Muscimol Analogues. II. Synthesis of Some Bicyclic 3-Isoxazolol Zwitterions.

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Abstract
Muscimol and related 5-aminoalkyl-3-isoxazol zwitterions are potent .gamma.-aminobutyric acid agonist. The syntheses of the 3-isoxazolol zwitterions 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (7a), 5,6,7,8-tetrahydro-4H-isoxazolo[5,4-c]-azepin-3-ol (7b), and 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-3-ol (7c) are described. The starting materials were the cyclic .beta.-oxoesters ethyl 1-methoxycarbonyl-3-oxopiperidine-4-carboxylate (2a), ethyl 1-methoxycarbonyl-3-carboxylate (2c). The ethylene acetals of 2a-c were treated with hydroxylamine, and deacetalization and cyclization of the intermediate .beta.-oxohydroxamic acid ethylene acetals gave the respective 3-isoxazolol derivatives methyl 3-hydroxy-4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-6-carboxylate, methyl 3-hydroxy-4,5,6,8-tetrahydro-7H-isoxazolo[5,4-c]-azepine-7-carboxylate, and methyl 3-hydroxy-4,6,7,8-tetrahydro-5H-isoxazolo[4,5-c]-azepine-5-carboxylate, which were transformed into the zwitterions 7a-c. The pKA values of 7a-c were determined.

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