Catalysts For Kinetic Resolution Research Articles

Encapsulation of lipase in zeolitic imidazolate framework-8 induced by polyethyleneimine to form a honeycomb structure with enhanced activity

Embedding an enzyme in the metal-organic frameworks (MOFs) gives good protection to the fragile enzyme. However, this may also restrain the enzyme activity because of the decreased substrate accessibility. Encapsulation of lipase AK from Pseudomonas fluorescens for preparing the enzyme-MOF composite (AK@ZIF-8-PEI) was performed through a new strategy based on polyethyleneimine and enzyme induced in-situ growth of zeolitic imidazolate framework-8 (ZIF-8). Characterizations indicate that AK@ZIF-8-PEI has a honeycomb structure and the hierarchical porosity formed during the preparation, which provides adequate mass transfer channels for catalytic applications. Activity evaluation shows that specific activity of AK@ZIF-8-PEI is 8-fold than the commercial lipase powder. AK@ZIF-8-PEI is demonstrated as an efficient catalyst in kinetic resolution of α-naphthol enantiomers through enantioselective transesterification. Within 12 h, the conversion and substrate enantiomeric excess (ees) reaches 49.8 % and 96.4 %, achieving an improved resolution than previous researches.

Lipase/H2SO4‐Cocatalyzed Dynamic Kinetic Resolution of Alcohols in Pickering Emulsion

AbstractThis study reports the first chemoenzymatic dynamic kinetic resolution (DKR) of racemic sec‐alcohols by simultaneously using immobilized lipase and aqueous sulfuric acid as catalysts for kinetic resolution and racemization, respectively. The nanoparticle‐stabilized phase separation in a Pickering emulsion enabled the use of these inherently incompatible catalysts in a single vessel. The racemization reaction in the aqueous sulfuric acid solution significantly suppressed the dehydrative side reactions that form alkenes and dimeric ethers, which are often observed in racemization using Brønsted/Lewis acids or oxovanadium compounds in organic solvents. The efficacy of the Pickering emulsion was confirmed by the significantly lower catalytic performance in DKR without emulsification. This method achieved high yields and high optical purities in the production of a wide range of sec‐alcohols.

Methionine Sulfoxide Reductase as an Efficient Catalyst for Kinetic Resolution of the Chiral Sulfoxides

Key words chiral sulfoxides - kinetic resolution - reductases - rational mutagenesis

Development of Dynamically Chiral Helical Polymer Catalysts Based on Post-Polymerization Modification of Boronyl Pendants

Catalytic asymmetric synthesis is one of the most efficient methods for the preparation of chiral compounds with high optical purity. Although a variety of robust chiral scaffolds have been developed to achieve efficient chiral catalysts which show high catalytic activities and stereoselectivities, use of dynamic chiral scaffold is desired for the development of advanced chiral catalysts featuring stimuli-responsive properties such as chirality-switching and asymmetric amplification. We have developed chirality-switchable helical polymer ligands bearing monodentate phosphine pendants, which exhibit high enantioselectivities based on solvent-dependent dynamic screw-sense control of poly(quinoxaline-2,3-diyl)s (PQXs) having chiral side chains. However, the application has been limited to palladium-catalyzed asymmetric reactions. This article describes the development of helically chiral polymer catalysts based on post-polymerization modification of bornyl pendants (-B(OH)2) attached to the PQXs. Introduction of 2,2′-bipyridine pendants to chiral PQXs through Suzuki-Miyaura coupling at the boronyl pendants led to the development of chirality-switchable helical polymer ligands for copper-catalyzed asymmetric reactions. In addition, introduction of 4-aminopyridine pendants into the chiral PQXs provided chirality-switchable efficient asymmetric nucleophilic catalysts for kinetic resolution of secondary alcohols and asymmetric Steglich-type acyl rearrangements. Furthermore, by using the boronyl pendants as molecular recognition sites for screw-sense induction to achiral PQXs, a chiral-guest-responsive helical polymer ligand bearing monodentate phosphine pendants was developed for the palladium-catalyzed asymmetric reaction. Using an amino alcohol as a chiral additive, the screw-sense induction proceeded with asymmetric amplification, giving the corresponding product with higher optical purity than that of the chiral additive.

In depth analysis of heterogeneous catalysts for the chemoenzymatic dynamic kinetic resolution of β-amino esters

The chemoenzymatic dynamic kinetic resolution of β-amino esters is established after detailed evaluation of metal-based heterogeneous catalysts for racemization and enzyme catalysts for kinetic resolution.

Enhanced Production of (S)-2-arylpropionic Acids by Protein Engineering and Whole-Cell Catalysis.

Esterases are important biocatalysts for chemical synthesis. Several bHSL family esterases have been used to prepare (S)-2-arylpropionic acids with stronger anti-inflammatory effects via kinetic resolution. Here, we presented the discovery of key residues that controlled the enantioselectivity of bHSL family esterases to ethyl 2-arylpropionates, through careful analysis of the structural information and molecular docking. A new bHSL family esterase, Est924, was identified as a promising catalyst for kinetic resolution of racemic ethyl 2-arylpropionates with slight (R)-stereopreference. Using Est924 as the starting enzyme, protein engineering was conducted at hotspots, and the substitution of A203 was proved to enhance the enantioselectivity. The stereopreference of the mutant M1 (A203W) was inverted to ethyl (S)-2-arylpropionates, and this stereopreference was further improved in variant M3 (I202F/A203W/G208F). In addition, the optimal variant, M3, was also suitable for the resolution of ibuprofen ethyl ester and ketoprofen ethyl ester, and their efficient (S)-isomers were synthesized. Next, the whole-cell catalyst harboring M3 was used to prepare (S)-ketoprofen. (S)-ketoprofen with 86%ee was produced by whole-cell catalyst with a single freeze-thaw cycle, and the cells could be reused for at least five cycles. Our results suggested that Est924 variants could kinetically resolve economically important racemates for industrial production and further offer the opportunity for the rational design of enzyme enantioselectivity. Moreover, it is an economical process to prepare optically pure (S)-ketoprofen and (S)-naproxen by using an engineered strain harboring M3 as the catalyst.

Chiral Bifunctional Metalloporphyrin Catalysts for Kinetic Resolution of Epoxides with Carbon Dioxide.

Chiral binaphthyl-strapped Zn(II) porphyrins with triazolium halide units were synthesized as bifunctional catalysts for kinetic resolution of epoxides with CO2. Several catalysts were screened by changing the linker length and nucleophilic counteranions, and the optimized catalyst accelerated the enantioselective reaction at ambient temperature to produce optically active cyclic carbonates and epoxides.

A novel approach for bioconjugation of Rhizomucor miehei lipase (RML) onto amine-functionalized supports; Application for enantioselective resolution of rac-ibuprofen

Since the amine groups are highly reactive toward various functional moieties, the formation of covalent bonds between a biomolecule and an insoluble amine-functionalized support is the most frequently used technique in immobilization protocols. A new approach based on the Ugi four-component reaction was used for immobilization of Rhizomucor miehei lipase (RML) as a model enzyme on amine-functionalized silica and silica nanoparticles (SBA-15). For this, the amine-modified supports were prepared and the structural properties of the functionalized supports, prior to and after functionalization were characterized by using IR, SEM, TGA, DTA, TEM. Immobilization of RML on the aminated carriers was performed under extremely mild conditions (25 °C, pH 7).The results revealed very rapid immobilization of 150 and 200 mg of RML on 1 g of silica-NH2 and SBA-NH2, respectively, producing 95–100% of immobilization yield. The specific activity and optimum pH of the immobilized preparations and the effect of temperature and co-solvents on their stabilities as well as the reusability of the derivatives were tested. The immobilized preparations were also used as enantioselective catalyst in kinetic resolution of racemic ibuprofen. Among them, Silica-RML showed the best selectivity with 92.2% enantiomeric excess (ee) and E-value of 33.9.

Organic Solvent-Tolerant Marine Microorganisms as Catalysts for Kinetic Resolution of Cyclic β-Hydroxy Ketones.

Chiral cyclic β-hydroxy ketones represent key motifs in the production of natural products of biological interest. Although the molecules are structurally simple, they require cumbersome synthetic steps to get access to them and their synthesis remains a challenge in organic chemistry. In this report, we describe a straightforward approach to enantiomerically enriched (R)- and (S)-3-hydroxycyclopentanone 2a, (R)- and (S)-3-hydroxycyclohexanone 2b, and (R)- and (S)-3-hydroxycycloheptanone 2c involving a transesterification resolution of the racemates using whole cells of marine microorganisms as catalysts and vinyl acetate the acyl donor and solvent. Twenty-six strains from a wide collection of isolates from marine sediments were screened, and seven strains were found to markedly catalyze the resolution in an asymmetric fashion. Using the strain Serratia sp., (R)-2a was isolated in 27% yield with 92% ee and (S)-2a in 65% yield with 43% ee, corresponding to an E-value of 37; (R)-2b was isolated in 25% yield with 91% ee and (S)-2b in 67% yield with 39% ee, corresponding to an E-value of 40; and (R)-2c was isolated in 30% yield with 96% ee and (S)-2c in 63% yield with 63% ee, corresponding to an E-value of 75.

Immobilization of Lipase from Pseudomonas fluorescens on Porous Polyurea and Its Application in Kinetic Resolution of Racemic 1-Phenylethanol.

A porous polyurea (PPU) was prepared through a simple protocol by reacting toluene diisocyanate with water in binary solvent of water-acetone. Its amine group was determined through spectrophotometric absorbance based on its iminization with p-nitrobenzaldehyde amines. PPU was then used as a novel polymer support for enzyme immobilization, through activation by glutaraldehyde followed by immobilization of an enzyme, lipase from Pseudomonas fluorescens (PFL), via covalent bonding with the amine groups of lipase molecules. Influences of glutaraldehyde and enzyme concentration and pH in the process were studied. The results revealed that the activity of the immobilized PFL reached a maximum at GA concentration of 0.17 mol/L and at pH 8. Immobilization rate of 60% or higher for PFL was obtained under optimized condition with an enzyme activity of 283 U/mg. The porous structure of PPU, prior to and after GA activation and PFL immobilization, was characterized. The activity of the immobilized PFL at different temperature and pH and its stability at 40 °C as well as its reusability were tested. The immobilized enzyme was finally used as enantioselective catalyst in kinetic resolution of racemic 1-phenylethanol (1-PEOH), and its performance compared with the free PFL. The results demonstrate that the enzyme activity and stability were greatly improved for the immobilized PFL, and highly pure enantiomers from racemic 1-PEOH were effectively achieved using the immobilized PFL. Noticeable deactivation of PFL in the resolution was observed by acetaldehyde in situ formed. In addition, the immobilized PFL was readily recovered from the reaction system for reuse. A total of 73% of the initial activity was retained after 5 repeated reuse cycles. This work provides a novel route to preparation of a polyurea porous material and its enzyme immobilization, leading to a novel type of immobilized enzyme for efficient kinetic resolution of racemic molecules.

Bi-aryl rotation in phenyl-dihydroimidazoquinoline catalysts for kinetic resolution of arylalkyl carbinols

Chiral nucleophilic catalysts, 6-aryl-phenyl-dihydroimidazoquinolines (PIQs), were designed, synthesised and applied to the kinetic resolution of arylalkyl carbinols with very high selectivity (S) factors (up to 530).

In Situ Evaluation of Kinetic Resolution Catalysts for Nitroaldol by Rationally Designed Fluorescence Probe

Development of effective chemical catalysts is a key concern in organic chemistry. Therefore, convenient screening systems for chemical catalysts are required, and although some fluorescence-based HTS systems have been developed, little attempt has been made to apply them to asymmetric catalysts. Therefore, we tried to develop a chiral fluorescence probe which can evaluate the reactivity and enantioselectivity of asymmetric catalysts. We focused on kinetic resolution catalysts as a target of our novel fluorescence probe, employing β-elimination following acylation of nitroaldol. Once the hydroxyl group of nitroaldol is acylated, β-elimination occurs immediately, affording nitro olefin. Therefore, we designed and synthesized a fluorescence probe with an asymmetric nitroaldol moiety. Its fluorescence intensity decreases dramatically upon β-elimination, so the fluorescence decrease is an indicator of the reaction yield. Thus, the enantioselectivity of kinetic resolution catalysts can be assessed simply by measuring the fluorescence intensities of the reaction mixtures of the two enantiomers; it is not necessary to purify the product. This fluorescence probe revealed that benzotetramisole is a superior catalyst for kinetic resolution of nitroaldol. Furthermore, we established an HTS system for asymmetric catalysts, using a fluorescence probe and benzotetramisole. To our knowledge, this is the first fluorescence-based HTS system for asymmetric catalysts.

最近の研究に観る非酵素触媒を用いた速度論的分割

Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Recently, development of new artificial catalysts enables to accomplish higher performance of enantiodiscrimination than that by enzymatic catalysts in kinetic resolution.

Dynamic Kinetic Resolution of rac-2-Hydroxy-1-indanone by using a Heterogeneous Ru(OH)3/Al2O3 Racemization Catalyst and Lipase

Kinetic resolution and dynamic kinetic resolution, in particular, provide practical tools for synthesis of enantiomerically pure compounds. in the present work, the resolution of rac 2-hydroxy-1-indanone and racemization of (S)-2 - hydroxy-l-inda-none were investigated. Immobilized lipase AK (Pseudomonas fluorescens) was found as the best enzyme catalyst for kinetic resolution and ruthenium supported on Al 2 O 3 as a potential heterogeneous catalyst for racemization of the starting material. By combining the two reactions, a simple dynamic kinetic resolution of rac-2-hydroxy-1-indanone producing (R)-1-oxo- , indan-2-yl butanoate was developed. Under optimal conditions, the product was obtained in 92% ee at approximately 90% conversion.

Dimeric & Polymeric Chiral Schiff Base Complexes and Supported BINOL Complexes as Potential Recyclable Catalysts in Asymmetric Kinetic Resolution and C–C Bond Formation Reactions

This review is based on dimeric and polymeric chiral Schiff base metal complexes and chiral BINOL supported metal complexes as potential recyclable catalysts for kinetic resolution of racemic and meso epoxide and asymmetric C–C bond formation reactions e.g., asymmetric addition of diethylzinc to aldehydes, enantioselective addition of phenylacetylene to aldehydes, asymmetric nitro-Aldol reactions and asymmetric cyanation reaction.

Supported Vanadium Catalysts for Kinetic Resolution

Supported Vanadium Catalysts for Kinetic Resolution

Tandem reactions for streamlining synthesis: enantio- and diastereoselective one-pot generation of functionalized epoxy alcohols.

[Reaction: see text] In 1980, Sharpless and Katsuki introduced the asymmetric epoxidation of prochiral allylic alcohols (the Sharpless-Katsuki asymmetric epoxidation), which enabled the rapid synthesis of highly enantioenriched epoxy alcohols. This reaction was a milestone in the development of asymmetric catalysis because it was the first highly enantioselective oxidation reaction. Furthermore, it provided access to enantioenriched allylic alcohols that are now standard starting materials in natural product synthesis. In 1981, Sharpless and co-workers made another seminal contribution by describing the kinetic resolution (KR) of racemic allylic alcohols. This work demonstrated that small-molecule catalysts could compete with enzymatic catalysts in KRs. For these pioneering works, Sharpless was awarded the 2001 Nobel Prize with Knowles and Noyori. Despite these achievements, the Sharpless KR is not an efficient method to prepare epoxy alcohols with high enantiomeric excess (ee). First, the racemic allylic alcohol must be prepared and purified. KR of the racemic allylic alcohol must be stopped at low conversion, because the ee of the product epoxy alcohol decreases as the KR progresses. Thus, better methods to prepare epoxy alcohols containing stereogenic carbinol carbons are needed. This Account summarizes our efforts to develop one-pot methods for the synthesis of various epoxy alcohols and allylic epoxy alcohols with high enantio-, diastereo-, and chemoselectivity. Our laboratory developed titanium-based catalysts for use in the synthesis of epoxy alcohols with tertiary carbinols. The catalysts are involved in the first step, which is an asymmetric alkyl or allyl addition to enones. The resulting intermediates are then subjected to a titanium-directed diastereoselective epoxidation to provide tertiary epoxy alcohols. Similarly, the synthesis of acyclic epoxy alcohols begins with asymmetric additions to enals and subsequent epoxidation. The methods described here enable the synthesis of skeletally diverse epoxy alcohols.

First Example of Chiral N‐Heterocyclic Carbenes as Catalysts for Kinetic Resolution.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Display of bacterial lipase on the Escherichia coli cell surface by using FadL as an anchoring motif and use of the enzyme in enantioselective biocatalysis.

We have developed a novel cell surface display system by employing FadL as an anchoring motif, which is an outer membrane protein involved in long-chain fatty acid transport in Escherichia coli. A thermostable Bacillus sp. strain TG43 lipase (44.5 kDa) could be successfully displayed on the cell surface of E. coli in an active form by C-terminal deletion-fusion of lipase at the ninth external loop of FadL. The localization of the truncated FadL-lipase fusion protein on the cell surface was confirmed by confocal microscopy and Western blot analysis. Lipase activity was mainly detected with whole cells, but not with the culture supernatant, suggesting that cell lysis was not a problem. The activity of cell surface-displayed lipase was examined at different temperatures and pHs and was found to be the highest at 50 degrees C and pH 9 to 10. Cell surface-displayed lipase was quite stable, even at 60 and 70 degrees C, and retained over 90% of the full activity after incubation at 50 degrees C for a week. As a potential application, cell surface-displayed lipase was used as a whole-cell catalyst for kinetic resolution of racemic methyl mandelate. In 36 h of reaction, (S)-mandelic acid could be produced with the enantiomeric excess of 99% and the enantiomeric ratio of 292, which are remarkably higher than values obtained with crude lipase or cross-linked lipase crystal. These results suggest that FadL may be a useful anchoring motif for displaying enzymes on the cell surface of E. coli for whole-cell biocatalysis.

04/01360 Biodiesel production from waste cooking oil: 1. Process design and technological assessment: Zhang, Y. et al. Bioresource Technology, 2003, 89, (1), 1–16

Since the amine groups are highly reactive toward various functional moieties, the formation of covalent bonds between a biomolecule and an insoluble amine-functionalized support is the most frequently used technique in immobilization protocols. A new approach based on the Ugi four-component reaction was used for immobilization of Rhizomucor miehei lipase (RML) as a model enzyme on amine-functionalized silica and silica nanoparticles (SBA-15). For this, the amine-modified supports were prepared and the structural properties of the functionalized supports, prior to and after functionalization were characterized by using IR, SEM, TGA, DTA, TEM. Immobilization of RML on the aminated carriers was performed under extremely mild conditions (25 °C, pH 7).The results revealed very rapid immobilization of 150 and 200 mg of RML on 1 g of silica-NH2 and SBA-NH2, respectively, producing 95–100% of immobilization yield. The specific activity and optimum pH of the immobilized preparations and the effect of temperature and co-solvents on their stabilities as well as the reusability of the derivatives were tested. The immobilized preparations were also used as enantioselective catalyst in kinetic resolution of racemic ibuprofen. Among them, Silica-RML showed the best selectivity with 92.2% enantiomeric excess (ee) and E-value of 33.9.