Ester hydrolysis, acyl transfer

Ester hydrolysis can also be promoted by nucleophilic catalysis. If a component of the reaction system is a more effective nucleophile toward the carbonyl group than hydroxide ion or water under a given set of conditions, an acyl-transfer reaction can take place to form an intermediate ... 

In 1991, Jacobs analysed 18 examples of antibody catalysis of acyl-transfer reactions as a test of the Pauling concept, i.e. delivering catalysis by TS stabilization. The range of examples included the hydrolysis of aryl carbonates and of both aryl and alkyl esters. In some cases more than one reaction was catalysed by the same antibody, in others the same reaction was catalysed by different antibodies. 

Phosphonates and phosphonamidates were selected as transition-state analogs for carbonate and ester hydrolysis they are relatively stable molecules, they are known inhibitors of acyl transfer enzymes and they imitate the initial negative charge of the tetrahedral oxyanion of acyl transfer enzymes (such as serine proteases) in the dipole of the P=0 bond. 

Acyl transfer to alcohols and amines is related mechanistically to ester hydrolysis but yields a complementary set of products that are useful in their own right and as chiral synthons for the preparation of more complex materials. Such transformations can be difficult to achieve in water, however, because the solvent, which is present in vast excess, can participate directly in the reaction as a reactant. Enzyme-like specificity is thus required to favor the bimolecular reaction between alcohol and ester and prevent spontaneous hydrolysis of the acyl donor. 

The trypsin family of serine proteases includes over 80 well-characterized enzymes having a minimum sequence homology of >21%. Two amino acid residues are absolutely conserved (Cysl82, Glyl96) within their active sites [26,27]. These proteases have similar catalytic mechanisms that lead to hydrolysis of ester and amide bonds. This occurs via an acyl transfer mechanism that utilizes proton donation by histidine to the newly formed alcohol or amine group, dissociation and formation of a covalent acyl-enzyme complex. 

The fluorogenic hydroxyketone 14 discussed above (Scheme 1.4) can also be used to form esters such as 26 which can be used as fluorogenic substrates for lipases [37]. In this case, however, the esters are quite unstable despite being ali-phahc alcohol esters. The relatively rapid spontaneous hydrolysis in this case is probably due to an assisted mechanism involving acyl transfer in the hydrated form of the ketone. 

Alkylation products of pseudoephedrine amides are readily transformed in a single operation into highly enantiomerically enriched carboxylic acids, aldehydes, ketones, lactones or primary alcohols. Alkylated pseudoephedrine amides can be hydrolyzed under acidic or basic conditions to form carboxylic acids. Simply heating a pseudoephedrine amide at reflux in a 1 1 mixture of sulfuric acid (9-18 N) and dioxane affords the corresponding carboxylic acid in excellent chemical yield with little or no epimerization (eq 7). Under these conditions, the substrate initially undergoes a rapid N— -0 acyl transfer reaction followed by rate-limiting hydrolysis of the resulting (3-ammonium ester intermediate to form the carboxylic acid. ... 

Table 6). Where the expense of tetra-n-butylammonium hydroxide is a consideration, or in cases where the product carboxylic acid is poorly soluble in ether (making extractive removal of tetra-n-butylammonium salts difficult), an alternative procedure employing sodium hydroxide in a mixture of water, methanol, and ferf-butyl alcohol can be used. The mechanism of the base-induced hydrolysis reaction is believed to involve initial rate-limiting intramolecular N- O acyl transfer, followed by rapid saponification of the resulting (3-amino ester. ... 

The mechanism of ester hydrolysis in acid (shown in Mechanism 22.8) is the reverse of the mechanism of ester synthesis from carboxylic acids (Mechanism 22.6). Thus, the mechanism consists of the addition of the nucleophile and the elimination of the leaving group, the two steps common to all nucleophilic acyl substitutions, as well as several proton transfers, because the reaction is acid-catalyzed. 

Most acyltransferases catalyze acyl transfer to a hydroxyl or amine group of the acceptor substrate, whereas CoA ester hydrolysis by thioesterases is in effect acyl transfer to water. 

Figure 26.2. Synthesis of an Ether Phospholipid. Steps in the synthesis include (1) acylation of dihydroxyacetone phosphate by acyl CoA, (2) exchange of an alcohol for the carboxylic acid, (3) reduction by NADPH, (4) acylation by a second acyl CoA, (5) hydrolysis of the phosphate ester, and (6) transfer of a phosphocholine moiety.

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