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


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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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.

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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).

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