Chemistry:Hydrastine

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Hydrastine is an isoquinoline alkaloid which was discovered in 1851 by Alfred P. Durand.[1] Nitric acid induced hydrolysis of hydrastine yields hydrastinine, which was patented by Bayer as a haemostatic drug in the early 1900s.[2] It is present in Hydrastis canadensis (thus the name) and other plants of the family Ranunculaceae.

Total synthesis

The first attempt for the total synthesis of hydrastine was reported by Sir Robert Robinson and co-workers[3] in 1931. Following studies[4][5] 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[6] 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.

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.[7]

See also

References

  1. ↑ "On Hydrastine, an Alkaloid Occurring in Hydrastis Canadensis.". Pharmaceutical Journal: A Weekly Record of Pharmacy and Allied Sciences (J. Churchill): 547–. July 1862. https://books.google.com/books?id=IusKAAAAYAAJ&pg=PA547. 
  2. ↑ Römpp CD, Georg Thieme Verlag, 2006 
  3. ↑ "XXXI.—A synthesis of hydrastine. Part I". J. Chem. Soc.: 236–247. 1931. doi:10.1039/JR9310000236. ISSN 0368-1769. 
  4. ↑ "Synthesis of Hydrastine". Nature 165 (4196): 529. 1950. doi:10.1038/165529a0. ISSN 0028-0836. Bibcode: 1950Natur.165..529H. 
  5. ↑ "360. A new route to the phthalide-isoquinoline bases, and a synthesis of (–)-hydrastine". J. Chem. Soc.: 1776–1780. 1950. doi:10.1039/JR9500001776. ISSN 0368-1769. 
  6. ↑ "An intramolecular passerini reaction: Synthesis of hydrastine.". Tetrahedron Letters 22 (7): 619–620. 1981. doi:10.1016/S0040-4039(01)92504-3. ISSN 0040-4039. 
  7. ↑ Huang, J. H.; Johnston, G. A. (April 1990). "(+)-Hydrastine, a potent competitive antagonist at mammalian GABAA receptors". British Journal of Pharmacology 99 (4): 727–730. doi:10.1111/j.1476-5381.1990.tb12997.x. ISSN 0007-1188. PMID 2163278. PMC 1917537. https://pubmed.ncbi.nlm.nih.gov/2163278. 

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