Kinetic resolution terms

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. 

For most chemical transformations, especially for industrial applications, the yield of 50% cannot be accepted. Since each enantiomer constitutes only 50% of the racemic mixture, the best way to increase the yield of the desired enantiomer is racemization of the unwanted one (Scheme 5.7). This reaction mustproceed simultaneously with the enzymatic kinetic resolution. In order to indicate the dynamic character of such processes, the term dynamic kinetic resolution has been introduced. 

Two types of sulfoximinocarboxylates (analogous to sulfinylcarboxylates 16), namely 5 -aryl-5 -methoxycarbonylmethyl-A(-methyl sulfoximine 36 and -methyl-5 -phenyl-A(-ethoxycarbonyl sulfoximine 37, were subjected to hydrolysis in the presence of PLE in a phosphate buffer. As a result of a kinetic resolution, both the enantiomerically enriched recovered substrates and the products of hydrolysis and subsequent decarboxylation 38 and 39, respectively, were obtained with moderate to good ees (Equations 20 and 21). Interestingly, in each case the enantiomers of the substrates, having opposite spatial arrangement of the analogous substituents, were preferentially hydrolysed. This was explained in terms of the Jones PLE active site model. ... 

To avoid the inherent limitations of a kinetic resolution process, the reaction was extended to desymmetrization of prochiral meso epoxides. A number of cyclic di-methylidene epoxides were synthesized and subjected to treatment with Et2Zn in the presence of Cu(OTf)2 and ligands 42 or 43. As in the case mentioned above, ligand 42 was superior in terms of selectivity. Cydohexane derivative 46 gave the ring-opened product with a 97% ee and in a 90% isolated yield, with a y/a ratio of 98 2 (Scheme 8.28). The other substrates investigated produced sigmficantly lower ees of between 66% and 85%. 

Figure 2b shows the other extreme, whereby the rate of epimerization is fast relative to the rate of substitution. In this case, Curtin-Hammett kinetics apply, and the product ratio is determined by AAG. In the specific case of organolithium enantiomers that are rendered diastereomeric by virtue of an external chiral ligand, such a process may be termed a dynamic kinetic resolution. Both of these processes are also known by the more general term asymmetric transformation One should be careful to restrict the term resolution to a separation (either physical or dynamic) of enantiomers. An asymmetric transformation may also afford dynamic separation of equilibrating diastereomers, but such a process is not a resolution. "... 

It is emphasized that in the case of kinetic resolution, the MS measurements must be performed in the appropriate time window (near 50% conversion). If this is difficult to achieve due to different amounts or activities of the mutants being screened in the wells of microtiter plates, the system needs to be adapted in terms of time resolution. This means that samples for MS evaluation need to be taken as a function of time. Finally, it is useful to delineate the possibility of multi-substrate ee screening using the MS-based assay, which allows for enzyme fingerprinting with respect to the enantioselectivity of several substrates simultaneously. 

Some Equivalent Nonsystematic Terms (Kinetic Resolution, Meso-Trick)... 

It should be noted that some of the Izumi - Tai terms are also known by other designations. For example, the term enantiomer-differentiating reaction is equivalent to the classical term kinetic resolution, and as both are sufficiently clear they will be used here. 

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 ). 

Before commencing, the attention of the reader is drawn to the terms enantiofacial selectivity and diastereoselectivity. The usage in this chapter does not conform to the strictest possible definitions of these terms. In particular, enantiofacial selectivity is used with reference to the selection and delivery of oxygen by the epoxidadon catalyst to one face of the olefin in preference to the other. This usage extends to chiral allylic alcohols (primarily the 1-substituted allylic alcohols) when the focus of the discussion is on face selection in the epoxidation process. Diastereoselectivity is used in the discussion of kinetic resolution when the generation of diastereomeric compounds is emphasized. 

Steric effects were evaluated by a study of the DMAP-catalysed acylation of 1 y, 2y and 3y alcohols by acetic, propionic, isobutyric, isovaleric, and pivalic anhydrides in CH2C12 at 20 °C. In all cases the reaction kinetics could be described by rate laws containing a DMAP-catalysed term and an uncatalysed (background) term. Steric effects were evident in both reactions, but were generally greater for the DMAP-catalysed reaction. For example, the uncatalysed reactions between cyclohexanol and acetic and pivalic anhydrides differed about 500-fold, but for the corresponding DMAP-catalysed reactions the factor was 8000-fold. The implications of these findings for the kinetic resolution of alcohols were discussed.32... 

While enzymes and chiral chemical catalysts compete for best performance in a variety of situations, they have also been used jointly to afford a desired reaction result (Choi, 1999). By far the most frequent application of this concept, termed an enzyme-metal combi reaction (EMCR) , is the dynamic kinetic resolution (DFR) of a racemic mixture with a lipase and an organometallic complex to afford in-situ racemization. 

Parallel kinetic resolution of chiral, racemic anhydrides The term parallel kinetic resolution (PKR) implies that the two substrate enantiomers (Scheme 13.1, bottom... 

This result, caused by the proximity effect between peripheral catalytic sites, can translate into higher or lower catalytic activity of the metallodendrimer in homogeneous catalysis, and is commonly termed the dendritic effect. In the above case, a negative dendritic effect is observed. An interesting example of a positive dendritic effect on catalyst activity was reported by Jacobsen et al. in the hydrolytic kinetic resolution of terminal epoxides by peripherally Co(salen)-substituted PAMAM dendrimers [39]. 

A Merck group reported an interesting kinetic resolution of a racemic di-bromocyclophane via Pd-catalyzed amination [91]. While BINAP was a poor ligand for the reaction in terms of selectivity, the C2-symmetric cyclophane-derived PHANEPHOS (17) proved to be optimal. Reaction of the cyclophane derivative with benzylamine afforded the unreacted dibromide in 45% ee after 37% conversion, corresponding to a selectivity factor of 12, Eq. (78). 

Methods for chemical kinetic resolution to give products of high enantiomeric purity are less well known. Perhaps the most successful and one complementary in terms of the products obtained with the enzymic methods, is the epoxidation of a racemic secondary aUylic alcohol (13). When this epoxidation is carried out using f-butylhydroperoxide as oxidant in the presence of a titanium catalyst that is chirally modified by an ester of tartaric acid, the selectivity for one enantiomer of the starting alcohol is often virtually complete. 

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