A cascade annulation based convergent approach to racemic tetrodotoxin

European Journal of Organic Chemistry

Volumn , Issue 35, 2010, Pages 6741-6747

  Cagide Fagín, Fernando ^a   Alonso, Ricardo ^a  

^a UNIVERSITY OF SANTIAGO DE COMPOSTELA   (Spain)

Author keywords

(Hetero)aryl nitro enals; 2 2 Dimethyl 1 3 dioxan 5 one; Annulation; Cyclitols; Natural products

Indexed keywords

EID: 78650167368     PISSN: 1434193X     EISSN: 10990690     Source Type: Journal    
DOI: 10.1002/ejoc.201001159     Document Type: Article

References (53)

1. A. M. Walji, D. W. C. MacMillan, Synlett 2007, 1477-1489.
2. Tetrodotoxin, tarichatoxin, and chiriquitoxin: historical perspectives, in, F. A. Fuhrman, Ann. N. Y. Acad. Sci. 1986, 479, 1-14.
3. Tetrodotoxin, Saxitoxin, and the Molecular Biology of the Sodium Channel:, C. Y. Kao, S. R. Levinson, Ann. N. Y. Acad. Sci. 1986, 479.
4. D. B. Tikhonov, B. S. Zhorov, Biophys. J. 2005, 88, 184-197.
5. S. L. Geffeney, E. Fujimoto, E. D. Brodie, E. D. Brodie, P. C. Ruben, Nature 2005, 434, 759-763.
6. M. Noda, S. Shimizu, T. Tanabe, T. Takai, T. Kayano, T. Ikeda, H. Takahashi, H. Nakayama, Y. Kanaoka, N. Minamino, K. Kangawa, H. Matsuo, M. A. Raftery, T. Hirose, S. Inayama, H. Hayashida, T. Miyata, S. Numa, Nature 1984, 312, 121-127.
7. F. Hucho, Angew. Chem. Int. Ed. Engl. 1995, 34, 39-50.
8. For the period 2005-2009, SciFinder Scholar retrieves around 700 references per year for tetrodotoxin in the Chemical Abstracts database, mostly relating to neurological and pharmacological studies.
9. The chemistry of tetrodotoxin, in:, H. S. Mosher, Ann. N. Y. Acad. Sci. 1986, 479, 32-43.
10. Tetrodotoxin is the main lead compound in WexPharmaceuticals' drug development program:.
11. For recent papers on the therapeutic potential of sodium channel blockers, see
12. R. J. French, H. Terlau, Curr. Med. Chem. 2004, 11, 3053-3064.
13. J. N. Wood, J. Boorman, Curr. Top. Med. Chem. 2005, 5, 529-537.
14. I. Tarnawa, H. Bolcskei, P. Kocsis, Recent Pat. CNS Drug Discov. 2007, 2, 57-78.
15. W. E. Childers, A. M. Gilbert, J. D. Kennedy, G. T. Whiteside, Expert Opin. Ther. Pat. 2008, 18, 1027-1067.
16. The structural determination of tetrodotoxin was reported at the 3rd IUPAC Symposium on the Chemistry of Natural Products, Kyoto, Japan, April 13, 1964 by the groups led by Tsuda, Hirata, Woodward, and Mosher
17. K. Tsuda, O. Amakasu, S. Ikuma, M. Kawamura, C. Tamura, R. Tachikawa, K. Sakai, Chem. Pharm. Bull. 1964, 12, 1357.
18. T. Goto, Y. Kishi, S. Takahashi, Y. Hirata, Tetrahedron 1965, 21, 2059-2088.
19. R. B. Woodward, Pure Appl. Chem. 1964, 9, 49.
20. R. B. Woodward, J. Z. Gougoutas, J. Am. Chem. Soc. 1964, 86, 5030.
21. H. S. Mosher, H. G. Fischer, F. A. Fuhrman, H. D. Buchwald, Science 1964, 144, 1100-1111.
22. Y. Kishi, M. Aratani, T. Fukuyama, F. Nakatsubo, T. Goto, S. Inoue, H. Tanino, S. Sugiura, H. Kakoi, J. Am. Chem. Soc. 1972, 94, 9217-9219.
23. Y. Kishi, T. Fukuyama, M. Aratani, F. Nakatsubo, T. Goto, S. Inoue, H. Tanino, S. Sugiura, H. Kakoi, J. Am. Chem. Soc. 1972, 94, 9219-9221.
24. More recently, the group led by Sato reported a stereocontrolled synthesis of racemic tetrodotoxin from myo-inositol:, K.-I. Sato, S. Akai, N. Sugita, T. Ohsawa, T. Kogure, H. Shoji, J. Yoshimura, J. Org. Chem. 2005, 70, 7496-7504.
25. N. Ohyabu, T. Nishikawa, M. Isobe, J. Am. Chem. Soc. 2003, 125, 8798-8805.
26. A. Hinman, J. Du Bois, J. Am. Chem. Soc. 2003, 125, 11510-11511.
27. T. Nishikawa, D. Urabe, M. Isobe, Angew. Chem. Int. Ed. 2004, 43, 4782-4785.
28. P. Noheda, "Synthesis of tetrodotoxin, its analogues and intermediates thereof" EP 1785427, 2007.
29. K.-I. Sato, S. Akai, H. Shoji, N. Sugita, S. Yoshida, Y. Nagai, K. Suzuki, Y. Nakamura, Y. Kajihara, M. Funabashi, J. Yoshimura, J. Org. Chem. 2008, 73, 1234-1242.
30. S. Akai, H. Seki, N. Sugita, T. Kogure, N. Nishizawa, K. Suzuki, Y. Nakamura, Y. Kajihara, J. Yoshimura, K. Sato, Bull. Chem. Soc. Jpn. 2010, 83, 279.
31. For other synthetic efforts directed towards tetrodotoxin, see the following articles and the references cited therein
32. J. F. W. Keana, J. S. Bland, P. J. Boyle, M. Erion, R. Hartling, J. R. Husman, R. B. Roman, G. Ferguson, M. Parvez, J. Org. Chem. 1983, 48, 3627-3631.
33. R. J. Nachman, M. Honel, T. M. Williams, R. C. Halaska, H. S. Mosher, J. Org. Chem. 1986, 51, 4802-4806.
34. C. S. Burgey, R. Vollerthun, B. Fraser-Reid, J. Org. Chem. 1996, 61, 1609-1618.
35. T. Itoh, M. Watanabe, T. Fukuyama, Synlett 2002, 1323-1325.
36. T. Umezawa, T. Hayashi, H. Sakai, H. Teramoto, T. Yoshikawa, M. Izumida, Y. Tamatani, T. Hirose, Y. Ohfune, T. Shinada, Org. Lett. 2006, 8, 4971.
37. D. F. Taber, P. H. Storck, J. Org. Chem. 2003, 68, 7768-7771.
38. L. Ozores, F. Cagide, R. Alonso, Synlett 2004, 2746-2750.
39. B. A. Mendelsohn, M. A. Ciufolini, Org. Lett. 2009, 11, 4736.
40. [13a-13c] above) are long (>25 steps) and follow a linear, strategy. The hexasubstituted cyclohexane intermediate makes a convergent strategy, which may reduce the number of steps to less than 20, very difficult but not, impossible. Because of its structural complexity and functional-group density, tetrodotoxin will remain a prime synthetic target."
41. [11,12,13a-13c,13e], are: 29 (0.66 %), 40 (0.14 %), 69 (0.17 %), 32 (0.49 %), 62 (1 %) and 34 (0.38 %), respectively.
42. J. C. Ortiz, L. Ozores, F. Cagide-Fagin, R. Alonso, Chem. Commun. 2006, 4239-4241.
43. P. Martínez-Bescos, F. Cagide-Fagin, L. F. Roa, J. C. Ortiz-Lara, K. Kierus, L. Ozores-Viturro, M. Fernández-González, R. Alonso, J. Org. Chem. 2008, 73, 3745-3753.
44. [19]), we prepared it more than 15 times in batches of 65 g without a single incident according to the procedure reported in:, D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155-4156.
45. Caution ! IBX is explosive under impact or heating above 200 °C:, J. B. Plumb, D. J. Harper, Chem. Eng. News 1990, 68, 3. see also comments in
46. G. Tojo, M. Fernández, in Basic Reactions in Organic Synthesis Oxidation of Alcohols to Aldehydes and Ketones, Springer, New York, 2006, chapter 3, pp. 203 and 183, respectively, and references therein.
47. For experimental procedures to prepare 2,2-dimethyl-1,3-dioxan-5-one (5), see
48. D. Enders, M. Voith, S. J. Ince, Synthesis 2002, 1775-1779.
49. [20a,20b] are 58 % (on the 25 g scale) and 73 % (10 g scale), respectively.
50. A timetable for the whole process-the preparations of IBX, the nitroenal 3, the dioxanone 5, and the protected nitrocyclitol 7-is included in the Supporting Information
51. Detailed experimental procedures for the gram-scale preparation of 7 and its precursor 3 are described in the Experimental Section and the Supporting Information, respectively.
52. 2) cleavage at their carbonyl groups as a result of the addition of a range of agents (water, alcohols, amines, thiols, etc.); see for example:, R. H. Fischer, H. M. Weitz, Synthesis 1980, 261-282.
53. P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem. 1981, 46, 3936-3938.