Synthesis and reactivity of silylmethylcyclopropanes

Abstract

Substituted tetrahydrofurans (THFs) are common structural motifs found in natural products. The biological activity and structural complexity of these compounds makes their efficient construction with controlled regio- and stereochemistry a significant challenge in organic synthesis. This thesis is concerned with investigating the use of silylmethylcyclopropanes as precursors for the efficient and practical synthesis of tetrahydrofurans. The first chapter consists of a review of the relevant literature comprising of four sections. The first section is a brief review of the current methods for the synthesis of tetrahydrofurans with discussions of the advantages and disadvantages of these methods. Next, the concept of donoracceptor cyclopropanes is introduced and examples of how they have been employed in tetrahydrofuran synthesis are given. The third section outlines the uses of silicon in organic synthesis with particular reference to the physical and electronic influences of silicon on organic molecules. Finally, the chapter concludes with an overview of the application of Lewis acid promoted cycloadditon reactions of allylsilanes and silymethylcyclopropanes to the preparation of tetrahydrofurans. The second chapter discusses the preparation and purification of unsubstituted silylmethylcyclopropanes outlining various conditions tried and the array of different substituents that may be attached to the silicon. The successful Lewis acid promoted [3+2] cycloaddition reaction of various silylmethylcyclopropanes with -keto-aldehydes is presented, together with a detailed account of the screening studies of different Lewis acids and aldehydes, and optimisation of reaction conditions. The advantages of having a ketone functionality in the final compound are practically demonstrated by way of several synthetic modifications to produce a range of chemically diverse compounds containing the tetrahydrofuran substructure. The third chapter presents the synthesis of substituted silylmethylcyclopropanes and their attempted cyclisations using the conditions previously developed for unsubstituted silylmethylcyclopropanes. Following attempts to use Lewis acid-activated aldehydes in [3+2] cycloaddition reactions, and the consequent disadvantage of randomly trialling Lewis acids, chapter four presents our 4 investigations into the use of NMR spectroscopy as a probe to establish a relative quantitative scale of carbonyl activation with different Lewis acids. Our studies into this method are presented along with the NMR data of several carbonyl-based Lewis bases complexed to the Lewis acids that proved successful in the cycloaddition reactions. Chapter five provides detailed experimental procedures and characterisation data for the compounds described within this thesis.