Cinchona alkaloid structure, synthesis

Chondrodendron polyanthum, 371 Chondrodendron tomentosum, 363, 371, 373, 377, 391 alkaloids, 376 Chondrodine, 363, 364 Chondrofoline, 364, 365 Chrycentrine, 172, 313 Chiysanthemine, 773 Chrysanthemum cineraricefoHum, 773 Chuchuara, 781 Chuehuhuasha, 781 Cicuta virosa, 13 Cinchamidine, 419, 429 Cinchene, 439 Cinchenine, 438, 439, 440 apoCinchenine, 440, 441 Cincholoipon, 438 Cincholoiponic acid, 438, 443 Cinchomeronic acid, 183 Cinchona alkaloid structure, synthesis, 457 Cinchona alkaloids, bactericidal action of some derivatives, 478 centres of asymmetry, 445 constitution, 435 formulae and characters of transformation products, 449, 451 general formula, 443 hydroxydihydro-bases, 448, 452-4 melting-points and specific rotations, 446... 

The first work on the stereochemistry and optical properties of the cinchona bases was undertaken by Pasteur (70, 145) in 1852. In the course of these investigations Pasteur achieved one of the greatest initial triumphs of stereochemistry, by showing that racemic acids could be resolved through combination with asymmetric alkaloidal bases. He also made the observation, which was to be of fundamental importance in studies on the structure, stereochemistry, and synthesis of the cinchona alkaloids, that the bases were convertible to isomeric substances, now known as toxines, and first classified the natural alkaloids on the basis of their optical properties. Thus, at this early date, the stereochemical relationship of the dextro rotatory substances, quinidine and cinchonine. 

Asymmetric phase-transfer catalysis is a method that has for almost three decades proven its high utility. Although its typical application is for (non-natural) amino acid synthesis, over the years other types of applications have been reported. The unique capability of quaternary ammonium salts to form chiral ion pairs with anionic intermediates gives access to stereoselective transformations that are otherwise very difficult to conduct using metal catalysts or other organocatalysts. Thus, this catalytic principle has created its own very powerful niche within the field of asymmetric catalysis. As can be seen in Table 5 below, the privileged catalyst structures are mostly Cinchona alkaloid-based, whereas the highly potent Maruoka-type catalysts have so far not been applied routinely to complex natural product total synthesis. 

Chiral base catalysis is one of the most versatile and broadly applicable types of catalysis. In particular, the potential of tertiary amines to act both as a base and as a nucleophilic catalyst makes chiral tertiary amines like Cinchona alkaloids a privileged catalyst structure in modem synthesis chemistry. In addition, the field of achiral phosphine and carbene catalysis has proven its potential in numerous applications in the past and it is probably only a matter of time until chiral phosphines and carbenes will also be used routinely for other presently demanding natural product total synthesis (Table 7). 

For almost two centuries, the bark was used in medicine as a powder, extract, or infusion. In 1820 Pelletier and Caventou isolated quinine and cinchonine from cinchona, and the use of the alkaloids as such gained favor rapidly. Extensive and classic studies led to elucidation of the structure of quinine (Figure 2) (4) and to its total synthesis in 1944 (5). Cinchona contains 25 closely related alkaloids, of which the most important are quinine, quinidine, cinchonine, and cinchonidine. The average yield of alkaloid is about 6-7 %, of which one-half to two-thirds is quinine. It has been said that quinine owes its dominant position in the treatment of malaria only to the fact that it was the first alkaloid isolated from cinchona, and that there is little among the four major alkaloids to choose from in treating this disease (6). 

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