Studies towards a biomimetic synthesis of α-cyclopiazonic acid: synthesis of 5-substituted isoxazole-4-carboxylic esters

Abstract

An efficient, high yielding synthesis of ethyl 5-hydroxymethyl-3-methylisoxazole-4-carboxylate has been developed, based on a procedure by Gelin which involves reaction of ethyl acetoacetate with chloroacetyl chloride followed by treatment with hydroxylamine hydrochloride. The product of this reaction was then converted into the bromide and reacted with tetrahydrothiophene to give sulfonium salts in up to 71% overall yield (from ethyl acetoacetate). The synthesis is suitable for use with a chiral sulfide and for large-scale use. The synthesis of ethyl 5-formyl-3-methyl-4-isoxazolecarboxylate and the corresponding tosylhydrazone are also reported. These isoxazoles are starting materials for a proposed convergent, biomimetic synthesis of α-cyclopiazonic acid.

Primary nitro compounds: progress in the synthesis of isoxazoles by condensation with aldehydes or activated ketones

“…4-Carboethoxy isoxazole 51 (R = Me) was designed as a precursor for the synthesis of α-cyclopiazonic acid 87 and as a precursor of isoxazole-chenodeoxycholic acid hybrids. The latter were synthesised and evaluated for their lipid-lowering effects.…”

“…The procedure has been extended to protected γ-amino esters (N-phthaloyl and N-carbobenzyloxy) or protected γ-hydroxy-β-keto esters (O-tert-butyl and O-benzyl) (Scheme 26). 86 4-Carboethoxy isoxazole 51 (R = Me) was designed as a precursor for the synthesis of α-cyclopiazonic acid 87 and as a precursor of isoxazole-chenodeoxycholic acid hybrids. The latter were synthesised and evaluated for their lipid-lowering effects.…”