Cinchona quinidine

QuinidJne. Quinidine, an alkaloid obtained from cinchona bark (Sinchona sp.), is the dextrorotatory stereoisomer of quinine [130-95-0] (see Alkaloids). The first use of quinidine for the treatment of atrial fibrillation was reported in 1918 (12). The sulfate, gluconate, and polygalacturonate salts are used in clinical practice. The dmg is given mainly by the oral (po) route, rarely by the intravenous (iv) route of adniinistration. It is the most frequentiy prescribed po antiarrhythmic agent in the United States. The clinical uses of quinidine include suppression of atrial and ventricular extrasystoles and serious ventricular arrhythmias (1 3). 

The disadvantage in war periods of relying on a single source of supply for an essential commodity became evident when Java was invaded by the Japanese in March 1942, the world being thereby deprived of about 90 per cent, of its customary supply of cinchona bark. Quinine was ther still considered an indispensable drug for the treatment of malaria an<3 its use had to be restricted to that purpose stocks of quinidine wew similarly reserved for use in cardiac disease, In efforts to deal with th<... 

The cinchona alkaloids of practical importance are quinine, quinidine, cinchonine and cinchonidine, but, in addition, over twenty others have been isolated from cinchona and cuprea species. Their names and formulae are as follows ... 

Cmchonine, C19H22ON2. This alkaloid is usually present in cinchona and cuprea barks. One of the best sources is Cinchona micrantha bark. It occurs in the crude quinine sulphate mother liquors. The mixed alkaloids recovered from these may be extracted with ether to remove quinidine and cinchonidine and the insoluble residue boiled with successive small quantities of alcohol, from which cinchonine crystallises on cooling. The crude alkaloid is neutralised with dilute sulphuric acid and the sulphate recrystallised from boiling water. Cinchonine so prepared contains quinidine, from which it may be freed by crystallisation from boiling alcohol until it ceases to exhibit fluorescence in dilute sulphuric acid. It will then still contain 10 to 15 per cent, of dihydrocinchonine, which may be removed by reprecipitation as the cuprichloride, B. 2HC1. CuClj, or by the simpler mercuric acetate process of Thron and Dirscherl. ... 

These changes have been experimentally demonstrated only for quinine and quinidine, but in view of the optical identity of the quinuclidine degradation products from the principal cinchona alkaloids, it may be assumed that in all of them the total dextrorotatory effect at C and C is made up of a dextrorotatory effect at C exceeding a laevorotatory effect at C. ... 

As found in commerce, the cinchona alkaloids are not necessarily pure quinidine, for example, may contain up to 30 per cent, of dihydroquinidine. Working with carefully pmdfied specimens of the four chief cinchona alkaloids and their dihydro-derivatives, Buttle, Henry and Trevan found the results recorded in the table (p. 471) in tests with malaria in canaries. The figures in brackets represent the dose of quinine necessary to produce the same degree of protection as unit dose of the alkaloid named. To the results are also added the data found later by the same authors, with Solomon and Gibbs, for some of the transformation products (p. 449) of quinine and quinidine. The Roman numeral at the head of each column refers to the type formula on p. 470. 

On these results the primary cinchona alkaloids and their dihydroderivatives arrange themselves in the following descending order of activity (1) dihydroquinine, (2) quinine, (3) dihydroquinidine, (4) cincho-nidine and quinidine, (5) cinchonine, dihydrocinchonidine and dihydrocinchonine. 

Of the other cinchona bases, the dextrorotatory forms cinchonine and quinidine have been used as anti-malarial drugs in cases of idiosyncrasy to quinine, a subject to which Dawson has given much attention. Quinidine is used to eontrol auricular fibrillation, and its value for this purpose in comparison with dihydroquinidine has been investigated by several workers. Dawes has recently devised a method of testing... 

Azirines can be prepared in optically enriched form by the asymmetric Neber reaction mediated by Cinchona alkaloids. Thus, ketoxime tosylates 173, derived from 3-oxocarhoxylic esters, are converted to the azirine carboxylic esters 174 in the presence of a large excess of potassium carbonate and a catalytic amount of quinidine. The asymmetric bias is believed to be conferred on the substrate by strong hydrogen bonding via the catalyst hydroxyl group <96JA8491>. 

Interestingly, certain chiral tertiary bases, viz., the Cinchona alkaloids, result in an asymmetric 1,3-elimination to give enantiomerically enriched azirine esters 29 (Scheme 15). The best results were obtained with quinidine in toluene as the solvent at a rather high dilution (2 mg mL ) at 0 °C. In an alcoholic solvent no asymmetric conversion was observed. It is of importance to note that the pseudoenantiomers of the alkaloid bases gave opposite antipodes of the azirine ester, whereby quinidine leads to the predominant formation of the (k)-enan-tiomer (ee = -80%). To explain this asymmetric Neber reaction, it is suggested... 

Fig. 3 Structiu-es of Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) transformed into their corresponding 1-N-oxide derivatives [34]...

Figure 3.59. Chiral quats derived from cinchona alkaloids R = H, derived from cinchonine, or MeO, derived from quinidine a and b are diastereomers aminoalcohol parts are enantiomeric.

Both quinine and dihydroquinine favored the required (S)-enantiomer. A small ee difference of the product might be due to inconsistent purity of the naturally obtained cinchona alkaloids. It was noted that quinidine (the pseudo-enantiomer of quinine) gave the (R)-enantiomer with a similar 55% ee. Since quinine was... 

The first attempt to effect the asymmetric cw-dihydroxylation of olefins with osmium tetroxide was reported in 1980 by Hentges and Sharpless.54 Taking into consideration that the rate of osmium(VI) ester formation can be accelerated by nucleophilic ligands such as pyridine, Hentges and Sharpless used 1-2-(2-menthyl)-pyridine as a chiral ligand. However, the diols obtained in this way were of low enantiomeric excess (3-18% ee only). The low ee was attributed to the instability of the osmium tetroxide chiral pyridine complexes. As a result, the naturally occurring cinchona alkaloids quinine and quinidine were derived to dihydroquinine and dihydroquinidine acetate and were selected as chiral... 

Wynberg3 has also effected stereoselective addition of (C2H5)2Zn to aryl aldehydes using cinchona alkaloids, particularly quinine and quinidine, which result in (R)- and (S)-alcohols in excess, respectively. The highest enantiomeric excess, 92% ee, was observed with o-ethoxybenzaldehyde catalyzed by quinine. 

The structures of quinine, cinchonidine, quinidine, and cinchonine are shown in Figure 3. Other workers (16,17) have discussed these alkaloids and their use as catalysts in some detail. An excellent discussion of cinchona-alkaloid-catalyzed reactions prior to 1968 was given by Pracejus (18). In this section we discuss only four aspects of these reactions. 

These reactions, performed many times, show, in addition to the reversal of the absolute configuration of the product with the change in the configuration at C-8 and C-9 of the alkaloids, a small but reproducible difference in the e.e. of the product. It is evident that the diastereomeric nature of quinine vs. quinidine and cinchonidine vs. cinchonine expresses itself via small but important energy differences in the best fits of the transition states. Noteworthy in this respect is the fine work of Kobayashi (20), who observed larger differences (in the e.e. s of products) when the diastereomeric cinchona alkaloids were used as catalysts after having been copolymerized with acrylonitrile (presumably via the vinyl side chain of the alkaloids). 

FIGURE 1.1 Chemistry and stereochemistry of the native cinchona alkaloids quinine, quinidine, cmchonidme, and cinchonine as well as their corresponding C9-epimeric compounds. 

The first silica-supported CSP with a cinchona alkaloid-derived chromatographic ligand was described by Rosini et al. [20]. The native cinchona alkaloids quinine and quinidine were immobilized via a spacer at the vinyl group of the quinuclidine ring. A number of distinct cinchona alkaloid-based CSPs were subsequently developed by various groups, including derivatives with free C9-hydroxyl group [17,21-27] or esterified C9-hydroxyl [28,29]. All of these CSPs suffered from low enantiose-lectivities, narrow application spectra, and partly limited stability (e.g., acetylated phases). 

FIGURE 1.2 Structure and stereochemistry of commercially available cinchona alkaloid CSPs, marketed under trade name CHIRALPAK by chiral technologies europe. QN denotes quinine- and QD quinidine-derived and AX refers to their anion-exchanger capabilities vide infra). 

It is also worthwhile to outline at this place the immobilization procedure that was used for the preparation of type I CSPs A bifunctional linker with a terminal isocyanate on one side and a triethoxysilyl group on the other end (3-isocyanatopropyl triethoxysilane) was reacted with the native cinchona alkaloids quinine and quinidine and subsequently the resultant carbamate derivative in a second step with silica [30], Remaining silanols have been capped with silane reagents, yet, are less detrimental for acidic solutes because of the repulsive nature of such electrostatic interactions. CSPs prepared in such a way lack the hydrophobic basic layer of the thiol-silica-based CSPs mentioned earlier, which may be advantageous for the separation of certain analytes. 

Buffered mobile phases are inherently used to adjust and control the adsorption-desorption process. These CSPs are especially useful for the separation of very polar charged analytes, such as sulphonic acids. Chiral anion-exchangers are the most successful CSPs and among them the cinchona alkaloids, quinine and quinidine (Figure... 

Quinidine (155) and dihydroquinidine (157) have been used for a long time for the treatment of cardiac antiarrythmia. These cinchona alkaloids (and their analogues in the quinine and cinchonidine family) are metabolized in animals and humans [234,235] to give, among several products, the corresponding (3S)-3-hydroxy derivatives (156,159) [236-240], which were shown to be pharmaco-... 

Quinine/Quinidine-Based Catalysts (e.g., Cinchona Alkaloids). 265... 

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