Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry, Organic

Date of Defense

11-22-2019

Graduate Advisor

Prof. Alexei V. Demchenko

Committee

Prof. Eike Bauer

Prof. Keith J. Stine

Prof. Chung F. Wong

Abstract

Carbohydrates are ubiquitous both in nature as biologically active compounds and in medicine as pharmaceuticals. Although there has been continued interest in the synthesis of carbohydrates, chemical methods require specialized knowledge and hence remain cumbersome. The need for development of rapid, efficient and operationally simple procedures has come to the fore. This dissertation focuses on the development of a fully automated platform that will enable both experts and non-specialists to perform the synthesis of glycans. Existing automated methods for the synthesis of oligosaccharides are highly sophisticated, operationally complex, and require significant user know-how. By contrast, high performance liquid chromatography (HPLC) equipment-based automation introduced by our lab represents a highly accessible method of synthesis. This approach offers operational simplicity by delivering all reagents using standard liquid handling components and convenient real-time reaction monitoring of every step using detectors and standard computer software and interface. Many operations still require the operator intervention, and the entire technology remains semi-manual.

Building upon promising preliminary results, this dissertation aimed to generate a universal platform for the fully automated synthesis of glycans. To achieve the complete automation of the solid phase synthesis that has the potential to revolutionize glycan synthesis, this dissertation focuses on the following aspects: 1) the development of new concepts for chemical glycosylation applicable to stereoselective formation of challenging 1,2-cis glycosidic bonds; 2) implementation of autosamplers and switch valves as new components to achieve operator-less automation; and 3) the development of new chemically stable resins for solid phase synthesis. With these key developments, we have acquired a reliable and simple platform for fully-automated oligosaccharide synthesis. The proof of concept was assessed by the synthesis of a number of target glycans. Synthesis of carbohydrates and other classes of biomolecules using this user-friendly and fully-automated platform will accelerate discovery in many scientific disciplines, most prominently chemistry, automation, and therapeutic-agents development.

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Panza-3MT.pptx (4148 kB)

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