Date of Degree
PhD (Doctor of Philosophy)
Hien M. Nguyen
The development of new glycosylation methods for the stereoselective synthesis of β-glycosides in the absence of the traditional C(2)-ester participatory group on glycosyl donors using cationic palladium catalyst Pd(PhCN)2(OTF)2, as well as the formation of 1.2-cis-2-amino glycosides via cationic nickel catalyzed α-selective glycosylation using C(2)-N-substituted benzylidene D-glucosamine and galactosamine trichloroacetimidates is described. In the formation of β-glycosides, the process relies on the ability of the cationic palladium catalyst Pd(PhCN)2(OTF)2, generated in situ from Pd(PhCN)2Cl2 and AgOTf, to direct β-selectivity. The new glycosylation reaction is highly β-selective, and proceeds under mild conditions with 1-2 % of catalyst loading. This β-glycosylation protocol has been applied to a number of glucose donors with benzyl, allyl and p-methoxybenzyl groups incorporated at the C(2)-position, as well as xylose and quinovose donors to prepare various disaccharides and trisaccharides with good to excellent β-selectivity. Mechanistic studies suggest that the major operative pathway is likely a seven-membered ring intermediate, wherein the cationic palladium complex coordinates to both the C(1)-imidate nitrogen and the C(2)-oxygen of the trichloroacetimidate donor. Formation of this seven-membered ring complex directs the selectivity, leading to the formation of β-glycosides. In the formation of 1,2-cis-2-amino glycosides, the method relies on the nature of nickel-ligand complex to control α-selectivity. The reactive sites of the nucleophiles as well as the nature of the protecting groups have little effect on the alpha-selectivity. This protocol is mild, highly α-selective, and has been successfully applied towards the stereoselective synthesis heparin disaccharides, α-GluNAc/GalNAc glycoconjugates, and GPI anchor pseudodisaccharides. The nickel catalyzed glycosylation protocol has also been successfully applied to both disaccharide donors and acceptors to provide the corresponding oligosaccharides in high yields, and with excellent levels of α-selectivity. Mechanistic studies suggests that the presence of the substituted benzylidene functionality at the C(2)-amino position of glycosyl donors is crucial for the high α-selectivity observed in the coupling products.
Copyright 2011 Enoch Akuamoah Mensah
Mensah, Enoch Akuamoah. "Palladium and nickel catalyzed stereoselective formation of glycosides." dissertation, University of Iowa, 2011.