Quinine types

Isoprenoids are one of the largest classes of natural products that comprise at least 35,000 reported members (48). Many of these compounds play crucial roles in human metabolism as hormones, vitamins (vitamins A, D, E and K), quinine-type cofactors of respiratory chain enzymes (ubiquinone), membrane constituents, and functionally important side chains of signal cascade proteins (Fig. 11). Chlorophyll (17, Fig. 2) and heme a (18) have isoprenoid side chains. 

Several covalently bound coenzymes, including pyruvoyl, methylidine imidazolone, topaquinone, and tryptophan trypto-phyl quinine-type prosthetic groups are generated by posttrans-lational modification (66). 

Genetic defects of molybdopterin biosynthesis (Fig. 3) also result in severe neurologic and developmental deflcits (74). Genetic defects in the biosynthesis of the quinine-type coenzyme QIO (97, Fig. 11) can result in encephalopathy, myopathy, and renal disease (53). 

The reported effect of artemisinin on systemic lupus erythematosus (196)is intriguing, given the history of use of quinine-type anti-malarials in this disease. 

The European Pharmacopoeia requires a minimum of 6.5% total alkaloids of which 30-60% are of the quinine type (comprising more than 30 compounds). The alkaloids are mainly bound to quinic acid. The most important are two pairs of stereoisomeric quinoline alkaloids, quinine and quinidine, and their demethoxy derivatives cinchonidine and cinchonine. The content of quinine varies in the different species. It is highest in C. led erima, where it constitutes approx. 30% of the total content of alkaloids. In the species C. pubescens the content of quinine is much lower instead the stereoisomers cinchonine and cinchonidine dominate with approx. 50% of the total content. 

K. Gyimesi-Forras, A. Leitner, K. Akasaka and W. Lindner, Comparative study on the use of ortho-phthalaldehyde, naphthalene-2,3-dicarboal-dehyde and anthracene-2,3-dicarboaldehyde reagents for a-amino acids followed by the enantiomer separation of the formed isoindolin-l-one derivatives using quinine-type chiral stationary phases,/. Chromatogr., A, 2005, 1083, 80-88. 

It has long been known that quaternary ammonium salts can exert a curare-like action, and in recent years much attention has been given to the synthesis and pharmacological testing of such products work on this subject up to 1936 has been reviewed by Ing, and more recently a theoretical discussion of the relationship between structure and action in drugs of this type has been provided by Holmes, Jenden and Taylor.Chase, Lehmann and Yonkmann have compared the action of quaternary salts of quinine with that of -erythroidine hydrochloride and of dihydro- -erythroidine hydrobromide. Quinine ethochloride shows marked curariform action of short duration. ... 

For the separate determination of the four principal components in the total alkaloids, the method in general use is based on the isolation of quinine and cinchonidine as d-tartrates, of cinchonine as the base in virtue of its sparing solubility in ether, and of quinidine as the hydriodide. Types of this method have been described by Chick, and special modifications designed for use in the analysis of totaquina are given in the British Pharmacopoeia 1932 and in a special report by the Malaria Commission of the League of Nations. Goodson and Henry have critically examined this process and shown that, with care, it gives satisfactory... 

In the ease of the dextrorotatory pair, einchonine and quinidine, these hydroxydihydro-bases may lose a molecule of water between the two. CHOH. groups at positions 9 and 10 with the formation of ether oxides, represented by formula (C) of which there should be a pair of stereoiso-merides for eaeh alkaloid. This type of compound has not been obtained from the laevorotatory bases, einchonidine and quinine. 

The important role played by the quinicines (rubatoxanones, quina-toxines) in the syntheses of the dihydrocinchona alkaloids and the possibility that such substances might be used for the preparation of products approaching quinine in therapeutical interest, has led to the production of a large number of quinolyl ketones of various types and the corresponding secondary alcohols, and other derivatives obtainable from them, of which mention may be made of Rubtzov s syntheses of several isomerides of dihydroquinine. ... 

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. 

Many racemic mixtures can be separated by ordinary reverse phase columns by adding a suitable chiral reagent to the mobile phase. If the material is adsorbed strongly on the stationary phase then selectivity will reside in the stationary phase, if the reagent is predominantly in the mobile phase then the chiral selectivity will remain in the mobile phase. Examples of some suitable additives are camphor sulphonic acid (10) and quinine (11). Chiral selectivity can also be achieved by bonding chirally selective compounds to silica in much the same way as a reverse phase. A example of this type of chiral stationary phase is afforded by the cyclodextrins. 

Only a few other cobalt complexes of the type covered in this review (and therefore excluding, for example, the cobalt carbonyls) have been reported to act as catalysts for homogeneous hydrogenation. The complex Co(DMG)2 will catalyze the hydrogenation of benzil (PhCOCOPh) to benzoin (PhCHOHCOPh). When this reaction is carried out in the presence of quinine, the product shows optical activity. The degree of optical purity varies with the nature of the solvent and reaches a maximum of 61.5% in benzene. It was concluded that asymmetric synthesis occurred via the formation of an organocobalt complex in which quinine was coordinated in the trans position (133). Both Co(DMG)2 and cobalamin-cobalt(II) in methanol will catalyze the following reductive methylations ... 

The cobalt complex 37 was used in combination with quinine as a chiral coordinating base to hydrogenate l,2-diphenyl-2-propene-l-one in 49% ee (Fig. 29.22) [50]. However, no further studies of this type of catalyst were reported. 

Although the cinchonan carbamate-based CSPs are of primary interest for the separation of chiral acids, it needs to be stressed that the scope of application is, however, not restricted to chiral acids. A few reports in the literature deal with the separation of the enantiomers of neutral and weakly basic chiral compounds, respectively, on quinine carbamate-type CSPs [50-54]. Both RP and NP modes may be applicable. 

Replacement of the carbamate group with isosteric functionalities such as an IV-methyl carbamate, urea, or amide group clearly confirmed the favorable qualities of the carbamate group [57], While the introduction of a urea group, as in case of iV-9-(tert-butylcarbamoyl)-9-desoxy-9-aminoquinine selector, instead of carbamate functionality turned out to be virtually equivalent in terms of enantiorecognition capabilities [57,58], the enantiomer separation potential was severely lost on iV-methylation of the carbamate group, like in 0-9-(N-me hy -N-tert-butylcarbamoyl)quinine [32,58], or its replacement by an amide, such as in case of Af-9-(pivaloyl)-9-desoxy-9-aminoquinine selector [57,58], For example, enantioselectivities dropped for DNB-alanine from 8.1 for the carbamate-type CSP, over 6.6 for thein-ea-type CSP, to 1.7 for the amide-type CSP, and 1.3 for the A -methyl... 

Carbamate-linked (epi) Quinine-calixarene Hybrid-type CSPs... 

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. 

The calorimetric binding isotherms of the carbamoylated quinine and quinidine selectors clearly reveal that the heats released upon binding are strongly different for 5- and R-enantiomers of DNB-Leu, which is commensurate with the remarkable enantioselective molecular recognition capability of these selectors (Figure 1.14a,b). As can be seen from Table 1.4, the binding constants for R- and 5-enantiomers differ by about one order of magnitude in case of the carbamate-type selectors. Furthermore,... 

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