Decarboxylation of P-keto acids

The thermal decarboxylation of p keto acids is the last step in a ketone synthesis known as the acetoacetic ester synthesis The acetoacetic ester synthesis is discussed in Section 21 6... 

For a review of the mechanism of the decarboxylation of P-keto acids, see Jencks, W.P. Catalysis in Chemistry and Enzjnology, McGraw-Hill NY, 1969, p. 116. 

You may have already come across the importance of six-membered ring transition states in organic chemistry, e.g. in the decarboxylation of P-keto acids (Scheme 5.14). 

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

These carbanions can be formed (Figure 5.8) by proton abstraction from ketones resulting in aldol condensations, by proton abstraction from acetyl CoA, leading to Claisen ester condensation, and by decarboxylation of p-keto acids leading to a resonance-stabilised enolate, which can likewise add to an electrophilic centre. It should be noted that the reverse of decarboxylation also leads to formation of a carbon—carbon bond (this is again a group transfer reaction involving biotin as the carrier of the activated CO2 to be transferred). 

Flavin-dependent decarboxylases catalyze the oxidative decarboxylation of the C-terminal peptidyl-cysteines to peptidylaminoenethils/aminoenethiolates during the biosynthesis of antibiotics. The key element of this conversion is an oxidation-reduction reaction. The CHjSH side chain of the C-terminal cysteine residue is oxidized to a thioaldehyde or to a tautomeric enethiol with the concomitant reduction of the flavin cofactor. Decarboxylation of the thioaldehyde/enethiolate intermediate occurs spontaneously, because this step is favored by the delocalization of the negative charge of the adjacent thioaldehyde group in a manner similar to the decarboxylation of p-keto acids (Figure 1.35). 

We will defer discussion of the decarboxylation of p-keto acids until we learn the utility of such compounds in Chapter 19, but carbonates and malonic acids will be mentioned here. 

The use of alkali-metal halides in dipolar aprotic media to effect direct decarboxylation of p-keto-acids has been successfully applied to the synthesis of a variety of cyclopropanes (28) from y-butyrolactones, and the method appears to have significant potential. ... 

Decarboxylation of p-keto acids occurs even at room temperature, giving an enol, which isomerizes to the corresponding ketone as the isolated product. 

Further, Lapworth s suggestion that enols are intermediates in these reactions has been established to apply to numerous other reactions of carbonyl compounds as well. Enols are intermediates in the hydration of alkynes (see Section 9.12) and the decarboxylation of P-keto acids and malonic acid derivatives (see Section 18.16). They are also intermediates in a number of biochemical processes including glucose metabolism and fatty acid biosynthesis. 

The decarboxylation of P-keto acids is an important biochemical reaction. The conversion of iso-citric acid to a-ketoglutarate in the citric acid cycle is one example. This reaction is catalyzed by isocitrate dehydrogenase, an NAD -dependent dehydrogenase. 

The biological decarboxylation of a P-keto acid presents a slight difficulty. We recall that carboxyhc acids exist as carboxylate anions at pH 7. And, the decarboxylation of P-keto acids occurs from the carboxylic acid, not the anion. Why, then, is this decarboxylation a favorable process Decarboxylation of oxalosuccinate produces an enolate anion. An enolate anion has a piST of -20 and is very unstable at pH 7. A reaction that produces an unstable intermediate has a high activation energy and is slow. Thus, the enzyme-catalyzed decarboxylation of the anionic form of a P-keto acid has to stabilize the enolate anion intermediate. Isocitrate dehydrogenase requires Mg ions. An Mg ion forms a complex with the carbonyl group of the P-keto acid. This has two effects. 

Inherently, the decarboxylation of p-keto acids and malonic acids (1) proceeds very smoothly, as the resulting product bearing anion adjacent to carbonyl group stabilizes as its enolate form (2) [Eq. (1)]. Enzyme-mediated reaction sometimes utilizes this facilitated decarboxylation. Indeed, isocitric acid (3) was oxidized to the corresponding keto acid, which subsequently decarboxylated to a-ketoglutaiic acid (4) by means of isocitrate dehydrogenase (EC 1.1.1.41) [Eq. (2)]. Another example is observed in the formation of acetoacetyl-CoA (5), which occupies the first step of fatty acid biosynthesis. A p-keto carboxylate 6, derived from the acetylation of malonyl-CoA with acetyl-CoA, decarbox-ylates to 5 by the action of 3-ketoacyl synthase [Eq. (3)]. 

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