Cinchona alkaloids quinine

Cinchona alkaloids have been used as drugs for the treatment of several diseases. Quinine is very popular as an antimalarial drug against the erythrocyte stage of the parasite [34]. Recently, Shibuya et al. (2003) reported the microbial transformation of four Cinchona alkaloids (quinine, quini-dine, cinchonidine, and cinchonine) by endophytic fungi isolated from Cin-... 

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

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

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... 

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). 

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... 

The Soos group, in 2005, prepared the first thiourea derivatives from the cinchona alkaloids quinine QN (8S, 9R-121), dihydroquinidine DHQD (8S, 9S-122), C9-epi-QN (8S, 9P-123), and quinidine QD (SR, 9R-124) via an experimentally simple one-step protocol with epimerization at the C9-position of the alkaloid starting material (Figure 6.39) [278]. The catalytic efficiency of these new thiourea derivatives and also of unmodified QN and C9-epi-QN was evaluated in the enan-tioselective Michael addition [149-152] of nitromethane to the simple model chal-cone 1,3-diphenyl-propenone resulting in adduct 1 in Scheme 6.119. After 99h reaction time at 25 °C in toluene and at 10 mol% catalyst loading QN turned out to be a poor catalyst (4% yield/42% ee (S)-adduct) and C9-epi-QN even failed to accelerate the screening reaction. In contrast, the C9-modified cinchona alkaloid... 

V. Cinchona alkaloids Quinine (as suiphate) 600 mg/day, oral TDS or 10 mg/kg with 5% glucose IV infusion TDS (for cerebral malaria) for 7 days... 

Following the development of synthetic antimalarial agents, such as chloroquine and mefloquine, the use of Cinchona alkaloid quinine declined. However, with the emergence of chloroquine-resistant and multiple-drug-resistant strains of malarial parasites, its use has become firmly reestablished. Quinine is the drug of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum. In the U.S., the related alkaloid quinidine is recommended because of its wide availability and use as an antiarrhythmic agent. In many clinics in the tropics, quinine is the only effective treatment for severe malaria unfortunately, decreasing sensitivity of P. falciparum to quinine has already been reported from Southeast Asia. 

Alkaloids containing quinoline as the principal nucleus include anemonine from Anemone tha-lietroides, galipine from Angostura bark (Galipea officinalis), and the cinchona alkaloids, quinine, quinidine, cinchonine, and cinchonidine (Figure 11.8). 

Phase-transfer catalysis has been widely been used for asymmetric epoxidation of enones [100]. This catalytic reaction was pioneered by Wynberg et al., who used mainly the chiral and pseudo-enantiomeric quaternary ammonium salts 66 and 67, derived from the cinchona alkaloids quinine and quinidine, respectively [101-105],... 

The starting materials for the synthesis (few steps) of these phase-transfer catalysts, i.e. the cinchona alkaloids (—)-quinine, (+)-quinidine, (+)-cinchonine and (—)-cinchonidine, are commercially available in large quantities. 

Cinchona alkaloids Quinine and cinchonine Partition Corasil II coated with Poly G-300 containing 1% diethylamine Heptane/ethanol (10 1)... 

Quinine [1, (8a,9/Q-6 -methoxy-9-cinchonanol] is the most familiar of the cinchona alkaloids. Quinine has been used as a catalyst in the enantioselective addition of zinc alkyls to aldehydes (together with its acetic ester) (Section D. 1.3.1.4.), for the addition of thiols and selenols to activated double-bond systems (Sections D.2.1., D.5. and D.6.), and as a chiral ligand for cobalt catalysts in the hydrogenation of 1,2-diketones to a-hydroxycarbonyl compounds (Section D.2.3.1.) and C-C double bonds (Section D.2.5.1.2.2.). Quinine and quinidine can also be incorporated into more complex systems (forming ethers and esters with its hydroxy function) where they may act as a chiral leaving group. This technique has been applied to the synthesis of chiral binaphthols (Section D.1.1.2.2.). 

These dose-related symptoms are characteristic adverse effects of cinchona alkaloids (quinine, quinidine) and are termed cinchonism. The answer is (D). 

A special subclass of brush-type chiral stationary phases are the ion-exchange CSPs developed by Lammerhofer and Lindner (1996). By introducing an additional ionic moiety, a strong interaction between the selector and the selectand can be achieved. The first commercial available phases are based on the Cinchona alkaloids Quinine and Quinidine with an additional weak anion-exchange function offering good separation possibilities for chiral acids. A strong dependence of the capacity from the counter ion of the mobile phase could be demonstrated by Arnell (2009). 

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. 

After Takemoto s studies, Bartoli and Melchiorre have successfully used 3-ketoesters and 1,3-diketones in the conjugate addition to iV-benzyl maleimides employing the natural cinchona alkaloids quinine or quinidine as catalysts [267]. The reaction, which is one of the few reported examples of a very stereoselective conjugate addition catalyzed by quinine (or quinidine), affords highly functionalized products with two adjacent stereogenic carbon atoms in high diastereo- (up to 92/2 dr) and enantioselectivity (up to 98% ee) with cyclic and acyclic P-ketoesters... 

Schans and co-workers envisioned the apphcation of cinchona alkaloids 47a-d as chiral Brpnsted base catalysts in the asymmetric Mannich reaction of acetoacetates 45 with iV-acylimines 23a, 46a-c (Schane 5.25) [35]. Promising results were reported when the chiral base cinchonine (47a) was employed, while the cinchona alkaloid quinine (47b) gave considerably lower selectivities. Opposite selectivities were observed when the pseudo-ematiamers cinchoitidine (47c) and qniitidine (47d) were used. 

Apart from these examples, there are some other receptors that have been discovered by chance. Such is the case of the responses induced by ammonium templates on the DCL prepared from the established building block 39 based on the dipeptide L-Pro-L-Phe (Scheme 3.15). The small DCL made from 39 was affected by the presence of the cinchona alkaloids quinine (71) and quinidine (72)... 

The Cinchona alkaloid, quinine (6.276), does not immediately seem... 

An asymmetric version of this reaction would be of great interest, since it would complement the asymmetric epoxidation. This has in fact been achieved by Sharpless. The source of asymmetry this time is a chiral tertiary amine, which forms a complex with osmium tetroxide. Taking their cue from the work of Wynberg (see section 6.1.1) Sharpless and co-workers discovered once again that chiral amines (66) and (67) derived from the cinchona alkaloids quinine and quinidine respectively performed well, affording enantiomeric excesses of 50-90%. 

In 1981 Matsumoto and Uchida [10] reported the first example of an enantiose-lective reaction catalyzed by chiral organic molecules performed under high-pressure conditions. These Japanese scientists studied the Michael addition of nitromethane to chalcone catalyzed by cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine), brucine, and strychnine. The authors did not... 

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