Issue in Honor of Prof. Lutz F. Tietze ARKIVOC 2007 (v) 139-151
Studies towards a biomimetic synthesis of a-cyclopiazonic acid: synthesis of 5-substituted isoxazole-4-carboxylic esters
Vijayalakshmi A. Moorthie,a,† Eoghan M. McGarrigle,a Rachel Stenson,b and Varinder K. Aggarwala,*
a School of Chemistry, Cantock's Close, Bristol BS8 1TS, England b Syngenta, PO Box A38, Leeds Rd, Huddersfield, W. Yorks. HD2 1FF, England E-mail: V.Aggarwal@bristol.ac.uk
Dedicated to Prof. Tietze on the occasion of his 65th birthday
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 a-cyclopiazonic acid.
Keywords: a-Cyclopiazonic Acid, sulfur ylide, isoxazole, sulfonium salt
Introduction
a-Cyclopiazonic acid (1) is a mycotoxic metabolite produced by Penicilum cyclopium Westling.1,2 It has a range of biological effects, most notably Ca2+-ATPase inhibition, and can be used as tool for the elucidation of intracellular Ca2+ influx.3-5 a-Cyclopiazonic acid is currently synthesized using fermentation, but a chemical synthesis would allow variation of the structure in a controlled way. The biological activity and structural complexity of 1 make it an attractive and challenging target for total synthesis. Since its isolation and characterization in 1968 by Holzapfel1,6,7 three racemic syntheses of a-cyclopiazonic acid have been reported by the groups
† Present address: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2 ISSN 1424-6376 Page 139 ©ARKAT USA, Inc.
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