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Synlett 2002(8): 1323-1325
DOI: 10.1055/s-2002-32984
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthetic Approach to Tetrodotoxin

Tetsuji Itoh, Manabu Watanabe, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax: +81(3)58028694; e-Mail: fukuyama@mol.f.u-tokyo.ac.jp;
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Publication History

Received 15 May 2002
Publication Date:
25 July 2002 (online)

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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

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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.