Cinchona alkaloids and derivatives

Piette V, Fillet M, Lindner W, Crommen J (2000) Non-aqueous capillary electrophoretic enantioseparation of N-derivatized amino acids using cinchona alkaloids and derivatives as chiral counter-ions. J Chromatogr A 875 353-360... 

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. 

Work also prepared a series of carbinolamines and polyamines without a quinoline nucleus but, in other respects, conforming in type and range of molecular weight, with quinoline compounds known to possess plasmocidal activity. As none of these were active, it seems clear that the quinoline nucleus in the cinchona alkaloids and in certain synthetic anti-malarials is a potent factor in the production of plasmocidal action. Later the same author made (1942) a series of lepidylamine derivatives of the form R. Q. CHj. NH[CH2] . NEtj, which were found to be inactive, in spite of their similarity to the active examples of the type R. Q. NH[CH2] . NEt2 prepared by Magidson and Rubtzow. Rubtzow (1939) has also shown that an isomeride of dihydroquinine (II) with the quinuclidine nucleus attached via the carbinol group at C in the quinoline nucleus was inactive in an infection of Plasmodium prcecox in finches. 

Quinidine (155) and dihydroquinidine (157) have been used for a long time for the treatment of cardiac antiarrythmia. These cinchona alkaloids (and their analogues in the quinine and cinchonidine family) are metabolized in animals and humans [234,235] to give, among several products, the corresponding (3S)-3-hydroxy derivatives (156,159) [236-240], which were shown to be pharmaco-... 

Modified Cinchona alkaloids catalysts have been developed in the last two decades to enhance further the bifunctional mode of the catalyst. Derivations at the C(9)-OH group, replacement of quinoline C(6 )-OCH3 with a hydroxyl group to enhance hydrogen bonding, syntheses of bis-Cinchona alkaloids, and development of thiourea-derived Cinchona alkaloids are most notable. 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

Scheme 1.7 Some cinchona alkaloids and cinchona-derived catalysts.

Kacprzak K, Gawronski J. Cinchona alkaloids and their derivatives versatile catalysts and ligands in asymmetric synthesis. Synthesis 2001 961-998. 

Much more successful turned out to be the concept of chiral anion exchangers. So far, there are mainly two significant contributions reported (1) the use of cationic. selectors derived from cinchona alkaloids and (2) the use of cationic selectors derived from ergot alkaloids. 

Active Sites in Cinchona Alkaloids and Their Derivatives 3... 

However, in general, these active sites in cinchona alkaloids and their derivatives act in catalysis not independently but cooperatively that is, they activate the reacting molecules simultaneously. Furthermore, in many cases, the catalysis is also supported by a n-n interaction with the aromatic quinoline ring or by its steric hindrance. 

As discussed, the solvent dipole moments, concentration, and temperature play a significant role in determining the structure of cinchona alkaloids and their derivatives in solution. In order to delineate the intimate details of the mechanism of action of cinchona alkaloids and their derivatives, a thorough understanding of their real structure in solution is needed. Furthermore, such detailed information on the real structure in solution would make it possible to develop new and more powerful chiral catalysts and discriminators. 

Cinchona Alkaloids and their Derivatives as Chirality Inducers in Metal-Promoted Enantioselective Carbon-Carbon and Carbon-Heteroatom Bond Forming Reactions... 

In this chapter, the current state of the art on the applications of cinchona alkaloids and their derivatives as chiral ligands or chiral cobase catalysts in metal-promoted asymmetric carbon-carbon and carbon-heteroatom bond forming catalytic reactions will be discussed. 

Table 4.8 Cinchona alkaloids and their derivatives promoted the enantioselective fluorination of 2-oxo-cyclopentanecarboxylic acid tert-butyl ester.

---