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Access Type

WSU Access

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

David Crich

Abstract

As one of the four major classes of macromolecule in living systems, the roles of carbohydrates as energy storage substances and structural components have long been recognized. However, the unique role of carbohydrates in cellular recognition processes has only been scrutinized since the 1960s, thanks to the progress in the research in both cell surface carbohydrates and carbohydrate-binding proteins (lectins). The advances in the research of such process demand the use of carbohydrates as basic tools. Therefore, the primary goal of glycochemistry has been to obtain complex carbohydrates and their analogs effectively. One common approach to the problem involves the chemical synthesis of carbohydrates, with glycosylation as the key reaction. The glycosylation reaction enables the attachment of a carbohydrate moiety to a non-carbohydrate carrier or another carbohydrate molecule and is currently under extensive research. An indirect approach to the problem uses rationally designed structural analogs to mimic the natural carbohydrates. The work conducted in this study is related to both of the approaches.

Chapter one surveys the background to the research. It starts with a brief introduction of the structure and energy-related functions of carbohydrates. Then cell surface carbohydrates, lectins, and the nature of their interactions are introduced. Chapter one also introduces the implications of carbohydrates in drug development. Progress in oligosaccharide synthesis, the general mechanism of glycosylation reactions, and neighboring group participation are briefly discussed at the end of the chapter.

Chapter two describes the use of a series of 2 O alkoxylcarbonylmethyl ether protected mannopyranosyl donors as probes for the stereodirecting participation of ester functionalities through six membered rings. The preparation of these mannopyranosyl donors, their glycosylation reactions, and the deprotection of the protecting groups are described. The results are discussed in the context of the possibilities of participation by these functionalities through six membered cyclic intermediates. On the basis of a conformational analysis of the putative dioxenium ions, DFT calculations are advanced which allow the comparison of the cyclization of the 2 O alkoxylcarbonylmethyl ether systems with hypothetical remote participation by an ester group at the 3 O position.

In chapter three, the general mechanisms and the progress in the development of photocatalytic glycosylation reactions are discussed. In order to solve the problems associated with the current methods, and inspired by an interesting method of generating simple alkyl cabocations, chapter three next describes the development of a new blue light photocatalytic glycosylation reaction employing stable and readily accessible Tempol glycosides as glycosyl donors. Good to excellent yields and generally clean reaction profiles establish the effectiveness of this method. The modest donor dependent stereoselectivities are discussed in terms of partially concerted reaction mechanisms.

In chapter four, the design and synthesis of a series of oligomeric thioether linked cabasugars as β glucan mimetics are presented. The 4 deoxy series of mimetics are prepared efficiently via a method featuring a thiol-Michael addition reaction. Results of biological tests are presented, which indicate that the oligomeric thioether linked cabasugars are able to bind to the common β glucan receptors CR3 and Dectin 1, and that they stimulate phagocytosis. The results suggest that the enhanced interaction between the ligands and the receptors is due to the increased hydrophobicity of the α faces of the ligand molecules, which is consistent with the conclusions draw from the previous studies in the Crich laboratory.

The thesis ends with a conclusion chapter and complete experimental details for the work presented.

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