Synthetic studies on the C20 backbone of the fumonisins using chiral sulfoxides

Abstract

Fusarium moniliforme is a common contaminant of maize, a basic staple of the diet of both humans and animals. The fungus is the causative agent of equine leucoencephalomalacia (LEM) and has been implicated in human oesaphageal cancer. The structure of the fumonisins, a family of structurally related mycotoxins isolated from cultures of F moniliforme responsible for LEM has been established. Thus fumonisin B1 is the diester formed by the Re carboxy group of propane-I, 2, 3-tricarboxylic acid with the C-14 and C-15 hydroxy groups of (2S,3S,5R, 1 OR, 12S, 14S,, l 5R, l 6R)-2-amino-12, 16-dimethyl-3,5, 10,- 14, 15-pentahydroxyicosane. Retrosynthetic analysis of the C20 backbone of fumonisin B1 by disconnection of the C-1 0-C-11 bond identifies 4,8-dimethyl-1,2,6, 7-tetrahydroxydodecane, synthon B and 7-amino-1,4,6-trihydroxy-octane, synthon C as the key intermediates in a proposed synthesis. The formation of the same bond in the synthetic direction is more demanding as it requires that the formation of the carbon-carbon bond generates at the same time a new stereogenic centre in a stereodefined fashion. The work described in this thesis investigates a strategy for the formation of the C-1 0-C-11 bond in the C20 backbone of fumonisin B1 with the concomitant introduction of the C-11 hydroxy group by employing chiral sulfoxide methodology. The methods used are based on the highly stereoselective reduction of J3-ketosulfoxides and the ability of the sulfoxide moiety to stabilise an a-carbanion in order to effect carbon-carbon bond formation by a nucleophilic substitution reaction. Various model compounds for parts of the C20 backbone were prepared to test the practicality of the outlined strategy. Both the synthesis of a number of chiral J3-ketosulfoxides and their stereoselective reduction were successfully completed. However, only limited success was achieved in the final carboncarbon bond formation reaction. From the results it became clear that an alternative strategy for carboncarbon bond formation using chiral sulfoxides is required and some possible strategies are discussed. During the course of this study a new method for the synthesis of chiral J3-ketosulfoxides from methyl ptolylsulfoxide and an aliphatic nitrile was developed. In addition an improved method for the synthesis of the synthon corresponding to the C- l -C-8 unit of the C20 backbone of the fumonisins is presented in the thesis.