Synthesis of rare sugar isomers through site-selective epimerization

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.

Data availability

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

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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.

Author information

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.

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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