EVALUATION OF PROTECTING GROUPS FOR 3-HYDROXYISOXAZOLES - SHORT ACCESS TO 3-ALKOXYISOXAZOLE-5-CARBALDEHYDES AND 3-HYDROXYISOXAZOLE-5-CARBALDEHYDE, THE PUTATIVE TOXIC METABOLITE OF MUSCIMOL

The regioselectivity of the 3-hydroxyisoxazole-5-ester 1 is studied wi th respect to O- versus N-alkylation. 3-O-Alkyl products 2 are highly favoured with benzyl, benzhydryl, and allyl bromide (greater than or e qual to 91:9), in contrast to known uses of 5-alkyl-3-hydroxyisoxazole s or when methylation with diazomethane (or methyl iodide) is effected . Methoxymethylation leads to the N-substituted isoxazolinone 3e only. On reduction with DIBAH, the esters 2 afford 3-O-protected 3-hydroxyi soxazole-5-carbaldehydes 4 (75-98%). For removal of the benzyl protect ing groups, three variations (HBr/HOAc, H-2/Pd/BaSO4, NBS/AIBN) were f ound useful with 5-ester, 5-formyl, and 5-hydroxymethyl derivatives. T he free 3-hydroxy-5-carbaldehyde 9, the putative toxic metabolite of t he GABA agonist muscimol, is prepared accordingly. The O-protected 3-h ydroxyisoxazole-5-carbaldehydes 4 constitute versatile intermediates i n various routes to analogues of CNS-active amino acids and can now be obtained in a highly efficient manner.