Date of Award

8-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

David C. Baker

Committee Members

Michael D. Best, Mark Dadmun, Paul D. Frymier

Abstract

This dissertation presents a state-of-the-art research of 1,2-cis-glycosides, including synthetic methodology development, combinatorial total synthesis of galactoside ligands, construction of glycomicroarray surfaces, and quantitative evaluation of carbohydrate–lectin binding properties.

In Chapter 1, as a general introduction, various strategies that have been developed for the stereoselective construction of 1,2-cis-O-glycosidic bond are reviewed. 1,2-cis-O-Glycoside structural units are ubiquitous in nature, and they are extensively involved in numerous biological activities. The systematic identification and evaluation of the roles of carbohydrates usually relies on practical synthetic approaches to afford pure carbohydrates in considerable quantities. Further development of general and efficient approaches to achieve the intrinsic organizational diversity of carbohydrates is still urged in order to meet the substantial carbohydrates in demand for biological, medicinal, and therapeutic studies.

In Chapter 2, I report a 1,2-cis-glycosidation protocol that makes use of unprotected phenyl 1-thioglycosyl donors. Glycosylation of various functionalized alcohols was accomplished in moderate to high yield and selectivity to give the 1,2-cis-glycosides. In order to quickly optimize glycosylation conditions, a flow injection analysis method was established that enabled rapid and quantitative evaluation of yield on small scale. This methodology, together with nuclear magnetic resonance spectroscopy, allowed for rapid evaluation of the overall reactions.

In Chapter 3, I describe the synthesis of alpha-linked propargyl terminated galactosides with various spatial presentations, which are set to be applied in the construction of synthetic carbohydrate microarrays to mimic featured carbohydrate presentations on a cell surface. Through the routes, glycosyl acceptors were obtained via flexible and efficient regioselective protection strategies, and they were glycosylated with an alpha-directing glycosyl donor to have the alpha-linked galactosides in exclusive stereoselective and satisfactory yield.

In Chapter 4, the establishment of a synthetic carbohydrate microarray is described. The carbohydrate surface was interrogated by a fluorescence-labeled lectin to quantitatively analyze the carbohydrate-binding affinities and dissociation constants. This study will add new dimensions to our understanding of the effects of spatial arrangement of carbohydrate ligands in carbohydrate–lectin binding, and shed light on elucidating the structure–affinity relationship of carbohydrate recognition with receptors.

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