Access Type

Open Access Dissertation

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

David Crich

Abstract

Sialic acids are molecules of importance in the fields of carbohydrate chemistry and glycoscience, and their diversity make them even more attractive to scientific research. Modifications of sialic acid derivatives may lead to several biological and chemical features that can be utilized for medicinal purposes. The modern drug therapy is dependent on the chemical discoveries of potent and effective molecules. N-Acetyl neuraminic acid is the parent and most common molecule in sialic acid family that received considerable attention in glycochemical research. This dissertation explores the scope as well as the limitations of the Zbiral oxidative deamination of N-acetyl neuraminic acid (NeuAc) by using various nucleophiles and protecting groups leading to the discovery of new general reaction pathway that may be useful for organic synthesis.

Chapter one discusses an overview and definition of carbohydrates and their importance in biology and chemistry. Common monosaccharides as well as construction of polysaccharides by the glycosidic linkages are defined. These are followed by brief discussion about sialic acid discovery as well as explanation of their diverse presence in nature. In chapter one also general discussion about deamination reaction is introduced. This is supported by literature review of sialic acid modification approaches. Finally, previously reported examples of oxidative deamination utilization in carbohydrate syntheses are also presented.

Chapter two proves that use of phenols and thiophenols are effective as nucleophiles for oxidative deamination of NeuAc with the discovery of novel intermediate vinyl diazonium ion. Firstly, chapter one introduces brief literature examples of a ring atom participation as well as ring contractions followed by earlier reported synthetic pathways of alkenediazonium ions. Then, novel and unusual structures of neuraminic acid derivatives are described to be isolated and characterized by the use of phenols nucleophiles in modified conditions of oxidative deamination. The weakly acidic nature of phenols plays an important role in the formation of the vinyl diazonium ion intermediate, which was a result of β-elimination of 4-acetoxy group after diazonium ion and diazoalkane interconversion. This is influenced by the pKa values of the nucleophiles that lead to the formation of the variety of products. Finally, the plausible mechanisms of products formation are explained according to the acidity of the reaction media.

Chapter three further supports the finding of the formation of vinyl diazonium ion as an intermediate, which afforded new products of sialic acid derivatives. Furthermore, chapter three describes the expansion of the range of nucleophiles for oxidative deamination of N-acetyl neuraminic acid showing that modifications at the 5-position of NeuAc by building N-O bond are accomplishable. Hydroxylamines, hydroxamic acids, oximes, amines are the nucleophile used to isolate structurally novel cyclic and substitution products with potential medicinal applications.

Chapter four illustrates the conclusions and the main contributions in this dissertation giving an overall reaction mechanism of the products formation in this oxidative deamination.

Chapter five describes the substrates syntheses and experimental procedures as well as the materials used for the characterization of the products.

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