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.

Total synthesis of brevianamide A

Abstract

The fungal-derived bicyclo[2.2.2]diazaoctane alkaloids are of interest to the scientific community for their potent and varied biological activities. Within this large and diverse family of natural products, the insecticidal metabolite (+)-brevianamide A is particularly noteworthy for its synthetic intractability and inexplicable biogenesis. Despite five decades of research, this alkaloid has remained an elusive target for chemical synthesis due to insurmountable issues of reactivity and selectivity associated with all previously explored strategies. We herein report the chemical synthesis of (+)-brevianamide A (seven steps, 7.2% overall yield, 750 mg scale), which involves a bioinspired cascade transformation of the linearly fused (−)-dehydrobrevianamide E into the topologically complex bridged-spiro-fused structure of (+)-brevianamide A.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Diels–Alder cycloaddition and representative examples of bicyclo[2.2.2]diazaoctane alkaloids, which are proposed to be biosynthesized via intramolecular hetero-Diels–Alder reactions.
Fig. 2: Previous biosynthetic proposals for brevianamides A and B.
Fig. 3: A modified biosynthetic proposal for brevianamides A and B.
Fig. 4: Total synthesis of brevianamides A and B.

Data availability

All the characterization data and experimental protocols are provided in this article and its Supplementary Information. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 1918446 (compound 1). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Nicolaou, K. C., Snyder, S. A., Montagnon, T. & Vassilikogiannakis, G. The Diels–Alder reaction in total synthesis. Angew. Chem. Int. Ed. 41, 1668–1198 (2002).

    CAS  Google Scholar 

  2. Stocking, E. M. & Williams, R. M. Chemistry and biology of biosynthetic Diels–Alder reactions. Angew. Chem. Int. Ed. 42, 3078–3115 (2003).

    CAS  Google Scholar 

  3. Oikawa, H. & Tokiwano, T. Enzymatic catalysis of the Diels–Alder reaction in the biosynthesis of natural products. Nat. Prod. Rep. 21, 321–352 (2004).

    CAS  PubMed  Google Scholar 

  4. Klas, K., Tsukamoto, S., Sherman, D. H. & Williams, R. M. Natural Diels–Alderases: elusive and irresistable. J. Org. Chem. 80, 11672–11685 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Minami, A. & Oikawa, H. Recent advances of Diels–Alderases involved in natural product biosynthesis. J. Antibiot. 69, 500–506 (2016).

    CAS  PubMed  Google Scholar 

  6. Jamieson, C. S., Ohashi, M., Liu, F., Tang, Y. & Houk, K. N. The expanding world of biosynthetic pericyclases: cooperation of experiment and theory for discovery. Nat. Prod. Rep. 36, 698–713 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Finefield, J. M., Frisvad, J. C., Sherman, D. H. & Williams, R. M. Fungal origins of the bicyclo[2.2.2]diazaoctane ring system of prenylated indole alkaloids. J. Nat. Prod. 75, 812–833 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Klas, K. R. et al. Structural and stereochemical diversity in prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring system from marine and terrestrial fungi. Nat. Prod. Rep. 35, 532–558 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Robertson, A. P. et al. Paraherquamide and 2-deoxy-paraherquamide distinguish cholinergic receptor subtypes in Ascaris muscle. J. Pharmacol. Exp. Ther. 303, 853–860 (2002).

    Google Scholar 

  10. Little, P. R. et al. Efficacy of a combined oral formulation of derquantel-abamectin against the adult and larval stages of nematodes in sheep, including anthelmintic-resistant strains. Vet. Parasitol. 181, 180–193 (2011).

    CAS  PubMed  Google Scholar 

  11. Buxton, S. K. et al. Investigation of acetylcholine receptor diversity in a nematode parasite leads to characterization of tribendimidine- and derquantel-sensitive nAChRs. PLoS Pathog. 10, e1003870 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. Martínez-Luisa, S. et al. Malbrancheamide, a new calmodulin inhibitor from the fungus Malbranchea aurantiaca. Tetrahedron 62, 1817–1822 (2006).

    Google Scholar 

  13. Lin, Z. et al. Chrysogenamide A from an endophytic fungus associated with Cistanche deserticola and its neuroprotective effect on SH-SY5Y cells. J. Antibiot. 61, 81–85 (2008).

    CAS  PubMed  Google Scholar 

  14. Qian-Cutrone, J. et al. Stephacidin A and B: two structurally novel, selective inhibitors of the testosterone-dependent prostate LNCaP cells. J. Am. Chem. Soc. 124, 14556–14557 (2002).

    CAS  PubMed  Google Scholar 

  15. Kato, H. et al. Notoamides A–D: prenylated indole alkaloids isolated from a marine‐derived fungus, Aspergillus sp. Angew. Chem. Int. Ed. 46, 2254–2256 (2007).

    CAS  Google Scholar 

  16. Birch, A. J. & Wright, J. J. The brevianamides: a new class of fungal alkaloid. J. Chem. Soc. D 644–645 (1969).

  17. Paterson, R. R. M., Simmonds, M. J. S., Kemmelmeier, C. & Blaney, W. M. Effects of brevianamide A, its photolysis product brevianamide D, and ochratoxin A from two Penicillium strains on the insect pests Spodoptera frugiperda and Heliothis virescens. Mycol. Res. 94, 538–542 (1990).

    CAS  Google Scholar 

  18. Bird, B. A. & Campbell, I. M. Brevianamides A and B are formed only after conidiation has begun in solid cultures of Penicillium brevicompactum. Appl. Environ. Microbiol. 42, 521–525 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Bird, B. A., Remaley, A. T. & Campbell, I. M. Disposition of mycophenolic acid, brevianamide A, asperphenamate, and ergosterol in solid cultures of Penicillium brevicompactum. Appl. Environ. Microbiol. 43, 345–348 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Porter, A. E. A. & Sammes, P. G. A Diels–Alder reaction of possible biosynthetic importance. J. Chem. Soc. D 1103a–1103a (1970).

  21. Dan, Q. et al. Fungal indole alkaloid biogenesis through evolution of a bifunctional reductase/Diels–Alderase. Nat. Chem. 11, 972–980 (2019).

    CAS  PubMed  Google Scholar 

  22. Li, S. et al. Comparative analysis of the biosynthetic systems for fungal bicyclo[2.2.2]diazaoctane indole alkaloids: the (+)/(−)-notoamide, paraherquamide and malbrancheamide pathways. Med. Chem. Commun. 3, 987–996 (2012).

    CAS  Google Scholar 

  23. Miller, K. A., Tsukamoto, S. & Williams, R. M. Asymmetric total syntheses of (+)- and (–)-versicolamide B and biosynthetic implications. Nat. Chem. 1, 68–69 (2009).

    Google Scholar 

  24. Williams, R. M., Glinka, T. & Kwast, E. Facial selectivity of the intramolecular SN2′ cyclization: stereocontrolled total synthesis of brevianamide B. J. Am. Chem. Soc. 110, 5927–5929 (1988).

    CAS  Google Scholar 

  25. Williams, R. M., Glinka, T., Kwast, E., Coffman, H. & Stille, J. K. Asymmetric, stereocontrolled total synthesis of (−)-brevianamide B. J. Am. Chem. Soc. 112, 808–821 (1990).

    CAS  Google Scholar 

  26. Williams, R. M., Sanz-Cervera, J. F., Sancenón, F., Marco, J. A. & Halligan, K. Biomimetic Diels−Alder cyclizations for the construction of the brevianamide, paraherquamide sclerotamide, and VM55599 ring systems. J. Am. Chem. Soc. 120, 1090–1091 (1998).

    CAS  Google Scholar 

  27. Williams, R. M., Sanz-Cervera, J. F., Sancenón, F., Marco, J. A. & Halligan, K. Biomimetic Diels–Alder cyclizations for the construction of the brevianamide, paraherquamide, sclerotamide, asperparaline and VM55599 ring systems. Bioorg. Med. Chem. 6, 1233–1241 (1998).

    CAS  PubMed  Google Scholar 

  28. Adams, L. A., Valente, M. W. N. & Williams, R. M. A concise synthesis of d,l-brevianamide B via a biomimetically-inspired IMDA construction. Tetrahedron 62, 5195–5200 (2006).

    CAS  Google Scholar 

  29. Greshock, T. J. & Williams, R. M. Improved biomimetic total synthesis of d,l-stephacidin A. Org. Lett. 9, 4255–4258 (2007).

    CAS  PubMed  Google Scholar 

  30. Frebault, F. C. & Simpkins, N. S. A cationic cyclisation route to prenylated indole alkaloids: synthesis of malbrancheamide B and brevianamide B, and progress towards stephacidin A. Tetrahedron 66, 6585–6596 (2010).

    CAS  Google Scholar 

  31. Robins, J. G., Kim, K. J., Chinn, A. J., Woo, J. S. & Scheerer, J. R. Intermolecular Diels−Alder cycloaddition for the construction of bicyclo[2.2.2]diazaoctane structures: formal synthesis of brevianamide B and premalbrancheamide. J. Org. Chem. 81, 2293–2301 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Perkins, J. C., Wang, X., Pike, R. D. & Scheerer, J. R. Further investigation of the intermolecular Diels–Alder cycloaddition for the synthesis of bicyclo[2.2.2]diazaoctane alkaloids. J. Org. Chem. 82, 13656–13662 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Williams, R. M., Kwast, E., Coffman, H. & Glinka, T. Remarkable, enantiodivergent biogenesis of brevianamide A and B. J. Am. Chem. Soc. 111, 3064–3065 (1989).

    CAS  Google Scholar 

  34. Birch, A. J. & Wright, J. J. Studies in relation to biosynthesis—XLII: the structural elucidation and some aspects of the biosynthesis of the brevianamides-A and -E. Tetrahedron 26, 2329–2344 (1970).

    CAS  PubMed  Google Scholar 

  35. Birch, A. J. & Russell, R. A. Studies in relation to biosynthesis—XLIV: structural elucidations of brevianamides-B, -C, -D and -F. Tetrahedron 28, 2999–3008 (1972).

    CAS  Google Scholar 

  36. Baldas, J., Birch, A. J. & Russell, R. A. Studies in relation to biosynthesis. Part XLVI. Incorporation of cyclo-l-tryptophyl-l-proline into brevianamide A. J. Chem. Soc. Perkin Trans. 1, 50–52 (1974).

  37. Sanz-Cervera, J. F., Glinka, T. & Williams, R. M. Biosynthesis of brevianamides A and B: in search of the biosynthetic Diels-Alder construction. Tetrahedron 49, 8471–8482 (1993).

    CAS  Google Scholar 

  38. Domingo, L. R., Sanz-Cervera, J. F., Williams, R. M., Picher, M. T. & Marco, J. A. Biosynthesis of the brevianamides. An ab initio study of the biosynthetic intramolecular Diels–Alder cycloaddition. J. Org. Chem. 62, 1662–1667 (1997).

    CAS  Google Scholar 

  39. Steyn, P. S. The structures of five diketopiperazines from Aspergillus ustus. Tetrahedron 29, 107–120 (1973).

    CAS  Google Scholar 

  40. Scott, P. M., Kennedy, B. P. C., Harwig, J. & Chen, Y.-K. Formation of diketopiperazines by Penicillium italicum isolated from oranges. Appl. Microbiol 28, 892–894 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kaur, A., Raja, H. A., Deep, G., Agarwal, R. & Oberlies, N. H. Pannorin B, a new naphthopyrone from an endophytic fungal isolate of Penicillium sp. Magn. Reson. Chem. 54, 164–167 (2016).

    CAS  PubMed  Google Scholar 

  42. Liu, H., Pattabiraman, V. R. & Vederas, J. C. Stereoselective syntheses of 4-oxa diaminopimelic acid and its protected derivatives via aziridine ring opening. Org. Lett. 9, 4211–4214 (2007).

    CAS  PubMed  Google Scholar 

  43. Schkeryantz, J. M., Woo, J. C. G., Siliphaivanh, P., Depew, K. M. & Danishefsky, S. J. Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: novel constructions of 2,3-disubstituted indoles. J. Am. Chem. Soc. 121, 11964–11975 (1999).

    CAS  Google Scholar 

  44. Zhao, L., May, J. P., Huang, J. & Perrin, D. M. Stereoselective synthesis of brevianamide E. Org. Lett. 14, 90–93 (2012).

    CAS  PubMed  Google Scholar 

  45. Fisher, J. W. & Trinkle, K. L. Iodide dealkylation of benzyl, PMB, PNB, and t-butyl N-acyl amino acid esters via lithium ion coordination. Tetrahedron Lett. 35, 2505–2508 (1994).

    CAS  Google Scholar 

  46. Huy, P., Neudörfl, J.-M. & Schmalz, H.-G. A practical synthesis of trans-3-substituted proline derivatives through 1,4-addition. Org. Lett. 13, 216–219 (2011).

    CAS  PubMed  Google Scholar 

  47. Nigst, T. A., Antipova, A. & Mayr, H. Nucleophilic reactivities of hydrazines and amines: the futile search for the α-effect in hydrazine reactivities. J. Org. Chem. 77, 8142–8155 (2012).

    CAS  PubMed  Google Scholar 

  48. Kametani, T., Kanaya, N. & Ihara, M. Asymmetric total synthesis of brevianamide E. J. Am. Chem. Soc. 102, 3974–3975 (1980).

    CAS  Google Scholar 

  49. Ye, Y. et al. Cofactor-independent pinacolase directs non-Diels–Alderase biogenesis of the brevianamides. Preprint at https://doi.org/10.26434/chemrxiv.9122009.v1 (2019).

Download references

Acknowledgements

This work was supported by an EPSRC First Grant (EP/N029542/1) and a Marie Curie Career Integration Grant (631132, POSIN). We thank T. Herlt for assistance and advice regarding chromatography, and acknowledge SIRCAMS at the University of Edinburgh for mass spectrometry.

Author information

Authors and Affiliations

Authors

Contributions

R.C.G., N.J.G. and A.L.L. conceived, designed and carried out the synthetic experiments. G.S.N. performed the crystallographic studies. All authors discussed and co-wrote the manuscript.

Corresponding author

Correspondence to Andrew L. Lawrence.

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

Overview of previous total and formal syntheses of brevianamide B, Supplementary Tables 1–3, details of the materials and methods, experimental procedures and compound characterization data (1H NMR,13C NMR, IR, HRMS, optical rotations, chiral-HPLC and X-ray).

Crystallographic data

Crystallographic data for compound 1. CCDC 1918446.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Godfrey, R.C., Green, N.J., Nichol, G.S. et al. Total synthesis of brevianamide A. Nat. Chem. 12, 615–619 (2020). https://doi.org/10.1038/s41557-020-0442-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-020-0442-3

Further reading

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