Total synthesis of brevetoxin A

Abstract

Brevetoxin A is the most potent neurotoxin secreted by Gymnodinium breve Davis, a marine organism often associated with harmful algal blooms known as ‘red tides’1,2,3. The compound, whose mechanism of action involves binding to and opening of sodium channels4,5,6,7, is sufficiently toxic to kill fish at concentrations of nanograms per ml (refs 3, 4) and, after accumulation in filter-feeding shellfish, to poison human consumers. The precise pathway by which nature constructs brevetoxin A is at present unknown8,9, but strategies for its total synthesis have been contemplated for some time. The synthetic challenge posed by brevetoxin A reflects the high complexity of its molecular structure: 10 oxygen atoms and a chain of 44 carbon atoms are woven into a polycyclic macromolecule that includes 10 rings (containing between 5 and 9 atoms) and 22 stereogenic centres. Particularly challenging are the 7-, 8- and 9-membered rings which allow the molecule to undergo slow conformational changes and force a 90° twist at one of its rings1,2,3,4,5,6. Here we describe the successful incorporation of methods that were specifically developed for the construction of these rings10,11 into an overall strategy for the total synthesis of brevetoxin A in its naturally occurring form. The convergent synthesis reported here renders this scarce neurotoxin synthetically available and, more importantly, allows the design and synthesis of analogues for further biochemical studies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Molecular structure (a), strategic bond disconnections (b), and retrosynthetic analysis (c) of brevetoxin A (1).
Figure 2: Construction of the BCD bis-lactone system 16.
Figure 3: Construction of the BCDE lactone 26.
Figure 4: Construction of the BCDE phosphine oxide 2.
Figure 5: Construction of the GHIJ ring system 3.
Figure 6: Total synthesis of brevetoxin A (1).

References

  1. 1

    Shimizu, Y., Chou, H.-N. & Bando, H. Structure of brevetoxin A (GB-1 toxin), the most potent toxin in the Florida red tide organism Gymnodinium breve (Ptychodiscus brevis). J. Am. Chem. Soc. 108, 514–515 (1986).

    CAS  Article  Google Scholar 

  2. 2

    Shimizu, Y., Bando, H., Chou, H.-N., Van Duyne, G. & Clardy, J. C. Absolute configuration of brevetoxins. J. Chem. Soc., Chem. Commun. 1656–1658 (1986).

  3. 3

    Pawlak, J.et al. Structure of brevetoxin A as constructed from NMR and MS data. J. Am. Chem. Soc. 109, 1144–1150 (1987).

    CAS  Article  Google Scholar 

  4. 4

    Rein, K. S., Baden, D. G. & Gawley, R. E. Conformational analysis of the sodium channel modulator, brevetoxin A, comparison with brevetoxin B conformations, and a hypothesis about the common pharmacophore of the “site 5” toxins. J. Org. Chem. 59, 2101–2106 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Rein, K. S., Lynn, B., Baden, D. G. & Gawley, R. E. Brevetoxin B: chemical modifications, synaptosome binding, toxicity, and an unexpected conformational effect. J. Org. Chem. 59, 2107–21013 (1994).

    CAS  Article  Google Scholar 

  6. 6

    Yasumoto, T. & Murata, M. Marine toxins. Chem. Rev. 93, 1897–1909 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Gawley, R. E.et al. The relationship of brevetoxin “length” and A-ring functionality to binding and activity in neuronal sodium channels. Chem. Biol. 2, 533–541 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Chou, H.-N. & Shimizu, Y. Biosynthesis of brevetoxins. Evidence for the mixed origin of the backbone carbon chain and the possible involvement of dicarboxylic acids. J. Am. Chem. Soc. 109, 2184–2185 (1987).

    CAS  Article  Google Scholar 

  9. 9

    Lee, M. S., Qin, G.-W., Nakanishi, K. & Zagorski, M. G. Biosynthesis studies on brevetoxins, potent neurotoxins produced by the dinoflagellate Gymnodinium breve. J. Am. Chem. Soc. 111, 6234–6241 (1989).

    CAS  Article  Google Scholar 

  10. 10

    Nicolaou, K. C., Prasad, C. V. C., Hwang, C.-K., Duggan, M. E. & Veale, C. A. Cyclizations of hydroxydithioketals. New synthetic technology for the construction of oxocenes and related medium ring systems. J. Am. Chem. Soc. 111, 5321–5330 (1989).

    CAS  Article  Google Scholar 

  11. 11

    Nicolaou, K. C., Shi, G.-Q., Gunzner, J. L., Gärtner, P. & Yang, Z. Palladium-catalyzed functionalization of lactones via their cyclic ketene acetal phosphates. Efficient new synthetic technology for the construction of medium and large cyclic ethers. J. Am. Chem. Soc. 119, 5467–5468 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Nicolaou, K. C., Prasad, C. V. C., Somers, P. K. & Hwang, C.-K. Activation of 6-endo over 5-exo hydroxy epoxide openings. Stereo- and ringselective synthesis of tetrahydrofuran and tetrahydropyran systems. J. Am. Chem. Soc. 111, 5330–5334 (1989).

    CAS  Article  Google Scholar 

  13. 13

    Freeman, J. P. in Organic Syntheses (Collective Vol. VII) 139–141 (Wiley, New York, 1990).

    Google Scholar 

  14. 14

    Xie, M., Beges, D. A. & Robins, M. J. Efficient “dehomologation” of di-O-isopropylidenehexofuranose derivatives to give O-isopropylidenepentofuranose by sequential treatment with periodic acid in ethyl acetate and sodium borohydride. J. Org. Chem. 61, 5178–5179 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Mukaiyama, T., Banno, K. & Narasaka, K. New cross-aldol reactions. Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride. J. Am. Chem. Soc. 96, 7503–7509 (1974).

    CAS  Article  Google Scholar 

  16. 16

    Rodeheaver, G. T. & Hunt, D. F. Conversion of olefins into ketones with mercuric acetate and palladium chloride. Chem. Commun. 818–819 (1971).

  17. 17

    Tamura, Y., Ochiai, H., Nakamura, T. & Yoshida, Z. Arylation and vinylation of 2-carboethoxyethylzinc iodide and 3-carboethoxypropylzinc iodide catalyzed by palladium. Tetrahedr. Lett. 27, 955–958 (1986).

    Article  Google Scholar 

  18. 18

    Inanaga, J., Hirata, K., Saeki, H., Katsuki, T. & Yamaguchi, M. Arapid esterification by mixed anhydride and its application to large-ring lactonization. Bull. Chem. Soc. Jpn 52, 1989–1993 (1979).

    CAS  Article  Google Scholar 

  19. 19

    Arhart, R. J. & Martin, J. C. Sulfuranes, V. The chemistry of sulfur (IV) compounds. Dialkoxydiarylsulfuranes. J. Am. Chem. Soc. 94, 4997–5003 (1972).

    CAS  Article  Google Scholar 

  20. 20

    Hoveyda, A. H., Evans, D. A. & Fu, G. C. Substrate-directable chemical reactions. Chem. Rev. 93, 1307–1370 (1993).

    CAS  Article  Google Scholar 

  21. 21

    Nicolaou, K. C., McGarry, D. G. & Sommers, P. K. New synthetic strategies for the construction of medium-size cyclic ethers. Stereocontrolled synthesis of the BCD ring framework of brevetoxin A. J.Am. Chem. Soc. 112, 3696–3697 (1990).

    CAS  Article  Google Scholar 

  22. 22

    Corey, E. J. & Beames, D. J. Mixed cuprate reagents of type R1R2CuLi which allow selective group transfer. J. Am. Chem. Soc. 94, 7210–7211 (1972).

    CAS  Article  Google Scholar 

  23. 23

    Ley, S. V., Norman, J., Griffith, W. P. & Marsden, S. P. Tetrapropylammonium perruthenate, Pr4N+RuO4, TPAP: a catalytic oxidant for organic synthesis. Synthesis 639–666 (1994).

  24. 24

    Nicolaou, K. C.et al. New synthetic technology for the construction of 9-membered ring cyclic ethers. Construction of the EFGH ring skeleton of brevetoxin A. J. Am. Chem. Soc. 119, 8105–8106 (1997).

    CAS  Article  Google Scholar 

  25. 25

    Mahoney, W. S., Brestensky, D. M. & Stryker, J. M. Selective hydride-mediated conjugate reduction of α, β-unsaturated carbonyl compounds using [(Ph3P)CuH]6. J. Am. Chem. Soc. 119, 8105–8106 (1997).

    Article  Google Scholar 

  26. 26

    Feixas, J., Capdevila, A. & Guerrero, A. Utilization of neutral alumina as a mild reagent for the selective cleavage of primary and secondary silyl ethers. Tetrahedron 50, 8539–8550 (1994).

    CAS  Article  Google Scholar 

  27. 27

    Nicolaou, K. C.et al. Novel strategies for the construction of complex polycyclic ether frameworks. Stereocontrolled synthesis of the FGHIJ ring system of brevetoxin A. Angew. Chem. Int. Edn. Engl. 30, 299–303 (1991).

    Article  Google Scholar 

  28. 28

    Parikh, J. R. & Doering, W. vonE. Sulfur trioxide in the oxidation of alcohols by dimethyl sulfoxide. J.Am. Chem. Soc. 89, 5505–5507 (1967).

    CAS  Article  Google Scholar 

  29. 29

    Clayden, J. & Warren, S. Stereocontrol in organic synthesis using the diphenylphosphoryl group. Angew. Chem. Int. Edn. Engl. 35, 241–270 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Zagorski, M. G., Nakanishi, K., Qin, G.-W. & Lee, M. S. Assignment of 13C NMR peaks of brevetoxin A: application of two-dimensional Hartmann-Hahn spectroscopy. J. Org. Chem. 53, 4156–4157 (1988).

    CAS  Article  Google Scholar 

  31. 31

    Lee, M. S., Nakanishi, K. & Zagorski, M. G. Full proton assignment of BTX-A, C49H70O13. New J.Chem. 11, 753–756 (1987).

    CAS  Google Scholar 

  32. 32

    Klindgren, B. O. & Nilsson, T. Preparation of carboxylic acids from aldehydes (including hydroxylated benzaldehydes) by oxidation with chlorite. Acta Chem. Scand. 27, 888–890 (1973).

    Article  Google Scholar 

  33. 33

    Dess, D. B. & Martin, J. C. Readily accessible 12-I-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. J. Org. Chem. 48, 4155–4156 (1983).

    CAS  Article  Google Scholar 

  34. 34

    Schreiber, J., Maag, H., Hashimoto, N. & Eschenmoser, A. Dimethyl(methylene)ammonium iodide. Angew. Chem. Int. Edn. Engl. 10, 330–331 (1971).

    CAS  Article  Google Scholar 

  35. 35

    Nicolaou, K. C.et al. Total synthesis of brevetoxin B. 1. First generation strategies and new approaches to oxepane systems. J. Am. Chem. Soc. 117, 10227–10238 (1995).

    CAS  Article  Google Scholar 

  36. 36

    Nicolaou, K. C.et al. Total synthesis of brevetoxin B. 2. Second generation strategies and construction of the dioxepane region [DEFG]. J. Am. Chem. Soc. 117, 10239–10251 (1995).

    CAS  Article  Google Scholar 

  37. 37

    Nicolaou, K. C.et al. Total synthesis of brevetoxin B. 3. Final strategy and completion. J. Am. Chem. Soc. 117, 10252–10263 (1995).

    CAS  Article  Google Scholar 

  38. 38

    Nicolaou, K. C. The total synthesis of brevetoxin B: a twelve year odyssey in organic synthesis. Angew. Chem. Int. Edn. Engl. 35, 589–607 (1996).

    CAS  Google Scholar 

  39. 39

    Homaka, Y. Recent methods for detection of seafood toxins: recent immunological method for ciguatoxin and related polyethers. Food Addit. Contam. 10, 71–82 (1993).

    Article  Google Scholar 

  40. 40

    Anderson, D. M. Turning back the harmful red tide. Nature 388, 513–514 (1997).

    ADS  CAS  Article  Google Scholar 

  41. 41

    Barker, R. And the Waters Turned to Blood (Simon & Schuster, New York, 1997).

    Google Scholar 

  42. 42

    Anderson, D. M. Red tides. Sci. Am. 271, 62–68 (1994).

    CAS  Article  Google Scholar 

  43. 43

    Hall, S. & Strichartz, G. (eds) (American Chemical Society, Washington DC, 1990).

  44. 44

    Okaichi, T., Anderson, D. M. & Nemoto, T. (eds) Red Tides. Biology, Environmental Science, and Toxicology (Elsevier, New York, 1989).

    Google Scholar 

  45. 45

    Anderson, D. M. & White, A. W. Marine biotoxins at the top of the food chain. Oceanus 35, 55–61 (1992).

    Google Scholar 

Download references

Acknowledgements

We are indebeted to those of our collaborators whose early contributions on this project made its success possible; their names will appear in the full account of this work. We thank K.Nakanishi and Y. Shimizu for samples of natural brevetoxin A, and D. H. Huang, G. Siuzdak and R.Chadha for the NMR, mass spectroscopic and X-ray crystallographic assistance, respectively. This work was supported by the National Institutes of Health USA (GM), The Skaggs Institute for Chemical Biology, Novartis, Merck, Hoffmann-La Roche, Schering Plough, DuPont Merck, the American Chemical Society (graduate fellowship sponsored by Aldrich to J.L.G.) and the Foundation for the Promotion of Scientific Investigations (postdoctoral fellowship to P.G.). Z.Y. and G.S. contributed equally to this project.

Author information

Affiliations

Authors

Corresponding author

Correspondence to K. C. Nicolaou.

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nicolaou, K., Yang, Z., Shi, G. et al. Total synthesis of brevetoxin A. Nature 392, 264–269 (1998). https://doi.org/10.1038/32623

Download citation

Further reading

Comments

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.