Reverse Claisen

Various mechanisms are discussed for the migration of a benzyl group including, e.g., a two-stage Cope or reverse Claisen rearrangement as well as a preference of direct [l,5]-shift over successive Wagner-Meerwein migrations (equation 115)173. 

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. 

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. 

Fatty acid degradation involves a reverse Claisen... 

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... 

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. 

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. 

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