Biosynthetic studies on the fungal metabolite tenelln

Abstract

This thesis is divided into seven chapters plus appendices. The first chapter introduces tenellin (1), its origins, structure and biogenetic relationships to other metabolites. The second chapter concentrates on polyketides and through three representative examples explains their relationship to the fatty acids and current theories and evidence for a processive mechanism during their biosynthesis. An investigation carried out into the biosynthesis of the polyketide sidechain of tenellin (1) from sodium [l-(^13)C, 2-(^2)H(_3)] and [2-(^13)C, 2-(^2)H(_3)] acetates and L-[S-methyl-(^13)C(^2)2H(_3)]-methionine is described. The possible intermediacy of singly methylated diketides and doubly methylated triketides carrying stable isotopic labels during the biosynthesis of tenellin (1) is also tested experimentally and discussed. In the third chapter possible intermediates to both the 2-pyridone moiety of tenellin (1) and the tropic acid (42) moiety of the tropane alkaloids are discussed and tested experimentally. 3-Amino-2-phenylpropionic acid (104) was synthesised and rejected as an intermediate to tenellin (1) and tropic acid (42). In the case of tenellin (1) a tetramic add (139) was implicated as a possible intermediate by a biosynthetic feeding experiment. An alternative mechanism to account for 2-pyridone formation from a tetramic acid is put forward. In the fourth chapter the determination of the absolute configuration of tenellin (1) is described. The configuration of the chiral methyl bearing centre of tenellin (1) is compared to that of similar fungal polyketide derived molecules and the mode of reduction by various fungal PKS enoyl reductase systems is assessed. In the fifth chapter the syntheses and characterisations of the compounds labelled with (^14)c, (^13)c and (^2)H that were used in the biosynthetic studies on tenellin (1) and tropic acid (42) are described. Chapter six describes in detail the experimental procedures used in the syntheses of these compounds. Chapter seven consists of a description of the biological materials and methods used during this study. The appendices consist of abbreviations used in the text, and a list of lectures, seminars and coUoquia arranged within the Department of Chemistry and attended by the author.