Carbohydrates are involved in a wide range of biological processes1,2,3,4. These structurally diverse compounds are more complex than other biological polymers, and are often present as heterogeneous mixtures in nature. The chemical synthesis of carbohydrates is one way to obtain pure oligosaccharides, but it is hampered by difficulties associated with the regioselective protection of polyhydroxyls and challenges related to the stereoselective assembly of glycosidic linkages5,6,7,8,9,10,11,12,13,14. Here we describe a combinatorial, and highly-regioselective, method that can be used to protect individual hydroxy groups of a monosaccharide. This approach can be used to install an orthogonal protecting group pattern in a single reaction vessel (a ‘one-pot’ reaction), which removes the need to carry out the time-consuming isolation and purification of intermediates. Hundreds of building blocks have been efficiently prepared starting from d-glucose, and the iterative coupling of these building blocks enabled us to assemble β-1,6-glucans and a library of oligosaccharides based on the influenza-virus-binding trisaccharide.
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We thank C.-C. Liao and H.-J. Liu for their discussions. This work was supported by the National Science Council of Taiwan and the Academia Sinica. S.S.K. thanks Academia Sinica for a postdoctoral fellowship.
Author Contributions S.-C.H. conceived the idea of one-pot protection, supervised students to carry out the experiments, and outlined the figures in the manuscript. C.-C.W. initiated the extensive work on the protection of methyl glucopyranoside and carried out the synthesis of β-1,6-glucans and haemagglutinin-binding trisaccharides. S.-Y.L. synthesized additional methyl glucopyranosides. J.-C.L. standardized the initial reactions on thioglycosides. S.S.K. synthesized more thioglycosides and wrote the manuscript. Y.-W.H., C.-C.L. and K.-L.C. contributed a representative example each of d-galactoside, d-mannoside, and 2-azido-2-deoxy-d-glucoside, respectively.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
This file contains Supplementary Figures 1-6 with Legends: Supplementary Figures 1 and 2 introduce traditional and straightforward synthesis of carbohydrates, respectively. Cleavages of substituted and unsubstituted benzyl ethers under various conditions are shown in Supplementary Figure 3. Supplementary Figure 4 describes preparation of the 2,3,4,6-tetra-O-trimethylsilyl ethers 1a and 1b. A representative example for the one-pot protection of each 2-azido-2-deoxy-D-glucoside, D-mannoside, and D-galactoside is delineated in Supplementary Figure 5. Supplementary Figure 6 illustrates the synthesis of β-1,6-glucans via iterative one-pot glycosylation. (PDF 66 kb)
This file contains Supplementary Methods. This file encloses complete experimental protocols pertaining to one-pot protection of methyl α-glucoside 1a and β-thioglucoside 1b (Supplementary Tables 1-7), representative examples for the one-pot protection of 2-azido-2-deoxy-D-glucosamine, D-mannoside and D-galactoside, iterative one-pot glycosylation to the synthesis of β-1,6-glucans, and one-pot synthesis of influenza virus-binding trisaccharides. (PDF 106 kb)
This file contains Supplementary Tables 1-7. Supplementary Table 1 illustrates the reaction conditions, reagents and yields of one-pot synthesis of 2-alcohols. Supplementary Tables 2 and 3 indicate one-pot synthesis of the fully protected monosaccharides and 3-alcohols, respectively, involving basic conditions for alkylation/arylmethylation/acylation at the O2 position. Supplementary Tables 4 and 5 describe, one-pot synthesis of the fully protected monosaccharides and 3-alcohols, respectively, using TMSOTf as a single acid catalyst. Supplementary Tables 6 and 7 outline one-pot synthesis of 4-alcohols and 6-alcohols, respectively. (PDF 52 kb)
This file contains Supplementary Data which includes complete physical characterization data of new compounds (PDF 599 kb)
This file contains Supplementary Data which includes complete spectra of new compounds, including 1H, 13C, and some 2D NMR spectra. (PDF 32250 kb)
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Wang, C., Lee, J., Luo, S. et al. Regioselective one-pot protection of carbohydrates. Nature 446, 896–899 (2007). https://doi.org/10.1038/nature05730
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