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.

Synthesis of highly strained terpenes by non-stop tail-to-head polycyclization

Abstract

Non-stop carbocationic polycyclizations of isoprenoids have been called the most complex chemical reactions occurring in nature. We describe a strategy for the initiation of tail-to-head polycyclization that relies on the sequestration of the counteranion away from the carbocation, which allows full propagation of the cationic charge. If the anion is mobile, Coulombic forces hold this species in close proximity to the carbocation and cause preemptive termination through elimination. Anion sequestration is crucial for effecting the biomimetic synthesis of complex and unstable terpenes, including the highly strained funebrenes. This study illustrates the deleterious role of the counterion in tail-to-head carbocationic polycyclization reactions, which to the best of our knowledge has not been rigorously explored. These observations are also expected to find use in the design and control of cationic polycyclization along biosynthetic pathways that have previously been inaccessible in bulk solvent.

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.

$32.00

All prices are NET prices.

Figure 1: Different branches of terpene biosynthesis.
Figure 2: Mechanistic comparisons of bulk solvent and cyclase active sites.
Figure 3: Analysis of polycyclization outcomes.
Figure 4: Proposed reaction pathway.
Figure 5: Effect of a mobile anion.
Figure 6: Biomimetic total syntheses.

References

  1. Eschenmoser, A. Zur säurekatalysierten Zyklisierung bei Mono- und Sesquiterpenverbindungen. PhD thesis, E.T.H., Zurich (1952).

  2. Ruzicka, L., Eschenmoser, A. & Heusser, H. The isoprene rule and the biogenesis of terpenic compounds. Experientia 9, 357–367 (1953).

    Article  CAS  Google Scholar 

  3. Christianson, D. W. Structural biology and chemistry of the terpenoids cyclases. Chem. Rev. 106, 3142–3442 (2006).

    Article  Google Scholar 

  4. Tantillo, D. J. Biosynthesis via carbocations: theoretical studies on terpene biosynthesis. Nat. Prod. Rep. 28, 1035–1053 (2011).

    Article  CAS  Google Scholar 

  5. Alleman, R. K. Chemical wizardry? The generation of diversity in terpenoids biosynthesis. Pure Appl. Chem. 80, 1791–1798 (2008).

    Article  Google Scholar 

  6. Stork, G. & Burgstahler, A. W. The stereochemistry of polyene cyclization. J. Am. Chem. Soc. 77, 5068–5077 (1955).

    Article  CAS  Google Scholar 

  7. Eschenmoser, A., Ruzicka, L., Jeger, O. & Arigoni, D. A stereochemical interpretation of the biogenetic isoprene rule for the triterpenes. Helv. Chim. Acta 38, 1890–1904 (1955).

    Article  CAS  Google Scholar 

  8. Snyder, S. A., Treitler, D. S. & Brucks, A. P. Simple reagents for direct halonium-induced polyene cyclizations. J. Am. Chem. Soc. 132, 14303–14314 (2010).

    Article  CAS  Google Scholar 

  9. Ruzicka, L., Eschenmoser, A. & Heusser, H. Isoprene rule and the biogenesis of terpenic compounds. Experientia 9, 357–367 (1953).

    Article  CAS  Google Scholar 

  10. Wendt, K. U., Schulz, G. E., Corey, E. J. & Liu, D. R. Enzyme mechanisms for polycyclic triterpene formation. Angew. Chem. Int. Ed. 39, 2812–2833 (2000).

    Article  CAS  Google Scholar 

  11. Lodeiro, S. et al. An oxidosqualene cyclase makes numerous products by diverse mechanisms: a challenge to prevailing concepts of triterpene biosynthesis. J. Am. Chem. Soc. 129, 11213–11222 (2007).

    Article  CAS  Google Scholar 

  12. Johnson, W. S. Biomimetic polyene cyclizations. Angew. Chem. Int. Ed. 15, 9–17 (1976).

    Article  CAS  Google Scholar 

  13. Yoder, R. A. & Johnston, J. J. A case study in biomimetic total synthesis: polyolefin carbocyclizations to terpenes and steroids. Chem. Rev. 105, 4730–4756 (2005).

    Article  CAS  Google Scholar 

  14. Corey, E. J. & Staas, D. D. Demonstration of a common concerted mechanistic pathway for the acid-catalyzed cyclization of 5,6-unsaturated oxiranes in chemical and enzymatic systems. J. Am. Chem. Soc. 120, 3526–3527 (1988).

    Article  Google Scholar 

  15. Kronja, O., Orlovic, M., Humski, K. & Borcic, S. Lack of a secondary β-deuterium kinetic isotope effect in the solvolysis of 2-chloro-3-hydrosqualene. A case of extended π-participation and indication of concerted biomimetic polycyclization. J. Am. Chem. Soc. 113, 2306–2308 (1991).

    Article  CAS  Google Scholar 

  16. Li, B., Tan, L.-J. S., Shen, Z.-L. & Loh, T.-P. Enantioselective cationic polyene cyclization vs enantioselective intramolecular carbonyl–ene reaction. J. Am. Chem. Soc. 132, 10242–10244 (2010).

    Article  Google Scholar 

  17. Knowles, R. R., Lin, S. & Jacobsen, E. N. Enantioselective thiourea-catalyzed cationic polycylizations. J. Am. Chem. Soc. 132, 5030–5032 (2010).

    Article  CAS  Google Scholar 

  18. Semmler, F. W. & Spornitz, K. E. On knowledge of the constituents of essential oils (announcement on the sesquiterpene fraction of java-citronella-oil). Chem. Ber. 46, 4025–4029 (1913).

    Article  Google Scholar 

  19. Gutsche, C. D., Maycock, J. R. & Chang, C. T. Acid-catalyzed cyclization of farnesol and nerolidol. Tetrahedron 24, 859–876 (1968).

    Article  Google Scholar 

  20. Ohta, Y. & Hirose, Y. Electrophile induced cyclization of farnesol. Chem. Lett. 263–266 (1972).

  21. Kobayashi, S., Tsutsui, M. & Mukaiyama, T. Biogenetic-like cyclization of farnesol and nerolidol to bisabolene by the use of 2-fluorobenzothazolium salt. Chem. Lett. 10, 1169–1172 (1977).

    Article  Google Scholar 

  22. Sakane, S., Fujiwara, J., Maruoka, K. & Yamamoto, H. Chiral leaving group. Biogenetic-type asymmetric synthesis of limonene and bisabolenes. J. Am. Chem. Soc. 105, 6154–6155 (1983).

    Article  CAS  Google Scholar 

  23. Andersen, N. H. & Syrdal, D. D. Chemical simulation of the biosynthesis of cedrene. Tetrahedron Lett. 24, 2455–2458 (1972).

    Article  Google Scholar 

  24. Polovinka, M. P. et al. Cyclization and rearrangements of farnesol and nerolidol stereoisomers in superacids. J. Org. Chem. 59, 1509–1517 (1994).

    Article  CAS  Google Scholar 

  25. Polovinka, M. P. et al. Molecular rearrangements of (–)-α-cedrene in superacids. Tetrahedron Lett. 36, 8093–8096 (1995).

    Article  CAS  Google Scholar 

  26. Reed, C. A. Carborane acids. New ‘strong yet gentle’ acids for organic and inorganic chemistry. Chem. Commun. 1669–1677 (2005).

  27. Xu, M., Wilderman, P. R. & Peters, R. J. Following evolution's lead to a single residue switch for diterpene synthase product outcome. Proc. Natl Acad. Sci. USA 104, 7397–7401 (2007).

    Article  CAS  Google Scholar 

  28. Corey, E. J. & Sodeoka, M. An effective system for epoxide-initiated cation-olefin cyclization. Tetrahedron Lett. 32, 7005–7008 (1991).

    Article  CAS  Google Scholar 

  29. Lehmkuhl, H. & Kobs, H.-D. Untersuchungen uber die elektrolytische Dissoziation yon Alkylaluminium-Donator-Verbindungen. Liebigs Ann. Chem. 729, 11–19 (1968).

    Article  Google Scholar 

  30. Evans, D. A., Allison, B. D. & Yang, M. G. Chelate-controlled carbonyl addition reactions. The exceptional chelating ability of dimethylaluminum chloride and methylaluminum dichloride. Tetrahedron Lett. 40, 4457–4460 (1999).

    Article  CAS  Google Scholar 

  31. Snider, B. B., Rodini, D. J. & van Straten, J. Lewis acid induced conjugate addition of alkenes to α,β-unsaturated ketones or aldehydes. J. Am. Chem. Soc. 102, 5872–5880 (1980).

    Article  CAS  Google Scholar 

  32. Snider, B. B., Karras, M., Price, R. T. & Rodini, D. J. Alkylaluminum halide induced cyclization of unsaturated carbonyl compounds. J. Org. Chem. 47, 4538–4545 (1982).

    Article  CAS  Google Scholar 

  33. Brun, P. Synthesis of alpha-biotol and alpha-epibiotol. Tetrahedron Lett. 26, 2269–2272 (1977).

    Article  Google Scholar 

  34. Beauchamp, P. S. et al. California lomatiums, Part IVa: Composition of the essential oils of Lomatium rigidum (M.E. Jones) Jepson. Structures of two new funebrene epimers and a tridecatriene. J. Essent. Oil Res. 16, 571–578 (2004).

    Article  CAS  Google Scholar 

  35. Brown, G. D., Liang, G.-Y. & Sy, L.-K. Terpenoids from the seeds of Artemisia annua. Phytochemistry 64, 303–323 (2003).

    Article  CAS  Google Scholar 

  36. Stork, G. & Clarke, F. H. Jr. Cedrol: stereochemistry and total synthesis. J. Am. Chem. Soc. 83, 3114–3125 (1961).

    Article  CAS  Google Scholar 

  37. Tomita, B. & Hirose, Y. Allo-cedrol: a new tricarbocyclic sesquiterpene alcohol. Phytochemistry 12, 1409–1414 (1973).

    Article  CAS  Google Scholar 

  38. Cool, L. G. Sesquiterpenes from Cupressus macrocarpa foliage. Phytochemistry 66, 249–260 (2005).

    Article  CAS  Google Scholar 

  39. Sy, L.-K. & Brown, G. D. A sesquiterpene class from Illicium dunnianum. Phytochemistry 47, 301–302 (1998).

    Article  CAS  Google Scholar 

  40. Shenvi, R. A. & Corey, E. J. Synthetic access to bent polycycles by cation-π cyclization. Org. Lett. 12, 3548–3551 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank R. Mohan of Exelixis for the very generous donation of supplies and chemicals, and C. Moore and A. Rheingold for crystal X-ray diffraction data. The authors also thank J. Sears for technical assistance. Financial support was provided by the Scripps Research Institute (Novartis ADI Grant) and Eli Lilly.

Author information

Authors and Affiliations

Authors

Contributions

S.V.P. and R.A.S. contributed equally to the work.

Corresponding author

Correspondence to Ryan A. Shenvi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 5408 kb)

Supplementary information

Crystallographic data for the cocrystal of compounds 12 and 13 (CIF 19 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pronin, S., Shenvi, R. Synthesis of highly strained terpenes by non-stop tail-to-head polycyclization. Nature Chem 4, 915–920 (2012). https://doi.org/10.1038/nchem.1458

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1458

This article is cited by

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