Esterification of racemic alcohols

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. ... 

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

Horeau published in 1982 a pioneering work on the use of mass spectrometry to evaluate the extent of KR in the esterification of racemic alcohols by a chiral anhydride. The principle was to label by deuterium one of the enantiomers of the alcohol and use it to prepare a pseudo-racemic mixture of the alcohol [102]. Mass spectrometry revealed which enantiomer reacted preferentially with the chiral reagent... 

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). 

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. 

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. 

An enzyme-catalyzed enantioselective esterification of racemic LA 3 with -alcohols containing one to eight carbon atoms in hexane as a solvent, using Candida rugosa lipase <1997TA337>, has been described (Scheme 24). The best selectivity at 30% conversion was obtained with -hexanol, yielding the (3)-ester 176 with 72% ee, along with (K)-lipoic acid (20% ee) this decreased with -octanol (58% ee for an ester and 24% for acid) and there was a drastic drop... 

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 enzyme was not deactivated by SCCO2 and was active even in the absence of water, but the optimum rate was found at a water concentration of 0.5-1 mL/L. At 25% conversion, the e.e. of the ester was 92%, in favor of the S ester (e.e. = enantiomeric excess). The same reaction was found by Overmeyer et al. (76) to be catalyzed by a lipase from Candida antarctica B, which esterified the R enantiomer, but the enantioselectivity was poor. Wu and Liang (77) found that the enantioselectivity of esterification of racemic naproxen [Eq. (2)] was a strong function of the concentration of alcohol, with the greatest selectivity being obtained at lower alcohol concentrations. 

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. 

The same enzyme catalyses the esterification of racemic 129 in non-aqueous solution with vinyl acetate. The released alcohol is CH2=CHOH, the enol of acetaldehyde it immediately forms acetaldehyde which self condenses and is removed from the equilibrium. The enzyme is filtered off, the enantiomerically pure alcohol (S) -129 and acetate (R)-130 separated by flash chromatography, and the ester hydrolysed to the alcohol without racemisation. Either method (esterification or hydrolysis) gives both enantiomers of a range of secondary alcohols.31... 

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... 

Microwave radiation increased the rate 1- to 14-fold and the ee 3- to 9-fold (up to 92% ee for one isomer and 96% ee for the other) in the lipase-catalyzed esterification of an alcohol with vinyl acetate.34 Ultrasound increased the rate 7-to 83-fold. Directed evolution can occasionally be used to improve the enantioselectivity of lipases. A lipase for the hydrolysis of racemic p-nitrophenyl 2-methyldecanoate that gave 2% ee was run through four generations of error-prone polymerase chain reactions to raise the selectivity to 81% ee.35... 

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. 

Heumann et al. reported KRs of racemic alcohols and carboxylic acids through dicyclohexylcarbodiimide (DCC)-esterification methodology with enantiopure carboxylic acids (Equation 2.15) or secondary alcohols (Equation 2.16), respectively. Among various carboxylic acids tried, O-arylsubstituted (R)-lactic acids were the most effective for resolution of secondary alcohols, whereas (R)-l-(4-pyridyl)ethanol was chosen as the best enantioselective chiral reagent for carboxylic acids (34, 35]. 

The growing importance of 15 has lead to the development of alternative methodologies to obtain this compound enantiomerically pure. One of the most noteworthy uses the lipase from Pseudomonas fluorescens to effect a selective esterification of racemic 1-ferrocenylethanol 12a. At 50% conversion the unreacted alcohol (5)-(-l-)-12a was isolated with an enantiomeric excess of 92% and the acetate 16 had an enantiomeric purity of 96%. Simply stirring this acetate with aqueous dimethylamine resulted in formation of (/ )-(+)-lV,iV-dimethyl-a-ferrocenylethylamine with [a]o -I- 12.8, corresponding to an optical pxuity of 91%. ... 

A. Asymmetric Hydrolysis of Racemic Esters and Asymmetric Esterification or Lactonization of Racemic Alcohols... 

Esterification of racemic 2-phenoxypropanoic acids with arylalkanols can be doubly enantioselective for both compounds with Candida cylindracea lipase (CCL) in hexane [82]. The enantiomeric ratio E of acids and alcohols depend on the relative structures and, for instance, as shown in Scheme 10, a maximum value E = 108) is reached for the p-chlorophenoxy acid when the alcohol counterpart is 1-phenyl-1-ethanol E = 5.2). 

A secondary aromatic alcohol in (5) form, (5)-a-phenylethanol, did not serve as a substrate of the esterification by PEG-lipase. From the result obtained above, it can be concluded that PEG-lipase exhibited higher stereoselectivity for chiral secondary alcohols with a longer carbon chain or a phenyl group. In order to test the applicability of PEG-lipase to optical resolution of racemic alcohols, we conducted the esterification with PEG -lipase in 1,1,1-trichloroethane using racemic a-phenylethanol and dodecanoic acid [86]. As is shown in Fig. 13, the amount of the substrate, (R,5)-a-phenylethanol, decreased... 

The functions of chiral drugs in human body are closely related to their configurations. It has been reported that the R- and S-isomers of ibuprofen have quite different biological activities and toxicides. So it is imperative to prepare enan-tiomerically pure ibuprofen. Song el al. conducted a study on the lipase-catalyzed esterification of racemic ibuprofen with octanol in AOT reverse micelles [108,109] and found that the esterification is enantioselective and the main product is the corresponding S (-H)-ibuprofen ester, with the conversion yield and the enantiomer excess being about 36% and 0.9732, respectively. The water content and the concentration of AOT in the medium affected the conversion yield, but they had little influence on the enantiomeric excess (Table 15.7). Also, it was found that the chain lengths of alcohols affected both the rate of the reaction and the enantiomeric excess of the products. 

Amino alcohols can be resolved by a number of pathways including hydrolysis, esterification, and transesterification. For example, hydrolysis of Ai,0-diacet5l-2-amino-l-butanol with PPL followed by recrystallization results in (80a) with 95% ee (108). Hydrolysis of racemic acetates or butyrates of 2-[(aLkoxycarbonyl)amino]-l-aLkanols with PFL gives (R)-alcohol (81) with 95% ee (109). (3)-(81) can be obtained by transesterification of the racemic (81) with ethyl acetate which also serves as the reaction medium (109). 

Fipases and esterases are often used for Idnetic resolution of racemates, variously by hydrolysis, esterification, or transesterification of suitable precursors. Scheme 8.3-3 illustrates the principal for the resolution of a secondary alcohol by esterification with vinyl acetate. 

Orthoformates have been used in the lipase-catalyzed esterification aimed at the kinetic resolution of racemic acids such as flurbiprofen, a nonsteroidal anti-inflammatory drug (Figure 6.18). Orthoformates trap the water as it is formed through hydrolysis, and therefore prevent the reverse reaction, and, at the same time, provide the alcohol for the esteriflcation [65]. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

DKR of secondary alcohols with acidic zeolite (for racemization) and enzyme (CALB) (for esterification) LbL deposition onto zeolite itself... 

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