Kinetic resolution strategy

Scheme 2.10. Conversion of racemic 2-43 into enantiopure 2-45 using a kinetic resolution strategy.

Robinson, D. E. J. E. Bull, S. D. (2003) Kinetic resolution strategies using non-enzymatic catalysts.. Tetrahedron Asymmetry 14 1407-1446... 

List and coworkers reported an excellent approach to the enantioselective synthesis of P branched a amino phosphonates, which involved the extension of the dynamic kinetic resolution strategy (Scheme 3.53) [110] that was previously applied to the enantioselective reductive amination of a branched aldehydes by his research group (see Scheme 3.45). The method combines dynamic kinetic resolution with the parallel creation of an additional stereogenic center. They successfully accomplished the direct three component Kabachnik Fields reaction of 1 equiv each of the racemic aldehyde, p anisidine, and di(3 pentyl)phosphite in the presence of newly developed chiral phosphoric acid It. The corresponding p branched a amino phosphonates were obtained in high diastereo and enantioselectivities, especially for the aldehydes bearing a secondary alkyl group at the a position. 

One way of overcoming these problems is by kinetic resolution of racemic epoxides. Jacobsen has been very successful in applying chiral Co-salen catalysts, such as 21, in the kinetic resolution of terminal epoxides (Scheme 9.18) [83]. One enantiomer of the epoxide is converted into the corresponding diol, whereas the other enantiomer can be recovered intact, usually with excellent ee. The strategy works for a variety of epoxides, including vinylepoxides. The major limitation of this strategy is that the maximum theoretical yield is 50%. 

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. 

Biooxidative deracemization of racemic sec-alcohols to single enantiomers [47,48] is complementary to combined metal-assisted lipase-mediated strategies [49,50]. In general, deracemization can be realized by either an enantioconvergent, a dynamic kinetic resolution, or a stereoinversion process. The latter concept is particularly appealing, as only half of the substrate needs to be converted, as the remaining half already represents the product with correct stereochemistry. 

Kinetic resolution of racemic terminal epoxide with water (HKR) is an attractive strategy for the synthesis of valuable enantiopure terminal epoxide and corresponding diol. Easy availability of terminal epoxides at cheaper price and water as sole reagent with a recoverable chiral catalyst makes this solvent free protocol very attractive for its commercial exploitation [53, 54]. Both terminal epoxides and respective diols in their chirally pure form have wider applications in academics and industry [48, 50]. For the efficient resolution the reaction rates of the two enantiomers must be unequal and the reaction must be stopped when only one enantiomer reacts to give a maximum of 50% product leaving behind the other enantiomer unreacted. 

Monoacylation of achiral and meso diols has been a popular strategy for introducing asymmetry and, in addition to kinetic resolutions of secondary alcohols, a... 

Kinetic resolutions by means of the selective formation or hydrolysis of an ester group in enzyme-catalyzed reactions proved to be a successful strategy in the enantioseparation of 1,3-oxazine derivatives. Hydrolysis of the racemic laurate ester 275 in the presence of lipase QL resulted in formation of the enantiomerically pure alcohol derivative 276 besides the (23, 3R)-enantiomer of the unreacted ester 275 (Equation 25) <1996TA1241 >. The porcine pancreatic lipase-catalyzed acylation of 3-(tu-hydroxyalkyl)-4-substituted-3,4-dihydro-2/7-l,3-oxazines with vinyl acetate in tetrahydrofuran (THF) took place in an enantioselective fashion, despite the considerable distance of the acylated hydroxy group and the asymmetric center of the molecule <2001PAC167, 2003IJB1958>. 

Goti, Brandi, and co-workers have investigated this PKR strategy using two quasi-enantiomeric dihydropyrans 21 and 22 as complimentary reagents (Scheme 5) [9], They have shown that under a traditional kinetic resolution procedure the racemic syn-dihydroxypyrroline N-oxide 23 can be partially resolved using a 1,3-dipolar cycloaddition... 

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

This strategy was used repeatedly by Mori and co-workers (Brevet and Mori, 1992 Muto and Mori, 2003a, b Nakanishi and Mori, 2005), first using enzyme-based kinetic resolution of an achiral, mc.vo-diacctatc to generate an enantiomerically enriched epoxyalcohol synthon (Scheme 5A), which could be further purified if necessary by dinitroben-zoate derivatization and recrystallization. Conversion of the alcohol to a leaving group,... 

It is worth mentioning the emergence of sequential catalytic processes involving a ruthenium-catalyzed step followed by a catalytic enzymatic transformation. This strategy has been developed by the groups of J.E. Backvall, and M.-J. Kim and J. Park especially for the dynamic kinetic resolution of alcohols (Scheme 50) [107-109]. 

Sakai T (2004) Rational strategies for highly enantioselective lipase-catalyzed kinetic resolutions of very bulky chiral compounds substrate design and high-temperature biocatalysis. Tetrahedron Asymmery 15 2765-2770... 

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