Cinchonidine optically active acid

Using cinchonidine as a modifier of Pt-alumina catalysts, the reaction resulted in the formation of products with preponderances of one enantiomer of the resulting 2-hydroxycarboxylic acid or ester of (R)- configuration. But in many papers devoted to this process there is some confusion in the assignment of configuration to the optically active acid (or ester) Even the same... 

Optica] resolution of these and related carboxylic acids were achieved using salt formation with alkaloids (strychnine, brucine, cinchonidine) 33,39,44 or with optically active amines [1-phenyl- or l-( 3-naphthyl)ethylamine]4o,44). The following rotations [a]D have been reported [8]paracyclophanecarboxylic acid (13) +18° (chloroform)441 [10]homologue (14) +80° (chloroform)39 and +67° (chloroform)40 its methyl-derivative (75) —28° (methanol)44 . Dioxa[10]paracyclophanecarboxylic acid (16) + 104° (ethanol)36 and bromo-dioxa[12]paracyclophanecarboxylic acid (79) —37° (acetone)33). 

Optically active alkylphenylarsinous acid esters can be prepared by treating chloro-alkylphenylarsines with alcohols in the presence of ( —)-brucine or (— )-iV,iV-diethyl-a-methylbenzylamine. Secondary haloarsines react with the lithium derivative of (— )-cinchonidine to give the crystalline cinchonidine esters of arsinous acids 131 and 132 Another route to optically active arsinous acid esters is given in Scheme 14 ... 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug in an optically pure form. The original manufacturing process (Scheme 1) before product launch started from P-naphthol (1) which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give 2-bromo-6-hydroxy-naphthalene that was then methylated with methyl chloride in water-isopropanol to obtain 2-bromo-6-methoxynaphthalene (3) in 85-90% yield from p-naphthol. The bromo compound was treated with magnesium followed by zinc chloride. The resultant naphthylzinc was coupled with ethyl bromopropionate to give naproxen ethyl ester that was hydrolyzed to afford the racemic acid 4. The final optically active naproxen (5) was obtained by a classic resolution process. The racemic acid 4 was treated with cinchonidine to fonn diastereomeric salts. The S -naproxen-cinchonidine salt was crystallized and then released with acid to give S -naproxen (5) in 95% of the theoretical yield (48% chemical yield) [8,9]. 

A new kind of enantioselective [1,3]-proton transfer in aza-allylic systems was reported, namely, the N-benzylimines 30 were converted to the more thermodynamically favored N-benzylidene derivatives 31 as shown in Scheme 4. Among the chiral bases (i )-(-l-)-N,Ar-dimethyl-l-phenylethylamine, (li ,2S)-(-)-N-meth-ylephedrine, and (-)-cinchonidine employed as catalysts, only (-)-cinchonidine showed an asymmetric induction. A series of optically active 3-polyfluoroalkyl-P-amino acids 32, which are of great pharmaceutical interest, was prepared in 87 to 93% yields with ee s in the range of 15 to 36% [36]. 

Biemer et al. reported the enantioselective behaviors of a Pd catalysts supported on specially prepared silica gels, which have been precipitated from Na silicate wiA HCl in the presence of optically active alkaloids sulfates of quinine (Q), quinidine (Qd ), cinchonine (Cn), or cinchonidine (Cnd). These catalysts proved to be active in the asymmetric hydrogenation of 2-methyl-cinnamic acid (Scheme 3.1.) . 

In the early years of penem and carbapenem research, the easy preparation and commercial availability of azetidinone 10 prompted the devisal of several protocols for its conversion into an optically active equivalent (Scheme 1, F). Thus, acetate displacement with thioglycolic acid and resolution with d-( +)-ephedrine gave the 4/ -carboxymethylthio derivative 94, in turn elaborated to 95a [44], the 4R-enantiomer of the key intermediate of Woodward s first synthesis of racemic 6a-hydroxyethylpenems [45]. In another approach, analog 95b was obtained by diastereomer separation after displacement of 4-acetoxy-azetidinone with a chiral mercapto-alcohol [46]. Along a still different approach [43], optically active 93b was obtained from racemic 10 and thiophenol via asymmetric induction from the reaction medium (cinchonidine-containing benzene). 

Further work by Pasteur showed that it was also possible to separate or resolve the two isomers present in paratartaric acid by forming a salt with a naturally occurring optically active base such as /-cinchonidine. The two salts had markedly different solubilities and could be separated by fractional crystallisation. A third method, also discovered by Pasteur, was to use a microorganism which consumed one of the enantiomers but not the other. Thus he found that the mould Penicillium... 

EHsubstituted (—)-a-methyl-a-ethyl-]3-thiolactone (IX) was synthesized by Jerman and Fles [7 ] from (+)-methyl-ethylmalonic acid monoethyl ester (V), which was prepared by fractional crystallization of diastereomeric quinine salt for the (+)-antipode and cinchonidine salt for the (—)-antipode. Monoester (V) was converted to a-methyl-a-ethyl-/3-bromopropionic acid (VI) using essentially the method described by Sweeney and Casey [4] for the racemic compound. Optically active a-methyl-a-ethyl-j3-fiiiolactone (IX) was synthesized either via the dehydration of the /3-mercapto derivative (VII) or by debenzylation of the jS-benzyl-... 

Jamison and Turner (52) have worked intensively on optical activation of various substituted i f-benzoyIdiphenylamines by means of alkaloids and have achieved particularly interesting results with the acid, iV-benzoyl-2,4,4 -tribromodiphenylamine-6-carboxylicacid (X). Conditions were here suitable for demonstrating the fairly marked temperature coefficient of the inversion process, for the acid in acetone solution is optically labile at room temperature, but stable at — 15°C. Crystallization of an equimolecular solution of the dl acid and cinchonidine from acetone at room temperature led to separation of pure cinchonidine (-I-) salt in almost 100% yield, a typical second-order asymmetric transformation. However, the same process at — 15°C. led to crystallization of cinchonidine (-I-) salt in only about 50% yield, and the residue on evaporation of the cold filtrate in vacuo was about two-thirds cinchonidine (—) salt—in other words, a typical resolution by the classical salt-formation method. 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

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