Examples of Kinetic Resolutions

Figure 6.4 Some successful examples of kinetic resolution of allylic alcohols by enantioselective epoxidation [21, 27].

Numerous reactions of racemic sulfoxides with chiral reagents have been accomplished2,12. These examples of kinetic resolution usually lead to sulfoxides of low enantiomeric purity, but there are some exceptions. 

The hydrolysis of seven alkyl arenesulfinylalkanoates by the bacterium Corynebacterium equi IFO 3730 studied by Ohta and coworkers34 are recent examples of kinetic resolutions which give sulfoxides of high enantiomeric purity and in reasonable yield. Compounds 16a, 16b and 16c were recovered in 30 to 43% yield and in 90 to 97% e.e. The S enantiomers underwent hydrolysis more rapidly than the R isomers. Sulfoxide 17 was isolated in 22% yield and 96% e.e., but sulfoxide 18 was completely metabolized. Esters other than methyl gave inferior results. The acids formed upon hydrolysis, although detected, were for the most part further metabolized by the bacterium. 

Finally, as an old example of kinetic resolution of racemic mixtures, mention must be made on the report of Kise and Tomiuchi on the significant effect of acetonitrile on the enantioselectivity of different proteases toward the kinetic resolution of aromatic amino acid ethyl esters (5-8). For instance, (l)-DOPA (8) was obtained with 99% ee in the presence of 90% v/v acetonitrile [9]. 

In the case of the ketone (12), a racemic mixture was converted to an optically active mixture (optical yield 46%) by treatment with the chiral base (13). This happened beeause 13 reacted with one enantiomer of 12 faster than with the other (an example of kinetic resolution). The enolate (14) must remain coordinated with the chiral amine, and it is the amine that reprotonates 14, not an added proton donor. 

Scheme 12.53 Example of kinetic resolution of alkyl-aryl alcohols...

Substituted acrylates (which reseitible the enamide substrates employed 1n asymmetric hydrogenation) may be deracemized by reduction with an optically active catalyst, especially DIPAMPRh . Selectivity ratios of 12 1 to 22 1 have been obtained for a variety of reactants with compounds of reasonable volatility, separation of starting material and product may be effected by preparative GLC. Recovered starting material can then be reduced with an achiral catalyst to give the optically pure anti product. Examples of kinetic resolutions by this method are given in Table II. More recently very successful kinetic resolutions of allylic alcohols have been carried out with Ru(BINAP) catalysts. 

The first example of kinetic resolution catalyzed by an organometallic compound was the partially enantiomer-selective polymerization of racemic propylene oxide induced with a diethylzinc optically active alcohol system (50). 

Scheme 21). Scheme 22 illustrates an example of kinetic resolution of a racemic allylic alcohol with a 1,3-hydrogen shift. When racemic 4-hydroxy-2-cyclopentenone is exposed to a cationic (/ )-BINAP-Rh complex in THF, the S enantiomer is consumed five times faster than the R isomer (32). The slow-reacting stereoisomer purified as the crystalline ferf-butyldimethylsilyl ether is an intermediate in prostaglandin synthesis (33). These isomerizations may occur via initial Rh-olefinic bond interaction (34). 

For examples of kinetic resolution of alcohols using chiral acylating agents, see Evans DA, Anderson JC, Taylor MK (1993) Tetrahedron Lett 34 5563-5566 Vedejs E, Chen X (1997) J Am Chem Soc 119 2584-2585... 

It should finally be mentioned that chiral base methodology is not limited to the desymmetrization of meso-epoxides but also enables kinetic resolution of racemic epoxides [57, 63, 65], This (organocatalytic) type of reaction seems, however, to be less prominent than the desymmetrization of meso-epoxides. Some examples of kinetic resolution of chiral epoxides are summarized in Scheme 13.35. 

If racemic sec alcohols (e.g., butan-2-ol, 52) undergo partial acylation with an acid anhydride in the presence of an optically active amine, an enantiomer differentiation occurs in the example shown, the (S)-alcohol reacts preferentially forming but-2-yl acetate, 53, which is levorotatory, and leaving behind unchanged alcohol which has been optically enriched [68]. This is a process under kinetic control. For further examples of kinetic resolutions, see [69]. 

Kinetic Resolution by Transesterification. Asymmetric transformation involving acylation of chiral alcohols is by far the most common example of kinetic resolution by lipase-catalyzed transesterification, most commonly with irreversible vinyl esters. This field is now becoming the most widely applied technique involving lipases. Recent reports of the numerous secondary alcohol substrates include various monocyclic (eq 6) andacyclic compounds, cyanohydrins, sulfones, and glycals, to name a few. 

The lipase-catalysed enantioselective acylation of allylic alcohols in an ionic liquid solvent was demonstrated by Itoh et al. [16] (Fig. 7.7). They found that the acylation rate was strongly dependent on the counter anion of the imidazolium salt, while the lipase-catalysed acylation proceeded with high enantioseleclivity in all ionic liquid tested. Good results were obtained when the reaction was carried out in [bmimT [PFg ] or [bmun" ][BF ]. Other examples of kinetic resolution of allylic alcohols catalysed by lipases in ionic liquids were also reported by these authors [71, 72]. The transesterification of 5-phenyl-l-penten-3-ol under reduced pressure at 27 hPa and 40°C was carried out using methyl phenylthioacetate as acyl donor in [bmim+] [PF ] and [bdmim ][BF ], for obtaining the corresponding acylated compound in optically pure form [71], The acetylation of methyl mandelate catalysed by immobilised P5L in [bdmim ][BF ] is another example reported by these authors about the successful application of ionic liquids as reaction media in racemic resolutions... 

We will see Sharpless epoxidation reactions in the Double Methods section towards the end of the chapter. Interestingly, Sharpless other famous asymmetric method - dihydroxylation - has not found widespread use in kinetic resolution. This is probably because the AD is just too powerful or, to be anthropomorphic, too wilful. In other words, it is not sensitive to the chirality of the substrate and charges ahead and reacts with both enantiomers. That is not to say there are not examples of kinetic resolution with dihydroxylation,19 but they are more rare. However, the dihydroxylation is even more useful and much more general than the kinetic resolution of allylic alcohols by asymmetric epoxidation and was discussed in Chapter 25. A slightly complicated case of kinetic resolution of alcohols by asymmetric dihydroxylation is in the Double Methods section. 

Examples of kinetic resolutions with lipases are numerous [9], Impressive enantioselectivities are often obtainable with secondary alcohols, e.g., in acetylations with vinyl acetate, or in hydrolysis of the racemic ester. Likewise, the corresponding amines can be resolved, e.g. by enantioselective acetylation with EtOAc as both acyl donor and solvent. This has been demonstrated by Gotor and coworkers using Novozym 435 [50]. The reaction (Scheme 13.3) follows Kazlauskas selectivity. In fact an impressive range of CALB (Novozym 435) catalyzed transformations on nitrogenated compounds have been collected in a recent review article [51]. 

Scheme 2.5 gives some specific examples of kinetic resolution procedures. Entries 1 to 3 in Scheme 2.5 are acylation reactions in which esters are formed. Either the... 

A few examples of kinetic resolutions are reported in Fig. 5. These have been selected among those reactions leading to the preparation of enantiomerically enriched compounds that do not feature a handle for classical resolutions. 

As already indicated, trans-cycloalkenes such as trans-cyclooctene are so strained that the complete lack of conformational equilibrium induces the existence of two enantiomeric structures at room temperature. Tl ans-acetyl-cyclooctene (t-ACO) can be produced from the cis isomer in a photostation-ary equilibrium. In the presence of chiral catalysis, we will describe one interesting example of kinetic resolution of unstable t-ACO. 

Scheme 1.16 Examples of kinetic resolution of a racemic sulfide by asymmetric oxidation, or of resolution by combination with a chiral auxiliary and subsequent diastereoselective oxidation...

Fig. 10. Example of kinetic resolution of a racemic secondary alcohol. One of the enantiomers reacts faster than the other and if the ratio between the reaction rates is sufficient, the slow-reacting enantiomer can be isolated with an acceptable 5ueld.

Examples of kinetic resolution catalyzed by antibodies 93F3 and 84G3. 

The asymmetric olefination of the racemic ketone 111 with the anion of the phosphinothioic amide 15 can be regarded as an example of kinetic resolution ... 

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