Synthetic Approach to Tetrodotoxin

Abstract

A novel and stereoselective approach to tetrodotoxin is described. The tricyclic compound having several key functional groups on the cyclohexane ring was synthesized from p-anisaldehyde with control of the four chiral centers. Iodoaminocyclization, 1,3-dipolar cycloaddition, and Baeyer-Villiger oxidation are the key steps of our approach.

Key words

tetrodotoxin - stereoselective - iodoaminocyclization reaction - intramolecular 1,3-dipolar cycloaddition - isoxazoline

References

• 1a Tetrodotoxin, Saxitoxin and the Molecular Biology of the Sodium Channels   479:  New York Academy of Sciences; New York: 1986.  p.1 
• 1b Mori K. In Comprehensive Natural Products Chemistry   Vol. 8:  Pergamon; Oxford: 1999.  p.480 
• 2a Goto T. Kishi Y. Takahashi S. Hirata Y. Tetrahedron  1965,  21:  2059 
• 2b Tsuda K. Ikuma S. Kawamura M. Tachikawa K. Sakai K. Tamura C. Akamatsu O. Chem. Pharm. Bull.  1964,  12:  1357 
• 2c Woodward RB. Pure Appl. Chem.  1964,  9:  47 
• Synthetic studies:
• 3a Keana JFW. Boyle PJ. Erion M. Hartling R. Husman JR. Richman JE. Roman RB. Wah RM. J. Org. Chem.  1983,  48:  3621 
• 3b Keana JFW. Bland JS. Boyle PJ. Erion M. Hartling R. Husman JR. Roman RB. Ferguson G. Parvez M. J. Org. Chem.  1983,  48:  3627 
• 3c Sato K. Kajihara Y. Nakamura Y. Yoshimura J. Chem. Lett.  1991,  1559 
• 3d Alonso R. A., Burgey C. S., Rao B. V., Vite G. D., Vollerthun R., Zottola M. A., Fraser-Reid B.; J. Am. Chem. Soc.; 1993, 115: 6666
• 3e Burgey CS. Vollerthun R. Fraser-Reid B. J. Org. Chem.  1996,  61:  1609 
• 3f Fraser-Reid B. Burgey CS. Vollerthun R. Pure Appl. Chem.  1998,  70:  47 
• 3g Noya B. Paredes MD. Ozores L. Alonso R. J. Org. Chem.  2000,  65:  5960 
• 3h Total synthesis of nonnatural (-)-5,11-dideoxytetrodotoxin: Nishikawa T. Asai M. Ohyabu N. Yamamoto N. Isobe M. Angew. Chem. Int. Ed.  1999,  38:  3081 
• 3i Asai M. Nishikawa T. Ohyabu N. Yamamoto N. Isobe M. Tetrahedron  2001,  57:  4543 
• 4a Kishi Y. Aratani Y. Fukuyama T. Nakatsubo F. Goto T. Inoue S. Tanino H. Sugiura S. Kakoi H. J. Am. Chem. Soc.  1972,  94:  9217 
• 4b Kishi Y. Fukuyama T. Aratani M. Nakatsubo F. Goto T. Inoue S. Tanino H. Sugiura S. Kakoi H. J. Am. Chem. Soc.  1972,  94:  9219 
• 5 Grehn M. Almeida LS. Ragnarsson U. Synthesis  1998,  992 
• 6 Fujita M. Kitagawa O. Suzuki T. Taguchi T. J. Org. Chem.  1997,  62:  7330 
• 9a Basel Y. Hassner A. Synthesis  1997,  309 
• 9b Other methods for the preparation of nitrile oxides from primary nitroalkanes: Mukaiyama T. Hoshino T. J. Am. Chem. Soc.  1960,  82:  5339 
• 9c Shimizu T. Hayashi Y. Shibafuchi H. Teramura K. Bull. Chem. Soc. Jpn.  1986,  59:  2827 
• 10 VanRheenen V. Kelly RC. Cha DY. Tetrahedron Lett.  1976,  17:  1973 
• 12 Dess DB. Martin JC. J. Am. Chem. Soc.  1991,  113:  7277 

7

The stereochemistry at C-9 position was confirmed by NOEs after conversion of 7 to 9. NOEs between C-8 and C-9, C-4a and C-10 were observed.

8

Prof. Taguchi and co-workers reported diastereoselective iodoaminocyclization and succeeded in construction of tertiary stereocenters, see ref. [6]

11

When NaHSO₃ was used instead of Na₂SO₃ as a reducing agent, no cyclization was observed and the expected diol was obtained.

13

It is known that C-9 position of tetrodotoxin sometimes epimerizes. We confirmed that epimerization at C-9 position of 2 did not occur because NOE between C-8 and C-9 was observed.