Investigations of the type ii intramolecular Diels-Alder reaction directed toward natural product synthesis

This thesis describes synthetic studies directed towards the total synthesis of the nakafuran and florlide marine natural products. Chapter One provides an overview of the importance of natural products to current medicinal chemistry and describes how the "supply issue" associated with these biologically derived compounds can be resolved through the process of total synthesis. Two families of marine natural products, the nakafurans and the florlides, are introduced as synthetic targets and strategies utilising a type II intramolecular Diels-Alder (IMDA) reaction to achieve their total synthesis are delineated. The efficient preparation of regio- and stereodefined vinyl coupling fragments via hydrostannylation and hydrohalogenation methodology is described in Chapter Two. The palladium-catalysed cross-coupling of these fragments, via Stille or Negishi coupling methodology, yielded dienes which were successfully advanced to IMDA triene precursors. Chapter Three describes investigation of the type II IMDA reaction to give bicyclo[4.3.1]decene carbocyclic skeletons. A facile acid-catalysed 6,7-alkene to 7,8-alkene olefinic isomerisation, via a proposed oxonium intermediate, and the inability to appropriately functionalise the desired adducts impeded progress along the synthetic route. Molecular modelling was conducted to investigate the causes of this unexpected reactivity. Investigations in Chapter Four describe the successful synthesis and cyclisation of homomethyl triene analogues prepared via application of enyne metathesis chemistry. The use of an exo-cyclopropylcarbinyl fragmentation was found to be unsuccessful as a means of installing the desired 6-methyl-bicyclo[4.3.1]decan-2-one core with a competing endo-ring expansion giving rise to a bicyclo[4.4.1]undecane ring system. Chapter 5 summarises the above results and gives a brief discussion of the future potential of this research to provide for a total synthesis of the nakafuran and florlide natural products

New insights into the mechanism of dihydrodipicolinate synthase using isothermal titration calorimetry

Andrew C. Muscroft-Taylor, Tatiana P. Soares da Costa and Juliet A. Gerrardhttp://www.elsevier.com/wps/find/journaldescription.cws_home/505803/description#descriptio

Dataset for: Structure and inhibition of <i>N</i>-acetylneuraminate lyase from methicillin-resistant <i>Staphylococcus aureus</i>

<i>N</i>-Acetylneuraminate lyase is the first committed enzyme in the degradation of sialic acid by bacterial pathogens. The kinetic parameters of MRSA <i>N</i>-acetylneuraminate lyase are reported and given a <i>K</i>_M of 3.2 mM, flux through the catabolic pathway is likely to be controlled by this enzyme. Sialic acid alditol, a known inhibitor of <i>N</i>-acetylneuraminate lyase enzymes, is a stronger inhibitor for MRSA <i>N</i>-acetylneuraminate lyase than <i>Clostridium perfringens N</i>-acetylneuraminate lyase. The crystal structure of ligand free and inhibitor bound MRSA <i>N</i>-acetylneuraminate lyase is presented. Subtle dynamic differences in solution and/or altered binding interactions within the active site may account for species-specific inhibition