A Fluoride Migration Approach to the Rapid Synthesis of Small Oligosaccharides

Abstract

Glycosidic bonds are ubiquitous in nature and their controlled formation is crucial for energy storage, cell-to-cell communication, transmission of the innate immune system from mother to child and much more. Despite their crucial role in biological systems, there is still a need for new methodologies and approaches for chemical glycosidic bonds formations. Being able to mimic the chemistry of biological systems is crucial for development of small molecule drugs, analytical standards, and biochemical probes. Major existing limitations of chemical glycosylations include a lack of catalytic approaches, a lack of user-friendly methodologies and limitations in the ability to synthesize 1,2-cis-glycosides reliably. Herein, I will demonstrate how the use of modern Lewis acid catalysts allowed for the development of an efficient catalytic system for glycosidic bonds formation, and how this approach can be leveraged to efficiently assemble small oligosaccharides rapidly and in a highly convergent manner. In Chapter 1, I provide an overview of some key functions of carbohydrates in biological systems, the nomenclature underpinning this subdiscipline and some key ideas about modern approaches to glycosidic bond formation. I also briefly discuss Lewis acids, with a focus on approaches to compare their relative strengths. In Chapter 2, I outline our work in developing a new approach to catalytic glycosidic bond formation, including the scope of this transformation, various control experiments to help discern the reaction mechanism and our work at developing bench stable pre-catalysts. In Chapter 3, I explain how this approach can be leveraged to form multiple glycosidic bonds in a single-pot, with control over both diastero- and regioselectivity. I then discuss our discovery of a novel side reaction, that involves the unprecedent direct exchange of fully protected sugars, how we determined the mechanism of this side reactivity, as well as how to suppress or enhance this new reactivity. Finally, in Chapter 4, I discuss new approaches to rapidly access, densely functionalized glycosyl fluorides. Building block synthesis is an unglamorous part of carbohydrate methodology, however efficient routes to access the desired glycosyl donors are crucial to the efficiency and success of such work. I included in this chapter a novel approach to the harvesting of complex monosaccharide donors from natural products using a combination of Lewis acids and thiols to directly access complex, deoxygenated thioglycosides, as well as a planned synthesis of oligosaccharides derived from cranberries that have potential antibiotic activity, as well as the synthesis of building blocks that I had planned to employ in this synthesis.