Alkaloids, cinchona

Groger, D. Alkaloids derived from tryptophan and anthranilic acid. In Encyclopedia of Plant Physiology, New Series, Vol. 8, Secondary Plant Products (E. A. Bell, B. V. Gharlwood, eds.), pp. 128-159. Springer, Berlin-Heidelberg-New York 1980 Groger, D. Alkaloids derived from tryptophan. In Biochemistry of Alkaloids (K. Mothes, H. R. 

Schiitte, M. Luckner, eds.). Deutscher Verlag der Wissenschaften, Berlin 1985 Hutchinson, R. C. Biosynthetic studies of antitumor indole alkaloids. In Indole and Bio-genetically Related Alkaloids (J. D, Phillipson, M. H. Zenk, eds.), pp. 143-158. Academic Press, New York 1980 

The most important Chinchona alkaloids are quinoline derivatives. The quinoline nucleus of these compounds is linked at position 4 via a secondary alcoholic group to the so-called quinuclidine nucleus, a system of two piperidine rings with a common nitrogen atom and three common C-atoms. A number of differently substituted and isomeric alkaloids exist. Of special importance are the alkaloids quinine and quinidine. 

In addition to the quinoline alkaloids indole alkaloids occur which, like cinchon-amine (Fig. 263), carry the quinuclidine ring system in position 2. 

All Cinchona alkaloids used as chiral organocatalysts are polyfunctional organic compounds capable of making reactive adducts with the substrates in numerous possible ways that makes the analysis of the mechanism of generation of chirtality an ambiguous and extensive task that hindered research in this area. Nevertheless, recently in several publications the mechanism of the generation of chirality in the reactions catalyzed by cinchona alkaloids was studied computationally. 

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. 

Cinchonine and cinchonidine are also used as antimalarials while quinidine is also used as a cardiac depressant (antiarrythmic). 

Quinine alkaloids have quinoline nuclei but are considered to be derived biogenetically via strictosidine, corynantheal, and other intermediates (Fig. 

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A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

Alkylation of protected glycine derivatives is one method of a-amino acid synthesis (75). Asymmetric synthesis of a D-cx-amino acid from a protected glycine derivative by using a phase-transfer catalyst derived from the cinchona alkaloids (8) has been reported (76). 

Mixtures of cinchona alkaloids, known as totaquine, are easier to produce and have been employed in treatment. Totaquine has been standardized to contain a minimum of 15% quinine. 

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 ... 

As the re-introduction of mixtures of cinchona alkaloids for use in medicine has given rise to some discussion, a list of the principal papers on this subject is given. Several of these provide analyses of locally produced totaquina. Applezweig and Ronzone have described an ion exchange process for the preparation of totaquina. 

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. 

Stereoisomerism in the Cinchona Bases It was at first common practice to number the four asymmetric carbon atoms indicated in the general formula (I), 1, 2, 3 and 4, but this is now replaced by the more general system introduced by Rabe, who suggested the name ruban for (HI), which can be regarded as the parent substance of the natural cinchona alkaloids, and rubatoxan (IV) for that of the quinicines (quinatoxines). The formifiae, with notation, for ruban (III) and rubatoxan (IV) are shown below, and the general formula (I) for cinchona bases has been numbered in accordance with that scheme. 

It has already been shown that both the laevorotatory and dextrorotatory cinchona alkaloids on degradation yield scission products from the quinuclidine nucleus, which are structurally and optically identical, for example, meroquinenine, [a] -f- 27 6° d-/3-cincholoiponic acid. 

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. ... 

A) Natural dihydro-cinchona alkaloids and their epimerides, CH, CH, — CH,. CH,. 

In the following table the characters of the principal isomerides and other transformation products of the cinchona alkaloids are summarised and references are given to the chief papers dealing with them, and upon which the foregoing account is based. The capital letters in brackets printed after the names of the substances refer to the formulae and explanatory footnote on p. 449. 

The cinchona alkaloids on degradation break down into derivatives of (1) quinoline and (2) quinuclidine and the synthesis of any one of them involves the preparation of each of these two halves in a form suitable for combination. 

There are a number of other synthetic substances analogous with or approximating to the cinchona alkaloid structure which it is more convenient to deal with in discussing the correlation of chemical structure with pharmacological action in this group (p. 469). 

Babe s general formula (p. 443) for the cinchona alkaloids was published in 1908 and a partial synthesis of quinine was effected by Babe and Kindler in 1918, but a complete synthesis of this alkaloid did not become available until 1945 when Woodward and Doering described their ingenious process. 

The remaining minor cinchona alkaloids are described in the tables on page 466. 

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. 

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