Applications of stable isotopes in biosynthetic studies of some fungal metabolites

Abstract

The first chapter is a general introduction to the thesis. It briefly covers the history and background to secondary metabolites and their biosynthetic pathways. The polyketide and isoprenoid pathways are discussed in some detail as they are relevant to the subsequent chapters. The use of stable isotopes, in conjunction with n.m.r. spectroscopic analysis, in biosynthetic studies is reviewed. Indirect n.m.r. analyses are compared and contrasted with direct methods.

Chapter 2 covers the results from stable isotope studies on monocerin, a fungal polyketide produced by Drechsleraravenelii. The incorporation of [1-13C]-, [1 ,2 — 13C2] — ,[1-13C ,2H 3]-, [ 1-13C , 1802 ]-acetates and 1802 into monocerinwas assessed by indirect and direct n.m.r. methods. The results allowed proposals for the biosynthetic pathway to monocerin to be put forward, and are supported by isolation of co metabolites and some chemical evidence. The 13C and 1H n.m.r. spectra of monocerin are assigned and the relative configuration of monocerin is determined from n.O.e. irradiation studies.

The third chapter is concerned with the biosynthesis of four meroterpenoid metabolites, austin, andilesin A, andibenin B and territonin, and in particular the orsellinate-derived portion of the molecules. [1'tC]- And [13C ,-180]-labelled3,5-dimethyl orsellinates were synthesised and incorporated into the four metabolites. Aspergillus terreus, the culture producing territonin, was grown in an 1802-enriched atmosphere. The labelled metabolites from the stable isotope studies were (Vi)analysed indirectly by 13C n.m.r. spectroscopy. Informa­tion obtained on the origin of the oxygen atoms in the metabolites complements the results of other workers. The complex structural modifications to the orsellinate-derived portion of these metabolites are discussed in the light of these experimental conclusions.