P-Ketoacid

In addition to formation from a ketone, the hydra2ones can be obtained from dicarbonyl compounds by a Japp-Klingemann reaction. This is especially useful for P-ketoesters and P-ketoacids, which undergo either deacylation or decarboxylation. 

Ketene Insertions. Ketenes insert into strongly polarized or polarizable single bonds, such as reactive carbon—halogen bonds, giving acid hahdes (7) and into active acid haUdes giving haUdes of p-ketoacids (8) (46). Phosgene [77-44-5] (47) and thiophosgene [463-71-8] (48) also react with ketenes. 

Coenzyme M was shown to function as the central cofactor of aliphatic epoxide carboxylation in Xanthobacter strain Py2, an aerobe from the Bacteria domain (AUen et al. 1999). The organism metabolizes short-chain aliphatic alkenes via oxidation to epoxyalkanes, followed by carboxylation to p-ketoacids. An enzyme in the pathway catalyzes the addition of coenzyme M to epoxypropane to form 2-(2-hydroxypropylthio)ethanesulfonate. This intermediate is oxidized to 2-(2-ketopropylthio)ethanesulfonate, followed by a NADPH-dependent cleavage and carboxylation of the P-ketothioether to form acetoacetate and coenzyme M. This is the only known function for coenzyme M outside the methanoarchaea. 

The overall rate law is, however, found to contain a term involving [ketoacid] (47) as well as the term involving [ketoacid anion]. The ready decarboxylation of the p-ketoacid itself is probably due to incipient proton transfer to C=0 through hydrogen-bonding in (47) ... 

This means that a reverse Claisen reaction can occur if a P-ketoester is treated with base. This is most likely to occur if we attempt to hydrolyse the P-ketoester to give a P-ketoacid using aqueous base. Note that the alcoholic base used for the Claisen reaction does not affect the ester group. 

P-ketoacid, but these compounds are especially susceptible to loss of carbon dioxide, i.e. decarboxylation. Although P-ketoacids may be quite stable, decarboxylation occurs readily on mild heating, and is ascribed to the formation of a six-membered hydrogen-bonded transition state. Decarboxylation is represented as a cyclic flow of electrons, leading to an enol product that rapidly reverts to the more favourable keto tautomer. 

The second function, and the one pertinent to this section, is the decarboxylation of oxalosuccinic acid to 2-oxoglutaric acid. This is simply a biochemical example of the ready decarboxylation of a P-ketoacid, involving an intramolecular hydrogen-bonded system. This reaction could occur chemically without an enzyme, but it is known that isocitric acid, the product of the dehydrogenation, is still bound to the enzyme isocitrate dehydrogenase when decarboxylation occurs. 

It is appropriate here to look at the structure of oxaloacetic acid, a critical intermediate in the Krebs cycle, and to discover that it too is a P-ketoacid. In contrast to oxalosuccinic acid, it does not suffer decarboxylation in this enzyme-mediated cycle, but is used as the electrophile for an aldol reaction with acetyl-CoA (see Box 10.4). 

To get the final product we need to lose the ester function. This is a standard combination of acid-catalysed ester hydrolysis followed by heating. The P-ketoacid forms a hydrogen-bonded six-membered ring that facilitates decarboxylation. 

The mechanism for the uncatalyzed decarboxylation of P-ketoacids had previously been established by Bredt and by Pedersen (Bredt, 1927 Pedersen, 1929 1936 Westheimer and Jones, 1941). The acid loses C02 to form the enol of the product, which subsequently ketonizes. The idea behind Pedersen s mechanism for aniline catalysis is that nitrogen is more basic than oxygen, and so could be protonated more readily the protonated imine would provide a better electron sink than the ketone. Although Pedersen offered little or no experimental support for his hypothesis, it provided a basis in physical organic chemistry for the mechanism of the corresponding enzymic process. 

Methylsuccinic anhydride is prepared by condensation of ethyl 2-bromopropionate with ethyl cyanoacetate followed by hydrolysis of the nitrile, decarboxylation of the resultant p-ketoacid, and dehydration. 

Upon heating, the P ketoacid becomes unstable and decarboxylates, forming a disubstituted acetic acid. 

The intermediate in this reaction is oxalosuccinate, an unstable P-ketoacid. While bound to the enzyme, it loses CO to form a-ketoglutarate. 

Because it is a P-ketoacid, acetoacetate also undergoes a slow, spontaneous decarboxylation to acetone. The odor of acetone may be detected in the breath of a person who has a high level of acetoacetate in the blood. 

Oxidative decarboxylation of isocitrate to a-ketoglutarate. A P-ketoacid intermediate is formed in both reactions. See question... 

It was shown that an enol intermediate was initially formed in the decarboxylation of l -ketoacids and presumably in the decarboxylation of malonic acids. It was found that the rate of decarboxylation of a,a-dimethylacetoacetic acid equalled the rate of disappearance of added bromine or iodine. Yet the reaction was zero order in the halogen . Qualitative rate studies in bicyclic systems support the need for orbital overlap in the transition state between the developing p-orbital on the carbon atom bearing the carboxyl group and the p-orbital on the i -carbonyl carbon atom . It was also demonstrated that the keto, not the enol form, of p ketoacids is responsible for decarboxylation of the free acids from the observa-tion that the rate of decarboxylation of a,a-dimethylacetoacetic acid k cid = 12.1 xlO sec ) is greater than that of acetoacetic acid (fcacw = 2.68x10 sec ) in water at 18 °C. Enolization is not possible for the former acid, but is permissible for the latter. Presumably this conclusion can be extended to malonic acids. 

Esters react with metalated carboxylic acids yielding P-ketoacids from which aldehydes50 and ketones51 may be derived. Like the Adam olefin... 

Monochlorodimedone, the substrate used for the detection and isolation of haloperoxidases and perhydrolases (Fig. 16.9-8), and other (3-diketones such as barbituric acid1621 is brominated at the 2-position by all known haloperoxidases and perhydrolases. Oxooctanoic acid and other p-ketoacids form mono- and dihalogen-ated ketones and carbon dioxide1631. When p-alanine and taurine were used as substrates for myeloperoxidase the corresponding N-chloroamines could be detected I64-651. 

The ketone 51, prepared as an enantiomeric mixture as described in scheme 9, is regioselectively carboxylated in the a position to give the p-ketoacid 60 which, without any manipulation, is immediately stereoselectively reduced to the P-hydroxyacid 61, with sodium borohydride. 

Unlike other neighboring group assisted allylborations which require a base such as EtsN, the allylboration of P-ketoacids can be carried out in the absence of added base. In fact, when the reaction is run in the presence of one equivalent of EtsN, decarboxylation occurs. A solvent study revealed that decarboxylation is also minimized when the reactions are carried out in ethereal solvents as opposed to less polar solvents such as dichloromethane. 

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