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Scheme 4 Synthesis of the hydroxylated main metabolites.
3 K. M. Hold, N. S. Sirisoma, T. Ikeda, T. Narahashi and J. E. Casida,
Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 3826.
enolacetate is formed by refluxing thujone in isopropenyl acetate
under acidic conditions. In contrast to the literature, we observed
the 2,3-enol acetate 13a as the main product (13a :14a = 8 :2).
Therefore, we decided to utilize this mixture to obtain both the
2-hydroxy and the 4-hydroxy derivative at once. The inseparable
mixture was oxidized with 3-chloroperoxybenzoic acid. In both
cases epoxidation was preferred from the convex bottom face,
delivering after migration of the acetate group the desired diastereo-
isomers 15 and 16. The isomers were separated by chromatography,
and subsequently deprotected to yield the metabolites 4 and 5,
respectively. Deprotection of 15 was successful only under acidic
conditions, as regular basic hydrolysis led to decomposition of the
material.
¨
4 K. M. Hold, N. S. Sirisoma and J. E. Casida, Chem. Res. Toxicol., 2001,
14, 589–595.
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In summary, we have developed a concise route to a-thujone,
which relies on the functionalization of dimethylfulvene. The
synthesis allows for the facile incorporation of inexpensive isotopic
labels by utilizing d6-acetone as a starting material. Furthermore,
the three main metabolites of a-thujone were prepared.
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Notes and references
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2 D. W. Lachenmeier, J. Emmert, T. Kuballa and G. Sartor, Forensic 17 N. S. Sirisoma, K. M. Hold and J. E. Casida, J. Agric. Food Chem.,
¨
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2001, 49, 1915.
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