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.

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

References

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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.

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

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

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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.