A-keto carboxylic acids

Even after SO years of continuous development carbonylation chemistry has still not achieved its full potential and new reactions are still being discovered, a good recent example being double carbonylation leading to a-keto carboxylic acids, a-keto esters and a-keto amides. ... 

In contrast to the oxidative generation of radicals described above, redactions of alkyl iodides nsing tris(trimethylsilyl)silane also produces alkyl radicals under conditions suitable for Minisci-type substitution. Carboxylic acids (a-keto acids) are also useful precursors for alkyC° and/or acyC radicals via silver-catalysed peroxide oxidation, or from their l-hydroxypyridine-2-thione derivatives, the latter in non-aqueous conditions. 

A stoichiometric amount (0.1 mM) each of enzyme-bound FAD and C-u-L-lysine (u = uniformly labelled) was incubated anaerobically until FAD was fully reduced. After deproteinization the reaction mixture was subjected to high voltage paper electrophoresis and paper chromatography. Most of the radioactivity appeared at the area corresponding to piperidine 2-carboxylic acid (a-keto-c-aminocaproic acid) (Figure 7), and a significant amount of carbon dioxide was not detected. When the reaction mixture was aerated to reoxidize FAD and then deproteinized, the radioactivity was also found at the position of piperidine 2-carboxylic acid. 

Dissolved organic species have been known to exist in sedimentary basin formation waters since before the turn of the century (5.6.71. A host of aqueous organic species have been identified in sedimentary formation waters including hydrocarbons, mono-, di- and tri-carboxylic acid anions, keto and hydroxy-acids, amino acids, phenols, cresols, and hydroxybenzoic acids (8.9.10.11.121. 

The a-ketoglutarate dehydrogenase complex is one of a three-member family of similar a-keto acid dehydrogenase complexes. The other members of this family are the pyruvate dehydrogenase complex, and the branched chain amino acid a-keto acid dehydrogenase complex. Each of these complexes is specific for a different a-keto acid structure. In the seqnence of reactions catalyzed by the complexes, the a-ketoacid is decarboxylated (i.e., releases the carboxyl gronp as CO2) (Fig.20.8). The keto gronp is oxidized to the level of a carboxylic acid, and then combined with CoASH to form an acyl CoA thioester (e.g., succinyl CoA). 

Although carboxylic acids can be readily determined by GLC methods, fluorescence labelling with Br-Mmc has nevertheless gained some importance for the sensitive derivatization of fatty acids [461-463] dicarboxylic acids, a-keto acids and other organic acids [460,464], prostaglandins and thromboxanes [465], glucuronides [466], giberellins [467], imides [461,468,469] and phenols [460]. 

Examples of SB formation are outlined in Figure 1.28. The reaction of 4-aminobutanal and succinaldehyde yields an SB which is the intermediate of dialdehyde amine, likely a precursor of the pyrrolizidine ring system. Another example is the piperidine-2-carboxylic acid (a precursor of anabasine) obtained from a-keto- -aminocapronic acid. 

There are many pharmaceutical preparations and biological compounds containing carboxylic group, i.e., fatty acids, prostaglandins, steroids, bile acids, a-keto acids, and glucuronic acid. These compounds play important physiological roles to achieve homeostasis. 

Research work by Soviet scientists has an important place in this work [1, 63, 64]. Devising a practical process for quinuclidine-2-carboxylic acid production provided a basis for the production of a variety of 2-substituted quinuclidines the first of which were alkaminoesters, amides and hydrazides of quinuclidine-2-carboxylic acid [90-93]. Analogous compounds were also synthesized starting from 3-methoxycarbonyl-quinuclidine-2-carboxylic acid, 5-keto-quinuclidine-2-carboxylic acid and other quinuclidine-2-carfeoxylic acids substituted in the quinuclidine ring [66-68, 76, 78]. 

Additional results were interpreted to indicate that the inactivation was A -3-ketosteroid dependent and was probably active site-directed. Cyclohexeneone which possesses the same chromphore as A -3-keto-steroids but is not a competitive inhibitor of the enzyme, stimulated photoinactivation only to a small extent even when present at more than ten times the concentration of compounds that markedly stimulated photoinactivation. It was noted that the first-order rate constant for photoinactivation increases with increasing affinity of the enzyme for the particular steroid, a pattern to be expected if the photoinactivation is active site-directed. In addition, the rate of photoinactivation promoted by 19-nortesto8terone acetate was decreased approximately 2-fold in the presence of 21 juM 3j8-hydroxy-5-androstene-17j8-carboxylic acid, a competitive inhibitor that does not support photoinactivation of the enzyme. This protective effect further strengthens the conclusion that photoinactivation is a catalytic site-directed reaction. 

Synthesis of Keto-acids.—a-Keto-acids are obtained in moderate to good yields by the reaction of carboxylic acid dianions with conjugated nitro-olefins at — 100°C, followed by acidic work-up. Another route to these compounds involves the C-silylation of butyrolactone enolate, followed by a Peterson-type olefination to give the vinylic ether (20), which is then oxidized to the y-keto-acid (Scheme 12). Eight examples, with yields of between 50 and 83%, along with one failure are reported. 

A cell suspension culture of Datura ferox, when supplied with dl-[2- C]-ornithine, yielded radioactive putrescine, citrulline, arginosuccinate, arginine, y-aminobutyric acid, glutamic acid, aspartic acid, a-keto-8-guanidovalerate, and a-keto-S-aminovalerate. However, none of the tropane alkaloids produced by this species was radioactive. It was suggested that this in vitro cell culture lacks the enzyme which catalysed the reaction between A -pyrroline-2-carboxylic acid (55) and acetoacetyl coenzyme A. The product of this condensation ultimately yields hygrine (57) and then tropine (56) as illustrated in Scheme 12. 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

The compounds most frequently encountered m this reaction are (3 keto acids that is carboxylic acids m which the (3 carbon is a carbonyl function Decarboxylation of (3 keto acids leads to ketones... 

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