Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry, Organic

Date of Defense

7-15-2021

Graduate Advisor

Prof. Alexei V. Demchenko, Ph.D.

Committee

Prof. Eike B. Bauer, Ph.D.

Prof. Bruce C. Hamper, Ph.D.

Prof. Keith J. Stine, Ph.D.

Abstract

Stereocontrolled Mannosylation by Hydrogen-Bond-Mediated Aglycone Delivery

Carbohydrates are the essential bio-molecules of life as they form the forefront of interactions with receptors, proteins, pathogens, or neighboring cells. On cell-surfaces, carbohydrates are mostly found as linear or branched glycoconjugates, and a majority of them are linked via either 1,2-cis or 1,2-trans O-glycosidic linkages. There is no template-driven pathway for achieving the synthesis of glycans unlike other biomolecules like proteins and nucleic acids. The synthesis of 1,2-trans glycosides can be reliably achieved via the neighboring group assistance. The synthesis of 1,2-cis glycosides is difficult because, beyond weak anomeric effects, there are no forces helping in directing the stereoselectivity. The synthesis of β-mannosides is complicated further because the anomeric effect is working against it. Current methods for β-mannosylation require specialized donors and super-low temperatures.

Hydrogen-bond-mediated aglycone delivery (HAD) method introduced by our lab makes use of remote picolinyl and picoloyl groups that are capable of providing a strong stereodirecting effect.Among a variety of targets and substrates investigated, a highly stereoselective formation of β-mannosidescan be achieved via the assistance of the remote 3-O-picoloyl group. This thesis is dedicated to the synthesis of novel glycosyl donors directed for achieving challenging β-mannosidic linkages present in the oligosaccharides containing D-mannosamine (ManNAc), D-mannuronic acid (ManA), and D-mannosaminuronic acid (ManNAcA). These residues are quite abundant in the microbial glycans, wherein they are connected via β-(1,2-cis) linkages and are deemed essential in the development of carbohydrate-based drug-conjugates.

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