6,7-dimethoxy-3-(6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5- g]isoquinolin-5-yl)-2-benzofuran-1(3 H)-one
C 21 H 21 N O 6
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Hydrastine is a natural alkaloid which was discovered in 1851 by Alfred P. Durand. Hydrolysis of hydrastine yields [1 ] hydrastinine, which was patented by Bayer as a haemostatic drug during the 1910s. [2 ]
It is naturally present in
(thus the name) and other plants of the Hydrastis canadensis ranunculaceae family.
Total synthesis [ edit ]
The first attempt for the
total synthesis of hydrastine was reported by Sir Robert Robinson and co-workers in 1931. Following studies, [3 ] [4 ] which were mostly troublesome for the synthesis of the key lactonic amide intermediate (structure 4 in Figure). The major breakthrough was achieved in 1981 when J. R. Falck and co-workers [5 ] reported a four-step total synthesis of hydrastine from simple starting materials. The key step in the Flack synthesis was using a [6 ] Passerini reaction to construct the lactonic amide intermediate 4.
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.
References [ edit ]
^ American Journal of Pharmacy, 1851: 112 .
^ Römpp CD, Georg Thieme Verlag, 2006 .
^ Hope, E.; Pyman, F. L.; Remfry, F. G. P.; Robinson, R., J. Chem. Soc. 1931, 236.
^ Haworth, R. D.; Pinder, A. R.; Robinson, R., Nature 1950, 165, 529.
^ Haworth, R. D.; Pinder, A. R., J. Chem. Soc. 1950, 1776.
^ Falck, J. R.; Manna, S., Tetrahedron Lett. 1981, 22, 619.
PAMs (abridged; see here for a full list) : α-EMTBL
Alcohols (e.g., ethanol)
Avermectins (e.g., ivermectin)
Barbiturates (e.g., phenobarbital)
Benzodiazepines (e.g., diazepam)
Bromide compounds (e.g., potassium bromide)
Carbamates (e.g., meprobamate)
Dihydroergolines (e.g., ergoloid (dihydroergotoxine))
Fenamates (e.g., mefenamic acid)
Flavonoids (e.g., apigenin, hispidulin)
Imidazoles (e.g., etomidate)
Kava constituents (e.g., kavain)
Neuroactive steroids (e.g., allopregnanolone, cholesterol)
Nonbenzodiazepines (e.g., β-carbolines (e.g., abecarnil), cyclopyrrolones (e.g., zopiclone), imidazopyridines (e.g., zolpidem), pyrazolopyrimidines (e.g., zaleplon))
Phenols (e.g., propofol)
Piperidinediones (e.g., glutethimide)
Pyrazolopyridines (e.g., etazolate)
Quinazolinones (e.g., methaqualone)
Skullcap constituents (e.g., baicalin)
Sulfonylalkanes (e.g., sulfonmethane (sulfonal))
Valerian constituents (e.g., valerenic acid)
Volatiles/ gases (e.g., chloral hydrate, chloroform, diethyl ether, paraldehyde, sevoflurane)
β-Lactams (e.g., penicillins, cephalosporins, carbapenems)
Fiproles (e.g., fipronil)
Flavonoids (e.g., amentoflavone, oroxylin A)
Fluoroquinolones (e.g., ciprofloxacin)
Iomazenil ( 123I)
Picrotoxin (i.e., picrotin and picrotoxinin)