Stereochemical studies on the fumonisins, metabolites of fusarium moniliforme

Abstract

Fusarium moniliforme, a common fungal contaminant of maize, has been implicated as the causative agent in human oesophageal cancer in the Transkei as well as equine leukoencephalomalacia in horses worldwide. Previous studies established that the fumonisins, a family of structurally related mycotoxins isolated from cultures of F. moniliforme, are the diesters of propane- 1 ,2,3-tricarboxylic acid and either 2-acetylamino- or 2-amino-1 2, 1 6-dimethyl- 3 ,5, 10, 14, 15-pentahydroxyicosane as well as in each case the C-10 deoxy analogue. In all cases both the C-14 and C-1 5 hydroxy groups are involved in ester formation. In the present study the mode of linkage of the propane-1,2,3-tricarboxylic acid groups to the C-14 and C-1 5 hydroxy groups in the fumonisin molecule was studied by selective reduction of the ester functionalities with sodium borohydride and subsequent characterization of the lactone. In this way it was established that in each case a terminal carboxy group of propane-1 ,2,3-tricarboxylic acid is involved in the ester linkage. The relative configuration of the different chiral centres present in the fumonisins was deduced from proton-proton coupling constants and proton-proton n.O.e. studies on 2,2-dimethyl-1 ,3-dioxolane, 1 ,3-dioxane, 2,2-dimethyl-1 ,3-dioxane and 2-oxazolidinone derivatives. The absolute configuration of the C-10 and C-5 chiral centres was determined by the method of Horeau. Oxidative cleavage of the C-14-C-15 dial moiety and comparison of the a-methyl-p-nitrobenzylamide derivative of the 2-methylhexanoic acid formed with a standard, established the absolute configuration at C-1 6. The stereochemical studies established the absolute configuration of fumonisin 8 1 as (2S,3S,5R, 1 OR, 12S, 14S, 15R, 16R)-1, 1 '-[14, 15-(2-amino-3,5, 1 0-trihydroxy-12, 16- dimethylicosandiyl)] di-(2,3-dihydrogen propane-1 ,2 ,3-tricarboxylate).