Claisen condensations reversal

The final step in the /3-oxidation cycle is the cleavage of the /3-ketoacyI-CoA. This reaction, catalyzed by thiolase (also known as j8-ketothiolase), involves the attack of a cysteine thiolate from the enzyme on the /3-carbonyI carbon, followed by cleavage to give the etiolate of acetyl-CoA and an enzyme-thioester intermediate (Figure 24.17). Subsequent attack by the thiol group of a second CoA and departure of the cysteine thiolate yields a new (shorter) acyl-CoA. If the reaction in Figure 24.17 is read in reverse, it is easy to see that it is a Claisen condensation—an attack of the etiolate anion of acetyl-CoA on a thioester. Despite the formation of a second thioester, this reaction has a very favorable A).q, and it drives the three previous reactions of /3-oxidation. 

Two possible mechanisms exist for the Friedlander reaction. The first involves initial imine formation followed by intramolecular Claisen condensation, while the second reverses the order of the steps. Evidence for both mechanisms has been found, both... 

Esters, like aldehydes and ketones, are weakly acidic. When an ester with an a- hydrogen is treated with 1 equivalent of a base such as sodium ethoxide, a reversible carbonyl condensation reaction occurs to yield a /3-keto ester. For example, ethyl acetate yields ethyl acetoacetate on base treatment. This reaction between two ester molecules is known as the Claisen condensation reaction. (We ll use ethyl esters, abbreviated "Et," for consistency, but other esters will also work.)... 

Step 4 of Figure 29.3 Chain Cleavage Acetyl CoA is split off from the chain in the final step of /3-oxidation, leaving an acyl CoA that is two carbon atoms shorter than the original. The reaction is catalyzed by /3-ketoacyl-CoA thiolase and is mechanistically the reverse of a Claisen condensation reaction (Section 23.7). In the forward direction, a Claisen condensation joins two esters together to form a /3-keto ester product. In the reverse direction, a retro-Claisen reaction splits a /3-keto ester (or /3-keto thioester) apart to form two esters (or two thioesters). 

An important group of acylation reactions involves esters, in which case the leaving group is alkoxy or aryloxy. The self-condensation of esters is known as the Claisen condensation.216 Ethyl acetoacetate, for example, is prepared by Claisen condensation of ethyl acetate. All of the steps in the mechanism are reversible, and a full equivalent of base is needed to bring the reaction to completion. Ethyl acetoacetate is more acidic than any of the other species present and is converted to its conjugate base in the final step. The (3-ketoester product is obtained after neutralization. 

In the synthesis route from acetyl-CoA to poly(3HB), at least three steps and three enzymes are involved (Fig. 1). The first step is catalyzed by the 3-keto-thiolase (EC 2.3.1.9) which reversibly links two acetyl-CoA moieties to aceto-acetyl-CoA in a Claisen-condensation. The conversion of acetoacetyl-CoA into D-(-)-3-hydroxybutyryl-CoA can be mediated by a reductase (step 2) or via a sequence catalyzed by a reductase (step 4) and two hydratases (steps 5,6). The last step, i.e., the polymerization, is catalyzed by a polymerase (step 3). This... 

In principle, the synthesis of a consonant molecule or a bifunctional relationship within a more complex polyfunctional molecule, does not offer too many difficulties. In fact, all the classical synthetic methods of carbon-carbon bond formation that utilise reactions which are essentially reversible, lead to consonant relationships. For instance, the book by H.O. House "Modem Synthetic Reactions" [22], after dealing, for almost 500 pages, with functional group manipulations, devotes the last 350 pages to carbon-carbon bond formation, all of which lead to consonant relationships. These methods can, actually, be reduced to the following four classical condensations (and their variants) Claisen condensation, aldol condensation, Mannich condensation and Michael addition (Table 2.5). 

In the case of a ketone with two active methylene groups, such as dibenzylketone, the reaction can take two courses. The pyranone results from Michael addition to the alkyne followed by normal ring closure. The second product, a resorcinol, arises from either Michael condensation followed by an intramolecular Claisen condensation or the order of these two reactions may be reversed (60JCS5153). 

Alkyl 3-oxobutanoic esters react with concentrated alkali by a different path to reverse the Claisen condensation ... 

The reverse of the above reaction is a key step in the oxidative degradation of fatty acids. This reverse Claisen condensation (catalyzed by thiolase) involves the cleavage of a carbon-carbon bond of a /3-keto ester of coenzyme A by another molecule of coenzyme A to give a new acyl derivative (RCO—SCoA) and ethanoyl (acetyl) derivative (CH3CO—SCoA) ... 

A subsequent hydrolytic cleavage of the C2-C3 bond of the carboxylation product (this amounts to a reverse Claisen condensation Section 18-8B) yields two molecules of D-3-phosphoglycerate.9... 

The formation of the poly-P-keto chain could be envisaged as a series of Claisen reactions, the reverse of which are involved in the 3-oxidation sequence for the metabolism of fatty acids (see page 18). Thus, two molecules of acetyl-CoA could participate in a Claisen condensation giving acetoacetyl-CoA, and this reaction could be repeated to generate a poly-P-keto ester of appropriate chain length (Figure 3.1). However, a study of the enzymes involved in fatty acid biosynthesis showed this simple rationalization could not be correct, and a more complex series of... 

A Claisen condensation is the acylation of an ester enolate by the corresponding ester. By deprotonating an ester with MOR, only a small concentration of the ester enolate is generated and this enolate is in equilibrium with the ester (cf. Table 13.1). The mechanism of the Claisen condensation is illustrated in detail in Figure 13.57 for the example of the condensation of ethyl butyrate. Both the deprotonation of the ester to give enolate A and the subsequent acylation of the latter are reversible. This acylation occurs via a tetrahedral intermediate (B in Figure 13.57) just like the acylations of other nucleophiles (Chapter 6). The equilibrium between two molecules of ethyl butyrate and one molecule each of the condensation product C and ethanol does not lie completely on the side of the products. In fact, Claisen condensations go to completion only... 

When p-keto esters are treated with concentrated base, cleavage occurs, but is on the keto side of the CR2 group (arrow) in contrast to the acid cleavage mentioned on page 838. The products are a carboxylic ester and the salt of an acid. However, the utility of the reaction is somewhat hmited by the fact that decarboxylation is a side reaction, even under basic conditions. p-Diketones behave similarly to give a ketone and the salt of a carboxylic acid. With both p-keto esters and p-chketones, OEt can be used instead of OH, in which case the ethyl esters of the corresponding acids are obtained instead of the salts. In the case of p-keto esters, this is the reverse of Claisen condensation (16-85). The similar cleavage of cychc a-cyano... 

The first reaction (1), catalyzed by thiolase, involves a Claisen condensation of two acetyl CoA s (essentially a reversal of the last reaction of beta-oxidation) to give acetoacetyl CoA - almost the final product The problem now is to remove the CoASH. 

Considerable attention was paid to the MS-MS characterization of TAG [2]. In an excellent study, Stroobant et al. [21] investigated the fragmentation of [M-H] of TAG, generated by desorption chemical ionization. A reversible rearrangement due to an internal Claisen condensation is proposed to explain the lower abundance of the DAG fragment resulting from the loss of the sn-2 fatly acid. Hsu and Turk [22]... 

Cydopentanone. 4. C, 1,3-cyclohexanedicarboxylic acid F, 1,4-cyclohexaoe-dicarboxylic acid H, succinic acid J, 1,2-cyclobutanedicarboxylic acid. 5. K, 1,5-hexadiene O, 2,5-dimethyicyclopentanecarboxylic acid. 7. (b) Intramol. aldol cond. (d) gives 3-methyl-2-cyclohexen-l-onc. 11. (a) Retro (reverse) Claisen condensation. 

Diketones and P-keto esters may be cleaved under basic conditions, in a reaction pathway that is essentially the reverse of the Claisen condensation. This cleavage reaction can occur for any compound that has a 1,3 arrangement of carbonyl groups. 

Elimination of a stable molecule, often C02 or a carbonyl compound, can give an anion which usually reacts further. Examples include elimination of carbon dioxide from acetates (reaction 4.9). The reaction of iodine with acetone (propanone) in the presence of base also involves a step of this type (reaction 4.17), as does the reverse of the Claisen condensation (reaction 4.34). 

The final reaction is essentially the reverse reaction of a Claisen condensation in organic chemistry, and acetic acid can eventually be formed by that reaction and utilized by the microorganism. 

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