Quinidine hydrolysis

Enantiopure p-lactones have been obtained from the reaction of acid chlorides or ketene with aldehydes in the presence of optically active tertiary amines. The reaction of ketene with chloral has been studied in considerable detail (Scheme 2). In the presence of 2 mol % of quinidine at -SO C die p-lac-tone is formed in virtually quantitative chemical and optical yield By proper choice of the catalyst, either enantiomer of the -lactone can be obtained. The transition state picture (4) has been propos for the ketene-chloral addition in the presence of quinidine. Hydrolysis converts the -lactone to malic acid with inversion of configuration (Scheme 2). ... 

We have studied this reaction in considerable detail (88) and have found that when one uses quinine (eq. [25]) or any one of the chiral bases, a variety of aldehydes react with ketene to form the corresponding p-lactones in excellent chemical and nearly quantitative enantiomeric yields. Equation [25] exemplifies the reaction. Note that mild basic hydrolysis of the lactone furnishes a trichlo-rohydroxy acid that was prepared earlier by McKenzie (89). If one uses quinidine as catalyst, the process furnishes the natural (S)-malic acid. Note that ketene first acylates the free hydroxyl group of quinine, so that the actual catalyst is the alkaloid ester. 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

The cycloaddition of ketene with chloral in the presence of catalytic quantities of quinidine or quinine leads to the oxetanones in high optical and chemical yield (Scheme 26.22). This reaction is practiced on an industrial scale with the chiral building blocks malic and citramalic acids being formed by hydrolysis.492... 

Ketene undergoes quinidine catalyzed cycloadditions with a variety of a,a-dichloroaldehydes (R = C6H5, primary alkyl) to give oxetanones in high yield and >90% ee47,48. The opposite enantiomer is obtained in 68 80 % ee with quinine. Hydrolysis with hydrochloric acid and hydrogenolysis leads to methyl (.S )-3-hydroxyalkanoates48. 

Ketene also undergoes quinidine catalyzed cycloaddition with a,a,a-trichloroacetone to give (R)-5 and with electron-deficient ct, ,a-trichloroacetophenones to give 4 with >90% ee. The opposite enantiomers were obtained in 65-85% ee with quinine. Basic hydrolysis of (R)-5 proceeds with inversion to give (.S )-citramalic acid49. 

The photochemical behavior of the W-oxides of the Cinchona alkaloids has been examined 49). Photolysis (> 300 nm) of the aromatic mono-iV-oxides 183 of the dihydro derivatives of quinine, quinidine, cincho-nidine, and cinchonine in alcoholic solvents gave the expected carbo-styrils 186 in yields of 70-85%. The same results were obtained with the corresponding AjiV-dioxides 184. An interesting rearrangement was observed in the case of the iV,A -dioxides of dihydrocinchonine and dihydrocinchonidine. Photolysis in benzene solution afforded, in addition to the carbostyrils, the iV -formylindole methanols 188 in 30% yield. The hydrolysis-sensitive benz[d]-l,3-oxazepines 185 were proposed as the probable intermediates. 

Lidocaine, similar to procaine, is an effective, clinically used local anesthetic (Fig. 26.11) (see Chapter 16). Its cardiac effects, however, are distinctly different from those of procainamide or quinidine. Lidocaine normally is reserved for the treatment of ventricular arrhythmias and, in fact, usually is the drug of choice for emergency treatment of ventricular arrhythmias. Its utility in these situations results from the rapid onset of antiarrhythmic effects on intravenous infusion. In addition, these effects cease soon after the infusion is terminated. Thus, lidocaine therapy may be rapidly modified in response to changes in the patient s status. Lidocaine is effective as an antiarrhythmic only when given parenterally, and the intravenous route is the most common. Antiarrhythmic activity is not observed after oral administration because of the rapid and efficient first-pass metabolism by the liver. Parenterally administered lidocaine is approximately 60 to 70% plasma protein bound. Flepatic metabolism is rapid (plasma half-life, -15-30 minutes) and primarily involves N-deethylation to yield monoethylglycinexylide, followed by amidase-catalyzed hydrolysis into N-ethylglycine and 2,6-dimethylaniline (2,6-xylidine) (Fig. 26.12). 

Asymmetric cycloaddition of ketene to chloral catalyzed by quinidine gives an (R)-product which on hydrolysis undergoes inversion of the absolute configuration to (S)-malic acid, and vice versa for catalysis by quinine. This reaction allows convenient access to either enantiomer of malic acid (Kilenyi and Aitken, 1992). 

MA-NVP quinidine (antiar-rhythmic) 6-aminohexanoic acid hydrolysis 114... 

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