Reagent-Controlled Dehydrative Glycosylation for Synthesis of 2‐Deoxy‐β‐Linked Sugars: Applications to Oligosaccharide Synthesis
Abstract: Development of versatile and efficient approaches to glycosylation has become a priority for the scientific community, with the goal of enabling studies of natural products for potential use in next-generation therapeutics. An emerging study area driven by recent advances is the development of new methodologies for direct synthetic approaches for β-linked 2-deoxy sugars. This dissertation ... read morefocuses on the development of a high-efficiency stereoselective procedure to generate these sugars. Three generations of reagent-controlled β-selective methodologies developed by our laboratory are described. The first generation uses promoter tosyl 4-nitroimidazole (TsImNO2) activated hemiacetal donors to form glycosyl sulfonates in situ (Chapter 2). This approach gave excellent yield and selectivity for TsImNO2 but showed limited yield for O-glycosyl acceptors. To overcome this limitation, a second-generation approach replaced tosyl 4-nitroimidazole with the more reactive sulfonate tosic anhydride (Ts2O), enabling the synthesis of larger oligosaccharide targets such as the hexasaccharide side chain of landomycin A. (Chapter 3). Although the second generation was powerful, the method encountered difficulties upon scaling up the reaction while maintaining high β-selectivity. Our third-generation methodology explored the use of tosyl chloride (TsCl) as an alternative promoter to Ts2O (Chapter 4). The TsCl promoted glycosylations showed improved yields and the ability to carry out glycosylations on gram-scale. These improvements were subsequently demonstrated to be versatile across a range of β-linked 2-deoxy sugars (Chapter 5). Oligosaccharide side chains of the natural products FD-594 and kigamicin E were constructed by this method, acting as a proof-of-concept for the reagent-controlled approach for β-selective glycosylations. The ultimate goal of this thesis work is the development of a general approach to glycosylation reactions. While our initial studies focused on β-linked 2-deoxy sugars, we see the potential for development of a framework for efficiently generating a variety of substrates important to the development of next-generation therapeutics.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Chemistry.
Advisor: Clay Bennett.
Committee: Krishna Kumar, Samuel Thomas, and Amit Basu.
Keywords: Chemistry, and Organic chemistry.read less