Date of Award

Fall 12-18-2020

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor

Matthew Brichacek

Second Committee Member

Alice E. Bruce

Third Committee Member

Barbara J.W. Cole

Additional Committee Members

William M. Gramlich

Angela Myracle

Abstract

The improved understanding of carbohydrate functions in biological systems has increased the demand for well-characterized and pure carbohydrates in biomedical research. Chemical synthesis is the most feasible method to satisfy the scientific demand despite the inherent challenges of the glycosylation reaction. Therefore, it is essential to investigate novel methods for the formation of glycosidic bonds. In this work, an intramolecular method was developed using a thio-methylene-silyl linker to tether a glycosyl donor and acceptor. The glycosylation conditions resulted in the formation of both anomeric isomers with a preference for the inversion pathway, which is inconsistent with an entirely intermolecular glycosylation mechanism. More specifically, the ⍺ anomer of the thio-methylene-silyl tethered glycosyl donor and acceptor formed glycosyl products in up to 70% yield (1:2.8 ⍺: β stereoselectivity) and the corresponding β anomer formed glycosyl products in up to 76% yield (2.2:1 ⍺: β stereoselectivity). A detailed study of the mechanism of the reaction was conducted using competition experiments, crossover experiments, and computational work. In a double-labeled crossover experiment, the ⍺ glycosylation product was produced by an intramolecular pathway 33% of the time and an intermolecular pathway the remaining 67%. Correspondingly, the β product is formed 38% by an intramolecular pathway and 62% by an intermolecular pathway. During the study, insight was gained regarding how intramolecular glycosylation proceeds and how novel linkers could improve stereoselectivity in glycosylation.

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