The aim of this project was to develop a synthetic strategy for the production of uncommon sugars thevetose (6-deoxy-3-O-methylglucose) and cymarose (2,6-dideoxy-3-O-methylallose or 2,6-dideoxy-3-O-methylaltrose) derivatives, present in the trisaccharide moiety of a pregnane glycoside with appetite-suppressant activity. A D-thevetose glycosyl donor was prepared from methyl D-glucopyranoside. The first step of the synthesis was the formation of a 4,6-O-benzylidene derivative that was selectively methylated on the 3-hydroxy group by using a copper mediated alkylation process. Treatment with NBS and reductive removal of the resultant bromide produced the required protected thevetose glycoside. This success is a vast improvement compared to the published results of the patent reporting this synthesis. Attempts to prepare the 2α-iodo derivative by direct nucleophilic substitution of a 2-O-triflate manno-derivative resulted in a most unusual rearrangement reaction. Allal derivatives as starting materials in the preparation of 2α-iodo sugars were also unsuccessful due to steric hindrance provided by the axial 3-methoxy group. Preparation of a cymaroside precursor was achieved by using glucal as a starting material and by the inversion of C-3 in a consecutive oxidation/reduction sequence of the iodo acetate. Lastly, the preparation of the β-oleandroside derivative of cholesterol was achieved in a model reaction. The sugar oleandrose is a C-3 epimer to cymarose and it can be found in pregnane and cardenolide glycosides. / Professor F.R. van Heerden

The mechanism of the carbonate catalyzed conversion of 2,4-dinitrophenyl 2 ,3 ,4,6-tetra-0-acetyl-β-D-glucopyranoside in DMSO to an equilibrated mixture of the α- and β-glycosides has been investigated using a variety of techniques. Pseudo-first-order rate constants (k) measured for the anomerization of the parent substrate and the 1-deuterio substrate indicated a secondary deuterium isotope effect of kH/kD = 1.09 ± 0.06. Pseudo-first-order rate constants measured for several deoxy and deoxyfluoro derivatives of the parent sugar showed that the deoxyfluoro sugars react at least as fast as the parent sugar whereas the deoxy sugars reacted more slowly. In addition to the 2,4-dinitro-phenyl glucoside, 2,6-dinitrophenyl glucoside also was found to anomerize, yet attempts to exchange the 2,4-dinitrophenolate groups of the glucoside with added 2,6-dinitrophenolate anion and vice versa were unsuccessful. Exchange of the proton at the anomeric carbon with a deuteron also does not occur when the anomerization is performed in the presence of a deuteron source (and vice versa). Exchange of the glucosyl residue was observed, however, when the 1-deuterio substrate was anomerized in the presence of non-deuterated 2,3,4,6-tetra-O-acetyl-D-glucopyranose. ¹H-n.m.r. of the 2,4-dinitrophenyl α-glucoside isolated from this reaction indicated that the a-glucoside possessed only 50% of the deuterium label, at the anomeric center. These results along with the observation of a Meisenheimer intermediate indicate that the anomerization proceeds via nucleophilic aromatic substitution and as such is novel mechanism for glycoside anomerization. / Science, Faculty of / Chemistry, Department of / Graduate

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Human angiotensin-converting enzyme (ACE) is a key enzyme in the regulation of blood pressure via the renin-angiotensin and kallikrein-kinin systems. A number of orally active drugs have been developed over the years that target somatic ACE, for the treatment of hypertension, myocardial infarction and congestive heart failure. Protein structural information about ACE is an important key for the understanding of the mechanism and substrate-specificity of the enzyme. However, this information has only begun to be elucidated in the past year, with the solution of crystal structures of human testis ACE (tACE), and homologues Drosophila AnCE and human ACE2. tACE is identical to the C-terminal domain of somatic ACE, which consists of two homologous domains, each having a slightly different substrate-specificity. This thesis describes the purification, crystallisation and X-ray crystal structure-determination of a glycosylation-deficient mutant of tACE, tACEG1,3, to 2.9 &Aring / .

L’objectif de nos travaux consiste en la préparation de C-glycosides et d’aminoacides glycosylés trifluorométhylés dans le but d'obtenir des structures biologiquement actives stabilisées. L'intérêt des C-glycosides est lié à leur stabilité autorisant une pharmacocinétique plus appropriée pour un usage thérapeutique. La 1ière partie de mon travail a été de créer une liaison C-C en position anomérique d'un sucre par différentes méthodes d’alkylation, d’alcynylation à l’indium et par la réaction de Réformatsky. Ensuite après avoir fonctionnalisé les C-glycosides synthétisés, une étude tournée vers la synthèse d’aminoacides C-glycosylés par le biais d’alkylations énantiosélectives a été réalisée. Ensuite nous avons étudié la synthèse d’aminoacides glycosylés stabilisés par l’introduction d’un groupement trifluorométhylé en une position stratégique. D’abord nous avons étudié la synthèse d’aminoacides N-glycosylés obtenus par la réaction entre un aminoacide trifluorométhylé et un sucre. Le groupe fluoré, en  de l’azote, diminue la basicité de l’amine et empêche sa protonation. Ainsi, l’hydrolyse du lien anomérique est très défavorisée. Plusieurs conditions réactionnelles ont été étudiées. Le milieu acide protonique a montré des résultats encourageant notamment entre le 2-déoxy-glucose et un dipeptide trifluorométhylé. Ensuite nous avons travaillé sur la synthèse de O-glycosides. 2 stratégies ont été développé à partir d’un sucre trifluorométhylé. D’abord l’éthérification de Williamson a été étudié entre un sucre trifluorométhylé et différents dérivés halogénés. Cette voie a donné des résultats satisfaisant avec des dérivés halogénés linéaires uniquements. Puis la réaction de Mitsunobu a été étudié entre un sucre trifluorométhylé et différents alcools. La réaction donne des résultats variés dépendant de l’alcool. Cette voie nous a aussi permis de synthétiser des aminoacides O-glycosylés trifluorométhylé en utilisant la sérine comme alcool. / The aim of our work consists in the preparation of C-glycosides and trifluorinated glycosylated aminoacids in order to obtain biogically active structures. The interest of such C-glycosides, is due to its stability. It allows a better pharmacokinetics to a therapeutic use. The first part of my work was to create a C-C bond at the anomeric position of a carbohydrate by different methods such as alkylation, alcynylation and Reformatsky reaction. Then, after functionalized these C-glycosides, a study on C-glycosylated aminoacids synthetized by an enantioselectiv alkylation way was made. The second part of my work was to synthesized stabilized glycoaminoacidsby the introduction of a trifluoromethylated group at a strategic position: at the anomeric position of the carbohydtare or at  position of the anomeric position of the carbohydtare. We first studied the synthesis of N-glycosides with a trifluoromethylated group at  position of the anomeric position of the carbohydtare. This strategy is based on the reaction of a protected sugar with a trifluoromethylated amine catalysed by an acid. Then we studied the synthesis of O-glycoaminoacids with a trifluoromethylated group at the anomeric position of the carbohydtare. Two strategies have been developed. The first one is the alkylation of Williamson. The second one is the reaction of Mitsunobu.

The development of new glycosylation methods for the stereoselective synthesis of β-glycosides in the absence of the traditional C(2)-ester participatory group on glycosyl donors using cationic palladium catalyst Pd(PhCN)2(OTF)2, as well as the formation of 1.2-cis-2-amino glycosides via cationic nickel catalyzed α-selective glycosylation using C(2)-N-substituted benzylidene D-glucosamine and galactosamine trichloroacetimidates is described. In the formation of β-glycosides, the process relies on the ability of the cationic palladium catalyst Pd(PhCN)2(OTF)2, generated in situ from Pd(PhCN)2Cl2 and AgOTf, to direct β-selectivity. The new glycosylation reaction is highly β-selective, and proceeds under mild conditions with 1-2 % of catalyst loading. This β-glycosylation protocol has been applied to a number of glucose donors with benzyl, allyl and p-methoxybenzyl groups incorporated at the C(2)-position, as well as xylose and quinovose donors to prepare various disaccharides and trisaccharides with good to excellent β-selectivity. Mechanistic studies suggest that the major operative pathway is likely a seven-membered ring intermediate, wherein the cationic palladium complex coordinates to both the C(1)-imidate nitrogen and the C(2)-oxygen of the trichloroacetimidate donor. Formation of this seven-membered ring complex directs the selectivity, leading to the formation of β-glycosides. In the formation of 1,2-cis-2-amino glycosides, the method relies on the nature of nickel-ligand complex to control α-selectivity. The reactive sites of the nucleophiles as well as the nature of the protecting groups have little effect on the alpha-selectivity. This protocol is mild, highly α-selective, and has been successfully applied towards the stereoselective synthesis heparin disaccharides, α-GluNAc/GalNAc glycoconjugates, and GPI anchor pseudodisaccharides. The nickel catalyzed glycosylation protocol has also been successfully applied to both disaccharide donors and acceptors to provide the corresponding oligosaccharides in high yields, and with excellent levels of α-selectivity. Mechanistic studies suggests that the presence of the substituted benzylidene functionality at the C(2)-amino position of glycosyl donors is crucial for the high α-selectivity observed in the coupling products.

Bibliography: p. 145-162. / xi, 162 p. : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Plant Science, 1995

Bibliography: p. 145-162.

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