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



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.

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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).


  1. 1

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

    CAS  Article  Google Scholar 

  2. 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. 3

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

    CAS  Article  Google Scholar 

  4. 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).

    CAS  Article  Google Scholar 

  5. 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. 6

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

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 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).

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 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).

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 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).

    CAS  Article  Google Scholar 

  19. 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).

    CAS  Article  Google Scholar 

  20. 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).

    CAS  Article  Google Scholar 

  21. 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).

    CAS  Article  Google Scholar 

  22. 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).

    CAS  Article  Google Scholar 

  23. 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. 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).

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 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. 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).

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 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).

    CAS  Article  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

  31. 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).

    CAS  Article  Google Scholar 

  32. 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).

    CAS  Article  Google Scholar 

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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.

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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.

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Correspondence to Bernd Plietker.

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Crystallographic data for compound 21 (CIF 23 kb)

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Biber, N., Möws, K. & Plietker, B. The total synthesis of hyperpapuanone, hyperibone L, epi-clusianone and oblongifolin A. Nature Chem 3, 938–942 (2011).

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