Hydrastine is an

isoquinoline Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquin ...

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...

which was discovered in 1851 by Alfred P. Durand. Hydrolysis of hydrastine yields

hydrastinine Hydrastinine is a semisynthetic alkaloid from the hydrolysis of the alkaloid hydrastine, which was found naturally in small quantities in ''Hydrastis canadensis'' L. (Ranunculaceae). Hydrastinine was produced by oxidative splitting of hydrastine ...

, which was patented by

Bayer Bayer AG (, commonly pronounced ; ) is a German multinational corporation, multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of busi ...

as a

haemostatic An antihemorrhagic (antihæmorrhagic) agent is a substance that promotes hemostasis (stops bleeding). It may also be known as a hemostatic (also spelled haemostatic) agent. Antihemorrhagic agents used in medicine have various mechanisms of action: ...

drug during the 1910s. It is present in ''

Hydrastis canadensis ''For the magazine from West Virginia see Goldenseal (magazine)'' Goldenseal (''Hydrastis canadensis''), also called orangeroot or yellow puccoon, is a perennial herb in the buttercup family Ranunculaceae, native to North America. It may be dis ...

'' (thus the name) and other plants of the family

Ranunculaceae Ranunculaceae (buttercup or crowfoot family; Latin "little frog", from "frog") is a family of over 2,000 known species of flowering plants in 43 genera, distributed worldwide. The largest genera are ''Ranunculus'' (600 species), ''Delphinium' ...

Total synthesis

The first attempt for the

total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...

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 The Passerini reaction is a chemical reaction involving an isocyanide, an aldehyde (or ketone), and a carboxylic acid to form a α- acyloxy amide. This addition reaction is one of the oldest isocyanide-based multicomponent reactions (IMCR) and wa ...

to construct the lactonic amide intermediate 4. : Starting from a simple phenylbromide variant 1, alkylation reaction with lithium methylisocyanide gives the

isocyanide An isocyanide (also called isonitrile or carbylamine) is an organic compound with the functional group –. It is the isomer of the related nitrile (–C≡N), hence the prefix is ''isocyano''.IUPAC Goldboo''isocyanides''/ref> The organic fragme ...

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 Reductive amination (also known as reductive alkylation) is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is considered ...

reaction with

formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...

References

External links

* {{GABAergics Benzylisoquinoline alkaloids GABAA receptor antagonists Total synthesis 3-(5,6,7,8-tetrahydro-(1,3)dioxolo(4,5-g)isoquinolin-5-yl)-3H-2-benzofuran-1-ones

Total synthesis

See also

References

External links