Acyl transfer reactions. See

Both the experimental and calculated equilibrium constants indicate the great thermodynamic instability of hemiorthoesters with respect to the corresponding esters and show why it is normally impossible to detect the tetrahedral intermediates in acyl-transfer reactions. On going from intermolecular to intramolecular reactions the tetrahedral intermediate becomes relatively more stable, and if the structure is more rigid (cf. [120], [121] in Table 17) or more sterically crowded (cf. [119]) the tetrahedral intermediate is more stable still. However, it is only with structues as rigid as tetrodotoxin or with the trifluoroacetate of pinacol that the hemiorthoester is more stable than the ester (see Section 1). ... 

For an account of enantioselective acyl transfer reactions using chiral phosphine catalysts see E. Vedejs,... 

Previous studies on amide bond formation via conversion of the bimolecular coupling reaction (see Scheme 1) into an intramolecular reaction by grafting the carboxy and amino component on a template has clearly demonstrated the strong entropic effect, i.e. the high effective local concentration on the subsequent base-catalyzed intramolecular acyl transfer reaction. 

An understanding of the molecular interactions between the acylenzyme and the attacking nucleophilic amine component allows an optimization of the acyl transfer efficiency. The efficiency of the nucleophilic attack of the amine component depends essentially on an optimal binding within the active site by S - P interactions (Fig. 12.5-11). Consequently, more information on the specificity of the S subsites of serine and cysteine peptidases are useful, which can be obtained by systematic acyl transfer studies using libraries of nucleophilic amine components. According to the definition of the p value (see above) small values of p indicate high S subsite specificity for the appropriate amine component in peptidase-catalyzed acyl transfer reactions. 

Other acyl group donors include thioesters and esters. As we will see in the final section of this chapter, acyl transfer reactions are very important in nature, particularly in the pathways responsible for breakdown of food molecules and harvesting cellular energy. 

Enzyme-mimicking systems that contain metal cations have also been designed. A very elegant supramolecular assembly was designed by Sanders et al.I l (see Fig. 7.11). They constructed trimeric porphyrin structures where Zn " " porphyrin moieties function as templates for the organization of substrates into a conformationaUy optimal configuration that undergoes an efficient acyl-transfer reaction or that lead to Diels Alder products. 

Several techniques of displacing the reaction equilibrium to reach a quasi-irreversible situation have been used previously. For a review of these, see Faber and Riva [119]. The techniques of using activated acyl donors when resolving chiral alcohols afford a more or less irreversible acylation step in the reaction mechanism since the first product is designed to be a poor nucleophile or is supposed to tautomerize or otherwise leave the re tion system (Scheme 3). Some examples of acyl donors frequently used include 2-haloethyl, cyanomethyl, oxime, and enol esters. The rates of the acyl transfer reactions of racemic 2-octanol with various esters catalyzed by porcine pancreatic lipase were one to two orders of magnitude faster when activated esters were used compared with methyl or ethyl al-kanoates [120]. 

We previously mentioned the importance of determining the appropriate solvent for acyl transfer reactions (esterification and transesterification). Nevertheless, it is difficult to select a universal solvent for the esterification of (R,S) 2-arylpropionic acids. In fact, hydrophobic solvents such as cyclohexane [98,102], isooctane [97], or the mixtures isooctane/ChC or isooctane/toluene [100] are recommended for the highly hydrophobic substrates naproxen and ibuprofen (see Tables 6 and 7). On the contrary, moderately hydrophilic acids such as ketoprofen (Table 5 [92]) or flurbiprofen (Table 8 [111]) are better esterified in sUghtly hydrophilic solvents such as cffisopropyl ether, methylwobutyl ketone, or 1,4-dioxane. Iherefore, we can conclude that depending on the hydrophobicity of the substrate we must select the organic solvent in order to obtain the best catalytic performance. 

Steps 1-2 of Figure 29.5 Acyl Transfers The starting material for fatty-acid synthesis is the thioesteT acetyl CoA, the ultimate product of carbohydrate breakdown, as we ll see in Section 29.6. The synthetic pathway begins with several priming reactions, which transport acetyl CoA and convert it into more reactive species. The first priming reaction is a nucleophilic acyl substitution reaction that converts acetyl CoA into acetyl ACP (acyl carrier protein). The reaction is catalyzed by ACP transacyla.se. 

The preparation of stereochemically enriched compounds by asymmetric acyl transfer in a stoichiometric sense can be divided into two broad classes [1] (1) those in which a racemic or achiral /weso nucleophile reacts diastereoselectively with an enantiomerically highly enriched acyl donor (Type I, see below) and (2) those in which an enantiomerically highly enriched nucleophile reacts diastereoselectively with a racemic or achiral/meso acyl donor (Type II, see below). When a racemic component is involved, the process constitutes a kinetic resolution (KR) and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoeselectivity - is 50%. When an achiral/meso component is involved, the process can constitute a site-selective asymmetric desymmetrization (ASD) or, in the case of 7r-nucleophiles and reactions involving ketenes, a face-selective addition process and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoselectivity - is 100% (Scheme 8.1). 

Better for the lateral lithiation of phenols are the N,N-dialkylcarbamate derivatives 444. These may be lithiated with LDA, allowing complete selectivity for the lateral position, presumably because this is the thermodynamic product.192 With s-BuLi ortholithiation is the predominant reaction pathway. If the lateral organolithium 445 is warmed to room temperature, an acyl transfer from O to C takes place, analogous to the anionic ortho-Fries (see section 2.3.2.1.4), giving amide 446.365... 

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