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Title: Methodology for the synthesis of carbohydrate and alkaloid derived natural products
Author: Archer, Robert Mark
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2012
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The first part of this thesis describes the synthesis, solution studies and biological evaluation of 2-keto-3-deoxy-ulosonic acids. A synthetic route was developed for 2-keto- 3-deoxy-gluconate (o-KDG) and 2-keto-3-deoxy-galactonate (D-KDGal) that provided the targets via concise four step routes from naturally occurring sugar substrates. These routes make use of Horner-Wadsworth-Emmons reactions between the anion of ethyl 2- ((terl-butyldimethylsi lyl)oxy)-2-(dimethoxy-phosphoryl) acetate 1 with enantiopure sugarderived aldehydes to afford silyl-enol et hers that cou d be globally deprotected to give the target 2-keto-3-deoxy-ulosonic acids in high purity (Scheme I). The effect of temperature on the isomeric composition of these C6-sugars was studied and they were then supplied as substrates for the directed evolution of a stereochemically promiscuous aldolase from Sulfolobus solfataricus, to develop mutant aldolases with high diastereoselectivity for the aldol reaction of D-glyceraldehyde 6 and pyruvate 7 to exclusively afford either D-KDG or D-KDGal. The synthetic methodology was then applied to the synthesis of enantiopure 2-keto-3- deoxy-D-xylonale (D-KDX) and 2-keto-3-deoxY-l-arabonate (l -KDA) and these C5-sugars were fully characterised by 1H and DC NMR spectroscopy for the first time and had their enantiopurity confirmed by optical rotatory dispersion analysis. The kinetic parameters for D-KDX and L-KDA using KOG aldolase were determined using a modified thiobarbituric aCid assay, with good catalytic efficiencies being found for each. enantiomer (0.45 and 0.53 s•1mM•1). This gives a more complete understanding of the metabolism of S. solfataricus confirming that the archaeon uses the same KDG aldolase for the catabolism of not only the diastereotopic C6-sugars D-KDG and D-KDGal but also for the ' enantiomeric CS-sugars D-KDX and L-KDA.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available