Cinchona active sites

Lohray and coworkers reported the first application of silica gel-supported Cinchona alkaloids in AD in 1996 [67], A 3,6-DHQ2-pyridazine derivative was linked to a silica gel support with an attachment point at one of the quinudidine moieties (Fig. 4, catalyst 13). The alkaloidic ligand was expected to bind to the silica surface resulting in better availability of the active site compared to polymer-... 

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

Figure 1.2 Active sites in cinchona alkaloids and thei...

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. 

There are a large number of alkaloids that contain the quinuclidine nucleus such as the sarpagine, ajmaline and cinchona families. The quinuclidines 1-3 have been used for the synthesis of such alkaloids. They have pharmacological activities. Thus, several reports have highlighted the potential of chiral hydroxylated quinuclidines in propping the active site of muscarinic receptors. Substituted quinuclidines may provide selective Vaughan Williams class 111 antiarrhythmic effects. " ... 

Several approaches can be used to design solid enantioselective catalysts [1-5]. In general, the solid material must combine catalytic activity with stereochemical control. The active site should be regarded as an ensemble of surface metal atoms which adsorb and activate the reactant and hydrogen and can also accommodate a soluble chiral modifier. For example, in the hydrogenation of ethyl pynivate over cinchona-modified Pt an ensemble of about 15-20 metal atoms is required to accommodate the bulky modifier, substrate, and hydrogen [6]. 

Besides several diastereoselective heterogeneous catalytic hydrogenations [1-3] only two enantioselective hydrogenation reactions are known the reduction of p-keto-esters with Raney-nickel modified by tartaric acid and of pyruvic acid esters with Pt modified by cinchona alkaloids. Garland and Blaser [4] described the reduction of pyruvic acid ester as a "ligand-accelerated" reaction with the adsorption of the modifier new active sites are generated on the catalyst surface. On these new centers the selective reaction is faster and the increased reaction rate is accompanied by greater enantioselectivities. 

The reaction was also described with a template model too [5-7] which presumes a nonclose packed ordered array of adsorbed cinchona alkaloid molecules. Wells supposed three types of active sites. Two of them are producing (R) or (S) product depending on the type of cinchona alkaloid and the third one that is an active site which is not templated produces the racemic product. This model concurs with that of proposed by Blaser. 

Recently, Wang [64] prepared by radieal copolymerization a cinchona alkaloid copolymer the methyl acrylate-co-quinine (PMA-QN (71)) (Scheme 34). Complexed with palladium(II), its catalytic activity in the heterogeneous catalytic reduction of aromatic ketones by sodium borohydride was studied. High yields in their corresponding alcohols are obtained but it is found that the efficiency of the catalyst depended on the nature of the solvent and the ketone which related to the accessibility of the catalytic active site. The optical yields in methanol and ethanol 95% were lower than in ethanol. This ability was attributed to a bad coordination between PMA-QN-PdCl2 and sodium borohydride and a reaction rate which was very rapid. The stability of the chiral copolymer catalyst was studied... 

Isocupreidines are Cinchona alkaloid derivatives with limited conformational flexibility and increased basicity and nucleophilicity due to the increased ring strain of the tricyclic skeleton. The C(6 )-OH on (3-ICPD offers two different sites of simultaneous activation of nucleophile and electrophile to enhance basicity and sterics of intermediate species. 

P-Hydroxyammonium salts can react under the strongly basic reaction conditions present in many phase-transfer reactions and the newly formed products could, in principle, serve either as effective or ineffective catalysts (Scheme 10.1) [9c]. The development of a new class of chiral phase-transfer catalysts, the W-alkyl-O-alkyl cinchona quats (Bactjve in Scheme 10.1 and 30 in Scheme 10.2), resulted from detailed mechanistic studies of these systems [5p,12], These catalysts are formed by in situ deprotonation of 28 to the alkoxide 29 followed by alkylation to form the active catalyst 30. Such catalysts offer an important second site of variation (R-, in 30) for catalyst development, which has been rapidly utilized for the preparation of more effective catalysts. 

HMWPs (c) that sites adjacent to steps are particularly active for the initiation of HMWP formation, and (d) that there is currently no evidence for chiral-chiral recognition of kink sites when cinchona alkaloids adsorb at these surfaces. ... 

The liver has been strongly implicated as the major site of cinchona alkaloid degradation. Thus Kelsey and Oldham (74) found that the liver of the rabbit was far more active than lung, kidney, spleen, adrenals, skeletal muscle, uterus, and intestine. Other investigators have found that excretion of unchanged quinine is increased by liver injury or partial hepa-tectomy (85). Knox (86) has studied the liver oxidase system responsible for quinine degradation and has concluded that the liver enzyme is a flavo-protein with functions like those of xanthine oxidase. 

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