Generation and Reactions of the Dianion of 3-Hydroxy-5-methylisoxazole, a Covenient β-Keto Amide Sython. Total Synthesis of Muscimol

Article abstract of DOI:10.1021/jo00171a030

The title compound (4) has been prepared by treatment of diketene with N,O-bis(trimethylsilyl)hydroxylamine (2) to give N-(trimethylsilyloxy)-N-(trimethylsilyl)acetoacetamide (3) as a stable liquid.Treatment of 3 with methanolic HCl removed the Me3Si protective groups and cyclized the resulting hydroxamic acid to isoxazole 4 in good yield.The dianion of 4 was generated with lithium diisopropylamide and was found to react exclusively at the 5-methyl group when treated with electrophiles.The reactions of the dianion which were accomplished included carboxylation with CO2, alkylation with benzyl chloride, condensation with benzophenone, and acylations with dimethyl carbonate, methyl acetate, N,N-dimethylacetamide, N-methoxy-N-methylacetamide, ethyl benzoate, and ethyl benzoylacetate.Hydrogenation of condensation products (10, 11, 13, 14, and 15) using optimum conditions of the catalyst and solvent gave the corresponding β-keto amides (16, 17, 18, 19, and 20, respectively) in excellent yields.Treatment of the dianion with isoamyl nitrite gave 3-hydroxy-5-isoxazolecarboxaldehyde oxime (21) in good yield.Acetylation of 21 to the diacetate 22 followed by reduction with BH3-THF gave muscimol (1), a constituent of the mushroom Amanita muscaria.