Excitatory amino acids. Improved synthesis of ibotenic acid and X-ray analysis of an unexpected reaction product,(RS)-N-[2-(3-benzyloxyisoxazol-5-yl)-1-phenylethyl]-3-oxobutyramide

Abstract

A new synthesis of the excitotoxic natural product Ibotenic acid (1) is described. Benzylation of 3-hydroxy-5-methylisoxazole (5) yielded 3-benzyloxy-5-methylisoxazole (7) and the isomeric isoxazol-3(2H)-one (6). While metallation of compound (7) by lithium di-isopropylamide followed by treatment with carbon dioxide gave an easily separable mixture of the acid (10) and the desired intermediate (11), reaction of compound (7) with butyl-lithium yielded the unexpected products (RS)-N-(1-phenylpentyl)-3-oxobutyramide (8) and (RS)-N-[2-(3-benzyloxyisoxazol-5-yl)-1-phenylethyl]-3-oxobutyramide (9). The structure of (9) was confirmed by X-ray analysis. Benzylation of (11) gave (12) in quantitative yield when benzyl chloroformate and triethylamine were used as reagents. The oxime (13), prepared by nitrosation of (12) under basic conditions, was reduced and deprotected by catalytic hydrogenation to give Ibotenic acid (1) in good yields and without formation of significant amounts of decarboxylated product.