Chiral auxiliaries for the stereoselective synthesis of glycosidic bonds and their application in complex oligosaccharide synthesis
Boltje, Thomas Jan
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The stereoselective synthesis of 1,2-cis-glycosidic bonds using a 2-O-(S)-(phenylthiomethyl)benzyl ether chiral auxiliary is descrided herein. Activation of a glycosyl donor protected with a 2-O-(S)-(phenylthiomethyl)benzyl ether chiral auxiliary results in the formation of an anomeric β-sulfonium ion, which can be displaced with sugar alcohols to afford the corresponding α-glycosides. Sufficient deactivation of such glycosyl donors by electron-withdrawing protecting groups is, however, critical to avoid glycosylation of an oxa-carbenium ion intermediate resulting in the formation of mixtures of anomers. The latter type of glycosylation pathway can also be suppressed by adding geminal substituents to the chiral auxiliary to promote the formation of the β-sulfonium ion. Adhering to these rules, the use of the 2-O-(S)-(phenylthiomethyl)benzyl ether chiral auxiliary was used to perform Solid Phase Oligosaccharide Synthesis (SPOS). Solid-phase oligosaccharide synthesis offers the promise of providing libraries of oligosaccharides for glycomics research. A major stumbling block to solid-phase oligosaccharide synthesis has been a lack of general methods for the stereoselective installation of 1,2-cis-glycosides, and intractable mixtures of compounds are obtained if several such glycosides need to be installed. We have prepared on-resin a biologically important glucoside containing multiple 1,2-cis-glycosidic linkages with complete anomeric control by using glycosyl donors having a participating (S)-(phenylthiomethyl)benzyl chiral auxiliary at C-2. The synthetic strategy made it possible to achieve partial on-resin deprotection of the completed oligosaccharide, thereby increasing the overall efficiency of the synthesis. The combination of classical and auxiliary-mediated neighboring-group participation for controlling anomeric selectivity is bringing the promise of routine automated solid-supported oligosaccharide synthesis closer. The use of the 2-O-(S)-(phenylthiomethyl)benzyl ether chiral auxiliary was also tested in the synthesis of substructures of the unusual core region of the lipopolysaccharide of Francisella tularensis. F.tularensis has been classified by the CDC as a Class A bio-terrorism agent. F. tularensis is highly virulent, requiring as few as 10-50 cells to cause human infection, which in an urban area would result in thousands of deaths. The lipopolysaccharide of F. tularensis is an attractive candidate for vaccine and diagnostic test development to combat such an event. Herein, the synthesis of the inner core hexasaccharide domain of F. tularensis is described.