Alkaloid cinchonidine/cinchonine

Keywords Alkaloids quinidine cinchona alkaloids cinchonidine cinchonine quinine... 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

The pseudoenantiomeric catalysts derived from the alkaloid pairs cinchonine/cinchonidine and quinidine/quinine (1/4 or 2/5, respectively) are related as diastereomers but are enantiomeric with respect to the front working-face defined by carbons 8 and 9. 

The other two cinchona alkaloids, cinchonidine and quinidine, are stereo-isomers of cinchonine and quinine. 

Platinum catalysts modified with members of the cinchona alkaloids are effective enantioselective catEilysts for the hydrogenation of a keto esters giving the chiral a hydroxy esters with ee s as high as 95%. >72 of the cinchona alkaloids, cinchonidine (30) and cinchonine (31) appear to be more effective than quinine (32) and quinidine (33). With cinchonidine the (R) lactate, 34, is... 

Conversely (Scheme 9), the threo aminoepoxides 96 and 97 were obtained from diphenylsulfoniumlepidylide (93) and iV-acetylmero-quinene aldehyde (55) (17). The ylide was formed from 4-methyl-sulfonylquinoline (91) and methylenediphenylsulfurane (92) and was treated with aldehyde 55 to give a mixture of the threo iV-acetyl epoxides 94 and 95. Removal of the. -acetyl group led to the aminoepoxides 96 and 97 which underwent intramolecular cyclization to give a mixture of the erythro alkaloids cinchonidine (98) and cinchonine (99). 

Cinchona alkaloids have been used since the sixteenth century to treat malaria. It is well established that quinine, quinidine, cinchonidine, cinchonine, and their dihydro derivatives exhibit similar antimalarial activity (50, 51). Quinine owes its favored position in malaria therapy to its earlier isolation. Its use is becoming increasingly important in treating infections caused by strains of Plasmodium falciparum which are resistant to all other antimalarial drugs (52). However, some of the... 

Whereas most alkaloids appear to be specifically directed towards animals, others show a broader activity spectrum. For example, alkaloids with marked antibacterial activities include ajmaline, berberine, boldine, cinchonidine, cinchonine, harmaline, harmine, lobeline, narcotine, norharman, quinidine, quinine, sanguinarine, strychnine and yohimbine (see reviews [5, 73, 96]. Only the benzophenanthridine alkaloid... 

The simplest cinchona alkaloids, cinchonidine and its 10,11-dihydro-derivative, have been shown by D-tracer studies and by NEXAFS and ATR-IR spectroscopy to adsorb by interaction of the quinoline moiety with the platinum surface. Mechanistic studies have established that a site exists adjacent to the open-3 conformation of adsorbed cinchonidine at which pyruvate ester can undergo selective enantioface adsorption. Hydrogenation of the preferred enantioface results in preferential formation of one enantiomer of the product, methyl lactate, MeC H(OH)COOMe. Pt modified by cinchonidine provides R-lactate preferentially, whereas the near enantiomer cinchonine provides 5-lactate in excess. Values of the enantiomeric excess of 75% can be obtained without optimisation, and of 98% under special conditions. In solution, conditions that achieve enantioselectivity normally promote the reaction rate by a factor of 2 to 100 depending on conditions. ... 

The alkaloids of the cinchona bark are natural products containing a quinoline structure [111]. Examples are the diastereoisomeric pairs quinine/quinidine and cinchonidine/cinchonine 108 and 109 in which a 4-methylquinoline unit is bonded to a vinyl-substituted quinuclidine system (1-azabi-cyclo[2.2.2]octane). Camptothecin 110, a highly toxic polycyclic quinoline alkaloid, was isolated from the stem wood of the Chinese tree Camphoteca acuminata (Nyssaceae). 

Table 5.4. The effect of the structure of modifier alkaloids, cinchonidine (Cnd) and cinchonine (Cn), on the enantioselective hydrogenation of ethyl pyruvate into ethyl lactate over 5% Pt-alumina.

Once the imprinting system has been devised to yield favorable monomer-template complexation and the necessary porosity, the preparation of monolithic polymer rods for HPLC is relatively simple. The general protocol detailed below uses an in situ polymerization method developed by Frechet and Svec [4]. This technique was used by Matsui in the preparation of MIP monolith rods for HPLC separation of antimalarial cinchona alkaloids, ( ) cinchonidine and (+) cinchonine, as well as the structural analogues quinidine and quinine [45]. 

Cinchona succirubra (Rubiaceae) is a tall tree that grows wild in the Andes of Peru and Brazil. It is cultivated in Java and Sumatra. The bark contains 5%-8% total alkaloids. The major alkaloid, quinine, has been used as an antimalarial agent. Cinchonidine, cinchonine, and quinidine have also been obtained. 

The species of cinchona officially recognised in the B.P.C. were C. cali-say a Weddell, C. ledgeriana Moens, C. officinalis Linn., C. succiruhra Pavon, and hybrids of either of the last two species with either of the first two. They contain from 5 to 10 per cent of total alkaloids, mainly quinine, cinchonidine, cinchonine and quinidine. 

The sum of the percentages of quinine, cinchonidine cinchonine and quinidine gives the percentage of crystallisable alkaloids. 

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 ... 

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... 

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. ... 

Detection. Cinchonine is sparingly soluble in all ordinary solvents, is not fluorescent in dilute sulphuric acid, is dextrorotatory, forms a soluble tartrate and hydriodide and does not give the thalleioquin reaction. Hesse s homocinchonine has been shown to be impure cinchonine. Cinchonidine, C49H22ON2. This alkaloid occurs in most varieties of cinchona bark, but especially in C. succiruhra. 

The ethereal solution of crude quinidine and cinchonidine, obtained as described under cinchonine, is shaken with dilute hydrochloric acid, the excess acid neutralised with ammonia and sodium potassium tartrate added. The base is recovered from the precipitated tartrate by dissolving the latter in dilute acid and pouring the filtered solution in a thin stream, slowly and with constant stirring, into excess of ammonia solution. The crude alkaloid is converted into the neutral sulphate, and this recrystallised... 

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