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Chemoenzymatic total synthesis of alchivemycin A

Nature Synthesis volume 3, pages 1124–1133 (2024)Cite this article

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Abstract

Alchivemycin A belongs to a unique class of polyketide natural products isolated from plant-derived actinomycete Streptomyces. It shows potent antibacterial activity and anti-tumour activity. However, its inherent structural complexity and high oxidation state, especially the 2H-tetrahydro-4,6-dioxo-1,2-oxazine (TDO) ring system, present synthetic challenges. Here we report the total synthesis of alchivemycin A using a chemoenzymatic approach that combines de novo skeleton construction and late-stage enzymatic oxidation reactions. The convergent synthesis of the highly functionalized unnatural tetramic acid-bearing intermediate is achieved by boron-alkyl Suzuki−Miyaura cross-coupling, macrolactamization and Lacey–Dieckmann condensation reactions. Efficient enzymatic epoxidations using the redox enzymes AvmO3 and AvmO2 allow rapid access to the desired diepoxide product regio- and stereoselectively. Subsequently, a flavin adenine dinucleotide-dependent enzyme AvmO1 variant optimized via rational protein engineering, AvmO1-Y282R, was used to convert the tetramic acid ring into the TDO ring through a Baeyer–Villiger-type transformation, completing the chemoenzymatic synthesis of alchivemycin A. This work paves the way to further explore the biological functions of alchivemycin A and highlights the utility of chemoenzymatic strategies to tackle synthetic challenges in complex molecule synthesis.

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Fig. 1: Background and structural analysis of alchivemycin A (1).
Fig. 2: Retrosynthetic analysis.
Fig. 3: Synthesis of the side-chain fragment 12.
Fig. 4: Convergent synthesis of the tetramic acid-bearing unnatural enzymatic substrate 8.
Fig. 5: Late-stage enzymatic synthesis of alchivemycin A (1).

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The data that support the findings of this study are available in this article and its Supplementary Information. Source data are provided with this paper.

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Acknowledgements

We thank the NMR facility of the National Center for Protein Sciences at Peking University and X. Niu for assistance in the NMR analysis. We thank X. Zhang, H. Fu and L. Wang of the Analytical Instrumentation Center at Peking University for assistance in the NMR analysis. We thank J. Zhou and X. He of the Analytical Instrumentation Center at Peking University for help with the HRMS analysis. This work was supported by the National Key Research and Development Plan (grant no. 2022YFC3401500 to X.L.), the National Natural Science Foundation of China (grant nos. 22193073 and 92253305 to X.L.) and the Beijing National Laboratory for Molecular Sciences (grant no. BNLMS-CXX-202106 to X.L.). A special research grant for biocatalyst development from Novartis Pharma is acknowledged. X.L. is supported by the New Cornerstone Science Foundation through the XPLORER PRIZE.

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Author notes

  1. These authors contributed equally: Haoran Dong, Nianxin Guo.

Authors and Affiliations

  1. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, People’s Republic of China

    Haoran Dong, Nianxin Guo, Dachao Hu, Benke Hong, Daohong Liao & Xiaoguang Lei

  2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, People’s Republic of China

    Nianxin Guo & Xiaoguang Lei

  3. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, People’s Republic of China

    Hong Jie Zhu, Zhang Yuan Yan & Hui Ming Ge

  4. Institute of Cancer Research, Shen Zhen Bay Laboratory, Shen Zhen, People’s Republic of China

    Xiaoguang Lei

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Contributions

X.L. conceived the research plan and initiated and supervised the project. X.L., H.D. and N.G. designed the experiments, analysed the data and prepared the paper with input from all other authors. H.D. conducted the chemical synthesis with the help of D.H., B.H. and D.L. N.G. and H.D. performed the biological assays and completed the enzymatic reactions with the help of H.M.G., H.J.Z. and Z.Y.Y.

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Correspondence to Xiaoguang Lei.

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Nature Synthesis thanks Rudi Fasan, Hiroki Oguri and Hans Renata for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Dong, H., Guo, N., Hu, D. et al. Chemoenzymatic total synthesis of alchivemycin A. Nat. Synth 3, 1124–1133 (2024). https://doi.org/10.1038/s44160-024-00577-7

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