Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Modular chemoenzymatic synthesis of ten fusicoccane diterpenoids

Nature Chemistry (2024)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Fusicoccane diterpenoids and overview of current study.
Fig. 2: Assembly of the fusicoccane core and completion of the synthesis of cotylenol and brassicicene I.
Fig. 3: Completion of the synthesis of additional fusicoccanes.

Similar content being viewed by others

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.

References

  1. De Boer, A. H. & de Vries-van Leeuwen, I. J. Fusicoccanes: diterpenes with surprising biological functions. Trends Plant Sci. 17, 360–368 (2012).

    Article  PubMed  Google Scholar 

  2. Ohkanda, J. Fusicoccin: a chemical modulator for 14-3-3 proteins. Chem. Lett. 50, 57–67 (2021).

    Article  CAS  Google Scholar 

  3. Sengupta, A., Liriano, J., Bienkiewicz, E. A., Miller, B. G. & Frederich, J. H. Probing the 14-3-3 isoform-specificity profile of protein-protein interactions stabilized by fusicoccin A. ACS Omega 5, 25029–25035 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Molzan, M. et al. Stabilization of physical RAF/14-3-3 interaction by cotylenin A as treatment strategy for RAS mutant cancers. ACS Chem. Biol. 8, 1869–1875 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Zheng, D. et al. Cytotoxic fusicoccane-type diterpenoids from Streptomyces violascens isolated from Ailuropoda melanoleuca feces. J. Nat. Prod. 80, 837–844 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Kim, S., Shin, D.-S., Lee, T. & Oh, K.-B. Periconicins, two new fusicoccane diterpenes produced by an endophytic fungus Periconia sp. with antibacterial activity. J. Nat. Prod. 67, 448–450 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Stevers, L. M. et al. Modulators of 14-3-3 protein-protein interactions. J. Med. Chem. 61, 3755–3778 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Ikejiri, F., Honma, Y., Okada, T., Urano, T. & Suzumiya, J. Cotylenin A and tyrosine kinase inhibitors synergistically inhibit the growth of chronic myeloid leukemia cells. Int. J. Oncol. 52, 2061–2068 (2018).

    CAS  PubMed  Google Scholar 

  9. Kasukabe, T., Okabe-Kado, J. & Honma, Y. Cotylenin A, a new differentiation inducer, and rapamycin cooperatively inhibit growth of cancer cells through induction of cyclin G2. Cancer Sci. 99, 1693–1698 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Asahi, K. et al. Cotylenin A, a plant-growth regulator, induces the differentiation in murine and human myeloid leukemia cells. Biochem. Biophys. Res. Commun. 238, 758–763 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Anders, C. et al. A semisynthetic fusicoccane stabilizes a protein-protein interaction and enhances the expression of K+ channels at the cell surface. Chem. Biol. 20, 583–593 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Hu, Z. et al. Fusicoccane-derived diterpenoids from Alternaria brassicicola: investigation of the structure–stability relationship and discovery of an IKKβ inhibitor. Org. Lett. 20, 5198–5202 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Li, F. et al. Modified fusicoccane-type diterpenoids from Alternaria brassicicola. J. Nat. Prod. 83, 1931–1938 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Tang, Y. et al. Structural revisions of a class of natural products: scaffolds of aglycon analogues of fusicoccins and cotylenins isolated from fungi. Angew. Chem. Int. Ed. 55, 4069–4073 (2016).

    Article  CAS  Google Scholar 

  15. Ohkanda, J. et al. Structural effect of fusicoccin upon upregulation of 14-3-3 phospholigand interaction and cytotoxic activity. Chem. Eur. J. 24, 16066–16071 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Inoue, T. et al. Semisynthesis and biological evaluation of a cotylenin A mimic derived from fusicoccin A. Bioorg. Med. Chem. Lett. 28, 646–650 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Ono, Y. et al. Dioxygenases, key enzymes to determine the aglycon structures of fusicoccin and brassicicene, diterpene compounds produced by fungi. J. Am. Chem. Soc. 133, 2548–2555 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Kato, N., Okamoto, H. & Takeshita, H. Total synthesis of optically active cotylenol, a fungal metabolite having a leaf growth activity. Intramolecular ene reaction for an eight-membered ring formation. Tetrahedron 52, 3921–3932 (1996).

    Article  CAS  Google Scholar 

  19. Williams, D. R., Robinson, L. A., Nevill, C. R. & Reddy, J. P. Strategies for the synthesis of fusicoccanes by Nazarov reactions of dolabelladienones: total synthesis of (+)-fusicoauritone. Angew. Chem. Int. Ed. 46, 915–918 (2007).

    Article  CAS  Google Scholar 

  20. Uwamori, M., Osada, R., Sugiyama, R., Nagatani, K. & Nakada, M. Enantioselective total synthesis of cotylenin A. J. Am. Chem. Soc. 142, 5556–5561 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Chen, B. et al. A two-phase approach to fusicoccane synthesis to uncover a compound that reduces tumourigenesis in pancreatic cancer cells. Angew. Chem. Int. Ed. 61, e202117476 (2022).

    Article  CAS  Google Scholar 

  22. Wang, Y.-Q., Xu, K., Min, L. & Li, C.-C. Asymmetric total syntheses of hypoestin A, albolic acid, and ceroplastol II. J. Am. Chem. Soc. 144, 10162–10167 (2022).

    Article  CAS  PubMed  Google Scholar 

  23. Sims, N. J., Bonnet, W. C., Lawson, D. M. & Wood, J. L. Enantioselective total synthesis if (+)-alterbrassicicene C. J. Am. Chem. Soc. 145, 37–40 (2023).

    Article  CAS  PubMed  Google Scholar 

  24. Zhang, X. et al. Divergent synthesis of complex diterpenes via a hybrid oxidative approach. Science 369, 799–806 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tazawa, A. et al. Total biosynthesis of brassicicenes: identification of a key enzyme for skeletal diversification. Org. Lett. 20, 6178–6182 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Chakrabarty, S., Wang, Y., Perkins, J. C. & Narayan, A. R. H. Scalable biocatalytic C–H oxyfunctionalization reactions. Chem. Soc. Rev. 49, 8137–8155 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fasan, R. Tuning P450 enzymes as oxidation catalysts. ACS Catal. 2, 647–666 (2012).

    Article  CAS  Google Scholar 

  28. Lange, G. L., Neider, E. E., Orrom, W. J. & Wallace, D. J. Synthesis of the spirosesquiterpene (–)-acorenone and related cyclopentanoid monoterpenes. Can. J. Chem. 56, 1628–1633 (1978).

    Article  CAS  Google Scholar 

  29. Uroos, M., Lewis, W., Blake, A. J. & Hayes, C. J. Total synthesis of (+)-cymbodiacetal: a re-evaluation of the biomimetic route. J. Org. Chem. 75, 8465–8470 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Fürstner, A. & Shi, N. Nozaki–Hiyama–Kishi reactions catalytic in chromium. J. Am. Chem. Soc. 118, 12349–12357 (1996).

    Article  Google Scholar 

  31. Cope, A. C., Martin, M. M. & McKervey, M. A. Transannular reactions in medium-sized rings. Q. Rev. Chem. Soc. 20, 119–152 (1966).

    Article  CAS  Google Scholar 

  32. Kilpatrick, M. & Luborsky, F. E. The conductance and vapor pressure of boron trifluoride in anhydrous hydrofuloric acid. J. Am. Chem. Soc. 76, 5865–5868 (1954).

    Article  CAS  Google Scholar 

  33. Vedejs, E., Engler, D. A. & Telschow, J. E. Transition-metal peroxide reactions. Synthesis of α-hydroxycarbonyl compounds from enolates. J. Org. Chem. 43, 188–196 (1978).

    Article  CAS  Google Scholar 

  34. Baek, M. et al. Accurate prediction of protein structures and interactions using a three-track neural network. Science 373, 871–876 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zallot, R., Oberg, N. & Gerlt, J. A. The EFI web resource for genomic enzymology tools: leveraging protein, genome, and metagenome databases to discover novel enzymes and metabolic pathways. Biochemistry 58, 4169–4182 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Jiang, Y. & Renata, H. Finding superior biocatalysts via homolog screening. Chem Catal. 2, 2471–2480 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kille, S. et al. Reducing codon redundancy and screening effort of combinatorial protein libraries created by saturation mutagenesis. ACS Synth. Biol. 2, 83–92 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Li, F., Deng, H. & Renata, H. Remote B-ring oxidation of sclareol with an engineered P450 facilitates divergent access to complex terpenoids. J. Am. Chem. Soc. 144, 7616–7621 (2022).

    Article  CAS  PubMed  Google Scholar 

  39. Li, J., Li, F., King-Smith, E. & Renata, H. Merging chemoenzymatic and radical-based retrosynthetic logic for rapid and modular synthesis of oxidized meroterpenoids. Nat. Chem. 12, 173–179 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, F. & Renata, H. A chiral-pool-based strategy to access trans-syn-fused drimane meroterpenoids: chemoenzymatic total syntheses of polysin, N-acetyl-polyveoline and the chrodrimanins. J. Am. Chem. Soc. 143, 18280–18286 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Li, J., Chen, F. & Renata, H. Concise chemoenzymatic synthesis of gedunin. J. Am. Chem. Soc. 144, 19238–19242 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Yu, J.-Q. & Corey, E. J. Diverse pathways for the palladium(II)-mediated oxidation of olefins by tert-butylhydroperoxide. Org. Lett. 4, 2727–2730 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Ting, C. P. & Maimone, T. J. Total synthesis of hyperforin. J. Am. Chem. Soc. 137, 10516–10519 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Ishiyama, S. & Mukaiyama, T. Novel method for the preparation of triethylsilyl peroxides from olefins by the reaction with molecular oxygen and triethylsilane catalyzed by bis(1,3-diketonato)cobalt(II). Chem. Lett. 18, 573–576 (1989).

    Article  Google Scholar 

  45. Crossley, S. W. M., Obradors, C., Martinez, R. M. & Shenvi, R. A. Mn-, Fe-, and Co-catalyzed radical hydrofunctionalizations of olefins. Chem. Rev. 116, 8912–9000 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Isayama, S. & Mukaiyama, T. A new method for preparation of alcohols from olefins with molecular oxygen and phenylsilane by the use of bis(acetylacetonato)cobalt(II). Chem. Lett. 18, 1071–1074 (1989).

    Article  Google Scholar 

  47. Hong, B., Luo, T. & Lei, X. Late-stage diversification of natural products. ACS Cent. Sci. 6, 622–635 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang, J. et al. Diversity-oriented synthesis of cyclohexenes by combining enzymatic intermolecular Diels-Alder reactions and decarboxylative functionalizations. Chem Catalysis 3, 100451 (2023).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

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

    Yanlong Jiang & Hans Renata

Authors
  1. Yanlong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans Renata
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Hans Renata.

Ethics declarations

Competing interests

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).

Peer review

Peer review information

Nature Chemistry thanks Jonathan George, Xiaoguang Lei and Hiroki Oguri for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1–25, Fig. 1 and General experimental information, including chemical and molecular biology protocols, experimental data and characterization data.

Reporting Summary

Supplementary Data 1

Crystallographic data for compound S9; CCDC reference 2158016.

Source data

Source Data Fig. 2

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.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, Y., Renata, H. Modular chemoenzymatic synthesis of ten fusicoccane diterpenoids. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01533-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41557-024-01533-w

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing