Scalable Synthesis of a New Dihydroxylated Intermediate for Tetrodotoxin and Its Analogues

Abstract

The synthesis of a novel intermediate for tetrodotoxin and its analogues, possessing two hydroxy groups at C-8 and C-11, is described. The procedure involves a Diels-Alder reaction between bromolevoglucosenone and a tert-butyldiphenylsilyl-protected isoprenol during which the C-11 group hydroxy is installed. Subsequent transformations, including an Overman rearrangement, affords a cyclohexene intermediate containing a trichloroacetamide moiety as a requisite amino functionality for installation of the guanidine unit present in tetrodotoxin. Hydroxylation at C-8 is carried out via neighboring group participation of the trichloroacet­amide to furnish the desired diol intermediate.

Key words

tetrodotoxin - Diels-Alder reaction - hydroxylation - neighboring group participation - Overman rearrangement

References

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7

Tetrodotoxin possesses an α configured hydroxy group at
C-8, however, a β-hydroxy group was important in the synthesis of 11-deoxytetrodotoxin (2) and tetrodotoxin (1), as the β configuration was crucial for further transformation of the corresponding epoxide into an allylic alcohol, see ref. 2.

10

The structure of the major compound 14a was determined by comparison with a similar compound reported previously (see ref. 5); the structure of the minor product 14b was not verified because of the difficulties experienced in separating it from the major product.

13

The configurations of the bromo substituents in 22 have not been determined due to a lack of conclusive spectroscopic data. However, the structure of a similar dibromide was discussed earlier in ref. 4b.