Cinchona alkaloid family

What makes cinchona alkaloids so unique in the molecular world The complex structure and multifunctional character of the four principal members of the cinchona alkaloid family - quinine, quinidine, cinchonine (CN), and cinchonidine... 

Scheme 12.5 Structures ofthe parent cinchona alkaloid families.

To improve the asymmetric induction in these reactions, numerous ligands were evaluated (over 500 have been tested in the Sharpless labs).19 Within the cinchona alkaloid family, over 75 derivatives were screened. The best ligands have been found to be analogs of dihydroquinine 20 and dihydroquinidine 23. The result of these studies are the DHQ 21 and DHQD 22 ligands, respectively. 

Isocupreidine ((3-ICD, 19), another compound in the cinchona alkaloid family, can also catalyze the a-amination of 1,3-dicarbonyl compounds enantioselectively [37]. The reaction of a-substituted 1,3-dicarbonyl compounds, including cyclic and acyclic (3-ketoesters and 1,3-diketones with di-tert-butyl azodicarboxylate, proceeded with high yield and enantioselectivity. 

The second class of chiral organocatalysts recently involved in domino Michael reactions of other-than-C-nucleophiles is constituted by the cinchona alkaloid family. In this area, Melchiorre et al. have involved a chiral primary amine salt derived from 9-amino-(9-deoxy)-epz-hydroquinine to induce chirality in aziridinations of enones. This domino iminium-enamine intramolecular sequence afforded a series of chiral protected aziridines derived from both... 

Quinine (QN) and quinidine (QD) are natural enantiomers belonging to the cinchona alkaloid family, an important subgroup of naturally occurring polycyclic P-carboline alkaloids. They are widely used as resolving agents for chiral acids via preferentially forming diastereomerie salts with one of the enantiomers [117]. From the reciprocity concept point of view, the logic path is that QN and QD are potential chiral selectors... 

Chiral Br0nsted base catalysis began with the recognition of a natural product class of compounds in the cinchona alkaloid family [2]. Cinchona alkaloids are templates for Br0nsted bases when their quinuclidine nitrogen is protonated by nucleophilic substrates, resulting in a stabilized chiral intermediate for stereochemical attack of an electrophile. Systematic evaluahon of structural variants to the scaffold... 

Tertiary Amines It is significant to note that in both Pracejus asymmetric ketene alcoholysis and Wynberg s ketene-chloral cycloaddition, the catalysts of choice were both members of the cinchona alkaloid family that promoted the desired asymmetric process in remarkably high levels of stereocontrol. In 1996, Calter reported a catalytic, asymmetric dimerization of methylketene 89 using cinchona alkaloid catalysts to afford enantiomerically enriched (3-lactones 90 that were reduced in situ using lithium aluminum hydride (LiAlH4) to afford l-hydroxy-3-ketones 91 (Scheme 3.20) [54]. 

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-... 

Several families of efficient chiral phase transfer catalysts are now available for use in asymmetric synthesis. To date, the highest enantiomeric excesses (>95% ee) are obtained using salts derived from cinchona alkaloids with a 9-anthracenylmethyl substituent on the bridgehead nitrogen (e.g. lb, 2b). These catalysts will be used to improve the enantiose-lectivity of existing asymmetric PTC reactions and will be exploited in other anion-mediated processes both in the laboratory and industrially. 

FIGURE 18.1 Structure, names, and abbreviations of the applied cinchona alkaloids. The Cn modifiers depicted on the left preferentially lead to (S)-alcohols, members of the Cd family to (f )-alcohols. 

BQC is derived from quinine, which is a member of the cinchona family of alkaloids. Ammonium salts derived from quinidine, a diastereomer of (1) at the hydroxyl substituent, have been used less frequently in catalysis than BQC. Quini-dinium salts often give rise to products with enantioselectivity opposite to that from (1). Other related compounds, such as those derived from cinchonine and cinchonidine (which lack the methoxy substituent on the quinoline nucleus), have found application in organic synthesis. The cinchona alkaloids, as well as salt derivatives in which the benzyl group bears various substituents, have also been studied. Results from polymer-bound catalysts have not been promising. ... 

From a chemotaxonomic point of view it is of interest to note that the distribution of the Cinchona alkaloids is not restricted to the aforementioned species. Quinidine has been isolated, although in small quantities, from the bark of two plants of the Anonaceae family. 

Similar methods have been used in syntheses (219, 230-232) from rubatoxine and its 6 -methoxy derivative (c/. Section IV, 3) of a large munber of derivatives of ruban (CXCIII) [named (146) from the plant family Rubiaceae, in members of which the cinchona alkaloids occur]. Thus, all four of the optically active 9-rubanols (CXCIV, R = H), as well as the corresponding 6 -methoxy derivatives (CXCIV, R OCHi) have been prepared. 

A number of terpenoid indole alkaloids have pharmaceutical interest. These alkaloids are isolated from plants belonging to the families Apocy-naceae, Loganiaceae, and Rubiaceae. For the production of alkaloids by means of plant cell cultures, plants of the latter two families have proved to be rather recalcitrant (e.g., see Cinchona alkaloids). On the other hand, it has been reported by Pawelka and Stockigt that all apocynaceous cell suspensions they studied did produce terpenoid indole alkaloids 588). Here we confine ourselves to alkaloids which have direct commercial interest the production of new, potentially interesting, compounds is not reviewed here. For this we refer the reader to reviews by Balsevich (589), van der Heijden et al. (tribe Tabernaemontaneae) (590), and Omar (Rhazya stricta) (591). 

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. 

Anthracenones are another class of C-H acidic compounds suitable to be employed in this reaction (Scheme 4.16) and, in fact, Takemoto s catalyst has been identified as the most efficient catalyst among a series of different thioureas tested, which also included a family of different cinchona alkaloid-derived candidates." The reaction proceeded satisfactorily for a wide variety of aromatic nitroalkenes tested but poorer results were obtained in the case of the p-alkyl substituted Michael acceptors. 

The efficiency of secondary amine catalysts is often eroded when moving from aldehydes to ketones as the donor carbonyl substrates, a trend that can be explained in terms of either the greater difficulty in the generation of the intermediate enamine species or their attenuated reactivity. To alleviate this situation, primary amines have emerged as a complementary family of amine catalysts. For instance, proline and related chiral secondary amines are not useful catalysts for the a-amination of aromatic enolizable ketones. As in other similar situations involving ketones as substrates, primary amines proved to be superior catalysts, although in these cases the presence of an acid co-catalyst seems to be crucial for reactivity. For instance (Scheme 11.4), primary amines derived from cinchona alkaloids can efficiently... 

Scheme 118 Cinchona alkaloid-catalyzed cyclopropanation in the synthesis of members of the oxylipin family...

Vhh conplings together with chemical shifts have been calcnlated by Chini et al for kedarcidin chromofore and palau amine in the attempt to establish the correct configuration of these two compoimds prior to their total synthesis. Kedarcidin chromofore is a compoimd that belongs to the enediyne family of antitumor antibiotics, whereas palau amine is an oroidin dimer, belonging to the class of pyrrole-imidazole alkaloid family isolated from the sponge Stylotella aurantiwn. Populations of conformers in three cinchona alkaloid O-ethers at ambient and low temperatnres have been estimated by Bnsygin et al ... 

The genus Cinchona (Rubiaceae) comprises about 25 species of tall, evergreen trees that grow in South America. The bark of these trees accumulates qumohue alkaloids that are, like camptotheciu, derived from tryptophan and secologaniu. Cinchona alkaloids are also found in the genus Remijia of the Rubiaceae family. 

The two Cinchona alkaloid selectors will be used to really get into a particular chiral recognition mechanism. Quinine is a natural alkaloid extracted from the bark of the South American Cinchona tree of the Rubiaceae family and used as an anti malaria drug (Fig. 6). Its 8 and 9 positions are, respectively, substituted in the S and R configuration. By chance, quinidine is the mirror image form of quinine, also found in the Cinchona bark with the 8R and 9S configuration. These two alkaloid enantiomers... 

---