Kinetic slow-reacting enantiomer

Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (J )-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7-28. (iS )-BINAP-Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the C C double bond in one enantiomer, the (S )-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20... 

Scheme 4.1 Enantioselective kinetic resolution of a racemate. = rate constants for the individual enantiomers of the substrate, E = enantiomeric ratio, i.e., the ratio between the specificity constants kat/Km for the fast and slow reacting enantiomer. If a racemate is used as substrate, then these concentrations are equal at the start (i.e. zero conversion), and hence E = kR/ks.

Kinetic resolutions, such as the ones discussed above, are limited to a 50% yield. Consequently, the undesired enantiomer needs to be recovered, racemized, and recycled, which makes the process more complex and leads to an increased solvent use. The obvious solution is to racemize the slow-reacting enantiomer in situ. With chiral alcohols, the racemization catalysts of choice are based on ruthenium (Figure 10.17). 

Dynamic kinetic resolution (DKR) is an important and useful method to generate enantiomerically pure compounds from racemic substrates [87]. In this case, an in situ racemization of slow reacting enantiomer of chiral alcohol has been successfully carried out by metal-enzyme catalyst where metal complex acts as a racem-izing catalyst (Scheme 10.6) [88]. The racemization was found to be more efficient... 

The success of an enzyme-catalyzed kinetic resolution is limited by the maximum chemical yield of 50% for each enantiomer. However, this drawback can be overcome by a process called dynamic kinetic resolution. The key idea of this principle is to racemize the slow reacting enantiomer continuously reproducing the faster one. In an ideal case at the end of the conversion one enantiomer is formed in 100% yield with 100% of enantiomeric excess[13S 1371. The kinetic requirements for a dynamic kinetic resolution are shown in Scheme 11.1-16[8bl. 

Several approaches have been developed in the last two decades to combine KR with in situ racemization, allowing the 50% yield barrier associated with KR to be overcome. The process involves the typical KR in which one of the enantiomers is transformed quickly leaving the other enantiomer unreacted. As the faster reacting enantiomer is depleted, the equihbrium of (R)-/(S)- is constantly readjusted by racemization of the slow reacting enantiomer (Scheme 4.19). The process is nonstatic leading to the appHcation of the term dynamic kinetic resolution (DKR). In contrast to KR, DKR can provide an enantiomerically pure compound in 100% theoretical yield [50]. For the most effective process, the rate of racemization should equal or exceed the rate of the enantioselective transformation [51]. Chemical, thermal, biocatalytical or even spontaneous racemization processes can be involved — essentially those that can be performed in a single step under mild conditions are suitable. It is important that the conditions are adjusted not to promote racemization of the product. 

It is the combination of these twin goals that has led to the evolution of classical kinetic resolution into dynamic kinetic resolution (DKR). In such a process, it is possible in principle to obtain a quantitative yield of one of the enantiomers. Effectively, DKR combines the resolution step of kinetic resolution, with in situ equilibration or racemisation of the chirally labile substrate (Figure i.2). In DKR, the enantiomers of a racemic substrate are induced to equilibrate at a rate faster than that of the slow-reacting enantiomer in reaction with the chiral reagent (Curtin-Hammett kinetics). If the enantioselectivity is sufficient, then isolation of a highly enriched non-racemic product is possible with a theoretical yield of 100% based on the racemic substrate. 

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.

Precatalysts 41a-c and 44 were activated with MAO and tested for kinetic resolution. Tetradecane was used as a solvent for these polymerizations at 25 °C. Kinetic resolution was reported by using stereoselectivity factors, or values, where s = (rate of fast reacting enantiomer)/(rate of slow reacting enantiomer). Experimentally, s may be calculated by using the following equation s = ln[(l -c)(l -ee)]/ln[(l - c)(l-fee)], where ee is the enantiomeric excess of the recovered olefin and c is the fraction conversion. If no kinetic resolution is achieved, s = 1. The authors assayed the fraction conversion, c, by gas chromatography (GC) analysis of two aliquots for each polymerization run (1) an aliquot removed immediately before the start of polymerization (i.e., immediately before the addition of zirconocene catalyst) and (2) an aliquot removed after the desired conversion was reached in all cases, tetradecane was used as the internal standard. 

The versatility of the combination of enzymes with metal catalysts is also well demonstrated by chemoenzymatic dynamic kinetic resolutions (DKRs). Indeed, to overcome the major drawback of kinetic resolution for which the maximum yield is limited to 50%, the combination of a metal-catalysed racemisation of the slow-reacting enantiomer with an enzyme-catalysed... 

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

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). 

The resolution of rac-20 represents a less common form of catalytic kinetic resolution (parallel kinetic resolution) [9]. In conventional kinetic resolution, one substrate enantiomer reacts preferably to leave behind the unreacted isomer in high optical purity (e.g., rac-18 (k)-19 in Scheme 4). In this instance, both starting material enantiomers undergo catalytic alkylation to give constitutional isomers. Since both enantiomers are consumed simultaneously, as the reaction proceeds, the amount of slow enantiomer (relative to the unreacted fast enantiomer) does not increase. Therefore, product ee remains high, even at relatively high conversions. 

Information about the degree of configurational stability of allenyltitanium compounds has been provided by Hoffmann and Hoppe (Scheme 35). Racemic allenyltitanium reagent (3) is prepared by sequential treatment of 3-methoxy-1,2-butadiene (2) with n-butyllithium and titanium tetraisopropoxide. In the reaction of the racemate with one equivalent of (S)-(4) or its racemate, products (5)-(8) are formed in 70-90% total yield in the ratios shown in Scheme 35. Since the product ratios from the two experiments are different, the equilibrium between the enantiomers of (3) must be slow compared to the rate of reaction of (3) with (4). Thus, (S)-(3) leads to (5) + (6) and (R)-(3) leads to (7) + (8) (i.e. 51 49). From experiment B, the combinations (S)-(3) + (S)-(4) and (/ )-(3) -t- (/ )-(4) are shown to react considerably more rapidly than that of the (R)/(.S) pairs (mutual kinetic resolution). ... 

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