Reverse Claisen reactions

Problem 23.12 As shown in Figure 23.5, the Claisen reaction is reversible. That is, a /3-keto ester can be cleaved by base into two fragments. Using curved arrows to indicate electron flow, show the mechanism by which this cleavage occurs. 

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). 

It is important to emphasise the complete reversibility of normal Claisen reactions under suitable conditions, e.g. the so-called acid decomposition (because both products—(117) and (118)—are derivatives of acids) of / -ketoesters (119) ... 

The present case simply illustrates another utility of the ester cleavage reaction, i.e., the cleavage of a /3-keto ester with con-ccanitant decarboxylation under only slightly basic conditions. The method should be particularly applicable to systems which are prone to undergo reverse Claisen reactions. 

However, the reaction is not quite that simple, and to understand and utilize the Claisen reaction we have to consider pAT values again. Loss of ethoxide from the addition anion is not really favourable, since ethoxide is not a particularly good leaving group. This is because ethoxide is a strong base, the conjugate base of a weak acid (see Section 6.1.4). So far then, the reaction will be reversible. What makes it actually proceed further is the fact that ethoxide is a strong base, and able to ionize acids. The ethyl acetoacetate prodnct is a 1,3-dicarbonyl componnd and has relatively acidic protons on the methylene between the two carbonyls (see Section 10.1). With... 

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. 

The reverse Claisen reaction is common, especially with cyclic P-ketoesters, such as one gets from the Dieckmann reaction (see Section 10.8). If one only wants to hydrolyse the ester, it thus becomes necessary to use the rather less effective acid-catalysed hydrolysis method (see Section 7.9.2). 

Cleavage of P-diketones, the products of a mixed Claisen reaction between an ester electrophile and a ketone nucleophile (see Box 10.13), behave similarly towards base, and a reverse Claisen reac-... 

Nevertheless, as we shall see in Section 10.9, it is also possible to exploit the reverse Claisen reaction to achieve useful transformations. 

Reverse Claisen reaction in biochemistry -oxidation of fatty acids... 

Perhaps the most important example of the reverse Claisen reaction in biochemistry is that involved in the P-oxidation of fatty acids, used to optimize energy release from storage fats, or fats ingested as food (see Section 15.4). In common with most biochemical sequences, thioesters rather than oxygen esters are utilized (see Box 10.8). 

The P-oxidation sequence involves three reactions, dehydrogenation, hydration, then oxidation of a secondary alcohol to a ketone, thus generating a P-ketothioester from a thioester. We shall study these reactions in more detail later (see Section 15.4.1). The P-ketothioester then suffers a reverse Claisen reaction, initiated by nucleophilic attack of the thiol coenzyme A (see Box 10.8). 

Note also that we can even make good use of the reverse Claisen reaction. Thus, alkylation of ethyl acetoacetate followed by suitable base treatment to effect a reverse Claisen reaction would also generate a substituted acid. Alcoholic base would... 

There follows cleavage of acetyl-CoA from the end of the chain via a reverse Claisen reaction (see Box 10.15). This requires use of a molecule of coenzyme A as nucleophile, with the loss of the enolate anion of acetyl-CoA as leaving group. The net result is production of a new fatty acyl-CoA that is two carbons shorter than the original, and a molecule of acetyl-CoA that can be metabolized via the Krebs cycle. 

In this case, we formulate the Claisen reaction between two ester molecules as enolate anion formation, nucleophilic attack, then loss of the leaving group. Now reverse it. Use hydroxide as the nucleophile to attack the ketone carbonyl, then expel the enolate anion as the leaving group. All that remains is protonation of the enolate anion, and base hydrolysis of its ester function. 

Q ,Q -disubstituted /1-ketoesters like 9, when treated with an alkoxide, can be cleaved into ordinary esters by the reverse of the condensation reaction, the retro-Claisen reaction. However the condensation of esters with only one a-hydrogen is possible in moderate yields by using a strong base, e.g lithium diisopropyl amide (LDA). ... 

The intramolecular carbon-carbon bond-forming reactions considered in this section are based on the aldol condensation (see Section 5.18.2, p. 799), the Claisen-Schmidt reaction (see Section 6.12.2, p. 1032), the Claisen ester condensation (see Section 5.14.3, p. 736), and the Claisen reaction (see Section 6.12.2, p. 1032). Since these carbonyl addition reactions are reversible, the methods of synthesis are most successful for the formation of the thermodynamically stable five- and six-membered ring systems. The preparation of the starting materials for some of these cyclisation reactions further illustrates the utility of the Michael reaction (see Section, 5.11.6, p. 681). 

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... 

Two different reactions are possible when ethyl acetoacetate reacts with ethoxide anion. One possibility involves attack of ethoxide ion on the carbonyl carbon, followed by elimination of the anion of ethyl acetate—a reverse Claisen reaction similar to the one illustrated in 23.40. More likely, however, is the acid-base reaction of ethoxide ion and a doubly activated a-hydrogen of ethyl acetoacetate. 

In contrast to the previous problem, this sequence is a reverse Claisen reaction. The first step (not illustrated) is the reaction of HSCoA with a base to form SCoA. 

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