. The (R)-(–)-3-hydroxy-4-aminobutyric acid derivative (5) yielded racemic (8). The cyclization reactions of (5) and (4) are believed to involve elimination of toluene-4-sulphonate giving the corresponding α,β-unsaturated ester as an intermediate.