Esters from alcohols with resolution

Other biocatalysts were also used to perform the dynamic kinetic resolution through reduction. For example, Thermoanaerobium brockii reduced the aldehyde with a moderate enantioselectivity [30b,c], and Candida humicola was found, as a result of screening from 107 microorganisms, to give the (Jl)-alcohol with 98.2% ee when ester group was methyl [30dj. 

With the appropriate choice of enzyme, it has been found that only one enantiomer of the racemic mixture is hydrolysed, whilst the other remains unreacted. It is then a simple matter to separate the unreacted ester from the alcohol. The unreacted ester may then be hydrolysed chemically, thus achieving resolution of the enantiomeric alcohols. 

Figure 2.11 Transesterification of a racemic mixture of a secondary alcohol (1 -phenoxy-2-propanol, 1 in Table 2.1) with a butanoic acyl donor follows a ping-pong bi-bi mechanism in which Substrate 1 (acyl donor) enters the enzyme, forms an acyl enzyme expelling Product 1 (the leaving alcohol from the acyl donor). Then another Substrate 2 (the enantiomers of the alcohol to be resolved) reacts with the acyl enzyme to liberate Product 2 (the enantiomers of the produced esters), leaving the enzyme in its original form. In a kinetic resolution one of the enantiomeric alcohols reacts faster than the other to form an excess of one enantiomer of the esters (ideally enantiopure, for 1 the (R)-ester was formed with very high ee). The success of the resolution is expressed by the enantiomeric ratio E, which depends on the difference in free energy of activation of the two diastereomeric transition states. These are in turn related to the two tetrahedral intermediates.

Esters are widespread in fruits and especially those with a relatively low molecular weight usually impart a characteristic fruity note to many foods, e.g. fermented beverages [49]. From the industrial viewpoint, esterases and lipases play an important role in synthetic chemistry, especially for stereoselective ester formations and kinetic resolutions of racemic alcohols [78]. These enzymes are very often easily available as cheap bulk reagents and usually remain active in organic reaction media. Therefore they are the preferred biocatalysts for the production of natural flavour esters, e.g. from short-chain aliphatic and terpenyl alcohols [7, 8], but also to provide enantiopure novel flavour and fragrance compounds for analytical and sensory evaluation purposes [12]. Enantioselectivity is an impor-... 

The Pasteur method can also be applied to the resolution of neutral racemates, if these can be first converted into an acidic or basic derivative from which eventually a mixture of crystalline diastereoisomeric salts may be prepared by appropriate neutralisation. Thus, a racemic alcohol (e.g. ( )-octan-2-ol, Expt 5.220) may be converted into the corresponding racemic hydrogen phthalate ester by heating with phthalic anhydride, and the ester is then resolved by the Pasteur procedure using an optically active base. The resulting optically active hydrogen phthalate ester is then carefully hydrolysed with aqueous sodium hydroxide to regenerate one of the optically active forms of the alcohol. 

Phthalic anhydrides readily form hydrogen phthalate esters on reaction with alcohols the derivatives from 3-nitrophthalic anhydride are usually nicely crystalline compounds and are hence suitable for purposes of characterisation. Hydrogen phthalate esters are also useful in appropriate instances for the resolution of racemic alcohols (Section 5.19). 

By far the commonest reaction used in kinetic resolution by enzymes is ester formation or hydrolysis. Normally one enantiomer of the ester is formed or hydrolysed leaving the other untouched so one has the easy job of separating an ester from either an acid or an alcohol. There are broadly two kinds of enzymes that do this job. Lipases hydrolyse esters of chiral alcohols with achiral acids such as 119 while esterases hydrolyse esters of chiral acids and achiral alcohols such as 122. Be warned this definition is by no mans hard and fast If the unreacted component (120 or 123) is wanted, the reaction is run to just over 50% completion, to ensure complete destruction of the unwanted enantiomer, while if the reacted component (121 or 124) is wanted it is best to stop short of 50% completion so that little of the unwanted enantiomer reacts. 

A chemical reaction is carried out between the racemate and an optically active form (either laevo-or dextro-) of a substance capable of reacting with the racemate. This other optically active compound is usually derived from a natural source. To resolve the racemates of amines (or other bases) and alcohols, for example, use may be made of the naturally occurring d-tartaric acid (from wine tartar). The reaction with amines gives salts and esters are formed with alcohols. For the resolution of racemates of acids, use is frequently made of alkaloids such as quinine or stiychnine extracted from plants in which each of these alkaloids is present in an optically active form. The racemate mixture forms two diastereoisomers (compounds that are stereoisomers of each other, but are not enantiomers) of a derivative, with the optically active reagent used. If the... 

The most familiar of the sulfonic adds derived from camphor is 10-camphorsulfonic add (44, Reychler s acid45). Both enantiomers are commercially available and convenient procedures exist for their preparation by sulfonation of camphor (ref 46 exemplifies the racemate, but the procedure works equally well for optically active camphor). The free acid is often applied to the resolution of basic compounds such as amines. A detailed review on the use of derivatives of this acid as auxiliaries has been given3. Esters of this add are normally obtained by the reaction of the alcohols with the sulfonyl chloride which is also commerdally available (or readily obtained by the reaction of the free acid with phosphorus pentachloride or thionyl chloride46,48). Such esters with unsaturated alcohols have been used for diastereoselective [1,2] sigma tropic rearrangements (Section D.1.6.3.3.). Allyl esters have been used for enantioselective alkylation reactions, in which camphorsulfonic acid reacts as the chiral leaving group (Section D.1.1.2.2.). 

In both cases, the process was repeated resulting in an improvement of the enantiomeric excesses of the recovered substrates or the produced esters. As an example, the (R)-enriched 1-phenylethanol (44% ee) obtained from resolution of the racemic alcohol with acid 1 was re-subjected to the same conditions to give 1-phenylethanol of improved enantiomeric excess (61%) together with an ester of depleted de (25%) in comparison with the first-resolution reaction (Equation 2.17). 

Similar reactions can be realized in the presence of acetone powder from germinating rapeseed [69] or with immobilized lipase in supercritical carbon dioxide [70]. The application of interesterification reactions to enantioselective resolutions has found scarce examples. For instance, it has been reported that when racemic 2-(p-chlorophenoxy)propionic acid is used to exchange with acetic acid of the racemic acetates of a bicycloheptanol and 2-methoxycyclohexanol, optically active p-chlorophenoxy esters are obtained (Scheme 4). The enzymatic process is diastereoselective and doubly enantioselective for the acid and alcohols [71]. Another example of enantioselective interesterification in organic solvents leading to a nearly optically pure octanoate (Scheme 5) proceeds via acid exchange of the formate of a pyranyl alcohol with methyl octanoate [72]. 

One approach called enzymatic resolution, involves treating a racemic mixture with an enzyme that catalyzes the reaction of only one of the enantiomers Some of the most commonly used ones are lipases and esterases enzymes that catalyze the hydrol ysis of esters In a typical procedure one enantiomer of the acetate ester of a racemic alcohol undergoes hydrolysis and the other is left unchanged when hydrolyzed m the presence of an esterase from hog liver... 

Both saturated (50) and unsaturated derivatives (51) are easily accepted by lipases and esterases. Lipase P from Amano resolves azide (52) or naphthyl (53) derivatives with good yields and excellent selectivity. PPL-catalyzed resolution of glycidyl esters (54) is of great synthetic utiUty because it provides an alternative to the Sharpless epoxidation route for the synthesis of P-blockers. The optical purity of glycidyl esters strongly depends on the stmcture of the acyl moiety the hydrolysis of propyl and butyl derivatives of epoxy alcohols results ia esters with ee > 95% (30). 

Two more examples ia Table 5 iaclude the hydrolysis of esters of trans-alcohols that proceed with high efficiency practically regardless of the nature of the substituents (72) and resolution of P-hydroxynitriles with Upase from Pseudomonas sp. In the latter case the enantioselectivity of the hydrolysis was improved by iatroduciag sulfur iato the acyl moiety (73). 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

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