Transesterification reaction, acyl transfer

Several additional points should be made. First, although oxygen esters usually have lower group-transfer potentials than thiol esters, the O—acyl bonds in acylcarnitines have high group-transfer potentials, and the transesterification reactions mediated by the acyl transferases have equilibrium constants close to 1. Second, note that eukaryotic cells maintain separate pools of CoA in the mitochondria and in the cytosol. The cytosolic pool is utilized principally in fatty acid biosynthesis (Chapter 25), and the mitochondrial pool is important in the oxidation of fatty acids and pyruvate, as well as some amino acids. 

A proposed mechanism for this transformation, provided in Scheme 42, is based on the identification of alcohol-carbene complexes by Movassaghi and Schmidt. Mesityl substituted imidazolinylidine carbene acts as a Brpnsted base as transesterification occurs to produce LXVII. Upon O N acyl transfer, the observed product is formed. The evidence provided for this mechanism includes the control experiment in which LXVII is resubjected to the reaction conditions and proceeds with amide formation. A similar mechanism has recently been reported in a theoretical study of transesterification by Hu and co-workers [139], In light of this work, it seems reasonable to suggest a similar that mechanism is operative in the transesterification reactions discussed throughout this section. 

As shown in previous sections, NHCs promote acyl transfer in transesterification reactions. In a similar manner, O C acyl transfer can be achieved with substrates such as 351 in the presence of 0.9 mol% of triazolium pre-catalyst 353 and KHMDS (Scheme 53). Moderate yields are obtained by varying substitution of the oxazole from R = Me, Ph, t-Bu, and t-Pr [171], Deprotonation of the triazolium salt followed by nucleophilic addition to the carbonate moiety of the oxazole results in enolate intermediate LXXXIII and activated carboxylate LXXXIV. Enolate addition and regeneration of the active catalyst provides quaternary stereocenters 352. 

Lin, M.-H. RajaBabu, T. V. Metal-catalyzed acyl transfer reactions of enol esters role of Y5(OiPr)i30 and (thd)2Y(OiPr) as transesterification catalysts. Org. Lett. 2000, 2, 997-1000. 

An interesting version of the transesterification reactions was reported by Movassaghi et al., with the amidation of unactivated esters with amino alcohols (Scheme 9.27) [73]. The amidation was explained by carbene-alcohol interactions. A nucleophilic activation of the hydroxyl group of the aminoalcohol 90 by the catalyst 11 is followed by transesterification to the ester 91 which is in-situ-converted to the amide 92 through a N —> O acyl transfer. Various aliphatic and aromatic esters with different functionalities, as well as chiral aminoalcohols, are suitable for this reaction. 

Under almost anhydrous conditions in organic medium, lipases can be used in the reverse mode for direct ester synthesis from carboxylic acids and alcohols, as well as transesterifications (acyl transfer reactions) which can be divided into alcoholysis (ester and alcohol), acidolysis (ester and acid), and interesterification (ester-ester interchange). The direct esterification and alcoholysis in particular have been most frequently used in asymmetric transformations involving lipases. The parameters that influence enzymatic catalysis in organic solvents have been intensively studied and discussed. ... 

Prochiral Compounds. The enantiodifferentiation of prochi-ral compounds by lipase-catalyzed hydrolysis and transesterification reactions is fairly common, with prochiral 1,3-diols most frequently employed as substrates. Recent reports of asymmetric hydrolysis include diesters of 2-substituted 1,3-propanediols and 2-0-protected glycerol derivatives. The asymmetric transesterification of prochiral diols such as 2-0-benzylglycerol and various other 2-substituted 1,3-propanediol derivatives is also fairly common, most frequently with Vinyl Acetate as an irreversible acyl transfer agent. 

The esterases and lipases are members of a still larger group of enzymes that catalyze acyl transfer, either in the direction of solvolysis or by acylation of the substrate. Both types of enzymes are called hydrolases. In water, hydrolysis occurs, but in the presence of alcohols, transesterification can occur. Reactions in the acylation direction are done in the presence of acyl donors. Esters of enols such as vinyl acetate or isopropenyl acetate are often used as sources of the acyl group. These enol esters are more reactive than alkyl esters, and the enol that is displaced on acyl transfer is converted to acetaldehyde or acetone. To avoid side products arising from these carbonyl compounds, one can use 1-ethoxyvinyl esters, which give ethyl acetate as the by-product. ... 

Before fatty acid synthesis can occur, however, the acyl groups of acetyl-CoA and malonyl-CoA are transferred to other thiols by means of a transesterification reaction. 

A second example involves a transesterification reaction catalyzed by an antibody generated against a phosphonate diester transition state analogue [11]. The antibody catalyzes the corresponding acyl transfer reaction of thymidine and an alanyl ester with an effective molarity of 3 x 10 m... 

Tetrasubstituted guanidines catalyse the methylation of phenols using dimethylcarbonate. When DBU is used as catalyst, the reaction temperature is lower. Methylation of acids has also been accomplished. TBD has been demonstrated to be an excellent catalyst for acyl transfer and transesterification reactions. Vinyl acetate with TBD forms AT-acetyl TBD that hy adding benzyl alcohol results in formation of the corresponding acetate and regeneration of the TBD. TBD has also heen used for the ring-opening polymerisation of cyclic esters. ... 

The most satisfactory method to carry out an irreversible transesterification is the reaction of acylation of an alcohol with vinyl acylates [130,131]. In this reaction the back reaction is prevented by the irreversible tautomerization of vinyl alcohol to acet dehyde. This latest product could cause the inhibition of the enzyme that has been hnmobilized to overcome this complication [132]. In some studies, however, a few cycles of reactions could be performed without affecting the enantioselectivity of the reaction [133]. Also oxime esters have been proposed as acyl transfer agents [134] for irreversible enzymatic transesterifications (Scheme 23). 

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. 

In a lipase-catalyzed reaction, the acyl group of the ester is transferred to the hydroxyl group of the serine residue to form the acylated enzyme. The acyl group is then transferred to an external nucleophile with the return of the enzyme to its preacylated state to restart the catalytic cycle. A variety of nucleophiles can participate in this process. For example, reaction in the presence of water results in hydrolysis, reaction in alcohol results in esterification or transesterification, and reaction in amine results in amination. Kirchner et al.3 reported that it was possible to use hydrolytic enzymes under conditions of limited moisture to catalyze the formation of esters, and this is now becoming very popular for the resolution of alcohols.4... 

The acyl-GoA can cross the outer mitochondrial membrane but not the inner membrane (Figure 21.5). In the intermembrane space, the acyl group is transferred to carnitine by transesterification this reaction is catalyzed by the enzyme carnitine acyltransferase, which is located in the inner membrane. Acyl-carnitine, a compound that can cross the inner mitochondrial membrane. 

The transesterification of N-(j3-hydroxyethyl)ethylenediamine by p-nitro-phenyl picolinate has been shown to be subject to zinc ion catalysis by Sigman and Jorgensen 27). Their investigations indicate that reaction very probably occurs through the formation of a ternary complex in which zinc ion functions both to lower the pKa of the hydroxyethyl moiety, and to serve as a template for the reaction. The high specificity manifest in this catalytic process is emphasized by the fact that no catalysis of acyl-group transfer occurs when N-((8-hydroxy-ethyl) ethylenediamine is replaced by ethylenediamine, 1,5-diaminopentane, di-ethylenetriamineor aminoethanol. Furthermore, the reactions of the p-nitrophenyl esters of isonicotinic and acetic acids with N-((8-hydroxyethyl) ethylenediamine are not subject to zinc ion catalysis. 

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