Racemic hydrolytic kinetic resolution

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... 

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 (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. 

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... 

A typical example that illustrates the method concerns the lipase- or esterase-catalyzed hydrolytic kinetic resolution of rac-1-phenyl ethyl acetate, derived from rac-1-phenyl ethanol (20). However, the acetate of any chiral alcohol or the acetamide of any chiral amine can be used. A 1 1 mixture of labeled and non-labeled compounds (S)- C-19 and (f )-19 is prepared, which simulates a racemate. It is used in the actual catalytic hydrolytic kinetic resolution, which affords a mixture of true enantiomers (5)-20 and (J )-20 as well as labeled and non-labeled acetic acid C-21 and 21, respectively, together with non-reacted starting esters 19. At 50% conversion (or at any other point of the kinetic resolution), the ratio of (5)- C-19 to (1 )-19 correlates with the enantiomeric purity of the non-reacted ester, and the ratio of C-21 to 21 reveals the relative amounts of (5)-20 and (J )-20 (98). 

Much activity continues to be centered around the preparation of enantioenriched epoxides using chiral Co(III)-, Mn(III)- and Cr(III)-salen complexes, particularly in the area of innovative methods. A recent brief review <02CC919> focuses on the synthesis, structural features, and catalytic applications of Cr(III)-salen complexes. In an illustrative example, Jacobsen and coworkers <02JA1307> have applied a highly efficient hydrolytic kinetic resolution to a variety of terminal epoxides using the commercially available chiral salen-Co(III) complex 1. For example, treatment of racemic m-chlorostyrene oxide (2) with 0.8 mol% of catalyst 1 in the presence of water (0.55 equiv) led to the recovery of practically enantiopure (> 99% ee) material in 40% yield (maximum theoretical yield = 50%). This method appears to be effective for a variety of terminal epoxides, and the catalyst suffered no loss of activity after six cycles. 

The hydrolytic kinetic resolution of racemic terminal epoxides using metal salen catalysts is one of the premier methods for the formation of enantioenriched oxiranes and/or 1,2-diols, e.g., <1997SCI936, 1998JOC6776, 2000AGE3604, 2002JA1307>. 

Several specific cases have been described in the literature [10,50], A new example concerns the hydrolytic kinetic resolution of the epoxide 1 catalyzed by an epoxide hydrolase (Fig. 11.5) [52], As in other kinetic resolutions, the reaction is allowed to reach the ideal value of 50 %. Instead of employing a genuine racemate (R)-1/(S)-1... 

Fig. 11.10. Hydrolytic kinetic resolution ofthe racemic ester 9 [8, 9].

A so far still unsolved problem is the direct enantioselective epoxidation of simple terminal olefins. For example the epoxidation of propylene that was achieved with a 41% ee almost twenty years ago by Strukul and his coworkers using Pt/diphosphine complexes is still unsurpassed. Unfortunately such low ee s are of no practical interest. The problem was circumvented by Jacobsen using hydrolytic kinetic resolution of racemic epoxides (Equation 26) and is practised on a multi 100 kg scale at Chirex. The strategy used is to stereose-lectively open the oxirane ring of a racemic chiral epoxide leaving the other enantiomer intact. Reactions are carried out to a 50% maximum conversion. The catalyst belongs to the metal-salen class described above and can be recycled. The products are separated by fractional distillation. 

Catalysts of this type can be used not only for the enantioseleetive generation of epoxides from alkenes, but also for the hydrolytic kinetic resolution (HKR) of racemic epoxides, particularly the terminal variety. For example, the cobalt(III)salen complex 2 catalyzed the enantioseleetive hydrolysis of racemic hexene oxide 3 in the presence of 0.5 equivalents of water to provide the f/ j-enantiomer in 99% ee. Here, the inorganic ligand was found to be important for catalyst activity and selectivity, with the conventional acetate ligand giving inferior results <03TL5005>. 

A synthetic strategy based on Jacobsen s hydrolytic kinetic resolution of readily available racemic epoxide 345 offers the possibility to produce in a good yield enantiomerically enriched (R,R) and (A,A)-epoxides 345 as chiral building blocks for the preparation of (R)-lipoic acid and (A)-lipoic acid (Scheme 66) <200681863>. 

FIGURE 3.28. Hydrolytic kinetic resolution of racemic acetates using ChiroCLEC-PC... 

The hydrolytic kinetic resolution (HKR) of racemic epoxides using Jacobsen s chiral Co(III)(salen)-OAc complex 36a as a catalyst is one of the most practical approaches to the preparation of enantiopure terminal epoxides (Scheme 7.15) [47, 53]. Although the chiral catalyst is readily accessible and displays high enantioselectivity, it provides only relatively low turnover numbers. Thus, in order to facilitate catalyst separation and reuse, several attempts were made to anchor Jacobsen s catalyst onto insoluble supports [54]. Although these heterogeneous... 

Kinetic resolution of ( ) diethyl 2,3-epoxypropylphosphonate by enantioselective hydrolysis has recently been described (Scheme 4.50). In the presence of (7 ,7 )-MA -(>w(3.5-di-tert-butyl-salicylidene)-l,2-cyclohexanediaininocobalt(lll) acetate and H2O for 19 h, racemic diethyl 2,3-epoxpropylphosphonate is converted into a mixture of (S )-)-) diethyl 2.3-epoxypropylphosphonate (82% ee) and diethyl (/ )-(-) 2,3-dihydroxypropylphosphonate (98% ee). An improved enantiomeric excess (93% ee) of (S)-(-) diethyl 2,3-epoxypropylphosphonate has been obtained after a 72-h hydrolytic kinetic resolution experiment.-" ... 

The hydrolysis of epoxides is a well-known reaction which can be exploited for various synthetically useful outcomes. Chiral nonracemic epoxides can be prepared from their racemates through the salen-mediated hydrolytic kinetic resolution (HKR). Racemic epichlorohydrin 53 was resolved in the presence of catalyst 52 and a slight excess of water under solvent-free conditions. The catalyst counterion exerts a significant effect on the course of the reaction, presumably due to competitive addition onto the epoxide, an effect which is evident in apparent reaction rates, but not enantioselectivities. Less nucleophilic counterions, such as tosylate, lead to more rapid resolution and lower catalyst loading requirements <04JA1360>. 

Industrialization studies of the Jacobsen hydrolytic kinetic resolution of racemic epichlorhy-drin... 

The hydrolytic kinetic resolution (HKR) of racemic terminal epoxides catalyzed by chiral (salen)-Co(III) complexes provides efficient access to epoxides and 1,2-diols, valuable chiral building blocks, in highly enantioenriched forms. While the original procedure has proved scalable for many substrates, several issues needed to be overcome for the process to be industrially practical for one of the most useful epoxides, epichlorohydrin. Combined with kinetic modelling of the HKR of epichlorohydrin, novel solutions were developed which resulted in linearly scalable processes that successfully addressed issues of catalyst activation, analysis and reactivity, control of exothermicity, product isolation, racemization, and side-product formation. 

The hydrolytic kinetic resolution addressed a long-standing problem in enan-tioselective epoxide synthesis. The ability to access almost any terminal epoxide or 1,2-diol in high enantiopurity greatly expanded the chiral pool of compounds available for asymmetric synthesis. Equally important was the demonstration of practicality and efficiency that renders the ARO of a racemic mixture a synthetically viable approach. 

Despite the phenomenal success of these homogeneous catalysts, further developments of new asymmetric catalysts, bio-catalysts and heterogeneous catalysts will benefit from a greater understanding of the mechanistic pathways involved in the catalytic reactions [7]. A good illustration of this process is the hydrolytic kinetic resolution of racemic epoxides using a Co-based Salen catalyst... 

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