Activated acyl donors

Acetyloximes have been shown to react faster than simple esters and enol esters, but a non-volatile oxime by-product is formed that may cause purification problems. The most popular choice of acyl donor is the vinyl ester, which give virtually irreversible acylation-forming volatile acetaldehyde as a by-product Acetaldehyde has been shown in some cases to inactivate the enzyme by imine formation with lysine residues. The use of anhydrides is also considered irreversible but releases 

Examples of Lipase-, Lipolase- and Hydrolase-Catalysed Reactions in Synthesis 

A large number of investigations have been reported on the use of lipases in KR of racemic alcohols, amines and esters. Accurate determination of the enantiomeric excess (ee) of both substrate and product wiU be crucial for reliability of the KR data obtained, and this in turn is dependent upon the development of a suitable analytical procedure for the baseline separation of substrate and product in a single chromatography run [9]. 

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Figure 6.45 Activated acyl donors for irreversible acylation of alcohols.

Besides allylic substitution reactions it was also shown that [Fe(CO)3(NO)] 76 is catalytically active in transesterification reactions under neutral conditions (Scheme 24) [70]. Various activated acyl donors 97 can be used to give rise to the corresponding carboxylic esters 100 in good to excellent yields. This reaction proceeds in the absence of additional ligands in nonpolar solvents, for example, hexane. Mechanistically, the reaction is assumed to proceed via a Fe-acyl-complex 98 (Scheme 24). 

In the presence of an active acyl donor such as isopropenyl acetate, a reductive acetylation of a ketone can be performed in the presence of MPVO catalysts... 

Table 2 Initial reaction rates and normalized reaction rates (between brackets) of alcohols and amines using a normal acyl donor or a p-oxygen-activated acyl donor[28]...

Scheme 4.4 Irreversible hydrolase-catalyzed acylation with an activated acyl donor.

In the kinetically controlled synthesis, an activated acyl donor (ester, amide, or anhydride) is used to form an acyl-enzyme intermediate. 

Once bearing some substituents, the decrease of polarity of the sucrose derivatives makes them soluble in less-polar solvents, such as acetone or tert-butanol, in which some lipases are able to catalyze esterifications. Unlike proteases, which necessitate most often the use of an activated acyl donor (such as vinyl or trifluoroethyl esters), lipases are active with simple esters and even the parent carboxylic acids in the presence of a water scavenger. The selectivity of the lipase-catalyzed second esterification is specific for OH-6 allowing the synthesis of mixed T,6 -diesters.123,124 For some lipases, a chain-length dependence on the regiochemistry was observed.125 Selectively substituted monoesters were thus prepared and studied for their solution and thermotropic behavior.126,127 Combinations of enzyme-mediated and purely chemical esterifications led to a series of specifically substituted sucrose fatty acid diesters with variations in the chain length, the level of saturation, and the position on the sugar backbone. This allowed the impact of structural variations on thermotropic properties to be demonstrated (compare Section III.l).128... 

Most of lipase-catalyzed acylations of sugars in organic solvents have been reported as transesterification rather than esterification reactions. The displacement of the equilibrium towards products has been accomplished by using activated acyl donors [58] such as 2,2,2-trichloroethyl esters and, more often, enol esters. The use of enol esters, such as a vinyl or an isopropenyl ester, was, in fact, first reported in lipase-catalyzed reactions with sugars [59]. In the reaction, an unstable enol is liberated which instantaneously tautomerizes to the corresponding aldehyde or ketone, making the reaction irreversible. 

Activated acyl donors such as vinyl esters, halogenated methyl or ethyl ester, oxime esters or carboxylic acid anhydrides are often preferred for acylation of alcohols. With vinyl esters, acylation is in general fast and quantitative, as the equilibrium is driven by the release of vinyl alcohol, which will spontaneously tautomerize to volatile acetaldehyde. Amine nucleophiles will typically react spontaneously with these acyl donors, which hence cannot be used for resolution of amines. Vinyl acetate and ethyl acetate are common reagents (and often also solvents) for enzymatic kinetic resolution of alcohols and amines, respectively [9],... 

Racemization of the activated acyl donor involving its a-center is largely suppressed. 

Scheme 4.5 Activated acyl donors and the by-products formed upon transesterification.

A useful class of activated acyl donors are enol esters, such as vinyl acetate or iso-propenyl acetate (Figure 5.4a). The product alcohol tautomerizes to a carbonyl compound, thereby driving the reaction toward product and eliminating possible inhibition by the released alcohol. Another activated acyl donor is succinic anhydride that yields a monosuccinate ester that can be easily separated from the starting alcohol by extraction with a basic aqueous phase. 

The success of chemoenz)nnatic peptide synthesis is critically dependent on the availability of effective peptide coupling and modification enzymes, both in the case of kinetically controlled synthesis with an activated acyl donor and in tire case of thermodynamically controlled synthesis starting with free amino acids or peptides. If the coupling reaction case is kinetically controlled, critical properties are a high synthesis/hydrolysis... 

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]. 

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