Cinchona salt

The kinetics of alkylation by benzyl bromide of the Schiff base esters of ammo acids (Ph2C=NCH2CC>2CMe3) in the presence of cinchona salts show features similar to those of enzyme-promoted reactions variable orders, substrate saturation, catalyst inhibition, and non-linear Arrhenius-type plots.125 A tight coordination of the Schiff base substrate by electrostatic interaction with the quaternary N of the cinchona salt provides a favourable chiral environment for asymmetric alkylation. 

A variety of chiral phase-transfer catalysts have been developed and successfully used in asymmetric syntheses of a-amino acids [19. 23, 24]. In 1984, researchers at Merck described the methylation of indanone 74 in the presence of the quaternized cinchona salt 75 as a chiral phase-transfer catalyst (Scheme 10.12) [66]. The alkylation product 76 was isolated in 92% ee and 95 % yield and subsequently elaborated into (-H)-indacrinone (77), which had previously only been prepared by resolution techniques. 

QuinidJne. Quinidine, an alkaloid obtained from cinchona bark (Sinchona sp.), is the dextrorotatory stereoisomer of quinine [130-95-0] (see Alkaloids). The first use of quinidine for the treatment of atrial fibrillation was reported in 1918 (12). The sulfate, gluconate, and polygalacturonate salts are used in clinical practice. The dmg is given mainly by the oral (po) route, rarely by the intravenous (iv) route of adniinistration. It is the most frequentiy prescribed po antiarrhythmic agent in the United States. The clinical uses of quinidine include suppression of atrial and ventricular extrasystoles and serious ventricular arrhythmias (1 3). 

Numerous new salts and additive compounds of cinchona alkaloids, and especially of quinine, have been described, of which only a few can be mentioned as examples quinine additive compounds with sulph-anilamide, t quinine salts of (+) and (—)-pantothenic acid, °( > quinine sulphamate and disulphamate, °( organo-mercury compounds of quinine and cinchonine such as quinine-monomercuric chloride. Various salts and combinations of quinine have also been protected by patent, e.g., ascorbates and nicotinates. 

None of the quaternary salts of the cinchona alkaloids have given promising results as pneumococcicidal agents, but quinine methochloride and ethochloride have received some attention recently as curarising drugs. ... 

One of the most significant developmental advances in the Jacobsen-Katsuki epoxidation reaction was the discovery that certain additives can have a profound and often beneficial effect on the reaction. Katsuki first discovered that iV-oxides were particularly beneficial additives. Since then it has become clear that the addition of iV-oxides such as 4-phenylpyridine-iV-oxide (4-PPNO) often increases catalyst turnovers, improves enantioselectivity, diastereoselectivity, and epoxides yields. Other additives that have been found to be especially beneficial under certain conditions are imidazole and cinchona alkaloid derived salts vide infra). 

Arai and co-workers have used chiral ammonium salts 89 and 90 (Scheme 1.25) derived from cinchona alkaloids as phase-transfer catalysts for asymmetric Dar-zens reactions (Table 1.12). They obtained moderate enantioselectivities for the addition of cyclic 92 (Entries 4—6) [43] and acyclic 91 (Entries 1-3) chloroketones [44] to a range of alkyl and aromatic aldehydes [45] and also obtained moderate selectivities on treatment of chlorosulfone 93 with aromatic aldehydes (Entries 7-9) [46, 47]. Treatment of chlorosulfone 93 with ketones resulted in low enantioselectivities. 

For enantioselectivity to be possible multipoint interaction between the catalyst and the reactant in the transition state is necessary. The most effective chiral onium salts are derivatives of cinchona alkaloids (see Fig. 3.59). 

While ephedrine derivatives showed some selectivity, the most promising results were obtained with cinchona alkaloids. Lithium alkoxides and lithium acetylides (n-BuLi or LiHMDS used to deprotonate both the acetylene and the alcohol) gave better results than the corresponding sodium or magnesium salts. Higher enan-tioselectivity was obtained in THF (homogeneous) than in toluene or diethyl ether (heterogeneous). 

Cinchona alkaloids now occupy the central position in designing the chiral non-racemic phase transfer catalysts because they have various functional groups easily derivatized and are commercially available with cheap price. The quaternary ammonium salts derived from cinchona alkaloids as well as some other phase transfer catalysts are... 

The asymmetric Darzens condensation, which involves both carbon-carbon and carbon-oxygen bond constructions, was realized by use of the chiral azacrown ether 75als2,s ,ss and the quaternary ammonium salts derived from cinchona alka-loids159"621 under phase transfer catalyzed conditions. The a,p-epoxy ketone 80 (R=Ph) was obtained with reasonable enantioselectivity by the reaction of... 

The overall steric demands of the catalyst and the substrate are important in the spatial arrangement of the H-bonded complex. Consequently, although the less rigid ephedrinium salts have been used with some success, they are generally less effective than the derivatives of the cinchona alkaloids, the rigidity of which imposes a greater stereochemical restraint on the structure of the H-bonded complexes. 

Poor stereoselectivity (<30% ee) is recorded for the Michael addition of 1,3-di-ketones with nitroalkenes using cinchona bases [50] and early work recorded <25% ee using N-methylquininium and quinidinium hydroxides [51, 52], In contrast, indanones have been reported to react with methyl vinyl ketone in the presence of a cinchoninium salts to produce a chiral (S)-product in >95% yield (80% ee) [7]. Surprisingly, the (R)-isomer is obtained less readily (ee 40-60%) using cinchoni-dinium salts. Both isomers are obtained in high optical purity (>80% ee) via alkylation with 1,3-dichlorobut-2-ene and subsequent ring closure yields the Robinson... 

Asymmetric induction of the Michael addition of thiols to electron-deficient alkenes (4.6.1) has been achieved in high overall conversion using both free [e.g. 12-20] and polymer-supported [e.g. 21, 22] cinchona alkaloids and their salts [23-25], but with varying degrees of optical purity. The corresponding asymmetric Michael addition of selenophenols to cyclohex-2-enones is promoted by cinchoni-dine to give a chiral product (43% ee) [26],... 

O Donnell (1989), Corey/Lygo (1997) cinchona alkaloid-derived quaternary ammonium salts Lewis Base Cataiysis... 

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

Alkylation of Schiff bases, derived from amino acid and non-optically active aromatic aldehydes by phase-transfer catalysis in the presence of cinchona alkaloid derived quaternary ammonium salts, gave ce values of up to 50% l42. 

Quinine Quinine, molecular formula C20H24N2O2, is a white crystalline quinoline alkaloid, isolated from Cinchona hark Cinchona succirubra), and is well known as an antimalarial drug. Quinine is extremely bitter, and also possesses antipyretic, analgesic and anti-inflammatory properties. While quinine is stiU the drug of choice for the treatment of Falciparum malaria, it can be also used to treat nocturnal leg cramps and arthritis. Quinine is an extremely basic compound, and is available in its salt forms, e.g. sulphate, hydrochloride and gluconate. 

Very successful results have been obtained with functionalized quaternary ammonium salts derived from cinchona alkaloids. An example... 

Corey employed a cinchona alkaloid-derived ammonium salt 5 for the solid-liquid phase transfer catalyst, and attained 99% ee in the addition of a glycine-derived imine to 2-cyclohexenone (Scheme 6) [13,14]. 

Most recently, silica gel-supported bis-cinchona alkaloid 20 was successfully employed in the A A of fraws-cinnamate derivatives [62b]. The resulting products had excellent enantiopuri-ties (>99% ee). Recovered samples of 20 contained osmium and could be used in the AA again, though with a slight loss of activity. Therefore, recovered catalyst was regenerated upon addition of osmium salts. 

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