Muscimol Analogues. I. Syntheses of 4- and 8-Aminocyclohepteno[1,2-d]isoxazol-3-ols and 4-(3-Aminopropyl)-5-methyl-3-isoxazolol.

Abstract

Mussimol and related 5-aminoalkyl-3-isoxazolol zwitterions are potent .gamma.-aminobutyric acid agonist. The syntheses of the zwitterions 4-(3-aminopropyl)-5-methyl-3-isoxazolol (10) and 4- and 8-aminocyclohepteno[1,2-d]isoxazol-3-ols (23) and (19), which are structural analogs of muscimol (5-aminomethyl-3-isoxazolol) and GABA, were described. The 3-isoxazolol zwitterion 10 was synthesized via ethyl 3-(3-hydroxy-5-methylisoxazol-4-yl)-propionate by using 1-methyl 5-ethyl 2-acetylglutarate as a starting compound. The zwitterions 19 and 23 were prepared via 3-methoxycyclohepteno[1,2-d]isoxazol-8-one (15) and 3-methoxycyclohepteno[1,2-d]isoxazol-4-one (16), respectively; 15 and 16 were prepared by chromic acid oxidation of 3-methoxycyclohepteno[1,2-d]isoxazole. The pKA values of 10, 19 and 23 were determined.