Synthesis of lasiodiplodin and other benzo-fused lactones - studies into N-(4-Pyridyl)amides

Abstract

Chapter 1 contains an overview of the origins, properties and syntheses of medium and large-ring lactones. A wide range of cyclisation methods is presented, including the acylative cleavage of tetrahydrofuran derivatives whose mechanism is discussed in detail. The origin and properties of the naturally-occuring macrolactone lasiodiplodin and other related resorcylic macrolides are explored, along with previous syntheses of this compound. Chapter 2 describes the attempted preparation of novel 8-, 9- and 10-membered benzo-fused lactones by acylative cleavage of tetrahydrofuran derivatives. A modified synthesis of a known 12-membered benzo-fused lactone by this method is given. The cyclisation of tetrahydrofuryl acid precursors of the 8- and 12- membered lactones result in the formation of the corresponding butanolide and endecanolide, respectively. A formal synthesis of lasiodiplodin is presented in Chapter 3. The first attempt, based on the previous synthesis of a 12-membered benzo-fused lactone, is unsuccessful. The second attempt provides O-methyllasiodiplodin which can be selectively deprotected to give lasiodiplodin. An alternative way of obtaining the same product is explored. Chapter 4 begins with the full characterisation of N-(4-pyridyl)formamide. A discussion of the cis / trans isomerism of amides follows, highlighting the various parameters influencing the dominance of one isomer on the other. The syntheses of several N-(4-pyridyl) hydroxy-amides are presented. Two of these compounds exhibit unusual stereoisomerism, which is explained by a number of potential intramolecular interactions.