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Chemoenzymatic synthesis of differentially protected 3-deoxysugars

Nature Chemistry volume 2, pages 102–105 (2010)Cite this article

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Abstract

3-Deoxysugars are important constituents of complex carbohydrates. For example, 2-keto-3-deoxy-D-manno-octulosonic acid (KDO) is an essential component of lipopolysaccharides in Gram-negative bacteria, 2-keto-3-deoxy-D-glycero-D-galacto-nonulosonic acid (KDN) is widely found in carbohydrates of the bacterial cell wall and in lower vertebrates, and sialic acid is a common cap of mammalian glycoproteins. Although ready access to such sugars would benefit the creation of vaccine candidates, antibiotics and small-molecule drugs, their chemical synthesis is difficult. Here we present a simple chemoenzymatic method for preparing differentially protected 3-deoxysugar derivatives from readily available starting materials. It exploits the promiscuous aldolase activity of the enzyme macrophomate synthase (MPS) to add pyruvate enolate diastereoselectively to a wide range of structurally complex aldehydes. A short synthesis of KDN illustrates the utility of this approach. Enzyme promiscuity, which putatively fosters large functional leaps in natural evolution, has great promise as a source of synthetically useful catalytic transformations.

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Figure 1: MPS-catalysed synthesis of representative 3-deoxysugars.
Figure 2: Selective deprotection of 3-deoxysugar derivatives provides strategic control of ring-closure.
Figure 3: Structural basis for MPS promiscuity.

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Acknowledgements

This work was supported by the ETH Zürich, a Marie Curie International Incoming Fellowship within the 7th European Community Framework Programme to D.G.G. (IIF-AEOM) and a PhD fellowship from the Studienstiftung des Deutschen Volkes to P.S.

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  1. Pierre Stallforth & Peter H. Seeberger

    Present address: Present address: Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany (P.S.), Institute of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany (P.H.S.),

  2. Dennis G. Gillingham and Pierre Stallforth: These authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Organic Chemistry, ETH Zurich, Zurich, 8093, Switzerland

    Dennis G. Gillingham, Pierre Stallforth, Alexander Adibekian, Peter H. Seeberger & Donald Hilvert

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Contributions

D.G.G., P.S., P.H.S. and D.H. designed research. D.G.G, P.S. and A.A. performed the experiments. D.G.G., P.S., P.H.S and D.H. analysed data. D.G.G., P.S., P.H.S. and D.H. wrote the paper.

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Correspondence to Peter H. Seeberger or Donald Hilvert.

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Gillingham, D., Stallforth, P., Adibekian, A. et al. Chemoenzymatic synthesis of differentially protected 3-deoxysugars. Nature Chem 2, 102–105 (2010). https://doi.org/10.1038/nchem.504

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