Racemates, resolution using

Scheme 2.2.5.2 Diastereoselective kinetic racemate resolution using the Class II aldolase FucA.

Stereoselective enzymatic hydrolyses of esters represent a further type of biotransformation that has been used for the synthesis of optically active organosilicon compounds. The first example of this particular type of bioconversion is illustrated in Scheme 15. Starting from the racemic (l-acetoxyethyl)silane rac-11, the optically active (l-hydroxyethyl)silane (5)-41 was obtained by a kinetic racemate resolution using porcine liver esterase (PLE E.C. 3.1.1.1) as the biocatalyst7. The silane (5)-41 (isolated with an enantiomeric purity of 60% ee bioconversion not optimized) is the antipode of compound (R)-41 which was obtained by an enantioselective microbial reduction of the acetylsilane 40 (see Scheme 8). 

Table 13.1 Selected examples of racemate resolution using cinchona alkaloids. 

So far, the P DC-catalyzed formation of (R)-PAC (whole cell biotransformation) is the only process for fhe synfhesis of chiral 2-hydroxyketones via carlioligallon used on an industrial scale. The transformations depicted in Scheme 4.3 might provide access to chiral intermediates used in fhe synthesis of biologically active compounds, like fhe antifungal Ro 09-3355 [24], the antidepressant bupropion [25], and the analgesic naproxen [26]. So far, such chiral building blocks have mostly been synthesized by racemic resolution using e. g. lipases. 

The enantiomers of the silanes 10 and 11 were obtained from the corresponding racemic mixtures rac-10 (for its synthesis see Scheme 4) and rac-11 (for its synthesis see Scheme 5) by a classical racemate resolution using the enantiomers of 0,0 -di-p-toluoyltartaric acid and l,l -binaphthyl-2,2 -diyl hydrogen phosphate, respectively, as resolving agents (for resolution by fractional crystallization of diastereomeric salts see Scheme The silanes (/f)-10, (5)-10, (/J)-ll and (S)- were isolated as almost... 

Four general methods have been used for obtaining chiral ligands resolution of a racemic mixture, use of a chiral naturally occurring product 33), and asymmetric homogeneous or heterogeneous hydrogenation. 

Based on chiral functional monomers such as (15), MICSPs can be prepared using a racemic template. Thus, using racemic A-(3,5-dinitrobenzoyl)-a-methylbenzy-lamine (16) as template, a polymer capable of racemic resolution of the template was obtained [67]. Another chiral monomer based on L-valine (17), was used to prepare MIPS for the separation of dipeptide diastereomers [68]. In these cases the configu-... 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

The most common method of resolution uses an acid-base reaction between a racemic mixture of chiral carboxylic acids (RC02H) and an amine base (RNH2) to yield an ammonium salt. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

The major drawback to using oxathianes 3 is that they are difficult to obtain in optically pure form because their synthesis includes a tedious racemate resolution. In order to circumvent this problem, oxathiane 11 was developed. Its synthesis starts with the readily available ( + )-10-camphorsulfonie acid (8)49. 

Another example of enzyme- and acid-catalyzed DKR has been reported by Bornscheuer [45]. Acyloins were racemized by using an acidic resin through the formation of enol intermediates. The enzymatic resolution was catalyzed by CALB. Since deactivation of this enzyme occurred in the presence of the acidic resin, they designed a simple reactor setup with two glass vials cormected via a pump to achieve a spatial separation between the acidic resin and the enzyme (Figure 4.20). 

Figure 10.17 Kinetic enantiopreference of class II DHAP aldolases useful for racemic resolution of a-hydroxyaldehydes.

Figure 10.32 Applications of bidirectional chain extension for the synthesis of disaccharide mimetics and of annulated and spirocyclic oligosaccharide mimetics using tandem enzymatic aldol additions, including racemate resolution under thermodynamic control.

Stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on page 132. A method has been developed to evaluate the enantiomeric ratio of kinetic resolution using only the extent of substrate conversion. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane, since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as (56 with one... 

The first reductive kinetic resolution of racemic sulphoxides was reported by Balenovic and Bregant. They found that L-cysteine reacted with racemic sulphoxides to produce a mixture of L-cystine, sulphide and non-reduced optically active starting sulphoxide (equation 147). Mikojajczyk and Para reported that the reaction of optically active phosphonothioic acid 268 with racemic sulphoxides used in a 1 2 ratio gave the non-reduced optically active sulphoxides, however, with a low optical purity (equation 148). It is interesting to note that a clear relationship was found between the chirality of the reducing P-thioacid 268 and the recovered sulphoxide. Partial asymmetric reduction of racemic sulphoxides also occurs when a complex of LiAlH with chiral alcohols , as well as a mixture of formamidine sulphinic acid with chiral amines, are used as chiral reducing systems. ... 

Figure 5.19 Recycling experiments in the kinetic resolution of racemic amine using the sol-gel CaLB immobilizate prepared with 18-crown-6 as an additive. (Reproduced from ref. 30, with permission.)... 

The kinetic resolution using a chiral zirconocene-imido complex 286 took place with high enantioselectivity to result in chiral allenes 287 (up to 98% ee) (Scheme 4.74) [116]. However, a potential drawback of these methods is irreversible consumption of half of the allene even if complete recovery of the desired enantiomer is possible. Dynamic kinetic resolutions avoid this disadvantage in the enantiomer-differentiating reactions. Node et al. transformed a di-(-)-L-menthyl ester of racemic allene-l,3-dicarboxylate [(S)- and (RJ-288] to the corresponding chiral allene dicarbox-ylate (R)-288 by an epimerization-crystallization method with the assistance of a catalytic amount of Et3N (Scheme 4.75) [117]. 

Reactivity of oxiranes with organolithium reagents TABLE 9. Kinetic resolution of racemic oxiranes using HCLA 53... 

Although planar structures for 111 and 112 were not attained, it is still likely that these novel diazabiaryls can serve as chiral ligands with C2 symmetry. In support of this likelihood, the resolution of 112 was accomplished recently on swollen, microcrystalline triacetylcellulose by Jan Sandstrom. The free energy barrier to ring inversion of 112 was found to be about 101 kJ/mol, through a thermal racemization process using chiral 112. ... 

There are basically two approaches to the synthesis of enantiomerically pure alcohols (i) kinetic resolution of the racemic alcohol using a hydrolase (lipase, esterase or protease) or (ii) reduction mediated by a ketoreductase (KRED). Both of these processes can be performed as a cascade process. The first approach can be performed as a dynamic kinetic resolution (DKR) by conducting an enzymatic transesterification in the presence of a redox metal [e.g. a Ru(ll) complex] to catalyze in situ racemization of the unreacted alcohol isomer [11] (Scheme 6.1). We shall not discuss this type of process in any detail here since it forms the subject of Chapter 1. 

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