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Stereoconvergent reduction of alkenes using a repurposed iron-based dioxygenase

Nature Synthesis (2025)Cite this article

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Abstract

The stereoconvergent reduction of alkenes for efficient synthesis of chiral compounds is a challenge in synthetic chemistry, even for exquisite enzymes in nature. Natural ene-reductases for example generally catalyse the reduction of alkenes in an enantiodivergent or resolution fashion. Here we report the repurposing of non-haem iron-based dioxygenases to catalyse the stereoconvergent reduction of alkenes through an iron hydride intermediate, by introducing silanes to the biocatalytic system. Directed evolution of gentisate 1,2-dioxygenase led to iron-based ene-reductases with high efficiency (up to 99% yield), excellent enantioselectivity (23 examples with >99% e.e.) and compatibility with a structurally diverse range of substrates. Experimental studies suggest the formation of iron hydride species in the enzyme and support the divalency of iron during the catalytic process. Computational studies show that the reaction is energetically feasible through an iron hydride mechanism and reveal the molecular mechanism of stereoconvergence.

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Fig. 1: Enzymatic reduction of an E/Z mixture of alkene.
Fig. 2: Discovery and directed evolution of non-haem iron enzymes for stereoconvergent alkene reduction.
Fig. 3: Substrate scope study results.
Fig. 4: Mechanistic experiments.
Fig. 5: Computational studies.

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Data availability

All of the data needed to support the conclusions of this study are available in the main text and Supplementary Information.

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Acknowledgements

We thank staff at the Chemistry Instrumentation Center of Zhejiang University for instrumental support, including Q. He and X. Li for help with high-resolution mass spectrometry, X. Wang and Y. Wang for EPR analysis and M. Yu for assistance with NMR. We thank B. Shan’s group at Zhejiang University for help with obtaining ultraviolet–visible spectroscopy data. We further acknowledge Y. Rao’s group at Jiangnan University for providing plasmid DNA coding for BTG13. This work was supported by the National Natural Science Foundation of China (22172142 (P.J.), 22377107 (P.J.) and 22303043 (X.Z.)), the Zhejiang Provincial Outstanding Youth Science Foundation (LR22B030004 (P.J.)), Fundamental Research Funds for the Central Universities (226-2024-00003 (P.J.)), the Key-Area Research and Development Program of Guangdong Province (2022B1111080005 (R.W.)), the Ningbo Yongjiang Talent Programme (2023A-378-G (X.Z.)), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0960201 (L.Y.)) and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022455 (L.Y.)).

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  1. These authors contributed equally: Zicong Wan, Xuan Zhang.

Authors and Affiliations

  1. Department of Chemistry, Zhejiang University, Hangzhou, China

    Zicong Wan, Helin Zhuang, Zihang Fu, Yang Sun, Wei Wang & Pengfei Ji

  2. Institute of Drug Discovery Technology, Ningbo University, Ningbo, China

    Xuan Zhang

  3. School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China

    Zhekai Xie & Ruibo Wu

  4. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Lu Yu

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Contributions

P.J. and Z.W. initiated this project. Z.W. developed the biocatalytic system and performed most of the experiments. H.Z., Z.F. and W.W. assisted with the synthesis of compounds. L.Y. carried out the spectroscopic studies. Y.S. assisted with protein expression and purification. X.Z. and Z.X. performed the computational studies with R.W. providing guidance. Z.W., X.Z. and P.J. wrote the manuscript. All authors reviewed and approved the manuscript.

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Correspondence to Ruibo Wu or Pengfei Ji.

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Supplementary Figs. 1–26, Tables 1–22, Experimental details and Characterization data.

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Supplementary Data

Primer sequences for site-specific mutagenesis.

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Wan, Z., Zhang, X., Zhuang, H. et al. Stereoconvergent reduction of alkenes using a repurposed iron-based dioxygenase. Nat. Synth (2025). https://doi.org/10.1038/s44160-025-00788-6

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