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Chemoenzymatic asymmetric synthesis of the metallo-β-lactamase inhibitor aspergillomarasmine A and related aminocarboxylic acids

Abstract

Metal-chelating aminocarboxylic acids are being used in a broad range of domestic products and industrial applications. With the recent identification of the fungal natural product aspergillomarasmine A as a potent and selective inhibitor of metallo-β-lactamases and a promising co-drug candidate to fight antibiotic-resistant bacteria, the academic and industrial interest in metal-chelating chiral aminocarboxylic acids further increased. Here, we report a biocatalytic route for the asymmetric synthesis of aspergillomarasmine A and various related aminocarboxylic acids from retrosynthetically designed substrates. This synthetic route highlights a highly regio- and stereoselective carbon–nitrogen bond-forming step catalysed by ethylenediamine-N,N′-disuccinic acid lyase. The enzyme shows broad substrate promiscuity, accepting a wide variety of amino acids with terminal amino groups for selective addition to fumarate. We also report a two-step chemoenzymatic cascade route for the rapid diversification of enzymatically prepared aminocarboxylic acids by N-alkylation in one pot. This biocatalytic methodology offers a useful alternative route to difficult aminocarboxylic acid products.

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Fig. 1: Natural aminocarboxylic acid products.
Fig. 2: One-pot, two-step chemoenzymatic synthesis of AMB and its homologues.
Fig. 3: Retrosynthesis of AMA and AMB.

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Acknowledgements

H.F. and J.Z. acknowledge funding from the China Scholarship Council. The authors thank A. Boltjes and W. Szymanski for insightful discussions, and R. H. Cool for assistance with enzyme purification.

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H.F., J.Z., M.S. and G.C. performed the preparative biotransformations and product analysis. H.F. and M.S. synthesized the starting substrates and reference compounds, and developed the one-pot chemoenzymatic cascade. J.Z. and P.G.T. performed the chiral high-performance liquid chromatography experiments. G.J.P. supervised the scientific work. All authors contributed to writing the paper.

Corresponding author

Correspondence to Gerrit J. Poelarends.

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The authors declare no competing interests.

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Supplementary Information

Supplementary Methods, Supplementary Figures 1–59, Supplementary Table 1 and Supplementary References

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Fu, H., Zhang, J., Saifuddin, M. et al. Chemoenzymatic asymmetric synthesis of the metallo-β-lactamase inhibitor aspergillomarasmine A and related aminocarboxylic acids. Nat Catal 1, 186–191 (2018). https://doi.org/10.1038/s41929-018-0029-1

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