Studies on the synthesis of functionalised lactones

Abstract

The research carried out in the present study focuses mainly on the synthesis of lactones via the acid-catalysed intramolecular acylative cleavage reactions of tetrahydrofuran derivatives. This thesis is divided into four chapters: Chapter 1 introduces medium- and large-ring lactones and describes the most significant general literature methodologies employed for their syntheses. Chapter 2 is concerned with the preparation of some ω-(tetrahydro-2'- furyl)alkanoic acids which may be used for the synthesis of naturally-occurring lactones. A novel route to these acids, involving the lithiation of furan derivatives and subsequent reactions with bromo-orthoesters, is reported. Chapter 3 describes the syntheses of various ω-(tetrahydro-2'-furyl)alkenoic acids and the subsequent intramolecular lactonisation reactions of the corresponding mixed anhydrides. It was found that the presence of a double bond of (Z)- configuration in the side-chain of 7-(5'-methyltetrahydro-2'-furyl)hept-3-enoic acid greatly improves the efficiency of the lactonisation reaction. This result led to the synthesis of the insect pheromone (±)-ferrulalactone II. The intramolecular acylative ring-switching reaction of the mixed anhydride derived from 5-(5'- methyltetrahydro-2'-furyl)-pent-3-enoic acid is also described. In this case, the presence of the (Z)-double bond results in the formation of a relatively rigid bicyclic acyloxonium intermediate which leads to the formation of a novel seven-membered lactone as the main product together with the expected ten-membered lactone. The mechanism of the reaction and the influence of the stereochemistry of the precursor acid are discussed. The acid-catalysed rearrangements of various ten- membered hydroxylactones into the corresponding more stable seven-membered lactones are also described. Chapter 4 is concerned with the attempted synthesis of the naturally-occurring lactone Salicylihalamide A. Various routes were explored and although some interesting results were obtained, the synthesis of the target lactone was not achieved. This work also led to the development of a one-step procedure for the synthesis of sulfoxides by the reaction of carbanions with phenyl benzenethiosulfinate. The procedure was applied to various representative ketone enolates and Grignard reagents.