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Towards the total synthesis of ficellomycin

By Maria Garcia

Abstract

Chapter One provides a review of the literature relating to the isolation, structure elucidation and biological activity of ficellomycin, a natural product with antibiotic activity. This chapter also provides an overview of published synthetic routes towards ficellomycin and l-azabicyclo[3.1.0]hexanes. Chapter Two describes our synthetic efforts to the l-azabicyclo[3.1.0]hexane core of ficellomycin. Initially, a model system developed in the group with a double cyclisation as key step was optimised. This involved the reduction of a 1,2-azido alcohol, using a solid-supported triphenylphosphine reagent, to an aziridine that undergoes conjugate addition onto a tethered dehydroamino acid in situ. Under these conditions, azido alcohol 94 led to the formation of the four stereoisomeric bicycles 45 alb, 142 alb, in 45% overall yield in a 3: I :5: I ratio. A second approach towards the natural product is also described. This involved the development of a system wherein the C-5 amino substituent is incorporated. Two open chain y-aldehydes 212 and 232, were made in 8 and 10 steps respectively from 168 using a sequence that involved anti-I,4-addition of azide onto 168, formation of Weinreb amides 211 and 231 and their chemoselective reduction as key steps. Reaction of these aldehydes with phosphonate 99 using DBN, produced alkenes 214 and 230 respectively, and exclusively, as the (Z)-isomers. Further stereocontrolled cyclisation to piperidines 220 and 235 possessing the required 38, 58, 6Rstereochemistry was achieved in good yields by hydrogenation using Lindlar's catalyst. We anticipate that these intermediates could be further advanced to the natural product. Chapter Three draws conclusions from the work to date, and discusses future options with respect to the completion of the synthesis to the natural product. Chapter Four contains detailed experimental procedures for the novel compounds described within this thesis

Topics: QD
OAI identifier: oai:wrap.warwick.ac.uk:1146

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