Document Type


Date of Degree

Spring 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In


First Advisor

Nguyen, Hien M.

First Committee Member

Freistad, Gregory K.

Second Committee Member

Quinn, Daniel M.

Third Committee Member

Small, Gary W.

Fourth Committee Member

Olivo, Horacio F.


Having access to mild and operationally simple techniques for attaining carbohydrate targets will be necessary to facilitate advancement in biological, medicinal, and pharmacological research. Even with the abundance of elegant reports for generating glycosidic linkages, the stereoselective construction of alpha- and beta-oligosaccharides and glycoconjugates is by no means trivial. In an era when expanded awareness of the impact we are having on the environment drives the state-of-the-art, synthetic chemists are tasked with developing cleaner and more efficient reactions for achieving their transformations. This movement imparts the value that prevention of waste is always superior to its treatment or cleanup. Chapter 1 of this thesis will highlight recent advancement, in this regard, by examining strategies that employ transition metal catalysis in the synthesis of oligosaccharides and glycoconjugates. These methods are mild and effective for constructing glycosidic bonds with reduced levels of waste through utilization of sub-stoichiometric amounts of transition metals to promote the glycosylation.

The development of a general and practical method for the stereoselective synthesis of beta-O-aryl-glycosides that exploits the nature of a cationic palladium(II) catalyst, instead of a C(2)-ester directing group, to control the beta-selectivity is described in chapter 2. The beta-glycosylation protocol is highly diastereoselective and requires 2-3 mol % of Pd(CH3CN)4(BF4)2 to activate glycosyl trichloroacetimidate donors at room temperature. The method has been applied to D-glucose, D-galactose, and D-xylose donors with a non-directing group incorporated at the C(2)-position to provide the O-aryl glycosides with good to excellent beta-selectivity. In addition, its application is widespread to electron-donating, electron-withdrawing, and hindered phenols. The glycosylation is likely to proceed through a seven-member ring intermediate, wherein the palladium catalyst coordinates both the C(1)-trichloroacetimidate nitrogen and C(2)-ether oxygen, blocking the alpha-face. As a result, the phenol nucleophile preferentially approaches from the top face of the activated donor, leading to the formation of the beta-O-aryl glycoside.

The area of sugar urea derivatives has received considerable attention in recent years because of the unique structural properties and activities that these compounds display. The urea-linkage at the anomeric center is a robust alternative to the naturally occurring O- and N-glycosidic linkages of oligosaccharides and glycoconjugates, and the natural products that have been identified to contain these structures show remarkable biological activity. While methods for installing the beta-urea-linkage at the anomeric center have been around for decades, the first synthesis of alpha-urea glycosides has been much more recent. In either case, the selective synthesis of glycosyl ureas can be quite challenging, and a mixture of alph- and beta-isomers will often result. Chapter 3 provides a comprehensive review of the synthetic approaches to alpha- and beta-urea glycosides and examines the structure and activity of the natural products, and their analogues, that have been identified to contain them.

There are only a handful of reports for the construction of beta-urea glycosides, and even fewer that are able to attain the alpha-urea structures. Chapter 4 will cover two of these methods, where a transition metal catalyst is employed to facilitate the alpha-selective transformation. The 1st-generation process, covered in section 4.1, involves the cationic palladium(II)-catalyzed rearrangement of glycal trichloroacetimidate to alpha-glycal trichloroacetamide in its key step. The transformation is carried out with only 0.5 mol% Pd(CH3CN)4(BF4)2 catalyst and is both highly alpha-selective and tolerant to a diverse array of protecting groups. The glycal product of the rearrangement is functionalized to pyranoside, protected, and then converted to glycosyl urea in 3-steps. A diverse array of primary and hindered secondary nitrogen nucleophiles have been coupled with the alpha-acetamide products, generating alpha-urea glycosides with retention of stereochemical integrity at the anomeric center. This is the first synthesis of alpha-glycosyl urea to rely on the nature of the catalyst/ligand complex, rather than substrate, to control selectivity. This method, however, suffers from limitations in scope and a dependence on toxic osmium tetroxide to functionalize the glycal.

In section 4.2, the development and mechanistic investigation of a 2nd-generation process, able to overcome the limitations of the glycal methodology to provide an efficient and highly stereoselective access to alpha-urea glycosides, is decribed. This two-step procedure begins with a highly selective nickel-catalyzed conversion of alpha-glycosyl trichloroacetimidate to alpha-trichloroacetamide. The alpha-selectivity in the reaction is controlled with a cationic nickel(II) catalyst, Ni(dppe)(OTf)2. Mechanistic studies have identified a coordination of the nickel catalyst with equatorial C2-ether group of the glycosyl trichloroacetimidate to be paramount for achieving an á-selective transformation. A cross-over experiment has indicated that the reaction does not proceed in an exclusively-intramolecular fashion. The alpha-trichloroacetamide products are directly converted into alpha-urea glycosides by reacting them with a variety of nucleophilic amines in presence of cesium carbonate. Only alpha-urea products are observed, as the reaction retains stereochemical integrity at the anomeric center during the urea-forming step.


alpha glycosyl urea, beta-O-aryl glycoside, carbohydrate, glycosylation, stereoselective, transition metal catalyst


xxvii, 334 pages


Includes bibliographical references (pages 316-334).


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Copyright 2014 Matthew Joseph McKay

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