Novel Routes to Substituted Dihydropyrans

Abstract

Dihydropyrans are important structural motifs that are found within many natural products and biologically active compounds. As such, a number of versatile methods have been developed for their construction. Chapter One provides several examples of interesting natural products which contain dihydropyran moieties and gives a brief summary of the existing methodology for the preparation of these heterocycles. Chapter Two gives a detailed account of the silyl-Prins reaction and explains how the methodology may be expanded to encompass new types of substituted dihydropyran. The first strategy was to develop a route to dihydropyrans with an incorporated ester moiety in the 2-position. The second strategy involved the preparation of exo-methylene tetrahydropyrans using silyl-Prins methodology. Thirdly, an investigation into the Mukaiyama-Aldol silyl-Prins reaction, as a potential route to dihydropyrans with an incorporated hydroxyethyl moiety, was performed. The first step was the development of an expedient route to a vinyl ether precursor which was then used to investigate preliminary Mukaiyama-Aldol silyl-Prins reactions. Chapter 3 provides a brief summary of the origin and pharmacology of (-)-centrolobine and kendomycin which both possess integral tetrahydropyran substructures making them attractive targets for synthesis using the silyl-Prins reaction. A literature overview of the existing methods for their syntheses is provided, with particular focus on the methodology used to construct the key tetrahydropyran core. Chapter 4 discusses the retrosynthetic analysis of (±)-centrolobine and describes the development of synthetic pathways to (±)-centrolobine which enable the silyl-Prins reaction to be employed in the key cyclisation step. Kendomycin is also retrosynthetically analysed and a number of routes to the synthesis of its integral tetrahydropyran component using the silyl-Prins methodology are investigated. Chapter 5 provides detailed experimental procedures and data for the compounds described in this thesis.