Hydrolytic kinetic resolution, epoxides

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). 

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. 

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... 

Scheme 2.1.6.5 Hydrolytic kinetic resolution (HKR) of terminal epoxides.

To investigate the catalytic activity of the materials prepared, hydrolytic kinetic resolution of terminal epoxides such as styrene oxide, 1,2-epoxyhexane, and epi-chlorohydrin was carried out using only water, which acts as a nucleophilic agent... 

The third investigation track demonstrated the immobilization of metal-salen complexes in mesoporous materials and their use in the hydrolytic kinetic resolution of meso and terminal epoxides. The best results were obtained over cobalt-Ja-cobsen catalysts. The catalytic activity of the (S,S)-Co(II)-Jacobsen complex immobilized on Al-MCM-41 was comparable with that of the homogeneous counterpart. Several other immobilization methods are still under investigation. 

Hydrolytic Kinetic Resolution of Terminal Epoxides with Water (Scheme 6.9)... 

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]. 

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>. 

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