Studies on the stereoselective synthesis of the C20 backbone of fumonisin B3 and B4 using Sharpless methodology

Abstract

Fusarium moniliforme Sheldon a common fungal contaminant of maize throughout the world has been associated with diseases in both man and animals. The structure of the fumonisins, a family of structurally related mycotoxins isolated from cultures associated with the high incidence of human oesophageal cancer in the Transkei region in South Africa and with equine leucoencephalomalacia, a neurological disorder in horses and donkeys, has been established. These mycotoxins in the case of fumonisin B3 and B4 consist of the diester formed by the C(14) and C(15) hydroxy groups of 2-amino-12,16-dimethyl-3,10,14,15-tetrahydroxyicosane and the C(10) deoxy analogue, respectively, with the Si carboxy group of propane-1,2,3-tricarboxylic acid. The aim of the synthetic study outlined in this dissertation is the development and implementation of methodology for the synthesis of the C(1)-C(8) unit of the C20 backbone of fumonisin B3 and B4 with the appropriate stereochemistry. Retrosynthetic analysis of the C20 backbone identifies (6S,7S)-7-amino-1,6-octanediol as the target structure. The use of t-butyldimethylsilyl and t-butyldiphenylsilyl, methoxymethyl and benzyl protecting groups in the proposed synthetic route, the stereochemical control in the creation of the stereogenic centres using Sharpless asymmetric epoxidation-kinetic resolution, and the introduction of the amino group, were initially investigated using pentane-1,5-diol as starting material. The findings were then applied in the synthesis of (2 S,3S)-3-benzyloxy-2-(t-butyloxycarbonyl)amino-8-[(t-butyldimethylsilyl)oxy]-octane, the synthetic intermediate corresponding to the target structure, from hexane-1,6-diol using t-butyldimethylsilyl and benzyl protecting groups. The structures of 3-epi-fumonisin B3 and -fumonisin B4 were deduced from 1H and 13C NMR data and confirmed by the data for a model compound, (5R,6S)-6-amino-1,5-heptanediol, prepared from pentane-1,5-diol using the methodology established earlier in the dissertation.