Kinetic resolution, hydrolytic

BimetaUic chiral cobalt salen catalysts containing transition-metal salts have also been demonstrated by Kim et al. [190] to be remarkably efficient and highly enantioselective in hydrolytic KRs of various epoxides. Enantioselectivity of up to 99% ee for the recovered epoxides combined with very high catalytic activity could be reached. Another means for fixing or linking two or more Co(salen) units in dose proximity to decrease the catalyst requirements by making the reaction of 

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Figure 2.9 Schematic summary of the directed evolution of enantioselective lipase variants originating from the WT PAL used as catalysts in the hydrolytic kinetic resolution of ester rac-1. CMCM = Combinatorial multiple-cassette mutagenesis [8c,22],...

Efforts were also made to invert the sense of enantioselectivity in the hydrolytic kinetic resolution of ester (1) using PAL with preferential formation of (R)-2 [40,411-Using epPCR and DNA shuffling, an (R)-selective mutant showing an E value of 30 was evolved by screening about 45 000 clones for the (R) enantiomer. The best mutant is characterized by 11 mutations, which are different from those of the best (S)-selective variant X [41]. 

Esterases have a catalytic function and mechanism similar to those of lipases, but some structural aspects and the nature of substrates differ [4]. One can expect that the lessons learned from the directed evolution of lipases also apply to esterases. However, few efforts have been made in the directed evolution of enantioselective esterases, although previous work by Arnold had shown that the activity of esterases as catalysts in the hydrolysis of achiral esters can be enhanced [49]. An example regarding enantioselectivity involves the hydrolytic kinetic resolution of racemic esters catalyzed by Pseudomonasfluorescens esterase (PFE) [50]. Using a mutator strain and by screening very small libraries, low improvement in enantioselectivity was... 

In another study a hyperthermophilic esterase from Aeropyrum pemix K1 (APE1547) was used as a catalyst in the hydrolytic kinetic resolution of rac-3-octanol acetate [53]. Following a single round of epPCR, a mutant displaying a 2.6-fold increase in enantioselectivity was identified having five amino acid substitutions, which were shown to be spatially distal to the catalytic center. 

Several reports regarding the directed evolution of enantioselective epoxide hydrolases (EHs) have appeared [23,57-59]. These enzymes constitute important catalysts in synthetic organic chemistry [4,60]. The first two reported studies concern the Aspergillus niger epoxide hydrolase (ANEH) [57,58]. Initial attempts were made to enhance the enantioselectivity of the AN E H -catalyzed hydrolytic kinetic resolution of glycidyl phenyl ether (rac-19). The WT leads to an Evalue of only 4.6 in favor of (S)-20 (see Scheme 2.4) [58]. 

In another study that appeared prior to the advent of CASTing, the traditional combination of epPCR and DNA shuffling was used to enhance the enantioselectivity of the hydrolytic kinetic resolution of p-nitro phenyl glycidyl ether and other epoxides catalyzed by the EH from Agrobacterium radiobacter [59]. Several mutants were obtained with up to 13-fold improved enantioselectivity. The amino acid exchanges took place around the active site. 

Figure 2.15 Iterative CASTing in the evolution of enantioseiective epoxide hydrolases as catalysts in the hydrolytic kinetic resolution ofrac-19[23].

Another application of salen ligands is the hydrolytic kinetic resolution of epoxides (Scheme 3). For this purpose cobalt complexes are efficient, and fiu-... 

The asymmetric ring opening (ARO) of racemic terminal epoxides with H2O via hydrolytic kinetic resolution provides an efficient synthetic route to prepare optically pure terminal epoxides. The dimeric type chiral Co(salen)AlX3 complex has great potential to catalyze HKR of terminal epoxides in a highly reactive and enantioselective manner in comparison to their monomeric analogy. 

The hydrolytic kinetic resolution of terminal epoxides catalyzed by the monomer la and dimer lb... 

The hydrolytic kinetic resolution (HKR) of terminal epoxides using Co-salen catalysts provides a convenient route to the synthesis of enantioemiched chiral compounds by selectively converting one enantiomer of the racemic mixture (with a maximum 50% yield and 100% ee) (1-3). The use of water as the nucleophile makes this reaction straightforward to perform at a relatively low cost. The homogeneous Co(III) salen catalyst developed by Jacobsen s group has been shown to provide high... 

Hydrolytic Kinetic Resolution (HKR) of epichlorohydrin. The HKR reaction was performed by the standard procedure as reported by us earlier (17, 22). After the completion of the HKR reaction, all of the reaction products were removed by evacuation (epoxide was removed at room temperature ( 300 K) and diol was removed at a temperature of 323-329 K). The recovered catalyst was then recycled up to three times in the HKR reaction. For flow experiments, a mixture of racemic epichlorohydrin (600 mmol), water (0.7 eq., 7.56 ml) and chlorobenzene (7.2 ml) in isopropyl alcohol (600 mmol) as the co-solvent was pumped across a 12 cm long stainless steel fixed bed reactor containing SBA-15 Co-OAc salen catalyst (B) bed ( 297 mg) via syringe pump at a flow rate of 35 p,l/min. Approximately 10 cm of the reactor inlet was filled with glass beads and a 2 pm stainless steel frit was installed at the outlet of the reactor. Reaction products were analyzed by gas chromatography using ChiralDex GTA capillary column and an FID detector. 

S,12S)-2,12-Diacetoxytridecane (17) is a component of the female pheromone of pea midges (Contarinia pisi). Kitching synthesized 17 as shown in Scheme 28 by employing Jacobsen s hydrolytic kinetic resolution of terminal epoxides with a (salen)Co(OAc) complex, (S,S)-B [46]. By this reaction bis-... 

Jacobsen et al. reported enhanced catalytic activity by cooperative effects in the asymmetric ring opening (ARO) of epoxides.[38] Chiral Co-salen complexes (Figure 4.27) were used, which were bound to different generations of commercial PAMAM dendrimers. As a direct consequence of the second-order kinetic dependence on the [Co(salen)] complex concentration of the hydrolytic kinetic resolution (HKR), reduction of the catalyst loading using monomeric catalyst leads to a sharp decrease in overall reaction rate. 

Covalent attachment chiral Co(salen) complexes to polystyrene and silica gave efficient and highly enantioselective catalysts for the hydrolytic kinetic resolution (HKR) of terminal epoxides, including epichlorohydrin. These systems provide practical solutions to difficulties with the isolation of reaction products from the HKR. Removal of the supported catalyst by filtration and repeated recycling was demonstrated with no loss of reactivity or enantioselectivity. The immobilised catalysts have been adapted to a... 

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). 

The same immobilized catalyst 36 [69] was also effectively used for dynamie hydrolytic kinetic resolution of epibromohydrin. Five reaction cycles performed with single eatalyst bateh provided combined yield of 94% with 96% ee and in 90% ehemieal purity for the product l-bromo-2,3-propandiol (Scheme 14). 

Cavazzini, M. Quid, S. Pozzi, G. (2002) Hydrolytic kinetic resolution of terminal epoxides eatalyzed by fluorous chiral Co(salen) complexes. Tetrahedron 58 3943-3949. 

Shepperson, L Cavazzini, M. Pozzi, G. Quici, S. (2004) Fluorous biphasic hydrolytic kinetic resolution of terminal epoxides, J. Fluor. Chem., 125 175-180. 

Zheng, X. Jones, C. W. Week, M. (2006) Poly(styrene)-supported Co-salen eomplexes as effieient recyclable catalysts for the hydrolytic kinetic resolution of epiehlorohydrin, Chem. Eur. J., 12 576 - 583. 

Annis, D. A. Jaeobsen, E. N. (1999) Polymer supported ehiral Co(salen) complexes synthetie applieations and mechanistic investigations in the hydrolytic kinetic resolution of terminal epoxides., Y. Am. Chem. Soc., 121 4147-4154. 

The importance of hydrolytic kinetic resolution (HKR) in providing a wide range of highly enantiomerically enriched terminal mono- and bis epoxides has been showed by the conversion of such epoxides efficiently to some important insect pheromones. 1 51... 

The first high-throughput ee assay used in the directed evolution of enantioselective enzymes was based on UV/Vis spectroscopy (16,74). It is a crude but useful screening system that is restricted to the hydrolytic kinetic resolution of racemic / -nitrophenyl esters catalyzed by lipases or esterases. The development of this assay arose from the desire to evolve highly enantioselective mutants of the lipase from Pseudomonas aeruginosa as potential biocatalysts in the hydrolytic kinetic resolution of the chiral ester rac-. The wild type leads to an E value of only 1.1 in slight... 

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