First kinetic resolution

This method relies on the chemical transformation of a racemate in which one of the enantiomers forms a product more rapidly than the other. The very first kinetic resolution of enantiomers was described by Pasteur [65]. This was the resolution of tartaric acid by fermenting yeast. Later, it was found that not only enzymes but also other chiral inductors such as chiral reagents, chiral catalysts, solvents or polarized light beam may effect kinetic resolution. It is important to note that the interaction time must be carefully controlled in kinetic resolution. The reaction has to be stopped at some point short of 100% conversion. Otherwise, both enantiomers of the starting material will be converted into the product, and no resolution is obtained. The slower interacting enantiomer can be obtained in an enantiomeri-cally enriched or even pure form. The product of a kinetic resolution may be either chiral or achiral. 

The ester 194b was obtained with 53 % yield and 44% ee (e.r. 194b enf-194b= 72 28) and the stannane e M98 was recovered (33%, 60% ee). The (l S)-enan-tiomer 198 is cleaved more rapidly than (ri )-198 (e M98). To our best knowledge, this reaction represents the first kinetic resolution by Hthiodestaimylation. 

The first kinetic resolutions of phosphine boranes have been recently reported by O Brien and co-workers (entry 5), via deprotonation with, s-BuLi/(-)-sp. With this procedure, products with up to 82% ee were obtained. 

The first application of the Jacobsen-Katsuki epoxidation reaction to kinetic resolution of prochiral olefins was nicely displayed in the total synthesis of (+)-teretifolione B by Jacobsen in 1995. 

Two recent reports described addition of nitrogen-centered nucleophiles in usefully protected fonn. Jacobsen reported that N-Boc-protected sulfonamides undergo poorly selective (salen) Co-catalyzed addition to racemic epoxides. However, by performing a one-pot, indirect kinetic resolution with water first (HKR, vide infra, Table 7.1) and then sulfonamide, it was possible to obtain highly enantiomer-ically enriched addition products (Scheme 7.39) [71]. These products were transformed into enantioenriched terminal aziridines in straightforward manner. 

Andersson also showed that, in addition to meso-desymmetrization, kinetic resolution of some cyclic epoxides by use of the first-generation catalyst was also possible, giving both epoxides and allylic alcohols in good yields (Scheme 7.51) [108], Kozmin reported the effective use of the same catalyst in the desymmetrization of diphenylsilacyclopentene oxide. The resulting products could be used in the ster-eocontrolled syntheses of various acyclic polyols (Scheme 7.52) [109]. 

Chiral sulphoxides are the most important group of compounds among a vast number of various types of chiral organosulphur compounds. In the first period of the development of sulphur stereochemistry, optically active sulphoxides were mainly used as model compounds in stereochemical studies2 5 6. At present, chiral sulphoxides play an important role in asymmetric synthesis, especially in an asymmetric C—C bond formation257. Therefore, much effort has been devoted to elaboration of convenient methods for their synthesis. Until now, optically active sulphoxides have been obtained in the following ways optical resolution, asymmetric synthesis, kinetic resolution and stereospecific synthesis. These methods are briefly discussed below. 

Several reports regarding the directed evolution of enantioselective epoxide hydrolases (EHs) have appeared [23,57-59]. These enzymes constitute important catalysts in synthetic organic chemistry [4,60]. The first two reported studies concern the Aspergillus niger epoxide hydrolase (ANEH) [57,58]. Initial attempts were made to enhance the enantioselectivity of the AN E H -catalyzed hydrolytic kinetic resolution of glycidyl phenyl ether (rac-19). The WT leads to an Evalue of only 4.6 in favor of (S)-20 (see Scheme 2.4) [58]. 

The choice of the particular upward pathway in the kinetic resolution of rac-19, that is, the specific order of choosing the sites in ISM, appeared arbitrary. Indeed, the pathway B C D F E, without utilizing A, was the first one that was chosen, and it led to a spectacular increase in enantioselectivity (Figure 2.15). The final mutant, characterized by nine mutations, displays a selectivity factor of E=115 in the model reaction [23]. This result is all the more remarkable in that only 20000 clones were screened, which means that no attempt was made to fully cover the defined protein sequence space. Indeed, relatively small libraries were screened. The results indicate the efficiency of iterative CASTing and its superiority over other strategies such as repeating cycles of epPCR. 

The phosphotriesterase from Pseudomonas diminuta was shown to catalyze the enantioselective hydrolysis of several racemic phosphates (21), the Sp isomer reacting faster than the Rp compound [65,66]. Further improvements using directed evolution were achieved by first carrying out a restricted alanine-scan [67] (i.e. at predetermined amino acid positions alanine was introduced). Whenever an effect on activity/ enantioselectivity was observed, the position was defined as a hot spot. Subsequently, randomization at several hot spots was performed, which led to the identification of several highly (S)- or (R)-selective mutants [66]. A similar procedure was applied to the generation of mutant phosphotriesterases as catalysts in the kinetic resolution of racemic phosphonates [68]. 

In an asymmetric synthesis, the enantiomeric composition of the product remains constant as the reaction proceeds. In practice, ho vever, many enzymatic desymmetrizations undergo a subsequent kinetic resolution as illustrated in Figure 6.5. For instance, hydrolysis of a prochiral diacetate first gives the chiral monoalcohol monoester, but this product is also a substrate for the hydrolase, resulting in the production of... 

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

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]. 

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

However, the most common and important method of synthesis of chiral non-racemic hydroxy phosphoryl compounds has been the resolution of racemic substrates via a hydrolytic enzyme-promoted acylation of the hydroxy group or hydrolysis of the 0-acyl derivatives, both carried out under kinetic resolution conditions. The first attempts date from the early 1990s and have since been followed by a number of papers describing the use of a variety of enzymes and various types of organophosphorus substrates, differing both by the substituents at phosphorus and by the kind of hydroxy (acetoxy)-containing side chain. 

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. ... 

A combination of an enzymatic kinetic resolution and an intramolecular Diels-Alder has recently been described by Kita and coworkers [23]. In the first step of this domino process, the racemic alcohols ( )-8-55 are esterified in the presence of a Candida antarctica lipase (CALB) by using the functionalized alkenyl ester 8-56 to give (R)-8-57, which in the subsequent Diels-Alder reaction led to 8-58 in high enantioselectivity of 95 and 91 % ee, respectively and 81 % yield (Scheme 8.15). In-... 

Scheme 17. The tandem Zr-catalyzed kinetic resolution and Mo-catalyzed conversion of styrenyl ethers to chromenes is used in the first convergent and enantioselective total synthesis of the antihypertensive agent (S,R,R,R) nebivolol...

Hydrogen transfer reactions are reversible, and recently this has been exploited extensively in racemization reactions in combination with kinetic resolutions of racemic alcohols. This resulted in dynamic kinetic resolutions, kinetic resolutions of 100% yield of the desired enantiopure compound [30]. The kinetic resolution is typically performed with an enzyme that converts one of the enantiomers of the racemic substrate and a hydrogen transfer catalyst that racemizes the remaining substrate (see also Scheme 20.31). Some 80 years after the first reports on transfer hydrogenations, these processes are well established in synthesis and are employed in ever-new fields of chemistry. 

Zirconocene-catalyzed kinetic resolution of dihydrofurans is also possible, as illustrated in Scheme 6.8 [18]. Unlike their six-membered ring counterparts, both of the heterocycle enantiomers react readily, albeit through distinctly different reaction pathways, to afford — with high diastereomeric and enantiomeric purities — constitutional isomers that are readily separable (the first example of parallel kinetic resolution involving an organome-tallic agent). A plausible reason for the difference in the reactivity pattern of pyrans and furans is that, in the latter class of compounds, both olefmic carbons are adjacent to a C—O bond C—Zr bond formation can take place at either end of the C—C 7T-system. The furan substrate and the (ebthi)Zr-alkene complex (R)-3 interact such that unfavorable... 

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