Cinchona roles

Since the initial work of Onto et al. (1) a considerable amount of work has been performed to improve our understanding of the enantioselective hydrogenation of activated ketones over cinchona-modified Pt/Al203 (2, 3). Moderate to low dispersed Pt on alumina catalysts have been described as the catalysts of choice and pre-reducing them in hydrogen at 300-400°C typically improves their performance (3, 4). Recent studies have questioned the need for moderate to low dispersed Pt, since colloidal catalysts with Pt crystal sizes of <2 nm have also been found to be effective (3). A key role is ascribed to the effects of the catalyst support structure and the presence of reducible residues on the catalytic surface. Support structures that avoid mass transfer limitations and the removal of reducible residues obviously improve the catalyst performance. This work shows that creating a catalyst on an open porous support without a large concentration of reducible residues on the Pt surface not only leads to enhanced activity and ee, but also reduces the need for the pretreatment step. One factor... 

A striking feature of the template model is the restriction of the role of the modifier to that of a template, which does not take into account direct binding interactions of the reactant with the modifier. Furthermore, there exists no experimental evidences for the formation of ordered arrays of cinchona molecules on a platinum surface. In 1995, Margitfalvi and Hegedus [235] criticized this model showing that the model is too idealistic and oversimplified. 

Other functionalized supports that are able to serve in the asymmetric dihydroxylation of alkenes were reported by the groups of Sharpless (catalyst 25) [88], Sal-vadori (catalyst 26) [89-91] and Cmdden (catalyst 27) (Scheme 4.13) [92]. Commonly, the oxidations were carried out using K3Fe(CN)g as secondary oxidant in acetone/water or tert-butyl alcohol/water as solvents. For reasons of comparison, the dihydroxylation of trons-stilbene is depicted in Scheme 4.13. The polymeric catalysts could be reused but had to be regenerated after each experiment by treatment with small amounts of osmium tetroxide. A systematic study on the role of the polymeric support and the influence of the alkoxy or aryloxy group in the C-9 position of the immobilized cinchona alkaloids was conducted by Salvadori and coworkers [89-91]. Co-polymerization of a dihydroquinidine phthalazine derivative with hydroxyethylmethacrylate and ethylene glycol dimethacrylate afforded a functionalized polymer (26) with better swelling properties in polar solvents and hence improved performance in the dihydroxylation process [90]. 

Aryl amino alcohol alkaloids from the bark of Cinchona sp. have played an invaluable role in the treatment of malaria since the 18th century when... 

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

In the initial screening of various Cinchona alkaloids, the addition of diethyl phosphate 41 to IV-Boc imine 40 in toluene revealed the key role of the free hydroxyl group of the catalyst. Replacing the C(9)-OH group with esters or amides only results in poor selectivity. Quinine (Q) was identified as an ideal catalyst. A mechanistic proposal for the role of quinine is presented. Hydrogen-bonding by the free C(9)-hydroxyl group and quinuclidine base activation of the phosphonate into a nucleophilic phosphite species are key to the reactivity of this transformation (Scheme 9). 

The efficiency with which modified Cinchona alkaloids catalyze conjugate additions of a-substituted a-cyanoacetates highlights the nitrile group s stereoselective role with the catalyst. Deng et al. [60] utilized this observation to develop a one-step construction of chiral acyclic adducts that have non-adjacent, 1,3-tertiary-quatemary stereocenters. Based on their mechanistic studies and proposed transition state model, the bifimctional nature of the quinoline C(6 )-OH Cinchona alkaloids could induce a tandem conjugate addition-protonation reaction to create the tertiary and quaternary stereocenters in an enantioselective and diastereoselective manner (Scheme 18). 

Fig. 5 Roles of Cinchona alkaloid-derived chiral thiourea catalyst...

Recent developments in the understanding of the mechanisms of catalytic and asymmetric dihydroxylation reactions are discussed in Section V,E,l,b. An important aspect of this work is the kinetics and thermodynamics of the formation of adducts with N heterocycles, which have an important role in promoting many reactions. The crystal structure of the [0s04] adduct with the cinchona alkaloid ligand (dimethyl-... 

As reviewed in this chapter, cinchona alkaloids have played a crucial role in the development of asymmetric phase-transfer catalysis since its advent, and today constitute a privileged structural motif that may be widely utilized for the design of new chiral quaternary ammonium salts. These benefits are due not only to the... 

Consequently, Dehmlow and coworkers modified the cinchona alkaloid structure to elucidate the role of each ofthe structural motifs of cinchona alkaloid-derived chiral phase-transfer catalysts in asymmetric reactions. Thus, the quinoline nucleus of cinchona alkaloid was replaced with various simple or sterically bulky substituents, and the resulting catalysts were screened in asymmetric reactions (Scheme 7.2). The initial results using catalysts 8-11 in the asymmetric borohydride reduction of pivalophenone, the hydroxylation of 2-ethyl-l-tetralone and the alkylation of SchifF s base each exhibited lower enantiomeric excesses than the corresponding cinchona alkaloid-derived chiral phase-transfer catalysts [14]. 

Extension of the approach described resulted in a short synthesis of (+)-mero-quinene (Fig. 13). Formation of this alkaloid also synthetically connects the indole with the quinoline alkaloids, a link which has been suggested from the biosynthetic point of view for multiple decades quinine alkaloids are expected to be enzymatically formed from the indole framework. Meroquinene is a simple piperidine derivative which can be obtained by degradation of cinchonine and other Cinchona alkaloids under acidic conditions. It also plays a key role in the chemical synthesis... 

The role of some chiral bifunctional amines and optically active cinchona alkaloid derivatives (Figure 3) as catalysts has been explored in catalytic asymmetric Staudinger reactions. Bicarbonate salts have been used as viable alternatives to... 

Sutherland, Ibbotson, Moyes and Wells have published a detailed account of the heterogeneous enantioseleetive hydrogenation of methyl pyruvate (CH3COCOOCH3) to R-(+)-methyl lactate over Pt/siliea surfaces modified by sorbed cinchona alkaloids.16 Kinetic, isotherm and molecular modeling calculations were used to develop an idea of the role of the cinchonidine modifier. This system is quite unusual high enantioselectivity is achieved only with Pt, only in the presence of cinchonidine modifiers and only for the hydrogenation of a-ketoesters. 

However, since the catalytic system is homogenous, carefully adjusted reaction conditions were needed to circumvent the second nonselective catalytic cycle. Slow addition of the alkene and the hydrogen peroxide was necessary to obtain good enantioselectivities (Table 6) [13]. Recently, Backvall s group reported that the Cinchona alkaloid ligand participated in the reoxidation process and took the role of NMO in the catalytic cycle [15]. Versions of the triple catalytic system with vanadyl acetylacetonate replacing the flavin analogue [16] or m-CPBA as the terminal oxidant [17] have been developed and successfully applied to racemic dihydroxylation reactions. 

Cinchona species (Rubiaceae) are sources of quinine and quinidine, containing a quinoline nucleus and derived through the extensive elaboration of strictosidine (Fig. 42). The intriguing history of the antimalarial quinine and its role in world politics over the past 350 years are legendary. It is frequently the only antimalarial drug to which patients are not resistant. Its widest use, however, is in the beverage industry in tonic water. Quinidine, an isomer of quinine, is used to treat cardiac arrythmias. 

Alkylations. Highly enantioselective alkylation of t-butyl 4,4-bis (p-dimethyl-aminophenyl)-3-butenoate and t-butyl A -diphenylmethyleneglycine in the presence of a quatemized cinchona alkaloid results. The salt plays a dual role in asymmetric induction and as a phase-transfer catalyst. The products from the former reaction can be cleaved at the double bond to furnish chiral malonaldehydic esters which have many obvious synthetic applications. A combination of PTC, LiCl, and an organic base (e.g., DBU) favors the enantioselective alkylation of a chiral A-acylimidazolidinone in which the acyl side chain is derived from glycine. ... 

The pivotal role of the conformational behavior of a cinchona alkaloid (e.g., cinchonidine) in its enantioselectivity was nicely illustrated in the platinum-catalyzed enantioselective hydrogenation of ketopantolactone in different solvents [18]. The achieved enantiomeric excess shows the same solvent dependence as the fraction of anti-open conformer in solution, suggesting that this conformer plays a crucial role in the enantiodifferentiation. As a more dramatic example, the solvent affects the absolute chirality of the product in the 1,3-hydron transfer reaction catalyzed by dihydroquinidine [20]. An NMR study revealed that the changes in the ratio between the two conformers of dihydroquinidine can explain the observed reversal of the sense of the enantioselectivity for this reaction when the solvent is changed from o-dichlorobenzene (open/closed 60 40) to DMSO (open/dosed 20 80). 

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. 

The use of chiral ligands has allowed the asymmetric oxidation of alkenes with osmium reagents in catalytic amounts [61-66], The cinchona alkaloids have played, and continue to play, a significant role in this useful synthetic methodology. 

The schemes exemplified in this chapter will demonstrate the indispensable role of cinchona alkaloids as catalysts in these important research areas. 

In this chapter, the current state of the art on the applications of cinchona alkaloids and their derivatives as chiral catalysts in the enantioselective nucleophilic addition of prochiral C=0 and C=N bonds is discussed. The schemes exemplified in this chapter demonstrate the indispensable role of cinchona alkaloids as catalysts in these important research areas. 

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