Studies toward the stereoselective synthesis of the C(10)-C(20) unit of the fumonisins using Sharpless methodology

Abstract

Fusarium verticillioides (=Fusarium moniliforme) 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. The main mycotoxin, fumonisin B₁ consists of the diester formed by the C(14) and C(15) hydroxy groups of (2S,3S,5R,10R,12S,14S,15R,16R)-2-amino-12,16-dimethyleicosane-3,10,14,15-pentaol with the Si carboxy group of propane-1,2,3-tricarboxylic acid. A comparison of the structures of the 28 known fumonisins isolated since 1988 reveals that they share a common structural motif for the C(11)–C(20) unit, and probably also the same stereochemistry for the 4 stereogenic centres present in this part of the C20 backbone. Disconnection of the C(9)–C(10) bond in a retrosynthetic analysis of the fumonisins identifies (3S,5S,6R,7R)-3,7-dimethylundecane-1,5,6-triol as a common building block for the synthesis of any of the fumonisins. In the dissertation the retrosynhetic analysis of this 3,7-dimethylundecane-1,5,6-triol building block identifies a simple precursor, ethyl 2-heptenoate, as the starting material for the proposed synthetic route toward this target. The Sharpless asymmetric epoxidation reaction plays a pivotal role in this synthetic route as all 4 stereogenic centres present in the 3,7-dimethylundecane-1,5,6-triol target are generated by this methodology at three different stages of the proposed synthesis. The epoxy alcohol formed at each stage was subjected to regioselective ring opening followed by a protective group strategy which allowed for the protection of the secondary hydroxyl group as the benzyl ether and left the primary hydroxyl group, available after oxidation to the aldehyde, for a two-carbon chain extension to an α,β-unsaturated ester. This ester in turn was reduced to an allylic alcohol which formed the starting material for a second cycle of reactions. In this manner a synthetic route towards the target compound was developed and problems associated with the route investigated. The dissertation shows that a viable route was developed with complete stereochemical control in the formation of the stereogenic centres, even though the final product, the protected 3,7-dimethylundecane-1,5,6-triol was not obtained due to time constraints and material shortages.