Alkaloids galanthamine

Pyrrolophenanthridines and Related Alkaloids Lycorine and Related Alkaloids Galanthamine and Related Alkaloids Crinine and Related Alkaloids Tazettine and Related Alkaloids... 

HBr in acetic acid (just the solvent) is used to remove the benzyl ether protecting groups in this example, which forms part of a synthesis of the alkaloid galanthamine. 

The contribution of plants to modern medicine can hardly be overstated. Many plant natural products are used in medicine in their native, undomesticated form and the anti-Alzheimer s alkaloid galanthamine and the anticancer diterpenoid paclitaxel are additions to the inventory of plant-derived drugs obtained by direct isolation.101... 

It is difficult to judge to what extent apogalanthamine [Apotamine, (33)] and apogalanthamine monomethyl ether [Apochlorine, (34)], derivatives of the phen-anthridine alkaloid galanthamine (32), are used clinically in Russia. Both (33) and (34) are obtained from (32) by treatment with acids... 

With the preparation of racemic drhydroisocodeine (79), Chida reported a formal synthesis of morphine [52], The synthesis is based on a cascade of sequential Claisen rearrangements of an allylic vicinal diol derivative as key steps. The Claisen rearrangement protocol, as an efficient strategy for the installation of the C13 quaternary carbon, was successfully employed in the preparation of the Amaryllidaceae alkaloid galanthamine, published 1 year before the synthesis of dihydroisocodeinone [64],... 

In 2009, Magnus published an approach towards codeine that also constitutes a formal synthesis of the Amaryllidaceae alkaloid galanthamine by the preparation of narwedine (90) via a common precursor [17]. Key step in the reaction sequence is an o-p-phenolic oxidation resulting in the aforementioned common precursor of galanthamine and codeine. 

Acid-catalyzed hydrolysis of 88 afforded 89, which upon reductive amination conditions followed by treatment with methanesulfonic acid gave narwidine (90). Racemic narwidine is known to yield enantiomerically pure galanthamine - the corresponding allylic alcohol - by spontaneous resolution and subsequent L-selectride reduction [66]. Thus, the preparation of narwidine concludes the formal synthesis of the Amaryllidaceae alkaloid galanthamine. 

The alkaloid galanthamine (169) has been obtained from various Amaryllidaceae species including daffodils, the red spider lily Lycoris radiata) and the Caucasian snowdrop (Galanthus woronowii). Its effectiveness as a centrally acting, selective, reversible and competitive inhibitor of acetylcholinesterase has resulted in galanthamine being introduced into the clinic in both the USA and Europe for the symptomatic treatment of mild to moderate forms of Alzheimer s disease [57]. These and various other intriguing feamres of this alkaloid have prompted extensive synthetic studies of it [57]. 

For example, oxidation of the allylic alcohol 33 gave the a, -unsaturated aldehyde 34, used in a synthesis of the macrolactone bafilomycin Ai (6.30). Chemose-lective oxidation of allylic or benzylic alcohols can be achieved in the presence of aliphatic alcohols. Thus, in a synthesis of the alkaloid galanthamine, treatment of the diol 35 with manganese dioxide promoted selective oxidation of the benzylic alcohol to give the aldehyde 36 (6.31). 

The alkaloid (—)-galanthamine (a.k.a. galantamine, 1, Figure 1) has been obtained from a variety of plant sources including Caucasian snowdrops... 

Phytochemistry Leaves contain 0.35-1 %, bulbs 0.8-0.9 %, and roots 2.5 % total alkaloids. Galanthamine, pancratine, narwedine, hordenine, and licorine have been isolated from the leaves. Similarly, galanthamine, licorine, pancratine, tatsetine, and hippeastrine have been isolated from the bulbs (Yunusov 1981). 

The alkaloid (—)-galanthamine, isolated from Caucasian snow-drop Galanthus woronowii) and other plant sources, is a competitive and reversible acetylcholinesterase inhibitor and an allosteric modulator of the neural nicotine receptors for acetylcholine. Galanthamine hydrobromide (commercially available as Razadyne) finds application in the treatment of symptoms of Alzheimer s disease [101]. Since the isolation of galanthamine (256) from natural sources is quite expensive, several total syntheses have been developed to date. The synthetic strategy to galanthamine (256) developed by Cho et al. [102] includes a domino Stille/Diels-Alder reaction as the key step (Scheme 14.39). 

Based on the Amaryllidaceae alkaloid galanthamine, a biomimetic solid-phase synthesis of 2527 compounds was reported by Shair and coworkers (Figure 11.13) The core scaffold, initially prepared in several steps, was diversified by means of four successive reactions Mitsunobu reaction of the phenolic moiety with five primary alcohols, Michael addition of the a, 3-unsatnrated cyclohexenone with thiols, iV-acylation or A -alkylation of the cyclic secondary amine, and treatment of the ketone with hydrazines and hydroxylamines. Further evaluation of library constituents for their ability to block protein trafficking in the secretory pathway of mammalian cells led to the discovery of sercramine as a potent inhibitor of the VSVG-GFP protein movement from the Golgi apparatus to the plasma m brane. 

Elchhom J, Takada T, Klta Y, Zenk MH (1998) Biosynthesis of the Amaryllidaceae alkaloid galanthamine. Phytochemistry 49 1037... 

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