The conceptually simple process of linking carbohydrate units by glycosylation has proven to be one of the most difficult synthetic processes to control from a stereochemical perspective. In particular it is the stereocontrolled synthesis of 1,2-cis glycosyl linkages (e.g. α-glucosides, β-mannosides) which poses the most difficult challenge. The research presented in this thesis describes new ways in which stereocontrol in glycosylation reactions can be achieved. New methods of neighbouring group participation have been explored, utilising novel protecting groups at the 2-postion of a series of glycosyl donors. In particular the use of glycosyl donors bearing a (thiophen-2-yl)methyl protecting group at the 2-hydroxyl have shown exceptional α-selectivity especially when used in conjunction with a sterically hindered glycosyl acceptor. Work within this thesis also describes the first use of chiral Brønsted acid catalysts in the activation of glycosyl donors. It has been clearly demonstrated that not only can such catalysts be used in glycosylation reactions, but also that the chirality of the catalyst can dictate the stereochemical outcome of the reaction. The preliminary studies presented demonstrate that this methodology warrants further investigation.

The cryopreservation of cells and tissues requires the addition of a cryoprotectant in order to prevent cellular damage caused by ice. Unfortunately, common cryoprotectants such as DMSO and glycerol exhibit significant toxicity which makes their use unfeasible for many clinical procedures. Our laboratory is interested in the development of alternative, non-toxic cryoprotectants which possess ice recrystallization inhibition (IRI) activity. Potent IRI activity has recently been discovered in certain small molecules, but the structural features required for this process are unclear. Herein we report the development of a library of O-aryl glycosides in order to probe the importance of electron density and hydrophobic moieties for IRI activity. It was found that the degree of electron density at the anomeric oxygen does not correlate with IRI ability in para-substituted aryl glycosides, nor does changing the position of the aryl substituent impart a predictable effect on activity. However, the addition of hydrophobic alkyl or acyl chains was beneficial for IRI activity; generally, increasing chain length was found to correlate with increasing activity. In some instances, an optimal alkyl chain length was identified, after which continued lengthening results in a loss of potency. We conclude from this study that a certain extent of hydrophobic character is beneficial for the IRI activity of aryl glycosides, and that a balance between hydrophobicity and hydrophilicity is required for optimum IRI ability. It is hoped that these findings will aid future efforts towards the rational design of novel cryoprotectants.

The Lattrell-Dax method of nitrite-mediated substitution of carbohydrate triflates is an efficient method to generate structures of inverse configuration. In this study it has been demonstrated that a neighboring equatorial ester group plays a highly important role in this carbohydrate epimerization reaction, inducing the formation of inversion compounds in good yields. Based on this effect, efficient synthetic routes to a range of carbohydrate structures, notably β-D-mannosides and β-D-talosides, were designed. By use of the ester activation effect for neighboring groups, a double parallel as well as a double serial inversion strategy was developed. / QC 20101111

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In this thesis the synthesis of several hydrolytically stable carbohydrate mimics with the potential to function as glycosidase or lectin inhibitors are described. This work is presented in Chapters 2-5. Chapters 2 and 3 describe synthetic efforts for producing carbasugars, and include the first synthesis of 1,2-bis-epi-valienamine and the preparation of two previously known aminocarbasugars. All three compounds were synthesised starting from D-mannose, using ring-closing metathesis as the key step. 1,2-Bis-epi-valienamine was found to inhibit Cellulomonas fimi β-mannosidase with a Ki value of 140 mM. Also included is the development of a novel synthetic route from cheap D-fructose to three mannose-mimicking carbasugars using a ring-closing metathesis strategy. Two of the compounds are potential inhibitors of the FimH adhesin. In Chapters 4 and 5 the synthesis of a number of pseudodisaccharides are presented; valienamine- and epi-valienamine-containing pseudodisaccharides and a small library of S-linked pseudodisaccharides were prepared. Various synthetic strategies were explored, including an alkylation strategy, Mitsunobu couplings, and sulfonate displacements. This is the first report on the synthesis of a valienamine pseudodisaccharide with β-lyxo-configuration. Two of the S-linked pseudodisaccharides were found to bind to Concanavalin A with high affinity. The final chapter (Chapter 6) of this thesis focuses on the development of a carbohydrate epimerisation method using transition metal catalysis. Two equilibrium constants involving gluco/manno- and gluco/allo-alcohols were determined via this method. / At the time od doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 5: Manuscript.

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I present detailed mechanistic analysis on the chemistry of glyoxylate as it pertains to forming biologically relevant molecules on the Hadean Earth. Chemistry covered includes: 1) the dimerization of glyoxylate to form dihydroxyfumarate(DHF), a heretofore unknown reaction, important to substantiating Eschenmoser's glyoxylate scenario. 2) Formation of sugars from polymerization of glyoxylate. 3) Formation of tartrate and sugar acids from high pH reactions of DHF. 4) Formation of glycine polypeptides from glyoxylate by transamination and coupling promoted by hexamethylenetetramine. 5) Formation of glyoxylate under conditions which could be plausibly found on the early earth.

Earnest carbohydrate research was initiated in the nineteenth century by several talented organic chemists. Carbohydrates, now known to play essential roles in a range of fundamental biological processes, are presently studied by a throng of scientists from many fields, including: biochemistry, molecular biology, immunology, structural biology, medicine, agriculture, pharmacology and, of course, chemistry. Organic chemistry remains as relevant to carbohydrate research as it has ever been; its practitioners, with their skills in synthesis and fundamental understanding of molecules, are truly indispensable. This thesis details various synthetic endeavours within the field of carbohydrate chemistry. It describes four projects with goals as diverse as natural product synthesis, rational inhibitor design and the development of new reagents in organic synthesis. The first chapter provides an account of the synthesis of compound 1, a potent germination stimulant present in smoke, from D-xylose. Many analogues of 1 were prepared from carbohydrates and evaluated as germination stimulants, which permitted the dissemination of several structure-activity relationships. Subsequent chapters describe the design and preparation of inhibitors for various carbohydrate-processing enzymes. Compounds 55 and 56 were sought after as putative synergistic inhibitors of a Vitis vinifera (grape) uridine diphospho-glucose:flavonoid 3-O-glucosyltransferase (VvGT1). It was hoped that crystallographic investigations of VvGT1-UDP-2/3 complexes by a collaborator, structural biologist Professor Gideon Davies, would aid in clarifying mechanistic aspects of this enzyme.Compounds 114, 115 and 118 were prepared as putative arabinanase inhibitors. Once again, this work was undertaken to assist in crystallographic studies that might provide a better understanding of how these enzymes operate. The thesis concludes by describing the development of compound 152.HCl, a novel reagent for the diazotransfer reaction. Previously, this reaction utilised trifluoromethanesulfonyl azide (TfN3), an expensive and explosive liquid with a poor shelf-life, to convert a primary amine directly into an azide. Reagent 152.HCl was developed to replace TfN3 in this useful synthetic transformation. A one-pot procedure enabled the simple and inexpensive preparation of 152.HCl, which was demonstrated to be shelf-stable, crystalline and, crucially, effective in the diazotransfer reaction.