Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry, Organic

Date of Defense

7-30-2015

Graduate Advisor

Alexei Demchenko, PhD

Committee

Cristina De Meo

Eike Bauer

Stephen Holmes

Abstract

Although carbohydrates are the most abundant molecules on Earth, our current knowledge of these fascinating natural compounds is still limited. Some aspects that are already known include the carbohydrate involvement in damaging cellular processes such as bacterial and viral infections, development of tumors, metastasis, septic shock, etc. Consequently the development of effective methods for the synthesis, isolation, analysis, and investigation of complex carbohydrates has become critical in all areas of glycoscience. Among various focus areas, stereocontrolled glycosylation has emerged as a topic of particular importance. Yet, it remains a remarkable challenge to chemists because a new chirality center is formed during glycosylation. A failure to control the stereoselectivity of glycosylation reactions will typically lead to mixtures of 1,2-cis and 1,2-trans diastereomers. The aim of stereocontrolling of glycosylation has been approached in a variety of ways and the effect of a neighboring acyl participating group has been among the most powerful stereodirecting factors known to date for obtaining 1,2-trans glycosides. The work presented herein is dedicated to broadening the scope of the stereodirected glycosylation using the concept of participating groups. Novel to this approach is the development of a well-rounded methodology that allows for synthesizing either 1,2-cis or 1,2-trans glycosides by simple switching of protecting groups. This is accomplished via novel glycosyl donors equipped either with picolinyl (2-pyridylmethyl ether) or picoloyl (2-pyridylcarbonyl ester) groups. A mechanistic understanding of various modes of action of these groups enhanced our ability to perform stereodirected glycosylations with exceptional stereoselectivity. This led to the development of a novel concept to stereocontrolled glycosylation that we named Hydrogen-bond-mediated Aglycone Delivery (HAD). The HAD concept has been extended to the synthesis of various linear and branched oligosaccharides and broadening of all aspects of the methodology. Furthermore, this study evolved into the development of a new type of glycosyl donors allowing for switchable stereoselectivity.

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Chemistry Commons

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