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Harnessing transaminases to construct azacyclic non-canonical amino acids

Nature Synthesis (2024)Cite this article

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Abstract

Non-canonical amino acids (ncAAs) are prized building blocks in the synthesis of natural products, designer peptides and drug molecules. Despite their general utility, the structural complexity of these molecules still presents an enormous challenge for chemical synthesis. Here we develop a one-pot chemoenzymatic approach for the construction of azacyclic ncAAs with multiple substitutions and various ring sizes. A promiscuous transaminase was identified to convert a wide range of diketoacids to the corresponding α-amino acids. A spontaneous cyclic imine formation was followed by a stereocontrolled chemical reduction to generate the corresponding products in one pot with high stereoselectivity. More than 25 azacyclic ncAAs were successfully prepared using this approach. This work demonstrates the value of developing hybrid biocatalytic–chemocatalytic approaches to prepare privileged small molecule motifs.

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Fig. 1: Importance and prevalence of azacyclic ncAAs.
Fig. 2: Preparation of 2,n-diketocarboxylic acid substrates.
Fig. 3: Substrate scope exploration of one-pot ncAA synthesis with MtIlvE and hydrogenation.
Fig. 4: Synthetic logic for accessing branched azacyclic ncAAs with our chemoenzymatic strategy.

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Data availability

Full experimental details, Supplementary Fig. 1 and Supplementary Tables 1 and 2 are available in the Supplementary Information. Crystallographic data for compound 16l-cis-trans reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition number CCDC 2278016. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Funding for this work is provided, in part, by the ACS Green Chemistry Institute Pharmaceutical Roundtable grant and the Welch Foundation (grant number C2159). T.-H.C. acknowledges fellowship support from the Ministry of Education, Taiwan. We thank M. Gantcher (Rice University) for his assistance in some of the experiments described in this work. We are grateful to the Shared Equipment Authority at Rice University for access to their instrumentation.

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Authors and Affiliations

  1. Department of Chemistry, BioScience Research Collaborative, Rice University, Houston, TX, USA

    Tsung-Han Chao, Xiangyu Wu, Yu Fu & Hans Renata

  2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Licheng Yang

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Contributions

T.-H.C., L.Y. and H.R. conceived the work. T.-H.C., X.W., Y.F., L.Y. and H.R. designed all the experiments described in the manuscript. T.-H.C., X.W. and H.R. wrote the manuscript.

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Correspondence to Hans Renata.

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Nature Synthesis thanks Andrew Buller, Sabine Flitsch and Elaine O’Reilly for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Experimental details, Supplementary Figs. 1 and 2, and Tables 1 and 2.

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Supplementary Data 1

X-ray crystallographic data for compound 16l-cis–trans, CCDC 2278016.

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Chao, TH., Wu, X., Fu, Y. et al. Harnessing transaminases to construct azacyclic non-canonical amino acids. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00514-8

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