Cinchona Group

6 Bioqenetically Related Quinoline Alkaloids 6.1 Cinchona Group. — In contrast to the bark, the leaves of 

Cinchona species have not been extensively studied. One such 

succirubra leaf, root, and suspension cultures has been 154 

X-ray crystal structure data for cinchonidine have been 

A number of acrylonitrile - Cinchona alkaloid copolymers have been prepared in which the vinyl group of the alkaloid has been modified, and the ability of these copolymers to act as asymmetric catalysts in the Michael addition of methyl vinyl ketone to methyl indan-l-one-2-carboxylate has been studied.In twelve cases, good enantiomeric yields, ranging from 41 to 56% ee, were obtained. 

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Cinchona Group.—Details of Brown s partial synthesis54 1 of dihydro-meroquinene from secologanin have been published.126... 

Cinchona Group.—The relationship between conformation and antimalarial activity in the quinine series has been discussed.142" Apparently there is no intramolecular hydrogen-bond in the active alkaloids conversely, the inactive ones exhibit intramolecular hydrogen-bonding. 

Perhaps the only contribution of much chemical interest in the Cinchona group during the year concerns the biotransformation of quinidine (234) in man, and the partial synthesis of one of the metabolites. The two metabolites identified were 3-hydroxyquinidine (235) and 2 -quinidinone, the 2-quinolone analogue of quinidine the former of these was prepared from quinidine by degradation to the ketone (236) (not previously prepared), and re-introduction of the vinyl group by a Grignard synthesis (Scheme 32). 

A second application of QM/MM methods to the quantification of steric effects is provided by the lMOMM(Becke3LYP MM3) study on the origin of enantioselectivity in the dihydroxylation of styrene by the (DHQD)2PYDZ-0s04 complex (21). The size and complexity of the catalyst, which can be seen in Figure 8, preclude the possibility of accurate pure QM calculations on the problem, because the selectivity is decided precisely by the bulky substituents in the NR3 cinchona group. The selectivity is defined by the initial approach of the substrate to the catalyst to form an osmate ester intermediate, and consequently a number of possible paths were analyzed. In particular, there are 12 such paths, defined by the three possible regions (A, B, and C) of approach of the substrate... 

Febrifugine is the first alkaloid to be isolated from a member of the Saxifragaceae, and it is the first known alkaloid outside the cinchona group to possess marked antimalarial activity. Its quinazoline structure is of particular interest in view of the recorded antimalarial activity of some synthetic quinazolines (49). A number of synthetic analogues of XXXII have been prepared and tested as antimalarials (51). 

To these requirements the alkaloids of the cinchona group correspond moderately well owing to the their peculiar structure. The quinoline group of the Cnd molecule provides strong adsorption of the modifier on the surface of Pt while the stereochemically important part of molecule provides energetic and stereochemical interactions with the pyruvate molecule through the N- atom of quinuclidine ring. 

The studies of platinum supported aluminum oxide modified with optically active alkaloids of the cinchona group are considered in Chapter 5, where more than 200 communications on this topic are summarized. The studies of Pt-alumina catalysts modified with cinchonidine allowed for the preparation of a number of very important chiral synthons and medicines. These publications give substantial information for better understanding of the mechanism of heterogeneous catalysts and of the stmcture of intermediate complexes in enantioselective hydrogenation reactions. 

CkiehonkMiie [(85,9/()-cinchonan-9-ol]. Formula, see quinine. C,9H22N20, Mr 294.40 plates or prisms, mp. 2I0 C, (a][) -110 (C2H5OH) well soluble in alcohol and chloroform. C. is an alkaloid of the Cinchona group ( Cinchona alkaloid), a quinoline alkaloid. C. is isolated from many Cinchona species (C. tucujensis, C. pubescens) and also occurs in Remijia species (Ruhi-aceae) and in some members of the olive family such as Olea europaea (olive tree) and Ligustrum vulgare (common privet). C. is obtained commercially from cinchona bark. 

In addition to the extensive older structural modification studies with the yohimbine group [1151-1170] - especially within the reserpine sub-group where there are several excellent reviews available [251, 252, 970] - the strychnine group [1171-1180], the emetine group [259] and the Cinchona group [1181 to 1201], there are a large number of more recent studies worthy of brief mention. These include structural modification studies with fusidic acid [1202-1205] which have served to indicate the crucial importance of the 17(20) double bond. 

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

This group of natural alkaloids occurs in the various species of the two Rubiaceous genera. Cinchona and Bemijia, indigenous to the eastern slopes of the Andes between latitudes 10° N. and 20° S. 

There are a number of other synthetic substances analogous with or approximating to the cinchona alkaloid structure which it is more convenient to deal with in discussing the correlation of chemical structure with pharmacological action in this group (p. 469). 

The central. CHOH. group in the cinchona alkaloids seems to be essential to anti-malarial activity Conversion into quinicines [quinatoxines (I) — (VII)] destroys activity and so do such changes as. CHOH. — . CHCl. (cinchona chlorides) or. CHOH. — . CHj. (deoxy-cinchona bases) or. CHOH. — . CO. quina-ketones), or acylation of the hydroxyl group except in the case of quinine ethylcarbonate. 

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. 

En route to the total synthesis of cinchona alkaloid meroquinene, a Hoffmann-La Roehe group took advantage of the Hofmann-Loffler-Freytag reaetion to funetionalize the ethyl side ehain in piperidine 49 to give ehloroethylpiperidine 51 via the intermediaey of protonated aminyl radieal 50. °... 

Another important reaction associated with the name of Sharpless is the so-called Sharpless dihydroxylation i.e. the asymmetric dihydroxylation of alkenes upon treatment with osmium tetroxide in the presence of a cinchona alkaloid, such as dihydroquinine, dihydroquinidine or derivatives thereof, as the chiral ligand. This reaction is of wide applicability for the enantioselective dihydroxylation of alkenes, since it does not require additional functional groups in the substrate molecule ... 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

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