Regioselective one-pot protection of carbohydrates

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: One-pot protection of carbohydrates.
Figure 2: Proposed mechanism for the TMSOTf-catalysed one-pot protection of carbohydrates.
Figure 3: One-pot synthesis of influenza virus-binding trisaccharide library using the sialyl donor 13 as the starting sugar unit.

References

  1. 1

    Varki, A. (eds) et al. Essentials of Glycobiology (Cold Spring Harbor Laboratory Press, New York, 1999)

  2. 2

    Ernst, B., Hart, G. W. & Sinaÿ, P. (eds) Carbohydrates in Chemistry and Biology Vol. 1 (Wiley, Weinheim, 2000)

  3. 3

    Bertozzi, C. R. Kiessling, L. L. Chemical glycobiology. Science 291, 2357–2364 (2001)

  4. 4

    Schofield, L. et al. Synthetic GPI as a candidate anti-toxin vaccine in model of malaria. Nature 418, 785–789 (2002)

  5. 5

    Yamada, H., Harada, T., Miyazaki, H. & Takahashi, T. One-pot sequential glycosylation: a new method for the synthesis of oligosaccharides. Tetrahedron Lett. 35, 3979–3982 (1994)

  6. 6

    Douglas, N. L., Ley, S. V., Lücking, U. & Warriner, S. L. Tuning glycoside reactivity: New tool for efficient oligosaccharide synthesis. J. Chem. Soc. Perkin Trans. I 51–65 (1998)

  7. 7

    Zhang, Z. et al. Programmable one-pot oligosaccharide synthesis. J. Am. Chem. Soc. 121, 734–753 (1999)

  8. 8

    Sears, P. & Wong, C.-H. Toward automated synthesis of oligosaccharides and glycoproteins. Science 291, 2344–2350 (2001)

  9. 9

    Plante, O. J., Palmacci, E. R. & Seeberger, P. H. Automated solid-phase synthesis of oligosaccharides. Science 291, 1523–1527 (2001)

  10. 10

    Danishefsky, S. J., McClure, K. F., Randolph, J. T. & Ruggeri, R. B. A strategy for the solid-phase synthesis of oligosaccharides. Science 260, 1307–1309 (1993)

  11. 11

    Kim, J.-H., Yang, H., Park, J. & Boons, G.-J. A general strategy for stereoselective glycosylations. J. Am. Chem. Soc. 127, 12090–12097 (2005)

  12. 12

    Flitsch, S. L. Glycosylation with a twist. Nature 437, 201–202 (2005)

  13. 13

    Demchenko, A. V. Stereoselective chemical 1,2-cis-O-glycosylation: from “sugar ray” to modern techniques of the 21st century. Synlett 1225–1240 (2003)

  14. 14

    Pellissier, H. Use of O-glycosylation in total synthesis. Tetrahedron 61, 2947–2993 (2005)

  15. 15

    Kocienski, P. J. Protecting Groups 3rd edn (Georg Thieme, Stuttgart, 2005)

  16. 16

    Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis 4th edn (John Wiley & Sons, New York, 2007)

  17. 17

    Wright, J. A., Yu, J. & Spencer, J. B. Sequential removal of the benzyl-type protecting groups PMB and NAP by oxidative cleavage using CAN and DDQ. Tetrahedron Lett. 42, 4033–4036 (2001)

  18. 18

    Plante, O. J., Buchwald, S. L. & Seeberger, P. H. Halobenzyl ethers as protecting groups for organic synthesis. J. Am. Chem. Soc. 122, 7148–7149 (2000)

  19. 19

    Jobron, L. & Hindsgaul, O. Novel para-substituted benzyl ethers for hydroxyl group protection. J. Am. Chem. Soc. 121, 5835–5836 (1999)

  20. 20

    Shie, C.-R. et al. Cu(OTf)2 as an efficient and dual-purpose catalyst in the regioselective reductive ring opening of benzylidene acetals. Angew. Chem. Int. Edn 44, 1665–1668 (2005)

  21. 21

    Tsunoda, T., Suzuki, M. & Noyori, R. A facile procedure for acetalization under aprotic conditions. Tetrahedron Lett. 21, 1357–1358 (1980)

  22. 22

    Hatakeyama, S. et al. Efficient reductive etherification of carbonyl compounds with alkoxytrimethylsilanes. Tetrahedron Lett. 35, 4367–4370 (1994)

  23. 23

    Wang, C.-C. et al. Synthesis of biologically potent α1,2-linked disaccharide derivatives via regioselective one-pot protection glycosylation. Angew. Chem. Int. Edn 41, 2360–2362 (2002)

  24. 24

    Huang, X., Huang, L., Wang, H. & Ye, X.-S. Iterative one-pot synthesis of oligosaccharides. Angew. Chem. Int. Edn 43, 5221–5224 (2004)

  25. 25

    Parrish, C. R. & Kawaoka, Y. The origins of new pandemic viruses: The acquisition of new host ranges by canine parvovirus and influenza A viruses. Annu. Rev. Microbiol. 59, 553–586 (2005)

  26. 26

    Gamblin, S. J. et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303, 1838–1842 (2004)

  27. 27

    Stevens, J. et al. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 303, 1866–1870 (2004)

  28. 28

    De Meo, C. & Parker, O. Thiomidoyl approach to the synthesis of α-sialosides. Tetrahedron Asymm. 16, 303–307 (2005)

  29. 29

    Lee, J.-C. et al. Synthesis of Heparin Oligosaccharides. J. Am. Chem. Soc. 126, 476–477 (2004)

Download references

Acknowledgements

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.

Author information

Correspondence to Shang-Cheng Hung.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

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)

Supplementary Methods

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)

Supplementary Tables 1-7

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)

Supplementary Data

This file contains Supplementary Data which includes complete physical characterization data of new compounds (PDF 599 kb)

Supplementary Data

This file contains Supplementary Data which includes complete spectra of new compounds, including 1H, 13C, and some 2D NMR spectra. (PDF 32250 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.