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Synthesis of rare sugar isomers through site-selective epimerization

Nature volume 578, pages 403–408 (2020)Cite this article

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Abstract

Glycans have diverse physiological functions, ranging from energy storage and structural integrity to cell signalling and the regulation of intracellular processes1. Although biomass-derived carbohydrates (such as d-glucose, d-xylose and d-galactose) are extracted on commercial scales, and serve as renewable chemical feedstocks and building blocks2,3, there are hundreds of distinct monosaccharides that typically cannot be isolated from their natural sources and must instead be prepared through multistep chemical or enzymatic syntheses4,5. These ‘rare’ sugars feature prominently in bioactive natural products and pharmaceuticals, including antiviral, antibacterial, anticancer and cardiac drugs6,7. Here we report the preparation of rare sugar isomers directly from biomass carbohydrates through site-selective epimerization reactions. Mechanistic studies establish that these reactions proceed under kinetic control, through sequential steps of hydrogen-atom abstraction and hydrogen-atom donation mediated by two distinct catalysts. This synthetic strategy provides concise and potentially extensive access to this valuable class of natural compounds.

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Fig. 1: Approaches to the epimerization of sugars.
Fig. 2: Epimerization of α-methylglucose to α-methylallose.
Fig. 3: Site-selective epimerization of saccharides and glycans.
Fig. 4: Mechanistic studies and proposed mechanism.

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All data supporting the findings of this paper are available within the Article and its supplementary information files.

References

  1. Varki, A. et al. (eds) Essentials of Glycobiology 3rd edn (Cold Spring Harbor Laboratory Press, 2017).

  2. de Leder Kremer, R. M. & Gallo-Rodriquez, C. Naturally occurring monosaccharides: properties and synthesis. Adv. Carbohydr. Chem. Biochem. 59, 9–67 (2004).

    Article  Google Scholar 

  3. Chheda, J. N., Huber, G. W. & Dumesic, J. A. Liquid-phase catalytic processing of biomass-derived oxygenated hydrocarbons to fuels and chemicals. Angew. Chem. Int. Ed. 46, 7164–7183 (2007).

    Article  CAS  Google Scholar 

  4. Imperiali, B. Bacterial carbohydrate diversity—a brave new world. Curr. Opin. Chem. Biol. 53, 1–8 (2019).

    Article  CAS  Google Scholar 

  5. Herget, S. et al. Statistical analysis of the Bacterial Carbohydrate Structure Data Base (BCSDB): characteristics and diversity of bacterial carbohydrates in comparison with mammalian glycans. BMC Struct. Biol. 8, 35 (2008).

    Article  Google Scholar 

  6. Frihed, T. G., Bols, M. & Pedersen, C. M. Synthesis of l-hexoses. Chem. Rev. 115, 3615–3676 (2015).

    Article  CAS  Google Scholar 

  7. Elshahawi, S. I., Shaaban, K. A., Kharel, M. K. & Thorson, J. S. A comprehensive review of glycosylated bacterial natural products. Chem. Soc. Rev. 44, 7591–7697 (2015).

    Article  CAS  Google Scholar 

  8. Angyal, S. The Lobry de Bruyn–Albereda van Ekenstein transformation and related reactions. In Glycoscience: Epimerisation, Isomerisation and Rearrangement Reactions of Carbohydrates (ed. Stütz, A. E.) 1–14 (Springer, 2001).

  9. Buchholz, K. & Seibel, J. Industrial carbohydrate biotransformations. Carb. Res. 343, 1966–1979 (2008).

    Article  CAS  Google Scholar 

  10. Bhosale, S. H., Rao, M. B. & Deshpande, V. V. Molecular and industrial aspects of glucose isomerase. Microbiol. Rev. 60, 280–300 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Wulf, P. & Vandamme, E. Production of d-ribose by fermentation. Appl. Microbiol. Biotechnol. 48, 141–148 (1997).

    Article  Google Scholar 

  12. Granström, T. B., Takata, G., Tokuda, M. & Izumori, K. Izumoring: a novel and complete strategy for the bioproduction of rare sugars. J. Biosci. Bioeng. 97, 89–94 (2004).

    Article  Google Scholar 

  13. Zhang, W., Zhang, T., Jiang, B. & Mu, W. Enzymatic approaches to rare sugar production. Biotechnol. Adv. 35, 267–274 (2017).

    Article  CAS  Google Scholar 

  14. Hossain, M. A. et al. Effect of the immunosuppressants FK506 and d-allose on allogenic orthotopic liver transplantation in rats. Transplant. Proc. 32, 2021–2023 (2000).

    Article  CAS  Google Scholar 

  15. Menavuvu, B. T. et al. Efficient biosynthesis of d-allose from d-psicose by cross-linked recombinant l-rhamnose isomerase: separation of product by ethanol crystallization. J. Biosci. Bioeng. 101, 340–345 (2006).

    Article  CAS  Google Scholar 

  16. Kudo, F., Hoshi, S., Kawashima, T., Kamach, T. & Eguchi, T. Characterization of a radical S-adenosyl-l-methionine epimerase, NeoN, in the last step of neomycin B biosynthesis. J. Am. Chem. Soc. 136, 13909–13915 (2014).

    Article  CAS  Google Scholar 

  17. Benjdia, A., Guillot, A., Ruffie, P., Leprince, J. & Berteau, O. Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis. Nat. Chem. 9, 698–707 (2017).

    Article  CAS  Google Scholar 

  18. Wang, Y. et al. Epimerization of tertiary carbon centers via reversible radical cleavage of unactivated C(sp 3)–H bonds. J. Am. Chem. Soc. 140, 9678–9684 (2018).

    Article  CAS  Google Scholar 

  19. Shin, N. Y., Ryss, J. M., Zhang, X., Miller, S. J. & Knowles, R. R. Light-driven deracemization enabled by excited-state electron transfer. Science 366, 364–369 (2019).

    Article  ADS  CAS  Google Scholar 

  20. Dimakos, V. & Taylor, M. S. Site-selective functionalization of hydroxyl groups in carbohydrate derivatives. Chem. Rev. 118, 11457–11517 (2018).

    Article  CAS  Google Scholar 

  21. Frihed, T. G., Bols, M. & Pedersen, C. M. C–H functionalization on carbohydrates. Eur. J. Org. Chem. 2740–2756 (2016).

  22. Jäger, M., Hartmann, M., de Vries, J. G. & Minnaard, A. J. Catalytic regioselective oxidation of glycosides. Angew. Chem. Int. Ed. 52, 7809–7812 (2013).

    Article  Google Scholar 

  23. Chung, K. & Waymouth, R. M. Selective catalytic oxidation of unprotected carbohydrates. ACS Catal. 6, 4653–4659 (2016).

    Article  CAS  Google Scholar 

  24. Muramatsu, W. Catalytic and regioselective oxidation of carbohydrates to synthesize keto-sugars under mild conditions. Org. Lett. 16, 4846–4849 (2014).

    Article  CAS  Google Scholar 

  25. Wan, I. C., Witte, M. D. & Minnaard, A. J. Site-selective carbon–carbon bond formation in unprotected monosaccharides using photoredox catalysis. Chem. Commun. 53, 4926–4929 (2017).

    Article  CAS  Google Scholar 

  26. Dimakos, V., Su, H. Y., Garrett, G. E. & Taylor, M. S. Site-selective and stereoselective C–H alkylations of carbohydrates via combined diarylborinic acid and photoredox catalysis. J. Am. Chem. Soc. 141, 5149–5153 (2019).

    Article  CAS  Google Scholar 

  27. Maiti, N. C., Zhu, Y., Carmichael, I., Serianni, A. S. & Anderson, A. E. 1JCH correlates with alcohol hydrogen bond strength. J. Org. Chem. 71, 2878–2880 (2006).

    Article  CAS  Google Scholar 

  28. Goldberg, R. N. & Tewari, Y. B. Thermodynamic and transport properties of carbohydrates and their monophosphates: the pentoses and hexoses. J. Phys. Chem. Ref. Data 18, 809–880 (1989).

    Article  ADS  CAS  Google Scholar 

  29. Jeffrey, J. L., Terrett, J. A. & Macmillan, D. W. C. O–H hydrogen bonding promotes H atom transfer from α C–H bonds for C–alkylation of alcohols. Science 349, 1532–1536 (2015).

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We thank A. Seim for checking the reaction procedure and X. Gu for help with substrate synthesis. A.E.W. also thanks E. Kwan, A. Radosevich, D. Suess and Z. Wickens for discussions. Financial support for this work was provided by the Massachusetts Institute of Technology and the National Science Foundation (NSF) for funding through the National Science Foundation Graduate Research Fellowships Program (NSF-GRFP) to H.M.C.

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Authors and Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

    Yong Wang, Hayden M. Carder & Alison E. Wendlandt

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  1. Yong Wang
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Contributions

A.E.W. and Y.W. conceived the work. A.E.W., Y.W. and H.M.C. designed the experiments. Y.W. and H.M.C. conducted the experiments. A.E.W. directed the research and wrote the manuscript with input from all authors.

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Correspondence to Alison E. Wendlandt.

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The authors declare no competing interests.

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Peer review information Nature thanks Christian Marcus Pedersen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Chemical and enzymatic isomerizations proceed through polar aldose-ketose mechanisms.

a, Chemical isomerization reactions of glucose lead to unselective and complex thermodynamic distribution of products. b, ‘Izumoring’ enzymatic synthesis of d-allose proceeds through reversible polar enolization mechanisms under equilibrium control; see ref. 12. d-XI is d-xylose isomerase; d-TE is d-tagatose 3-epimerase; and l-RhI is l-rhamnose isomerase.

Supplementary information

Supplementary Information

This file contains the following sections: 1. General Experimental Methods; 2. Materials and Reagents; 3. Instrumentation; 4. Synthesis of Catalysts (4CzIPN and 4-ClOBzBu4N) and Substrates; 5. General Reaction Procedure for Sugar Epimerization; 6. General Procedure for Purification of Epimeric Sugars; 7. Product Characterization; 8. Condition Optimization for Sugar Epimerization of 1a; 9. Mechanistic Studies; 10. References; and 11. NMR Spectra.

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Wang, Y., Carder, H.M. & Wendlandt, A.E. Synthesis of rare sugar isomers through site-selective epimerization. Nature 578, 403–408 (2020). https://doi.org/10.1038/s41586-020-1937-1

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