Kinetic resolution described

All of the kinetic resolutions described above have been characterized in terms of yields and ee values of the recovered substrate and the product. In principle the efficiency of a kinetic resolution can also be described by the selectivity factor S [lu], the ratio of the rate constants for the reactions of the enantiomers of the substrate with the catalyst. For a Pd-catalyzed kinetic resolution of an allylic substrate obeying first-order kinetics in regard to the reaction of the substrate with the catalyst (unimolecularity) S can be calculated according to Eq. (1), which contains as variables the conversion (c) and the ee value of the substrate (ee ). 

Quantitative Analysis of Selectivity. One of the principal synthetic values of enzymes stems from their unique enantioselectivity, ie, abihty to discriminate between enantiomers of a racemic pair. Detailed quantitative analysis of kinetic resolutions of enantiomers relating the extent of conversion of racemic substrate (c), enantiomeric excess (ee), and the enantiomeric ratio (E) has been described in an excellent series of articles (7,15,16). 

Another means of resolution depends on the difference in rates of reaction of two enantiomers with a chiral reagent. The transition-state energies for reaction of each enantiomer with one enantiomer of a chiral reagent will be different. This is because the transition states and intermediates (f -substrate... f -reactant) and (5-substrate... R-reactant) are diastereomeric. Kinetic resolution is the term used to describe the separation of enantiomers based on different reaction rates with an enantiomerically pure reagent. 

Both reactions were carried out under two-phase conditions with the help of an additional organic solvent (such as iPrOH). The catalyst could be reused with the same activity and enantioselectivity after decantation of the hydrogenation products. A more recent example, again by de Souza and Dupont, has been reported. They made a detailed study of the asymmetric hydrogenation of a-acetamidocin-namic acid and the kinetic resolution of methyl ( )-3-hydroxy-2-methylenebu-tanoate with chiral Rh(I) and Ru(II) complexes in [BMIM][BF4] and [BMIM][PFg] [55]. The authors described the remarkable effects of the molecular hydrogen concentration in the ionic catalyst layer on the conversion and enantioselectivity of these reactions. The solubility of hydrogen in [BMIM][BF4] was found to be almost four times higher than in [BMIM][PFg]. 

The empirical rule described above for the enantiofacial differentiation in AE of primary allylic alcohols also applies to secondary allylic alcohols. The new aspect that needs to be taken into consideration in this case is the steric hindrance arising from the presence of a substituent (R4) at the carbon bearing the hydroxy group (Figure 6.3). This substituent will interfere in the process of oxygen delivery, making the oxidation of one enantiomer much faster than the reaction of the other one. The phenomenon is so acute that in practice kinetic resolution is often achieved (Figure 6.4) [27]. 

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. 

Catalytic transformation based on combined enzyme and metal catalysis is described as a new class of methodology for the synthesis of enantiopure compounds. This approach is particularly useful for dynamic kinetic resolution in which enzymatic resolution is coupled with metal-catalyzed racemization for the conversion of a racemic substrate to a single enantiomeric product. 

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. 

An effective deoxygenation using enantiomerically pure epoxides from primary allylic alcohols ( Sharpless epoxides ) [44] to give enantiomerically pure secondary allylic alcohols was described by Yadav [45]. This approach circumvented a kinetic resolution of secondary allylic alcohols that implies a maximum yield of 50% ( Scheme 5). 

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-... 

Several other color tests useful in the kinetic resolution of chiral compounds have been developed, most of them being based on the concept of testing R- and S-substrates separately as described above.77-80... 

The chemistry described in this review article demonstrates the impressive positive influence that catalytic RCM has had on our research in connection to the development of other catalytic and enantioselective C-C bond forming reactions. There is no doubt that in the absence of pioneering work by Schrock and Grubbs, the Zr-catalyzed alkylation and kinetic resolution would be of less utility in synthesis. The number of unsaturated heterocyclic and carbocyclic substrates available for Zr-catalyzed asymmetric carbomagnesation would be far more limited without catalytic RCM. 

Historically, the thermal transesterification of (-)-ethyl p-toluene-sulfinate 224 with n-butanol affording (+)-n-butyl p-toluenesulfinate 225 described by Phillips in 1925 (100) is the first nucleophilic substitution reaction at chiral sulfur involving a Walden-type inversion. The evidence for inversion of configuration in this reaction was based on the assumption that both (-)-esters 224 and 225 obtained from the kinetic resolution have the same configuration. 

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

Chapter 3 describes the application of lipases, proteases and sulfatases for the kinetic resolution of a range of interesting molecules. A selection of dynamic kinetic resolution (DKR) procedures is disclosed in Chapter 4. DKRs are attracting a significant amount of... 

A very successful example for the use of dendritic polymeric supports in asymmetric synthesis was recently described by Breinbauer and Jacobsen [76]. PA-MAM-dendrimers with [Co(salen)]complexes were used for the hydrolytic kinetic resolution (HKR) of terminal epoxides. For such asymmetric ring opening reactions catalyzed by [Co(salen)]complexes, the proposed mechanism involves cooperative, bimetallic catalysis. For the study of this hypothesis, PAMAM dendrimers of different generation [G1-G3] were derivatized with a covalent salen Hgand through an amide bond (Fig. 7.22). The separation was achieved by precipitation and SEC. The catalytically active [Co "(salen)]dendrimer was subsequently obtained by quantitative oxidation with elemental iodine (Fig. 7.22). 

A novel continuous-flow SCCO2 process for the kinetic resolution of 1-phenyethanol enantiomers (Figure 30) using Novozym 435 immobilized enzyme from Candida antarctica was described by Matsuda et al. [51], The lipase enzyme, selectively acetylated the R)-alcohol component. A mixture of starting material and vinyl acetate was passed through the enzyme with supercritical carbon-dioxide (Figure 31). The reaction zone was pressurized and heated, so the reaction could be performed imder supercritical conditions, synthesizing the desired (i )-acetate with 99.7% ee. and 47% yield. 

In a succeeding publication, the same authors reported on an enantiose-lective approach to diquinane enones 6 and ent-6 by combining the above-described synthesis with an enzymatic kinetic resolution (Scheme 4) [12]. After lipase-catalyzed enantioselective transesterification of diol rac-12. 

The groups of Sigman and Stoltz have concurrently published the palladium-catalyzed oxidative kinetic resolution of secondary alcohols using molecular oxygen as the stoichiometric oxidant. Both communications also described a single example of a diol desymmetrization using a palladium catalyst in the presence of (—(-sparteine [Eqs. (10.42) ° and (10.43) ] ... 

Finally, in 2001 Tanaka and Suemune described kinetic resolutions and parallel kinetic resolutions of dienals through the use of cationic and neutral Rh(l)/B1NAP complexes, respectively (Eqs. 17 and 18) [20-22]. 

In one version, classical derivatization using a chiral reagent or NMR shift agent is simply parallelized and automated by the use of flow-through cells, with about 1400 ee measurements being possible per day with a precision of +5%. In the second embodiment, illustrated here in detail, a principle related to that of the MS system described in Section III.C is applied 98). Chiral or mexo-substrates are labeled to produce /. sewiio-enantiomers or psendo-meso-compo md that are then used in the actual screen. Application is thus restricted to kinetic resolution of racemates and... 

This preparation was previously described by Brandsma. Substrate 1 can be prepared In enantiomericeilly pure form beginning with chiral, non-racemic styrene oxide, available as either antipode from Aldrich Chemical Company, Inc., or by kinetic resolution of racemic styrene oxide. ... 

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