Carboxyl group reduction

From a study of the decompositions of several rhodium(II) carboxylates, Kitchen and Bear [1111] conclude that in alkanoates (e.g. acetates) the a-carbon—H bond is weakest and that, on reaction, this proton is transferred to an oxygen atom of another carboxylate group. Reduction of the metal ion is followed by decomposition of the a-lactone to CO and an aldehyde which, in turn, can further reduce metal ions and also protonate two carboxyl groups. Thus reaction yields the metal and an acid as products. In aromatic carboxylates (e.g. benzoates), the bond between the carboxyl group and the aromatic ring is the weakest. The phenyl radical formed on rupture of this linkage is capable of proton abstraction from water so that no acid product is given and the solid product is an oxide. 

Carboxyl group reduction of the CPS and LPS samples was performed as previously described.55 Briefly, LPS (10 mg) was dissolved in distilled water (10 ml) and following the addition of l-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonare (113 mg), the stirred mixture was maintained at pH 4.7 by titration with 0.1 moll-1 HC1 for 3 h. Following completion of the reaction a 2 moll-1 solution of sodium borohydride (12.5 ml) was added slowly and the reaction mixture was maintained at pH 7 by titration with 4moll-1 HC1. The reaction was allowed to proceed for 2 h at 22 °C, and the solution was dialyzed and lyophilized. The product was purified by gel permeation chromatography on Sephadex G-100 and lyophilized (yield 6 mg). 

The reduction of the carboxylic group is easier in the 2-position than in the 4- or 5-positions. These differences in reductibility run parallel to chemical reactivity (58). 

Carboxylic Acid Group. Reactions of the carboxyl group include decarboxylation, reduction to alcohols, and the formation of salts, acyl hahdes, amides, and esters. 

Generally, the carboxyl group is not readily reduced. Lithium aluminum hydride is one of the few reagents that can reduce these organic acids to alcohols. The scheme involves the formation of an alkoxide, which is hydroly2ed to the alcohol. Commercially, the alternative to direct reduction involves esterification of the acid followed by the reduction of the ester. 

Reactions of the carboxyl group include salt and acid chloride formation, esterification, pyrolysis, reduction, and amide, nitrile, and amine formation. Salt formation occurs when the carboxyUc acid reacts with an alkaline substance (22)... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Scheme 4 outlines the synthesis of key intermediate 7 in its correct absolute stereochemical form from readily available (S)-(-)-malic acid (15). Simultaneous protection of the contiguous carboxyl and secondary hydroxyl groups in the form of an acetonide proceeds smoothly with 2,2 -dimethoxypropane and para-toluene-sulfonic acid and provides intermediate 26 as a crystalline solid in 75-85 % yield. Chemoselective reduction of the terminal carboxyl group in 26 with borane-tetrahydrofuran complex (B H3 THF) affords a primary hydroxyl group that attacks the proximal carbonyl group, upon acidification, to give a hydroxybutyrolactone. Treat-... 

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