Racemic alcohol esterification

Resolution of racemic alcohols by acylation (Table 6) is as popular as that by hydrolysis. Because of the simplicity of reactions ia nonaqueous media, acylation routes are often preferred. As ia hydrolytic reactions, selectivity of esterification may depend on the stmcture of the acylatiag agent. Whereas Candida glindracea Upase-catalyzed acylation of racemic-cx-methylhenzyl alcohol [98-85-1] (59) with butyric acid has an enantiomeric value E of 20, acylation with dodecanoic acid increases the E value to 46 (16). Not only acids but also anhydrides are used as acylatiag agents. Pseudomonasfl. Upase (PFL), for example, catalyzed acylation of a-phenethanol [98-85-1] (59) with acetic anhydride ia 42% yield and 92% selectivity (74). 

Af-(ter -Butoxycarbonyl)-3-hydroxymethylpiperidine is a building block in the synthesis of a potent tryptase inhibitor. It is produced by stereospecific esterification of the racemic alcohol with succinic anhydride [30]. The enzymatic resolution is followed up by separation of... 

In particular, the combined action of a transition metal catalyst and a lipase in organic solvents for the racemization and esterification steps, respectively, has been applied for the conversion of racemic secondary alcohols into their esters... 

Lipases may also be most advantageously applied for kinetic enantiomer separation of racemic alcohols either through esterification in organic media or by hydrolysis of the corresponding acetates in water90 1161. 

Standard solid-phase peptide synthesis requires the first (C-terminal) amino acid to be esterified with a polymeric alcohol. Partial racemization can occur during the esterification of N-protected amino acids with Wang resin or hydroxymethyl polystyrene [200,201]. /V-Fmoc amino acids are particularly problematic because the bases required to catalyze the acylation of alcohols can also lead to deprotection. A comparative study of various esterification methods for the attachment of Fmoc amino acids to Wang resin [202] showed that the highest loadings with minimal racemization can be achieved under Mitsunobu conditions or by activation with 2,6-dichloroben-zoyl chloride (Experimental Procedure 13.5). iV-Fmoc amino acid fluorides in the presence of DMAP also proved suitable for the racemization-free esterification of Wang resin (Entry 1, Table 13.13). The most extensive racemization was observed when DMF or THF was used as solvent, whereas little or no racemization occurred in toluene or DCM [203]. 

Acid anhydrides have been also used due to the irreversibities of the reaction and the advantage in downprocessing.6 For example, the esterification of a racemic alcohol with succinic anhydride gives (S)-alcohol and (R)-ester (Figure 6(d)). The latter has an acid moiety so can be separated easily from the former due to the solubility difference in weakly basic water. 

Imagine the reaction between a chiral, but racemic alcohol and a chiral, but racemic carboxylic acid, to give an ester in an ordinary acid-catalysed esterification (Chapter 12). 

We could then reverse the esterification step, and hydrolyse either of these diastereoisomers, to regenerate racemic alcohol and racemic acid. 

Enzymatic hydrolysis of meso-substrates to enantiomericaily pure compounds is especially efficacious because the maximum theoretical conversion is 100%. However, racemic chiral alcohols can also be conveniently resolved via en-antioselective esterification" wherein an enzyme mediates acyl transfer to enantiomers of a given alcohol at different rates, albeit with a maximum theoretical conversion of only 50%.625 A practical application of such a kinetic resolution is shown in the PPL-mediated esterification of the racemic alcohol 332.1 [Scheme 4.332]636 and many other examples of equal efficiency are known. 

Lipases have been extensively used for the kinetic resolution of racemic alcohols or carboxylic acids in organic solvents. Chiral alcohols are usually reacted with achiral activated esters (such as vinyl, isopropenyh and trichloroethyl esters) for shifting the equilibrium to the desired products and avoiding problems of reversibility. For the same reasons, chiral acids are often resolved by using acidolysis of esters. In both cases, the overall stereoselectivity is affected by the thermodynamic activity of water of water favors hydrolytic reactions leading to a decrease in the optical purity of the desired ester. Direct esterifications are therefore difficult to apply since water formed during the reaction may increase the o of the system, favors reversibiUty, and diminishes the overall stereoselectivity. 

In addition to this, there are several reports of asymmetric esterification of racemic alcohols with anhydrides as acyl donors. Examples include various primary and secondary alcohols, bicyclic secondary alcohols of the norbomane type, amino alcohols, and ferrocenes. This is exemplified in eq 9 for 1 -phenylethanol. ... 

Kinetic Resolution by Direct Esterification. This is the least common strategy for kinetic resolution and is most commonly executed on racemic alcohols with carboxylic acids in organic solvents. Reports include several alicyclic secondary alcohols such as menthol and various aliphatic secondary alcohols. Kinetic resolution of a variety of racemic saturated, unsaturated, and a-substituted carboxylic acids has also been effected by direct esterification with various alcohols. ... 

Utilization of enzymes in organic synthesis to prepare chiral compounds of synthetic value is well documented.For instance, porcine pancreatic hpase (PPL, E.C. 3.1.1.3.) which is an inexpensive commercially available enzyme, specifically catalyzes the hydrolysis of esters of racemic alcohols and wc50-diols. Thus, on a preparative scale (0.25 mol) dimethyl 2-methyl-butanedioate, on treatment with PPL in buffered water at pH 7.2, underwent regio- and en-antioselective hydrolysis. Extraction with diethyl ether gave the unhydrolyzed dimethyl (/ )-2-methylbutanedioate (93%), while acidification of the aqueous phase provided the (5)-half ester,which on esterification with methanol (acidified by thionyl chloride) gave the dimethyl (5 )-2-methylbutanedioate (76%). 

The starting material 212 was chosen as it was available from natural arabinose and contains enough functionality for the purpose. Esterification with racemic alcohol 211 gave a mixture of esters 213. This does not seem to matter as that centre is destroyed in the Claisen-Ireland rearrangement giving 214 but this compound was formed as a 43 57 mixture of diastereoisomers. 

Enzymes can also be used in sc carbon dioxide.185 A Pseudomonas lipase immobilized on silica gel gave better conversions and enantioselectivity in the acetylation of racemic alcohols with acetic anhydride than when used in organic solvents.186 The lipase-catalyzed esterification of glycidol gave 83% enantioselectivity, which is as favorable as when the reaction is run in organic solvents.187 An immobilized lipase has been used in the ethanolysis of cod liver oil.188 Another immobilized lipase has been used to convert oleic acid to various esters.189 The use of a lipase in sc carbon dioxide for analyses of fats in foods cuts solvent use by 98%.190 Polyesters have been made enzymatically in carbon dioxide.191... 

Attack on Nitrogen, Chalcogen or Halogen. - Esterifications of racemic alcohols with acids have been realised with moderate enantiospecificity when... 

Scheme 3.6), the resolution of a racemic alcohol can be effected by enantioselec-tive hydrolysis of the corresponding ester or by esterification of the alcohol. As the biocatalyst displays the same stereochemical preference in both reactions, the desired product can be obtained with higher optical yields, if the two steps are coupled sequentially. The basis of this approach parallels that of product recycling in hydrolytic reactions. However, tedious chromatographic separation of the intermediates and the accompanying re-esterification is omitted. 

The expression KR emphasizes that the racemic mixture undergoes a separation under a chiral influence in a kinetically controlled process. In principle, the word resolution refers to the isolation of one of the enantiomers of racemic mixture after a partial transformation of the initial mixture. If the reaction product is chiral, as in the esterification of a racemic alcohol, then the KR will afford a product with some enantiomeric excess. The full transformation of a racemic mixture by coupling with a chiral auxiliary will give a 1 1 mixture of diastereomers and is not considered as a KR process, unless the reaction is stopped at an intermediate stage, leaving some enantioenriched starting material. 

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