Decarboxylation, of /3-ketoacids

An example of a reaction, first presented in Section 20.4, that falls under the pericyclic classification is the decarboxylation of /3-ketoacids produced in the malonic and acetoacetic ester syntheses ... 

Decarboxylation of /3-Ketoacids (Section 17.9A) S-Ketoacids decarboxyl-ate upon heating. The mechanism involves redistribution of electrons in a six-membered transition state to give COj and the enol of a ketone, which tautomerizes to give a ketone. The reaction is facilitated by a hydrogen bond between the carboxyl hydrogen atom and S-carbonyl oxygen. 

The project encompassed the comparative characterization of pyruvate decarboxylase from Z. mohilis (PDC) and benzoylformate decarboxylase from P. putida (BED) as well as their optimization for bioorganic synthesis. Both enzymes require thiamine diphosphate (ThDP) and magnesium ions as cofactors. Apart from the decarboxylation of 2-ketoacids, which is the main physiological reaction of these 2-ketoacid decarboxylases, both enzymes show a carboligase site reaction leading to chiral 2-hydroxy ketones (Scheme 2.2.3.1). A well-known example is... 

Some of the best-known examples of decarboxylation in organic chemistry include the conversion of 3-ketoacids to ketones in the acetoacetic ester synthesis and the conversion of malonate derivatives to substituted carboxylic... 

The stabilisation of an enolate (intermediate or product) is also important in the decarboxylation reaction of /3-ketoacids. The decarboxylation of such compounds is facile, and is the key to the synthetic utility of ethyl acetoacetate and diethyl malonate. The mechanism of decarboxylation involves the formation of an enol (Fig. 5-21), and so is expected to be subject to metal ion control. 

In decarboxylation, the loss of CO2 from the carboxylate anion is believed to involve a carbanion intermediate, which acquires a proton from solvent or other sources. The anion of (3-ketoacids can undergo facile decarboxylation (Scheme 2.19). 

Unlike other neighboring group assisted allylborations which require a base such as Et3N,6-7 the allylboration of (3-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 Et3N, 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. 

The enzymes described above that convert oxaloacetate to pyruvate and CO2 appear to use metal chelation to stabilize the enolate formed by decarboxylation. Many other /3-ketoacid decarboxylases use a similar mechanism. However, there are a few decarboxylations of /3-keto acids or their functional equivalents in which no metal ion is involved. One is the case of acetoacetate decarboxylase, which functions by means of a Schiif base mechanism. A few additional examples are described below. All these cases involve particularly stable enolates. 

Decarboxylation of /3-Dicarboxylic Acids (Section 17.9B) The mechanism of decarboxylation of a j8-dicarboxylic acid is similar to that for decarboxylation of a jS-ketoacid. 

Scheme 3.4 Enantioselective, decarboxylative protonation of 3-ketoacid in tetralone series...

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 (3-ketoacid itself is probably due to incipient proton transfer to 0=0 through hydrogen-bonding in (47) ... 

A methyl ester was formed by methanolysis of a trihalide (Equation 32) <2007S225>. Decarboxylation of the /3-ketoacid resulting from hydrolysis has also been reported (Equation 33) <1980LA1917>. A carboxylic acid substituent was reduced to aldehyde with LAH (Equation 34) <1974J(P1)2092>. Thiazine nitrogen probably participates in this reaction. 

If, instead of an ester, the Japp-Klingemann reaction is done with a salt of a [3-ketoacid, decarboxylation occurs and the eventual product is a 2-acyl-indole. 

We have presented evidence that pyrrole-2-carboxylic acid decarboxylates in acid via the addition of water to the carboxyl group, rather than by direct formation of C02.73 This leads to the formation of the conjugate acid of carbonic acid, C(OH)3+, which rapidly dissociates into protonated water and carbon dioxide (Scheme 9). The pKA for protonation of the a-carbon acid of pyrrole is —3.8.74 Although this mechanism of decarboxylation is more complex than the typical dissociative mechanism generating carbon dioxide, the weak carbanion formed will be a poor nucleophile and will not be subject to internal return. However, this leads to a point of interest, in that an enzyme catalyzes the decarboxylation and carboxylation of pyrrole-2-carboxylic acid and pyrrole respectively.75 In the decarboxylation reaction, unlike the case of 2-ketoacids, the enzyme cannot access the potential catalysis available from preventing the internal return from a highly basic carbanion, which could be the reason that the rates of decarboxylation are more comparable to those in solution. Therefore, the enzyme cannot achieve further acceleration of decarboxylation. In the carboxylation of pyrrole, the absence of a reactive carbanion will also make the reaction more difficult however, in this case it occurs more readily than with other aromatic acid decarboxylases. 

Figure 5-21. The concerted process for the decarboxylation of a /3-ketoacid. The carboxyl hydroxy group is hydrogen bonded to the carbonyl group. The product is an enol which usually tautomerises to the desired ketonic product.

Upon heating, the (3 ketoacid becomes unstable and decarboxylates, leading to the formation of the methyl ketone. 

On the other hand, l-(phenylethynyl)cyclopropanol 9 (R = Ph) underwent a C3 -> C4 ring expansion and subsequent decarboxylation when treated with MCPBA to yield the 2-phenylcyclobutanone 47, likely via the intermediate 2-(l-hydroxy-cyclopropyl)-2-phenyl ketene 44, formed by migration of the cyclopropyl group in the vinyl cation 43. The ketene 44 thus resulting could be attacked by a second equivalent of MCPBA and ring expanded to the (3-ketoacid 46 which would easily decarboxylate to yield 47, Eq. (15) 14>. 

When the /3-ketoacid is heated, carbon dioxide is lost. This step, a decarboxylation, occurs by a mechanism that is quite different from any other that we have encountered so far. Three bonds are broken and three bonds are formed in a concerted reaction that proceeds through a cyclic, six-membered transition state. The product of this step is an enol. which tautomerizes to the final product, a ketone ... 

The retro-ene reaction cleaves an unsaturated compound into two unsaturated fragments. A common example of a retro-ene reaction in organic synthesis is the acid-catalyzed decarboxylation of a (B-ketoester. The ester is hydrolyzed to the (3-ketoacid by the aqueous acid, which rapidly loses carbon dioxide to form enol. The loss of CO2 drives the reaction to the right-hand side. The enol rapidly tautomerizes to the methyl ketone (Scheme 8.17). 

Because it is a (3-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. 

One approach to this problem is the coupling of the transamination reaction to a second reaction that consumes the keto acid by product in an essentially irreversible step this drives the transamination reaction to completion. By using an aminotransferase that can utilize aspartic acid efficiently as the amino group donor (instead of glutamic acid), the corresponding 2-keto acid by product is oxaloacetate (rather than 2-ketoglutarate). Oxaloacetate is a (3-ketoacid and can be easily decarboxylated to pyruvate. This decarboxylation occurs spontaneously in aqueous solution, catalyzed... 

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