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.

  • Letter
  • Published:

Nineteen-step total synthesis of (+)-phorbol


Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to its intriguing chemical structure and the medicinal potential of phorbol esters1. Access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Despite efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies, owing to its complexity and unusual placement of oxygen atoms. Purely synthetic enantiopure phorbol has remained elusive, and biological synthesis has not led to even the simplest members of this terpene family. Recently, the chemical syntheses of eudesmanes2, germacrenes3, taxanes4,5 and ingenanes6,7,8 have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis in which powerful C–C bond constructions and C–H bond oxidations go hand in hand. Here we implement a two-phase terpene synthesis strategy to achieve enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this synthesis route is not to displace isolation or semisynthesis as a means of generating the natural product per se, but rather to enable access to analogues containing unique placements of oxygen atoms that are otherwise inaccessible.

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

Access options

Buy this article

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

Figure 1: A two-phase approach to ingenanes and tiglianes enables a concise approach to the phorbol structure.
Figure 2: 19-step total synthesis of 1.
Figure 3: Predicting the site of C–H functionalization on intermediate 7.

Similar content being viewed by others


  1. Wang, H.-B., Wang, X.-Y., Liu, L.-P., Qin, G.-W. & Kang, T.-G. Tigliane diterpenoids from the euphorbiaceae and thymelaeaceae families. Chem. Rev. 115, 2975–3011 (2015)

    Article  CAS  Google Scholar 

  2. Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009)

    Article  CAS  ADS  Google Scholar 

  3. Foo, K. et al. Scalable, enantioselective synthesis of germacrenes and related sesquiterpenes inspired by terpene cyclase phase logic. Angew. Chem. Int. Ed. 51, 11491–11495 (2012)

    Article  CAS  Google Scholar 

  4. Mendoza, A., Ishihara, Y. & Baran, P. S. Scalable enantioselective total synthesis of taxanes. Nature Chem. 4, 21–25 (2012)

    Article  CAS  ADS  Google Scholar 

  5. Wilde, N. C., Isomura, M., Mendoza, A. & Baran, P. S. Two-phase synthesis of (−)-taxuyunnanine D. J. Am. Chem. Soc. 136, 4909–4912 (2014)

    Article  CAS  Google Scholar 

  6. Jørgensen, L. et al. 14-step synthesis of (–)-ingenol from (+)-3-carene. Science 341, 878–882 (2013)

    Article  ADS  Google Scholar 

  7. McKerrall, S. J., Jørgensen, L., Kuttruff, C. A., Ungeheuer, F. & Baran, P. S. Development of a concise synthesis of (–)-ingenol. J. Am. Chem. Soc. 136, 5799–5810 (2014)

    Article  CAS  Google Scholar 

  8. Jin, Y. et al. C–H oxidation of ingenanes enables potent and selective protein kinase C isoform activation. Angew. Chem. Int. Ed. 54, 14044–14048 (2015)

    Article  CAS  Google Scholar 

  9. Isakov, N. & Altman, A. Regulation of immune system cell functions by protein kinase C. Front. Immunol. 4, 384 (2013)

    Article  Google Scholar 

  10. McKernan, L. N., Momjian, D. & Kulkosky, J. Protein kinase C: one pathway towards the eradication of latent HIV-1 reservoirs. Adv. Virol. 2012, 805347 (2012)

    Article  Google Scholar 

  11. Mackay, H. J. & Twelves, C. J. Targeting the protein kinase C family: are we there yet? Nature Rev. Cancer 7, 554–562 (2007); corrigendum 8, doi:10.1038/nrc2350 (2008)

    Article  CAS  Google Scholar 

  12. Wender, P. A. et al. Studies on tumor promoters. 8. The synthesis of phorbol. J. Am. Chem. Soc. 111, 8957–8958 (1989)

    Article  CAS  Google Scholar 

  13. Wender, P. A., Lee, H. Y., Wilhelm, R. S. & Williams, P. D. Studies on tumor promoters. 7. The synthesis of a potentially general precursor of the tiglianes, daphnanes, and ingenanes. J. Am. Chem. Soc. 111, 8954–8957 (1989)

    Article  CAS  Google Scholar 

  14. Wender, P. A., Rice, K. D. & Schnute, M. E. The first formal asymmetric synthesis of phorbol. J. Am. Chem. Soc. 119, 7897–7898 (1997)

    Article  CAS  Google Scholar 

  15. Wender, P. A. & McDonald, F. E. Studies on tumor promoters. 9. A second-generation synthesis of phorbol. J. Am. Chem. Soc. 112, 4956–4958 (1990)

    Article  CAS  Google Scholar 

  16. Lee, K. & Cha, J. K. Formal synthesis of (+)-phorbol. J. Am. Chem. Soc. 123, 5590–5591 (2001)

    Article  CAS  Google Scholar 

  17. Sugita, K., Shigeno, K., Neville, C. F., Sasai, H. & Shibasaki, M. Synthetic studies towards phorbols: synthesis of B or C ring substituted phorbol skeletons in the naturally occurring form. Synlett 1994, 325–329 (1994)

    Article  Google Scholar 

  18. Sugita, K., Neville, C. F., Sodeoka, M., Sasai, H. & Shibasaki, M. Stereocontrolled syntheses of phorbol analogs and evaluation of their binding affinity to PKC. Tetrahedr. Lett. 36, 1067–1070 (1995)

    Article  CAS  Google Scholar 

  19. Newhouse, T. & Baran, P. S. If C–H bonds could talk: selective C–H bond oxidation. Angew. Chem. Int. Ed. 50, 3362–3374 (2011)

    Article  CAS  Google Scholar 

  20. Zou, L. et al. Enhanced reactivity in dioxirane C–H oxidations via strain release: a computational and experimental study. J. Org. Chem. 78, 4037–4048 (2013)

    Article  CAS  Google Scholar 

  21. Michaudel, Q. et al. Improving physical properties via C–H oxidation: chemical and enzymatic approaches. Angew. Chem. Int. Ed. 53, 12091–12096 (2014)

    Article  CAS  Google Scholar 

  22. McCormick, J. P. & Barton, D. L. Synthetic applications of metal halides. Conversion of cyclopropylmethanols into homoallylic halides. J. Org. Chem. 45, 2566–2570 (1980)

    Article  CAS  Google Scholar 

  23. Miyoshi, N., Takeuchi, S. & Ohgo, Y. A facile synthesis of 2,3-dihydroxyketones from 1,2-diketones and aldehydes using samarium diiodide. Chem. Lett. 22, 959–962 (1993)

    Article  Google Scholar 

  24. Krohn, K., Frese, P. & Flörke, U. Biomimetic synthesis of the racemic angucyclinones of the aquayamycin and WP 3688-2 Types. Chemistry 6, 3887–3896 (2000)

    Article  CAS  Google Scholar 

  25. Bartsch, H. & Hecker, E. Zur chemie des phorbols, XIII. Über eine acyloin-umlagerung des 12-desoxy-12-oxo-phorbol-13.20-diacetats. Liebigs Ann. Chem. 725, 142–153 (1969)

    Article  CAS  Google Scholar 

  26. Salmond, W. G., Barta, M. A. & Havens, J. L. Allylic oxidation with 3,5-dimethylpyrazole. Chromium trioxide complex. Steroidal Δ5-7-ketones. J. Org. Chem. 43, 2057–2059 (1978)

    Article  CAS  Google Scholar 

  27. Sha, C.-K. & Huang, S.-J. Synthesis of β-substituted α-iodocycloalkenones. Tetrahedr. Lett. 36, 6927–6928 (1995)

    Article  CAS  Google Scholar 

  28. Stille, J. K. The palladium-catalyzed cross-coupling reactions of organotin reagents with organic electrophiles. Angew. Chem. Int. Ed. Engl. 25, 508–524 (1986)

    Article  Google Scholar 

  29. Nicolaou, K. C. & Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies, Methods 821 (Wiley, 1996)

  30. Gutekunst, W. R. & Baran, P. S. C–H functionalization logic in total synthesis. Chem. Soc. Rev. 40, 1976–1991 (2011)

    Article  CAS  Google Scholar 

Download references


This work was supported by LEO Pharma, the Uehara Memorial Foundation (postdoctoral fellowship to S.K.) and the National Institute of General Medical Sciences Grant GM-097444. We are especially grateful to S. Natarajan of KemXtree and his team for providing ample quantities of compound 5. We thank D.-H. Huang and L. Pasternack for assistance with NMR spectroscopy, and A. L. Rheingold and C. E. Moore for X-ray crystallographic analysis.

Author information

Authors and Affiliations



S.K. and P.S.B. conceived this work; J.F. provided compound 5; S.K., H.C. and P.S.B. designed the experiments and analysed that data; S.K. and H.C. conducted the experiments; S.K. performed the molecular mechanics calculations; and S.K. and P.S.B. wrote the manuscript.

Corresponding author

Correspondence to Phil S. Baran.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Metrical parameters for the structures of 12 and 19 are available free of charge from the Cambridge Crystallographic Data Centre (CCDC) under reference numbers 1434376 and 1434377.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data – see contents page for details. (PDF 4624 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawamura, S., Chu, H., Felding, J. et al. Nineteen-step total synthesis of (+)-phorbol. Nature 532, 90–93 (2016).

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