Hydrastine

Total synthesis

The first attempt for the total synthesis of hydrastine was reported by Sir Robert Robinson and co-workers in 1931. Following studies where the synthesis of the key lactonic amide intermediate (structure 4 in figure) was the most troublesome, the major breakthrough was achieved in 1981 when J. R. Falck and co-workers reported a four-step total synthesis of hydrastine from simple starting materials. The key step in the Falck synthesis was using a Passerini reaction to construct the lactonic amide intermediate 4. :[[File:Falck’s total synthesis of hydrastine, the mechanism of the Passerini reaction for synthesis of the key intermediate is also illustrated.png|class=skin-invert-image|Falck’s total synthesis of hydrastine, the mechanism of the Passerini reaction for synthesis of the key intermediate is also illustrated]] Starting from a simple phenylbromide variant 1, alkylation reaction with lithium methylisocyanide gives the isocyanide intermediate 2. Reacting isocyanide intermediate 2 with opianic acid 3 initiated the intramolecular Passerini reaction to give the key lactonic amide intermediate 4. The tetrahydro-isoquinolin ring was formed by first a ring-closure reaction under dehydration conditions using POCl3 and then a catalyzed hydrogenation using PtO2 as the catalyst. Finally, hydrastine was synthesized by installing the N-methyl group via reductive amination reaction with formaldehyde.

Biological action

Hydrastine acts as a convulsant in mice. It appears to do this by binding to bicuculline-sensitive GABAA receptors as a potent competitive antagonist. The action appears to be largely mediated by the (+) enantiomer (IC50 of 0.4µM), as (-)-hydrastine is 180 times less potent in regards to this effect.

References

References

1. (July 1862). "On Hydrastine, an Alkaloid Occurring in Hydrastis Canadensis.". J. Churchill.
2. (2006). "Römpp CD". Georg Thieme Verlag.
3. (1931). "XXXI.—A synthesis of hydrastine. Part I". J. Chem. Soc..
4. (1950). "Synthesis of Hydrastine". Nature.
5. (1950). "360. A new route to the phthalide-isoquinoline bases, and a synthesis of (–)-hydrastine". J. Chem. Soc..
6. (1981). "An intramolecular passerini reaction: Synthesis of hydrastine.". Tetrahedron Letters.
7. Huang, J. H.. (April 1990). "(+)-Hydrastine, a potent competitive antagonist at mammalian GABAA receptors". British Journal of Pharmacology.