Quinine and Cinchonine

Numerous new salts and additive compounds of cinchona alkaloids, and especially of quinine, have been described, of which only a few can be mentioned as examples quinine additive compounds with sulph-anilamide, t quinine salts of (+) and (—)-pantothenic acid, °( > quinine sulphamate and disulphamate, °( organo-mercury compounds of quinine and cinchonine such as quinine-monomercuric chloride. Various salts and combinations of quinine have also been protected by patent, e.g., ascorbates and nicotinates. 

The two alkaloids which have been most completely investigated are quinine and cinchonine. The scission products of both fall into two classes, viz., derivatives of quinoline and derivatives of a second heterocyclic ring system, formerly referred to as the second half of the... 

The relation of quinine and cinchonine to quinoline is shown by their oxidation products. As mentioned in connection with quinoline the alkaloid cinchonine when oxidized yields a mono-carboxy quinoline known as cinchoninic acid. Similarly quinine yields quininic acid which is a meth-oxy derivative of cinchoninic acid. 

The cinchona tree, from the bark of which these alkaloids are obtained, was originally found only on the eastern slope of the Andes in South America. The cultivation of this species, and other species of the same genus, was introduced into Java, India, Ceylon, Jamaica and Australia. At present the production of bark in Java is greater than in any other country. As early as 1639 the cinchona bark was introduced into Europe but it was not until 1792 that an impure alkaloid was isolated and a little later given the name quina. In 1820 this impure alkaloid was separated into two compounds named quinine and cinchonine. The bark contains about 3 per cent quinine combined with acids, tannic and quinic, from which it is set free by the action of lime. The free base is then extracted with petroleum ether or... 

Several optically active polymers of acrylates and methacrylates have been obtained by enantioselective polymerization of a racemic monomer initiated by a Grignard compound complexed with chiral reagent. Complexing agents for the polymerization of (K,S)-a-methylbenzyl methacrylate include chiral alcohols, such as quinine and cinchonine [63], (— )-sparteine and its derivatives [64-67], and other axially disymmetric biphenyl compounds [68,69]. Other racemic monomers used include (/ ,S)-a-methylbenzyl acrylate [70], (K,S)-l-phenylethyl acrylate, methacrylate and a-ethylacrylate [71], and 1,2-diphenylethylmethacrylate [72]. 

TTie cinchona tree produces four alkaloids that were, until recently, the prototypical molecules on which most untimu-larial drugs were based. TTiese alkaloids (Fig. 9-2) are the enantiomeric pair quinine and quinidine and their desmeth-oxy analogues, cinchonidine (for quinine) and cinchonine (for quinidine). (Unfortunately, the nomenclature for the two series of alkaloids is inconsistent.) Their numbering system is based on rubane. The stereochemistry differs at positions 8 and 9, with quinine and cinchonidine being S.R and quinidine (cinchonine) being R.S. Historically, quinine was the main treatment for malaria until the advent of World War II, when battle in areas where malaria was endemic led to the search for more effective agents. 

Quinine and Quinidine. Quinine has been used for "fevers" in South America since the 1600s. The pure alkaloids quinine and cinchonine were isolated in 1820. The stereoisomer, quinidine, is a more potent antimalarial, but it... 

For almost two centuries, the bark was used in medicine as a powder, extract, or infusion. In 1820 Pelletier and Caventou isolated quinine and cinchonine from cinchona, and the use of the alkaloids as such gained favor rapidly. Extensive and classic studies led to elucidation of the structure of quinine (Figure 2) (4) and to its total synthesis in 1944 (5). Cinchona contains 25 closely related alkaloids, of which the most important are quinine, quinidine, cinchonine, and cinchonidine. The average yield of alkaloid is about 6-7 %, of which one-half to two-thirds is quinine. It has been said that quinine owes its dominant position in the treatment of malaria only to the fact that it was the first alkaloid isolated from cinchona, and that there is little among the four major alkaloids to choose from in treating this disease (6). 

Cinchona alkaloids Quinine and cinchonine Partition Corasil II coated with Poly G-300 containing 1% diethylamine Heptane/ethanol (10 1)... 

Generally, the Cinchona alkaloids are found in the bark and leaves of Cinchona and Bemijia species. Recently, however, small amounts of quinine and cinchonine have been isolated from the heartwood of Cinchona ledgeriana Linn (I). 

Mthough by no means so complex as opium, cinchona bark contains a great number of substances quinine, cinchonine, quinidine, cinchomduie, aridtxc / quinic, quinotannic, and quinovic acids cinchona red, etc. Of these the most important are quinine and cinchonine. 

Asymmetric induction in Michael reactions. Wynberg and Helder have reported asymmetric syntheses of Michael adducts from inactive donors and methyl vinyl ketone in the presence of catalytic amounts of quinine and cinchonine. Enantiomeric ratios were affected by the solvent highest inductions were obtained in toluene and tetrachloromethane. Quinine and cinchonine favored different enantiomers of the adduct. The enantiomeric excess was determined in one case from PMR spectroscopy to be 68%. 

The 2 -hydroxy derivatives of quinine and cinchonine have been studied for antimalarial activity by several investigators. Both exhibit activity, but only one-fourth or less than that of the parent drugs (82-84). The activities of the other metabolic products have been assessed only superficially. At present, however, there is no indication that any metabolite of the four major cinchona alkaloids has enhanced antimalarial activity or is even as active as its parent drug. 

Quinine has long been known to exert a weak curare-hke action. Rosen-stein (102), applying the premise that onium ions are responsible for curariform activity, showed that quaternary derivatives of quinine and cinchonine have lissive activity. Harvey (103) examined quinine methochloride extensively and found it to be effective orally and to produce in cats a sequence of events similar to that produced by curare. A number of quaternary derivatives of the cinchona alkaloids have been evaluated as curarizing agents the results are summarized in Table 4. 

Cinchona preparations were introduced into medical use in Europe in the early seventeenth century, and were popularized through the efforts of the wife of the then Spanish Viceroy of Peru, the Countess of Chinchon, who in 1638 was successfully treated for malaria throu administration of the hitherto little known remedy. Almost two hundred years later, one of the most intensive chemical investigations of the nineteenth century began, with the isolation of a crude mixture of crystalline alkaloids from the bark by Gomes in Portugal in 1810, and of pure quinine and cinchonine by Pelletier and Caventou in 1820 (3). Subsequently, upwards of two dozen further bases have been isolated from Cinchona and Bemijia species of these only quinidine (van Hejningen, 4) and cinchonidine (Winckler, 5) need be mentioned here. 

Metabdic Reactions. Animal tissues appear to contain an enzyme system which catalyzes the oxidation of the cinchona alkaloids. A number of oxidation products is formed of which the 2 -hydroxy derivatives of quinine and cinchonine have been isolated and identified (143, 144). 

Full details are now available of the application of the L-proline-derived pyrrolidine (22) as ligand in the asymmetric addition to aldehydes of alkyl-lithiums (45—95% optical yields) and dialkylmagnesiums (22—92% optical yields). Modification of lithium (and sodium) tetra-alkylaluminates with the chiral amino-alcohols (-)-N-methylephedrine (13), quinine, and cinchonine (Scheme 10) produces reagents (23) that have been shown to give asymmetric alkyl transfer... 

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