Cinchona alkaloids, about

Small chiral molecules. These CSPs were introduced by Pirkle about two decades ago [31, 32]. The original brush -phases included selectors that contained a chiral amino acid moiety carrying aromatic 7t-electron acceptor or tt-electron donor functionality attached to porous silica beads. In addition to the amino acids, a large variety of other chiral scaffolds such as 1,2-disubstituted cyclohexanes [33] and cinchona alkaloids [34] have also been used for the preparation of various brush CSPs. 

Catalytic asymmetric hydrogenation is a relatively developed process compared to other asymmetric processes practised today. Efforts in this direction have already been made. The first report in this respect is the use of Pd on natural silk for hydrogenating oximes and oxazolones with optical yields of about 36%. Izumi and Sachtler have shown that a Ni catalyst modified with (i ,.R)-tartaric acid can be used for the hydrogenation of methylacetoacetate to methyl-3-hydroxybutyrate. The group of Orito in Japan (1979) and Blaser and co-workers at Ciba-Geigy (1988) have reported the use of a cinchona alkaloid modified Pt/AlaO.i catalyst for the enantioselective hydrogenation of a-keto-esters such as methylpyruvate and ethylpyruvate to optically active (/f)-methylacetate and (7 )-ethylacetate. 

The mobility factor acknowledges the fact that organic molecules seem to move about on surfaces. For example, Blackmond and Augustine and associates have identified an induction period in the cinchona alkaloid modified... 

Interestingly, the molecular structure of the 2,7-naphthyl catalysts 39 and 40 markedly resembles that of the 1,3-phenyl catalysts 37 and 38, respectively the only difference is the distance between the two cinchona alkaloid units. The naphthalene linker is about 2.4 A longer than the benzene linker. The Park-Jew group proposed that the reason for the higher enantioselectivity of the 2,7-naphthyl catalyst was that the 2,7-naphthalene linker might confer a spatial benefit to form a more favorable conformation by decreasing the steric hindrance between the two cinchona units compared to that in the 1,3-benzene linker. 

Other Cinchona Alkaloids Dissolve about 2.5 g of sample in 60 mL of water contained in a separator, add 10 mL of 6 A ammonium hydroxide, extract the mixture successively with 30 mL and 20 mL of chloroform, and evaporate the combined chloroform extracts to dryness on a steam bath. Dissolve 1.5 g of the residue in 25 mL of alcohol dilute the solution with 50 mL of hot water add 1 A sulfuric acid (about 5 mL) until the solution is acid, using 2 drops of methyl red TS as the indicator and neutralize the excess acid with 1 A sodium hydroxide. Evaporate the solution to dryness on a steam bath,... 

Bauer and Untz analyzed a series of cinchona alkaloids by means of straight-phase HPLC (Fig.5.15). They found that the addition of 2.65 ml of water to 1 liter of the mobile phase (chloroform - isopropanol - diethylamine(940 57 l)), which corresponds to about 75% saturation, gave optimum separation, as regards resolution versus time of analysis. To obtain the correct percentage of water in the mobile phase, the water content present in the mixture was deter-ined by the Karl Fischer method, and water was then added to obtain a final concentration of 2.65 ml/1. 

The chemistry of cinchona alkaloids is more than just a collection of exotic organic compounds. It is also about stereochemistry of a privileged class of natural products and, in its widest sense, about ideas, reaction mechanism, supramolecular chemistry, biological and catalytic activity, and beyond. The fascination and challenge of the organic chemistry of cinchona alkaloids need never stop. 

Recently, by the ligand-accelerated osmium catalyzed asymmetric hydroxylation using a cinchona alkaloid derivative, the 22/ ,23/ -epimer was obtained as the major product of the oxidation (77). Thus, epibrassinolide may be ideal for practical use, and, therefore, is one of the most desirable brassinosteroids because of the ease with which it can be synthesized. This compound showed about one tenth the activity of brassinolide in Raphanus and tomato bioassay (5). In field trials, the activity of epibrassinolide was about the same as of brassinolide. Epibrassinolide is a natural sterol. This was confirmed by GC-MS analysis, which identified epibrassinolide, along with co-existing brassinolide, brassinone, and castasterone, from the bee pollen of the broad bean Vida faba obtained in China (72). 

But matters were really significantly improved by Chen et al.52 If one cinchona alkaloid works, what about the double cinchona alkaloid ligands that are used in the asymmetric dihydroxylation reactions Amazingly, these ligands work really well for desymmetrisations of anhydrides such as 230. Only 5% of catalyst is needed and they can be done at room temperature or 20 °C for better enantiomeric excess. Once again a range of anhydrides can be used 232-234. 

In view of these developments, one must be somewhat pessimistic about the future of cinchona alkaloids and other plant products in the treatment of malaria. Certainly the extensive researches on cinchona alkaloids offer little hope that an improved drug will be found in this field. The situation with respect to development of better antimalarials from other plant sources seems to be even less hopeful. 

The discussion about the possible formation of metalla-2-oxetanes in transition metal-mediated oxidation reactions began with the ground breaking work of Sharpless in the field of enantioselective dihydroxylation of olefins with osmium tetraoxide using cinchona alkaloids as ligands [6]. The transfer of the stereochemical information of the chiral ligand to the substrate was explained by Sharpless with a two-step mechanism for the addition reaction, which should occur rather than a concerted [3+2] addition as originally proposed [110] (Fig. 15). 

Of the various pharmaceuticals derived from plants, the Cinchona alkaloids are probably, by volume the largest market, with an estimated production of 300-500 metric tons a year of pure quinine (32) and quinidine (33). These alkaloids are extracted from the bark of Cinchona trees, which require about 10 years to mature before harvesting. Furthermore most of the plantations are in areas not easily accessible, often threatened by infections with Phytophthora cinnamomi. This leads to many uncertainties in planning of the production, and as a result alternative sources for the alkaloids are of interest. Various synthetic aproaches have been used (552) but are not of industrial interest. Therefore, interest in biotechnological approaches is large. Patents related to the production of quinoline alkaloids by means of plant cell cultures are summarized in Table XXVIII. 

With a year production of 300-500 tons (26), the Cinchona alkaloids (quinine 1 and quinidine 2) probably form one of the largest markets of fine chemicals derived from higher plants. They are extracted from stem and rootbark of Cinchona trees, containing 5-18Z of alkaloid, with an average of about 8X (27). Because of the high demand a number of attempts have been made to develop a commercial synthesis (28 and references cited therein) of the quinoline alkaloids. Although successful syntheses have been reported they could not be commercialized. 

Because of the value and the widespread use of Cinchona alkaloids, many attempts to produce alkaloids in plant tissue cultures and cell cultures from this group of plants have been made (Verpoorte et al., 1991). Trees require about 10 years before they can be harvested. Cell cultures of Cinchona ledg-eriana and C. succirubra produce largely cinchonine (67) and cinchonidine (68), although small quantities of quinine and quinidine were produced. Only small amounts of total alkaloids were produced (Ellis, 1988). 

The catalytic capacity of Cinchona alkaloids was exploited by DuPont chemists in the synthesis of enantiomers of Indoxacarb, a crop insecticide manufactured in racemic form at the time. Initially, Sharpless AD-mix-a and p were attempted for a direct hydrojqrlation of starting p-ketoester with about 50% ee outcome. To render the process suitable for scale up, tert-butyl hydroperoxide (TBHP) was used as an oxidant, with a catal5Aic amount of cinchonine (CN) to obtain the correct enantiomer (Scheme 15.22). ... 

Structurally similar acids, phthalic and m-benzoic exhibit levo rotation. Other studies show similar rotations when the cinchona alkaloids are used with various other diphenic acids. It has been suggested by Kuhn that a stereospecificity exists with these alkaloids in causing rotation of one phenyl group about the biphenyl bond leading to an unsymmetrical complex. Since no active phase (other than the original alkaloid) is isolable the system may be classified as a first order asymmetric transformation. 

The genus Cinchona (Rubiaceae) comprises about 25 species of tall, evergreen trees that grow in South America. The bark of these trees accumulates qumohue alkaloids that are, like camptotheciu, derived from tryptophan and secologaniu. Cinchona alkaloids are also found in the genus Remijia of the Rubiaceae family. 

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