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:

The total synthesis of hyperpapuanone, hyperibone L, epi-clusianone and oblongifolin A

Subjects

Abstract

Polyprenylated polycyclic acylphloroglucines (PPAPs) are a family of natural products that possess a wide range of different important biological activities because of the relative position and configuration of four substituents that decorate one common central bicyclo[3.3.1]nonane-2,4,9-trione core. The rigid bicyclic framework with its lipophilic side chains and its hydrophilic trione moiety represents a nature-derived lead structure that arranges the substituents (R1 to R4) into a defined topographical orientation. As the substituents are responsible for the biological activities, the seven-step synthetic approach presented here sets the stage for an iterative introduction of R1 to R4 and thus generates structurally diverse trans-type B PPAPs. Four natural and one non-natural trans-type B PPAPs were prepared starting from acetylacetone with overall yields that ranged from 6 to 22%. The concept of separating framework construction from decorating transformations plus the minimization of protecting-group operations are the key issues for the realization of our synthetic approach.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Classification of PPAPs and total syntheses accomplished.
Figure 2: Retrosynthetic analysis.
Figure 3: Total synthesis of oblongifolin A (1), hyperpapuanone (4), epi-clusianone (2), hyperibone L (3) and regio-hyperpapuanone (5).
Figure 4: Stereochemical rationale for the allylations and Dieckmann condensation.
Figure 5: Structural confirmation of hyperpapuanone (4).

Similar content being viewed by others

References

  1. Ciochina, R. & Grossman, R. B. Polycyclic polyprenylated acylphloroglucinols. Chem. Rev. 106, 3963–3986 (2006).

    Article  CAS  Google Scholar 

  2. McCandlish, L. E., Hanson, J. C. & Stout, G. H. The structures of two derivatives of bicyclo[3.3.1]nonane-2,4,9-trione. A natural product: clusianone, C33H42O4, and trimethylated catechinic acid, C18H20O6 . Acta Crystallogr. B 32, 1793–1801 (1976).

    Article  Google Scholar 

  3. Ito, C. et al. Polyprenylated benzophenones from Garcinia assigu and their potential cancer chemopreventive activities. J. Nat. Prod. 66, 206–209 (2003).

    Article  CAS  Google Scholar 

  4. Piccinelli, A. L. et al. Structural revision of clusianone and 7-epi-clusianone and anti-HIV activity of polyisoprenylated benzophenones. Tetrahedron 61, 8206–8211 (2005).

    Article  CAS  Google Scholar 

  5. Santos, M. H., Nagem, N. L. & De Oliveira, T. T. Epiclusianone: a new natural product derivative of bicyclo[3.3.1]nonane-2,4,9-trione. Acta Crystallogr. C 54, 1990–1992 (1998).

    Article  Google Scholar 

  6. Murata, R. M. et al. Antiproliferative effect of benzophenones and their influence on cathepsin activity. Phytother. Res. 24, 379–383 (2010).

    Article  CAS  Google Scholar 

  7. Neves, J. S. et al. Antianaphylactic properties of 7-epiclusianone, a tetraprenylated benzophenone isolated from Garcinia brasiliensis. Planta Med. 73, 644–649 (2007).

    Article  CAS  Google Scholar 

  8. Cruz, A. J., Lemos, V. S., dos Santos, M. H., Nagem, T. J. & Cortes, S. F. Vascular effects of 7-epiclusianone, a prenylated benzophenone from Rheedia gardneriana, on the rat aorta. Phytomedicine 13, 442–445 (2006).

    Article  CAS  Google Scholar 

  9. Pereira, I. O. et al. Leishmanicidal activity of benzophenones and extracts from Garcinia brasiliensis Mart. fruits. Phytomedicine 17, 339–345 (2010).

    Article  CAS  Google Scholar 

  10. Almeida, L. S. B. et al. Antimicrobial activity of Rheedia brasiliensis and 7-epiclusianone against Streptococcus mutans. Phytomedicine 15, 886–891 (2008).

    Article  CAS  Google Scholar 

  11. Alves, T. M. et al. Biological activities of 7-epiclusianone. J. Nat. Prod. 62, 369–371 (1999).

    Article  CAS  Google Scholar 

  12. Martins, F. T. et al. Natural polyprenylated benzophenones inhibiting cysteine and serine proteases. Eur. J. Med. Chem. 44, 1230–1239 (2009).

    Article  CAS  Google Scholar 

  13. Hamed, W. et al. Oblongifolins A–D, polyprenylated benzoylphloroglucinol derivatives from Garcinia oblongifolia. J. Nat. Prod. 69, 774–777 (2006).

    Article  CAS  Google Scholar 

  14. Tanaka, N. et al. Prenylated benzophenones and xanthones from Hypericum scabrum. J. Nat. Prod. 67, 1870–1875 (2004).

    Article  CAS  Google Scholar 

  15. Winkelmann, K., Heilmann, J., Zerbe, O., Rali, T. & Sticher, O. New prenylated bi- and tricyclic phloroglucinol derivatives from Hypericum papuanum. J. Nat. Prod. 64, 701–706 (2001).

    Article  CAS  Google Scholar 

  16. Kuramochi, A., Usuda, H., Yamatsugu, K., Kanai, M. & Shibasaki, M. Total synthesis of (±)-garsubellin A. J. Am. Chem. Soc. 127, 14200–14201 (2005).

    Article  CAS  Google Scholar 

  17. Siegel, D. R. & Danishefsky, S. J. Total synthesis of garsubellin A. J. Am. Chem. Soc. 128, 1048–1049 (2006).

    Article  CAS  Google Scholar 

  18. Rodeschini, V., Ahmad, N. M. & Simpkins, N. S. Synthesis of (+/–)-clusianone: high-yielding bridgehead and diketone substitutions by regioselective lithiation of enol ether derivatives of bicyclo[3.3.1]nonane-2,4,9-triones. Org. Lett. 8, 5283–5285 (2006).

    Article  CAS  Google Scholar 

  19. Qi, J. & Porco, J. A. Rapid access to polyprenylated phloroglucinols via alkylative dearomatization–annulation: total synthesis of (+/–)-clusianone. J. Am. Chem. Soc. 129, 12682–12683 (2007).

    Article  CAS  Google Scholar 

  20. Tsukano, C., Siegel, D. R. & Danishefsky, S. J. Differentiation of nonconventional ‘carbanions’ – the total synthesis of nemorosone and clusianone. Angew. Chem. Int. Ed. 46, 8840–8844 (2007).

    Article  CAS  Google Scholar 

  21. Nuhant, P., David, M., Pouplin, T., Delpech, B. & Marazano, C. α,α′-Annulation of 2,6-prenyl-substituted cyclohexanone derivatives with malonyl chloride: application to a short synthesis of (±)-clusianone. Formation and rearrangement of a biogenetic-like intermediate. Org. Lett. 9, 287–289 (2007).

    Article  CAS  Google Scholar 

  22. Shimizu, Y., Shi, S., Usuda, H., Kanai, M. & Shibasaki, M. Catalytic asymmetric total synthesis of ent-hyperforin. Angew. Chem. Int. Ed. 49, 1103–1106 (2010).

    Article  CAS  Google Scholar 

  23. Simpkins, N. S., Taylor, J. D., Weller, M. D. & Hayes, C. J. Synthesis of nemorosone via a difficult bridgehead substitution reaction. Synlett 4, 639–643 (2010).

    Article  Google Scholar 

  24. Garnsey, M. R., Lim, D., Yost, J. M. & Coltart, D. M. Development of a strategy for the asymmetric synthesis of polycyclic polyprenylated acylphloroglucinols via N-amino cyclic carbamate hydrazones: application to the total synthesis of (+)-clusianone. Org. Lett. 12, 5234–5237 (2010).

    Article  CAS  Google Scholar 

  25. Zhang, Q., Mitasev, B., Qi, J. & Porco, J. A. Jr Total synthesis of plukenetione A. J. Am. Chem. Soc. 132, 14212–14215 (2010).

    Article  CAS  Google Scholar 

  26. Fleming, I. & Lee, D. A synthesis of (±)-lavandulol using a silyl-to-hydroxy conversion in the presence of 1,1-disubstituted and trisubstituted double bonds. J. Chem. Soc. Perkin Trans. 1 17, 2701–2710 (1998).

    Article  Google Scholar 

  27. Qi, J., Beeler, A. B., Zhang, Q. & Porco, J. A. Jr Catalytic enantioselective alkylative dearomatization–annulation: total synthesis and absolute configuration assignment of hyperibone K. J. Am. Chem. Soc. 132, 13642–13644 (2010).

    Article  CAS  Google Scholar 

  28. Huckin, S. N. & Weiler, L. C-Acetylation of ketones. Can. J. Chem. 52, 1379–1380 (1974).

    Article  CAS  Google Scholar 

  29. Amat, M., Llor, N., Checa, B., Molins, E. & Bosch, J. A synthetic approach to ervatamine-silicine alkaloids. Enantioselective total synthesis of (−)-16-episilicine. J. Org. Chem. 75, 178–189 (2010).

    Article  CAS  Google Scholar 

  30. Plietker, B. A highly regioselective salt-free iron-catalyzed allylic alkylation. Angew. Chem. Int. Ed. 45, 1469–1473 (2006).

    Article  CAS  Google Scholar 

  31. Plietker, B., Dieskau, A., Möws, K. & Jatsch, A. Ligand dependant mechanistic dichotomy in iron-catalyzed allylic substitutions – σ-allyl- vs. π-allyl mechanism. Angew. Chem. Int. Ed. 47, 198–201 (2008).

    Article  CAS  Google Scholar 

  32. Holzwarth, M., Dieskau, A., Tabassam, M. & Plietker, B. Preformed π-allyl iron complexes as potent, well-defined catalysts for the allylic substitution. Angew. Chem. Int. Ed. 48, 7251–7255 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Dedicated to Barry M. Trost on the occasion of his 70th birthday. The authors thank the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe e.V., the Landesgraduiertenstiftung Baden-Württemberg (PhD grant for N.B.) and the Studienstiftung des deutschen Volkes (PhD grant for K.M.) for financial support.

Author information

Authors and Affiliations

Authors

Contributions

N.B. prepared the natural products 1 5 . K.M. was involved in model studies towards the synthesis of O-methyl hyperibone and crystallized this compound (see Supplementary Information). B.P. designed the study, analysed the data and wrote the paper. All the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Bernd Plietker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 1036 kb)

Supplementary information

Crystallographic data for compound 21 (CIF 23 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Biber, N., Möws, K. & Plietker, B. The total synthesis of hyperpapuanone, hyperibone L, epi-clusianone and oblongifolin A. Nature Chem 3, 938–942 (2011). https://doi.org/10.1038/nchem.1170

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1170

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