Methodology for the Synthesis of Carbohydrate and Alkaloid Derived Natural Products

Abstract

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 (D-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-((tert-butyldimethylsilyl)oxy)-2-(dimethoxy-phosphoryl) acetate 1 with enantiopure sugar-derived aldehydes to afford silyl-enol ethers that could 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 suppliedas 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-xylonate (D-KDX) and 2-keto-3-deoxy-L-arabonate (L-KDA) and these C5-sugars were fully characterised by 1H and 13C 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 KDG 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 C5-sugars D-KDX and L-KDA.

The second part of this thesis is directed towards development of methodology for the total synthesis of histrionicotoxin (HTX). As part of this synthesis, an aza-Michael reaction was required to convert bis-α,β-unsaturated ester 4 into mono-β-amino ester 5 in high enantiomeric excess. Chapter 4 describes the development of methodology that allows the stereoselective mono-addition of a nitrogen nucleophile to 4, with subsequent oxidative nitrogen deprotection to reveal the primary amino functionality. Chapter 5 then details the progress made towards HTX including synthesis of the acyclic carbon backbone, aza-Michael addition, cyclisation and attempted spirocyclisation.

Date of Award	31 Dec 2012
Original language	English
Awarding Institution	University of Bath
Supervisor	Steven Bull (Supervisor) & Caroline L. Winn (Supervisor)