Amide hydrolysis, acyl transfer

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

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. 

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. ... 

The mechanism of amide hydrolysis in base has the usual two steps of the general mechanism for nucleophilic acyl substitution—addition of the nucleophUe followed by loss of a leaving group— plus an additional proton transfer. The initially formed carboxylic acid reacts further under basic conditions to form the resonance-stabilized carboxylate anion, and this drives the reaction to completion. Mechanism 22.10 is written for a 1° amide. 

The resolving agent must now be removed by hydrolysis of the amide. This is a risky business as enolisation would destroy the newly formed stereogenic centre, and a cunning method was devised to rearrange the amide 30 into a more easily hydrolysed ester by acyl transfer from N to O. The rest of the synthesis is as before. By this means the alcohol 28 was obtained almost optically pure, <0.4% of the other enantiomer being present. No further reactions occur at the newly formed stereogenic centre, so the absolute chirality of 22 is as shown. 

Catalytic antibodies have been produced to catalyze an impressive variety of chemical reactions. For instance, stable phosphonic esters (or lactones, respectively) have been used as transition state mimics for the hydrolysis of esters and amides [555-557], acyl transfer [558] and lactonization [559] reactions, which all proceed via a tetrahedral carbanionic intermediate. In some instances, the reactions proved to be enantiospecific [560]. Elimination reactions [561, 562], reductions [563], formation and breakage of C-C bonds [564,565] and even photochemical reactions [566] can be catalyzed. The cleavage of an ether [567] and cis-trans isomerization of alkenes have been reported [568]. 

Acyl-transfer reactions such as ester and amide hydrolysis have most often been the target of antibody catalysis due to the broad utility of hydrolytic enzymes and the availability... 

---