Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry

Date of Defense

11-12-2021

Graduate Advisor

Dr. Alexei V. Demchenko

Committee

Dr. Alexei V. Demchenko

Dr. Eike B. Bauer

Dr. Cristina De Meo

Dr. Keith J. Stine

Abstract

From their ubiquitous presence in Nature to their vital roles in biology and medicine, carbohydrates (sugars or glycans) are essential molecules of life, which are made and/or utilized by every living organism. Our cells are coated with sugars that are involved in almost every biological process and defensive mechanism in our body. To mention some of their crucial biological functions, carbohydrates are essential source of energy, they participate in blood coagulation, immune defense, cell growth, cell-cell interaction, and anti-inflammatory processes. Understanding of glycan functions and structure is crucial for the development of vaccines and therapeutics. Producing complex carbohydrates in sufficient quantities and purity and making them available for the general medical, chemical, and industrial audience is a goal that could only be achieved by the development of efficient strategies for their production. Among a variety of methodologies available for glycan synthesis, thioglycosides, sugars equipped with the anomeric sulfur atom, have been the most commonly used synthetic building blocks to date. A wide variety of reactions with thioglycosides have been developed, some of which are reviewed in the introductory part (Chapter 1). However, the field still lacks accessible methodologies that would provide an efficient, high-yielding, and stereoselective outcome of reactions, all in one universal platform. Presented herein are our efforts dedicated to the development of accessible and reliable strategies for the synthesis, activation, and application of thioglycosides, from traditional manual reactions performed in flasks to sophisticated, fully automated technologies. Over the course of this study, a new method for the synthesis of thioglycosides has been established (Chapter 2). The synthesized thioglycosides have been investigated in the context of novel palladium-catalyzed activation pathways (Chapter 3) and applied for streamlining the regenerative glycosylation strategy (Chapter 4). The developed methods and strategies have then been implemented into the high-performance liquid chromatography equipment-based automation (HPLC-A) platform. Differently from the previously developed HPLC-A approaches, which were exclusively based on the solid-phase synthesis, reported herein is a solution-phase automation (Chapter 5). We expect that new methods, strategies, and technologies described herein will open now exciting avenues for the synthesis and application of complex carbohydrate molecules.

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