Abstract
Fusicoccane diterpenoids display intriguing biological activities, including the ability to act as modulators of 14-3-3 protein–protein interactions. However, their innate structural complexity and diverse oxygenation patterns present enormous synthetic challenges. Here we develop a modular chemoenzymatic approach that combines de novo skeletal construction and late-stage hybrid C–H oxidations to achieve the synthesis of ten complex fusicoccanes in 8–13 steps each. A convergent fragment coupling strategy allowed rapid access to a key tricyclic intermediate, which was subjected to chemical and enzymatic C–H oxidations to modularly prepare five oxidized family members. We also conceived a complementary biomimetic skeletal remodelling strategy to synthetically access five rearranged fusicoccanes with unusual bridgehead double bonds. This work may facilitate future investigation into the biological activities of the fusicoccanes and also inspire the implementation of similar hybrid strategies to provide family-level synthetic solutions to other natural product scaffolds.
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Data availability
Full experimental details and Supplementary Tables 1–25 are available in the Supplementary Information. Crystallographic data for compound S9 reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition number CCDC 2158016. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this paper.
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Acknowledgements
We acknowledge funding from the National Institutes of Health grant R35GM128895 (H.R.), the Cancer Prevention and Research Institute of Texas (CPRIT) grant RR220087 (H.R.) and the Sloan Foundation (H.R.). We thank X. Yu for assistance with docking studies. We are grateful to the Shen and Bannister labs at the Wertheim UF Scripps Institute for Biomedical Innovation and Technology, and to the Nicolaou, Kürti and Xiao labs and the Shared Equipment Authority at Rice University for generous access to their reagents and instrumentation. H.R. is a CPRIT scholar in cancer research. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Y.J. and H.R. conceived the work. Y.J. and H.R. designed all the experiments described in the manuscript. H.R. wrote the manuscript; Y.J. assisted in writing and editing the manuscript.
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Y.J. and H.R. are inventors on a patent application by The Wertheim UF Scripps Institute that covers the method to synthesize cotylenol and related fusicoccanes (patent application no. US 63/374522).
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Nature Chemistry thanks Jonathan George, Xiaoguang Lei and Hiroki Oguri for their contribution to the peer review of this work.
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Supplementary Tables 1–25, Fig. 1 and General experimental information, including chemical and molecular biology protocols, experimental data and characterization data.
Supplementary Data 1
Crystallographic data for compound S9; CCDC reference 2158016.
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Raw data for product ratios and conversions shown in Fig. 2b, and Pymol session file for the docking of compound 20 in MoBsc9, shown in Fig. 2b.
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Jiang, Y., Renata, H. Modular chemoenzymatic synthesis of ten fusicoccane diterpenoids. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01533-w
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DOI: https://doi.org/10.1038/s41557-024-01533-w