Alkaloids cinchonine

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

The use of compounds with activated methylene protons (doubly activated) enables the use of a mild base during the Neber reaction to 277-azirines. Using ketoxime 4-toluenesulfonates of 3-oxocarboxylic esters 539 as starting materials and a catalytic quantity of chiral tertiary base for the reaction, moderate to high enantioselectivity (44-82% ee) was achieved (equation 240). This asymmetric conversion was observed for the three pairs of Cinchona alkaloids (Cinchonine/Cinchonidine, Quinine/Quinidine and Dihydro-quinine/Dihydroquinidine). When the pseudoenantiomers of the alkaloid bases were used, opposite enantioselectivity was observed in the reaction. This fact shows that the absolute configuration of the predominant azirine can be controlled by base selection. 

Leaves of Cinchona succirubra Pav. from a trial plantation in the north of Thailand have been reported to contain the typical bases of quinoline alkaloids (cinchonine, cinchonidine, quinidine, quinine, di-hydroquinidine, and dihydroquinine) together with the indole bases quina-mine and 3-epiquinamine (97,98). 10-Methoxycinchonamine (92) has also been isolated from this plant for the first time. Except for the inclusion of alkaloid 92, the alkaloid pattern in C. succirubra is the same as that in the cross-species C. succirubra x C. ledgeriana from Guatemala. 

The relation of quinine and cinchonine to quinoline is shown by their oxidation products. As mentioned in connection with quinoline the alkaloid cinchonine when oxidized yields a mono-carboxy quinoline known as cinchoninic acid. Similarly quinine yields quininic acid which is a meth-oxy derivative of cinchoninic acid. 

Cincholoipon ethyl ester (168), available from the commercial Cinchona alkaloid (+)-cinchonine in 50% overall yield according to the classical... 

Modifier The effect of the modifier structure is also quite similar to that found for a-ketoesters [7]. Cinchonidine derivatives and quinine lead to an excess of the (R)-hydroxy-acid while the pseudo-enantiomeric cinchona alkaloids (cinchonine and quinidine) give preferentially (S)-product but with much lower enantioselecdvity. Changing the substituent Y at C9 has only an effect on the degree of asymmetric induction but not its direction. OMe and OH are more effective than OAc or H. An interesting exception are the Nj alkylated Cd derivatives which are completely ineffective in the case of the ester. Here, N-methyl-Cd+Cr gives a small excess of the R-enantiomer while N-benzyl-Cd Cl leads an 33% excess of (S)-4-phenyl-2-hydroxybutyric acid ... 

Quinoline, bp 237°C, is a colourless steam-volatile liquid of characteristic odour. Quinoline was first obtained by alkaline degradation of the alkaloid cinchonine (see below, Gerhard 1842). It possesses a lower dipole moment (p = 2.16 D) than pyridine (p = 2.22 D) and isoquinoline (p = 2.60 D). Quinoline, because of the nitrogen link with the fused benzene ring, is a weaker base (pAT = 4.87) than isoquinoline (p = 5.14). 

It produces stable combinations with proteins. At a pH between 3 and 5, tannin solutions produce a blue-black precipitate in the presence of ferric salts. Tannin solution also precipitates alkaloids (cinchonine sulfate). 

Cmchona alkaloids. Indole alkaloids (cinchonamine group) and quinoline alkaloids (cinchonine group), only the latter group is of therapeutic significance. C. a. are isolated from Cinchona bark (Jesuit s bark Cin-chonae cortex). The name is derived from the Indian word quina (bark). The drug consists of the dried tube... 

The existence of a peculiar principle, cinchonin, in Peruvian bark was suspected by A. Duncan junr. The bark was also investigated by Vauquelin. The alkaloids cinchonine and quinine were discovered in it by Pelletier and Caventou. Quinine, cinchonine, and quinic acid were investigated by E. O. Henry. ... 

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, aeyl, ear-bamoyl) are employed as aeceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Sehaus and eoworkers reported the highly enantioselective Mannich reaction of acetoacetates and cyclic 1,3-dicarbonyl compounds with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor. 

In addition to flavone synthesis, Hintermann also studied the kinetics and mechanism of natural Cinchona alkaloids (cinchonine and cinhonidine) catalysed oxa-Michael cyclisation of 4-(2-hydroigratyl)-2-hutenoates. Various henzodihydrofuranyl acetates and related products were obtained in up to 99% yield and with 91% ee. ... 

A further example of the diastereomeric relationship is provided by the naturally occurring alkaloids cinchonine and cinchonidine and their methoxy derivatives quinidine and quinine which all occur together in the bark of the cinchona tree. Note that while the stereogenic centres at C-8 and C-9 have the opposite configuration, the three... 

Today, three Cinchona species are cultivated for the production of quinine. C sticcirubra yields the red bark , C. legderiana the brown bark , and C. calisaya the yellow bark (Dewick, 2002). In addition to quinine, the barks contain significant amounts of three other quinoline alkaloids quinidine, the diastereomer of quinine, which is used as an antiarrhythmic, and 6-demethoxy analogs of the two alkaloids, cinchonine and cinchonidine. 

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