Skip to main content

Thank you for visiting 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.

A 16-step synthesis of the isoryanodane diterpene (+)-perseanol


(+)-Perseanol is an isoryanodane diterpene that is isolated from the tropical shrub Persea indica1 and has potent antifeedant and insecticidal properties. It is structurally related to (+)-ryanodine, which is a high-affinity ligand for and modulator of ryanodine receptors—ligand-gated ion channels that are critical for intracellular Ca2+ signalling in most multicellular organisms2. Ryanodine itself modulates ryanodine-receptor-dependent Ca2+ release in many organisms, including mammals; however, preliminary data indicate that ryanodane and isoryanodane congeners that lack the pyrrole-2-carboxylate ester—such as perseanol—may have selective activity in insects3. Here we report a chemical synthesis of (+)-perseanol, which proceeds in 16 steps from commercially available (R)-pulegone. The synthesis involves a two-step annulation process that rapidly assembles the tetracyclic core from readily accessible cyclopentyl building blocks. This work demonstrates how convergent fragment coupling, when combined with strategic oxidation tactics, can enable the concise synthesis of complex and highly oxidized diterpene natural products.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: The ryanodane and isoryanodane diterpenes.
Fig. 2: Fragment preparation for the synthesis of (+)-perseanol.
Fig. 3: Sixteen-step synthesis of (+)-perseanol.

Data availability

Characterization data for all compounds produced in this study are available in Supplementary Information or on request from the corresponding author. Metrical parameters for the structures of 32 and S21 are available free of charge from the Cambridge Crystallographic Data Centre (CCDC, under reference numbers 1909375 and 1914686, respectively.


  1. González-Coloma, A., Terrero, D., Perales, A., Escoubas, P. & Fraga, B. M. Insect antifeedant ryanodane diterpenes from Persea indica. J. Agric. Food Chem. 44, 296–300 (1996).

    Article  Google Scholar 

  2. Sutko, J. L., Airey, J. A., Welch, W. & Ruest, L. The pharmacology of ryanodine and related compounds. Pharmacol. Rev. 49, 53–98 (1997).

    CAS  PubMed  Google Scholar 

  3. Gonzalez-Coloma, A., Reina, M., Gutierrez, C. & Fraga, B. M. in Studies in Natural Products Chemistry Vol. 26 (ed. Rahman, A.) 849–879 (Elsevier, 2002).

  4. R.E.D. Facts Ryanodine. EPA-000-F-99-002 (United States Environmental Protection Agency, 1999).

  5. Lahm, G. P. et al. in Pesticide Chemistry: Crop Protection, Public Health, Environmental Safety (eds Ohkawa, H. et al.) 111–120 (Wiley-VCH, 2007).

  6. Cordova, D. et al. in Pesticide Chemistry: Crop Protection, Public Health, Environmental Safety (eds Ohkawa, H. et al.) 121–126 (Wiley-VCH, 2007).

  7. Nohara, T. et al. Cinncassiol D1 and its glucoside, novel pentacyclic diterpenes from Cinnamomi cortex. Tetrahedr. Lett. 21, 2647–2648 (1980).

    Article  CAS  Google Scholar 

  8. Chai, X. Y. et al. Six insecticidal isoryanodane diterpenoids from the bark and twigs of Itoa orientalis. Tetrahedron 64, 5743–5747 (2008).

    Article  CAS  Google Scholar 

  9. Zeng, J. et al. Diterpenoids with immunosuppressive activities from Cinnamomum cassia. J. Nat. Prod. 77, 1948–1954 (2014).

    Article  CAS  Google Scholar 

  10. Ling, S. Q., Xu, Y. N., Gu, Y. P., Liu, S. Y. & Tang, W. W. Toxicity and biochemical effects of itol A on the brown planthopper, Nilaparvata lugens (Stål) (Hemiptera: Delphacidae). Pestic. Biochem. Physiol. 152, 90–97 (2018).

    Article  CAS  Google Scholar 

  11. Sattelle, D. B., Cordova, D. & Cheek, T. R. Insect ryanodine receptors: molecular targets for novel pest control chemicals. Invert. Neurosci. 8, 107–119 (2008).

    Article  CAS  Google Scholar 

  12. Koshimizu, M., Nagatomo, M. & Inoue, M. Construction of a pentacyclic ring system of isoryanodane diterpenoids by SmI2-mediated transannular cyclization. Tetrahedron 74, 3384–3390 (2018).

    Article  CAS  Google Scholar 

  13. Bélanger, A. et al. Total synthesis of ryanodol. Can. J. Chem. 57, 3348–3354 (1979).

    Article  Google Scholar 

  14. Chuang, K. V., Xu, C. & Reisman, S. E. A 15-step synthesis of (+)-ryanodol. Science 353, 912–915 (2016).

    Article  CAS  ADS  Google Scholar 

  15. Xu, C., Han, A., Virgil, S. C. & Reisman, S. E. Chemical synthesis of (+)-ryanodine and (+)-20-deoxyspiganthine. ACS Cent. Sci. 3, 278–282 (2017).

    Article  CAS  Google Scholar 

  16. Luparia, M., Vadalà, A., Zanoni, G. & Vidari, G. 1,2-Bisanionic coupling approach to 2,3-disubstituted cyclopentenols and cyclopentenones. Org. Lett. 8, 2147–2150 (2006).

    Article  CAS  Google Scholar 

  17. Marx, J. N. & Norman, L. R. Synthesis of (–)-acorone and related spirocyclic sesquiterpenes. J. Org. Chem. 40, 1602–1606 (1975).

    Article  CAS  Google Scholar 

  18. Shen, Y. et al. Protecting-group-free total synthesis of (−)-jiadifenolide: development of a [4 + 1] annulation toward multisubstituted tetrahydrofurans. Org. Lett. 17, 5480–5483 (2015).

    Article  CAS  Google Scholar 

  19. Yasuda, A., Yamamoto, H. & Nozaki, H. Highly stereospecific isomerization of oxiranes into allylic alcohols by means of organoaluminum amides. Bull. Chem. Soc. Jpn. 52, 1705–1708 (1979).

    Article  CAS  Google Scholar 

  20. Steves, J. E. & Stahl, S. S. Copper(i)/ABNO-catalyzed aerobic alcohol oxidation: alleviating steric and electronic constraints of Cu/TEMPO catalyst systems. J. Am. Chem. Soc. 135, 15742–15745 (2013).

    Article  CAS  Google Scholar 

  21. Iimura, S., Overman, L. E., Paulini, R. & Zakarian, A. Enantioselective total synthesis of guanacastepene N using an uncommon 7-endo Heck cyclization as a pivotal step. J. Am. Chem. Soc. 128, 13095–13101 (2006).

    Article  CAS  Google Scholar 

  22. Mewshaw, R. E. Vilsmeier reagents: preparation of β-halo-α,β-unsaturated ketones. Tetrahedr. Lett. 30, 3753–3756 (1989).

    Article  CAS  Google Scholar 

  23. Helal, C. J. & Meyer, M. P. in Lewis Base Catalysis in Organic Synthesis 1st edn (eds Vedejs, E. & Denmark, S. E.) 387–455 (Wiley-VCH, 2016).

  24. Corey, E. J. & Link, J. O. A new chiral catalyst for the enantioselective synthesis of secondary alcohols and deuterated primary alcohols by carbonyl reduction. Tetrahedr. Lett. 30, 6275–6278 (1989).

    Article  CAS  Google Scholar 

  25. Nwoye, E. O. & Dudley, G. B. Synthesis of para-methoxybenzyl (PMB) ethers under neutral conditions. Chem. Commun. 1436–1437 (2007).

  26. Wu, L. P. et al. Palladium-catalyzed carbonylative transformation of C(sp3)–X bonds. ACS Catal. 4, 2977–2989 (2014).

    Article  CAS  Google Scholar 

  27. Odell, L. R., Russo, F. & Larhed, M. Molybdenum hexacarbonyl mediated CO gas-free carbonylative reactions. Synlett 5, 685–698 (2012).

    Article  Google Scholar 

  28. Ueda, T., Konishi, H. & Manabe, K. Palladium-catalyzed carbonylation of aryl, alkenyl, and allyl halides with phenyl formate. Org. Lett. 14, 3100–3103 (2012).

    Article  CAS  Google Scholar 

  29. Ueda, T., Konishi, H. & Manabe, K. Palladium-catalyzed fluorocarbonylation using N-formylsaccharin as CO source: general access to carboxylic acid derivatives. Org. Lett. 15, 5370–5373 (2013).

    Article  CAS  Google Scholar 

  30. Jiang, X. et al. Palladium-catalyzed formylation of aryl halides with tert-butyl isocyanide. Org. Lett. 16, 3492–3495 (2014).

    Article  CAS  Google Scholar 

  31. Krasovskiy, A., Kopp, F. & Knochel, P. Soluble lanthanide salts (LnCl3·2LiCl) for the improved addition of organomagnesium reagents to carbonyl compounds. Angew. Chem. Int. Ed. 45, 497–500 (2006).

    Article  CAS  Google Scholar 

  32. Baldwin, J. E. et al. 5-endo-trigonal reactions: disfavoured ring-closure. J. Chem. Soc. Chem. Commun. 736–738 (1976).

  33. Wolleb, H. & Carreira, E. M. Total synthesis of (+)-dendrowardol C. Angew. Chem. Int. Ed. 56, 10890–10893 (2017).

    Article  CAS  Google Scholar 

Download references


We acknowledge S. Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment; L. Henling and J. Hofstra for X-ray data collection and data refinement, respectively, for the structures of 32 and S21; Y. Zhang for providing original spectral data of perseanol; and K. Chuang for contributions to the synthetic design. Fellowship support was provided by the National Institutes of Health (NIH; Nos. 5T32GM007616-37 and 1F31GM120821, to A.H.). S.E.R. is a Heritage Medical Research Investigator. Financial support from the NIH (Nos. NIGMS RGM097582-01 and R35GM118191-01), Eli Lilly and Novartis is acknowledged.

Author information

Authors and Affiliations



A.H. and S.E.R. conceived this work; A.H., Y.T. and S.E.R. designed the experiments and analysed the data; A.H. and Y.T. conducted the experiments; and A.H. and S.E.R. wrote the manuscript.

Corresponding author

Correspondence to Sarah E. Reisman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Supplementary Information

This file contains: General Procedures; Positional Numbering; Synthetic Scheme of Inoue’s Isoryanodane Approach; Synthetic Procedures; 1H and 13C NMR Comparison Tables for Perseanol; Single Crystal X-Ray Diffraction Data; Supplementary References and 1H and 13C NMR Spectral Data.

Supplementary Data

This zipped file contains checkcif files for compounds 32 and S21.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Han, A., Tao, Y. & Reisman, S.E. A 16-step synthesis of the isoryanodane diterpene (+)-perseanol. Nature 573, 563–567 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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