Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Herzon, Seth

Abstract

In this thesis, I describe the development of an anionic glycosylation strategy toform 2-deoxy-O-glycosides (referred to as “2-deoxyglycosides” hereafter) with control of anomeric stereochemistry. Control over glycosidic bond stereochemistry is a central challenge in carbohydrate chemistry, and decades of research have yielded reliable and general methods to synthesize α- or β-linked 2-oxygenated glycosides. However, methods for the direct stereocontrolled synthesis of 2-deoxyglycosides are lacking. This is problematic because 2-deoxyglycosides are present in a variety of natural products and medicinal agents, including the calicheamicins, ivermectin, and vancomycin. These glycosides are formed in nature as specific α- or β-anomers, and the composition and stereochemical array of the glycosides is often essential for activity. Additionally, 2-deoxyglycosides are less stable toward acidic hydrolysis than their fully-substituted counterparts: the presence of fewer inductively electron-withdrawing oxygen substituents in 2-deoxyglycosides renders generation of an oxacarbenium ion more facile. Consequently, classical glycosylation conditions that employ these substrates tend to favor α-oriented products arising from kinetically-controlled addition to an electrophilic ii or cationic intermediate, and the synthesis of β-2-deoxyglycosides is particularly challenging. Herein, I describe the development of a mechanistically-distinct glycosylation reaction that is particularly well-suited to the construction of 2-deoxy- and 2,6- dideoxyglycosides. The strategy involves the generation of a stereodefined 2- lithiotetrahydropyranyl anion (aka, anomeric anion) by reductive lithiation of 1-thiophenyl glycosides. In most instances, the α-anomeric anion is formed kinetically and can be equilibrated to the more stable β-diastereomer, as desired. The addition of an alkyl 2-(2- methyltetrahydropyranyl) peroxide to either anion then provides the O-glycoside with retention of anomeric stereochemistry. In this way, both α- or β-products can be accessed from a common starting material. The method we developed was extended toward the diastereoselective synthesis of 2-deoxyaminoglycosides bearing basic nitrogen (which are notoriously difficult to synthesize using conventional pathways) and to 2-deoxyglycosides bearing free hydroxyl substituents. Additionally, we demonstrated the application of this method to the one-flask stereocontrolled synthesis of oligosaccharides.

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