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Integrating ReSET with Glycosyl Iodide Glycosylation in Step-Economy Syntheses of Tumor-Associated Carbohydrate Antigens and Immunogenic Glycolipids

Hsieh, Hsiao-Wu, Schombs, Matthew W., Gervay-Hague, Jacquelyn
Journal of organic chemistry 2014 v.79 no.4 pp. 1736-1748
acetates, antigens, chemical structure, ethers, glycoconjugates, glycolipids, glycosylation, immunostimulants, immunotherapy, iodides, organic chemistry, regioselectivity, synthesis, trisaccharides
Carbohydrates mediate a wide range of biological processes, and understanding these events and how they might be influenced is a complex undertaking that requires access to pure glycoconjugates. The isolation of sufficient quantities of carbohydrates and glycolipids from biological samples remains a significant challenge that has redirected efforts toward chemical synthesis. However, progress toward complex glycoconjugate total synthesis has been slowed by the need for multiple protection and deprotection steps owing to the large number of similarly reactive hydroxyls in carbohydrates. Two methodologies, regioselective silyl exchange technology (ReSET) and glycosyl iodide glycosylation have now been integrated to streamline the synthesis of the globo series trisaccharides (globotriaose and isoglobotriaose) and α-lactosylceramide (α-LacCer). These glycoconjugates include tumor-associated carbohydrate antigens (TACAs) and immunostimulatory glycolipids that hold promise as immunotherapeutics. Beyond the utility of the step-economy syntheses afforded by this synthetic platform, the studies also reveal a unique electronic interplay between acetate and silyl ether protecting groups. Incorporation of acetates proximal to silyl ethers attenuates their reactivity while reducing undesirable side reactions. This phenomenon can be used to fine-tune the reactivity of silylated/acetylated sugar building blocks.