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Chiral-auxiliary-mediated 1,2-cis-glycosylations for the solid-supported synthesis of a biologically important branched α-glucan

Abstract

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 C2. A branching point could be installed by using 9-fluorenylmethyloxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc) as a versatile set of orthogonal protecting groups. 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 neighbouring-group participation for controlling anomeric selectivity is bringing the promise of routine automated solid-supported oligosaccharide synthesis closer.

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Figure 1: Stereoselective introduction of glycosidic linkages.
Figure 2: Structure of an α-glucan pentasaccharide repeating unit found in A. carmichaeli.
Figure 3: Stereoselective solid-supported synthesis of pentasaccharide 22 using monosaccharide building-blocks 1–4 and linker-modified resin 7.
Figure 4: NMR data for pentasaccharide 21.
Figure 5: Stereoselective solid-supported synthesis of galactoside-containing analogue 26.

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Acknowledgements

This research was supported by the National Institute of General Medicine (NIGMS) of the National Institutes of Health (grant numbers 2R01GM065248 and 2R01GM061761).

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Contributions

T.J.B., J.-H.K. and G.J.B. conceived and designed the experiments. T.J.B. carried out the solid-supported synthesis of 22 and 26 and analysed the results. J.-H.K. carried out the solution-phase synthesis of a pentaglucoside. J.P. carried out the solution synthesis of a galactoside containing trisaccharide. T.J.B. and G.J.B. wrote the paper.

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Correspondence to Geert-Jan Boons.

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The authors declare no competing financial interests.

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Boltje, T., Kim, JH., Park, J. et al. Chiral-auxiliary-mediated 1,2-cis-glycosylations for the solid-supported synthesis of a biologically important branched α-glucan. Nature Chem 2, 552–557 (2010). https://doi.org/10.1038/nchem.663

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