Enantioselective Transesterification Research Articles

Total Synthesis of (±)-Carquinostatin A, and Asymmetric Total Synthesis of (<i>R</i>)-(−)-Carquinostatin A and (<i>S</i>)-(+)-Carquinostatin A

Total syntheses of (±)-carquinostatin A (1), and (R)-(-)-carquinostatin A (1a) together with its enantiomer, (S)-(+)-carquinostatin A (1b), possessing radical scavenging activity, were newly achieved. (±)-Carquinostatin A (1) was synthesized from 1-acetonyl-6-bromo-3-ethoxy-2-methylcarbazole (6), which was derived from the known 1-acetonyl-3-ethoxy-2-methylcarbazole (5). Introduction of a prenyl group at the 6-position of carbazole was successful in two steps. For the synthesis of (R)-(-)-carquinostatin A (1a) and (S)-(+)-carquinostatin A (1b), (R)-(-)-1-(2-acetoxypropyl)-3-hydroxy-2-methylcarbazole (15a) and (S)-(+)-3-hydroxy-1-(2-hydroxypropyl)-2-methylcarbazole (15b), prepared by lipase-QLM catalyzed enantioselective transesterification of 3-hydroxy-1-(2-hydroxypropyl)-2-methylcarbazole (14), were used as the chiral starting material.

Novel and highly effective chemoenzymatic synthesis of (2R)-2-[4-(4-cyano-2-fluorophenoxy)phenoxy]butylpropanoate based on lipase mediated transesterification

(2R)-2-[4-(4-Cyano-2-fluorophenoxy)phenoxy]butylpropanoate (cyhalofop-butyl, CyB) was synthesized by a chemoenzymatic route involving enantioselective transesterification with Candida antarctica lipase B (Novozym 435). The optimum organic solvent, acyl donor, a ( w ), reaction temperature and shaking rate for the transesterification were acetonitrile, n-butanol, 0.11, 45°C and 200 rpm, respectively. Under the optimum conditions, the maximum substrate conversion and the enantiomeric purity of the product were 96.9 and >99%, respectively. The total yield and enantiomeric purity of CyB by this chemoenzymatic synthesis were 60.4 and >99%, respectively; 15.3 and 21% higher than that of the traditional way (45 and 78%).

Kinetic resolution of 2-chloro-3,3,3-trifluoropropanoic acid esters catalyzed by lipase from Candida rugosa

By screening around 30 commercially available lipases and esterases, two enzymes, C. rugosa lipase and P. fluorescens esterase, were found to posess catalytic activity and enantioselectivity (E˜10) for the hydrolysis of 2-chloro-3,3,3-trifluoropropanoic acid (CTFPA) methyl and ethyl ester. Both enzymes were tentatively assigned to be (S)-selective based on the assumption that they have the same stereopreference as in the hydrolysis of methyl 2-chloropropanoate, which is a non-fluorinated analogue of CTFPA. The enzymes were applied in the kinetic resolution of CTFPA ethyl ester and 95% ee of the remaining ester could be achieved at 60% conversion. The crosslinked enzyme aggregate (CLEA) of C. rugosa lipase was found to catalyze enantioselective transesterification (E˜40) of CTFPA methyl ester with ethanol. By conducting the transesterification in a 10-mL packed-bed reactor containing CLEA, it was possible to convert racemic CTFPA methyl ester into the mixture of (S)-methyl and (R)-ethyl esters with 82% and 90% ee, respectively, at 4.0 g/L-1/h-1 space-time yield, which decreased to 1.0 g/L-1/h-1 after four repetitive batches.

Resolution of 2-nitroalcohols by Burkholderia cepacia lipase-catalyzed enantioselective acylation

Racemic 2-nitro-1-phenylethanol was resolved by via enantioselective transesterification catalyzed by Burkholderia cepacia lipase. The reaction afforded excellent E values (E > 200) and enantioselectivity (up to >99% enantiomeric excesses [ee]) of both remaining substrates and acetylated product. Moreover, the lipase displayed high enantioselectivity in the resolution of additional 2-nitroalcohols (E up to >200). This method provides an efficient alternative for obtaining enantiopure 2-nitroalcohols.

ChemInform Abstract: Enantioselective Transesterification of (.+‐.)‐6‐Benzyloxy‐2,5,7,8‐tetramethyl‐3,4‐dihydro‐2H‐1‐benzopyran‐2‐ylm ethanol Catalyzed by the Amano PS Lipase in the Ionic Liquid [bmim] PF6.

AbstractThe chiral benzopyran ((S)‐(—)‐I) represents a key intermediate for the synthesis of α‐tocopherol and α‐tocotrienol.

Optimised Dynamic Kinetic Resolution of benzoin by a chemoenzymatic approach in 2-MeTHF

Different influential parameters in the Dynamic Kinetic Resolution of racemic benzoin via lipase–ruthenium catalyst enantioselective transesterification have been improved in order to develop a more productive process. In this sense, 2-Methyltetrahydrofuran (2-MeTHF) is proposed as an excellent and greener substitute of THF for this biotransformation; on the other hand, by scaling up the reaction, much better results were obtained by using a much simpler one-pot methodology (compared to the previously described three-steps protocol), resulting not only in higher amounts of enantiopure product (85% conversion, >99% ee of the product), but also in an enhanced sustainability of the process, because lower acyl donor concentrations and lower ruthenium catalyst amounts (protected from oxygen deactivation) are required.

Optimization of APE1547-catalyzed enantioselective transesterification of (R/S)-2-methyl-1-butanol in an ionic liquid

Aeropyrum pernix esterase (APE1547) was successfully used to catalyze the enantioselective transesterification of (R/S)-2-methyl-1-butanol in an ionic liquid (IL). Effects of various reaction conditions on the synthetic activity of the enzyme as well as enantioselectivity, including the type of IL, acyl donor, temperature, water activity, and substrate molar ratio were inverstigated. APE1547 showed good catalytic performance (activity > 0.8 μmol/min/mg, E > 25), and the enzyme-IL mixture was recycled five times with only a slight decrease in catalytic performance.

Transdermal and oral dl‐methylphenidate – ethanol interactions in C57BL/6J mice: Locomotor activity and brain d‐, l‐methylphenidate and l‐ethylphenidate concentrations

The interaction of dl‐methylphenidate (MPH) and ethanol (EtOH) results in an elevation of the active d‐MPH plasma concentration and enantioselective transesterification to yield the biomarker l‐ethylphenidate (EPH). The present study reports on a C57BL/6J mouse model of dl‐MPH induced locomotor activity which was potentiated by an otherwise sedating dose of oral EtOH (3 g/kg). Concomitant oral dl‐MPH (7.5 mg/kg) and EtOH significantly increased the locomotor activity induced by oral dl‐MPH alone over a 100 min period. Transdermal dl‐MPH (¼ of a 12.5 cm2 patch; mean dose 7.5 mg/kg) induced locomotor activity only after a lag phase of 60 min and this effect was not potentiated by EtOH. Using chiral derivatization and GC‐MS, mean 3 h brain concentrations of d‐MPH found to be significantly elevated by EtOH in both the oral (65% increase) and transdermal (88% increase) groups. The corresponding l‐EPH brain concentrations were 10 ng/g and 130 ng/g for the oral and transdermal groups, respectively. Clinical implications of these findings will be presented in the context of increased abuse potential and side effect liability for this drug combination.

New possibilities in a synthesis of (2R,4'R,8'R)-α-tocopherol (natural vitamin E).

New methods for the synthesis of homochiral C14 and C15-terpenoids desired as building blocks for phytilic side chain of natural α-tocopherol have been developed. A natural phytone resulted from the proposed effective method of chlorophyll ozonolysis was used in a synthesis of optically active terpenoids. Chiral chroman compound for vitamin E, namely, (S)-(-)-6benzyloxy-3,4-dihydro-2,5,7,8-tetramethylchroman-2-methanol was obtained by enantioselective transesterification of the corresponding racemic alcohol catalysed by Amano PS lipase from Burkholderia cepacia in ionic liquid [bmim]PF6.

Enantioselective transesterification of (±)-6-benzyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-ylmethanol catalyzed by the Amano PS lipase in the ionic liquid [bmim]PF6

(S)-(-)-6-Benzyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-ylmethanol, a synthon for the design of natural α-tocopherol, was obtained by kinetically selective acetylation of the corresponding racemic alcohol in the presence of the Amano PS lipase from Burkholderia cepacia in the ionic liquid 1-butyl-3-methylimidazolinium hexafluorophosphate ([bmim]PF6).

ChemInform Abstract: Enantioselective Transesterification of 2-Methyl-1,3-propanediol Derivatives Catalyzed by Pseudomonas fluorescens Lipase in an Organic Solvent.

Abstract The irreversible transesterification of racemic 2-methyl-1,3-propanediol derivatives, the monoethers, 3a , 3b , 5a , and the monobenzoate 5b , with vinyl acetate catalyzed by Pseudomonas fluorescens lipase in chloroform affords enantiomerically pure chiral synthons.

Plasma‐Modified Polypropylene as Carrier for the Immobilization of Candida antarctica Lipase B and Pyrobaculum calidifontis Esterase

AbstractIn this work, the immobilization of two hydrolases on plasma‐modified polypropylene carriers was investigated. Treating Accurel MP1001 with an oxygen plasma was found most suitable to increase the hydrophilicity and to allow for efficient immobilization. Thus, for lipase B from Candida antarctica and for an esterase from Pyrobaculum calidifontis esterase (PestE) a 5‐fold and 14‐fold increase, respectively, in immobilization yield resulted compared to untreated carrier. In contrast to the oxygen‐modified support, modification of the polypropylene carrier with ammonia plasma showed no positive effect. Furthermore, it could be shown that immobilized PestE catalyzed enantioselective transesterification of α‐phenylethanol in vinyl acetate, whereas the free enzyme showed no activity. Both hydrolases could be recycled five times without significant loss of activity.

Enantioselective transesterification by Candida antarctica Lipase B immobilized on fumed silica

Enzymatic catalysis to produce molecules such as perfumes, flavors, and fragrances has the advantage of allowing the products to be labeled “natural” for marketing in the U.S., in addition to the exquisite selectivity and stereoselectivity of enzymes that can be an advantage over chemical catalysis. Enzymatic catalysis in organic solvents is attractive if solubility issues of reactants or products, or thermodynamic issues (water as a product in esterification) complicate or prevent aqueous enzymatic catalysis. Immobilization of the enzyme on a solid support can address the generally poor solubility of enzymes in most solvents. We have recently reported on a novel immobilization method for Candida antarctica Lipase B on fumed silica to improve the enzymatic activity in hexane. This research is extended here to study the enantioselective transesterification of (RS)-1-phenylethanol with vinyl acetate. The maximum catalytic activity for this preparation exceeded the activity (on an equal enzyme amount basis) of the commercial Novozyme 435 ® significantly. The steady-state conversion for (R)-1-phenylethanol was about 75% as confirmed via forward and reverse reaction. The catalytic activity steeply increases with increasing nominal surface coverage of the support until a maximum is reached at a nominal surface coverage of 230%. We hypothesize that the physical state of the enzyme molecules at a low surface coverage is dominated in this case by detrimental strong enzyme–substrate interactions. Enzyme–enzyme interactions may stabilize the active form of the enzyme as surface coverage increases while diffusion limitations reduce the apparent catalytic performance again at multi-layer coverage. The temperature-, solvent-, and long-term stability for CALB/fumed silica preparations showed that these preparations can tolerate temperatures up to 70 °C, continuous exposure to solvents, and long-term storage.

Enantioselective transesterification of glycidol catalysed by a novel lipase expressed fromBacillus subtilis

A novel plasmid (pBSR2) was constructed by incorporating a strong lipase promoter and a terminator into the original pBD64. The lipase gene from Bacillus subtilis strain IFFI10210 was cloned into the plasmid pBSR2 and transformed into B. subtilis A.S.1.1655 to obtain an overexpression strain. The recombinant lipase [BSL2 (B. subtilis lipase 2)] has been expressed from the novel constructed strain and used in kinetic resolution of glycidol through enantioselective transesterification. The effects of reaction conditions on the activity as well as enantioselectivity were investigated. BSL2 showed a satisfying enantioselectivity (E>30) under the optimum conditions [acyl donor: vinyl butyrate; the mole ratio of vinyl butyrate to glycidol was 3:1; organic medium: 1,2-dichloroethane with water activity (a(w))=0.33; temperature 40 degrees C]. The remaining (R)-glycidol with a high enantiomeric purity [ee (enantiomeric excess) >99%] could be obtained when the conversion was approx. 60%. The results clearly show a good potential for industrial application of BSL2 in the resolution of glycidol through enantioselective transesterification.

Efficient kinetic bioresolution of 2-nitrocyclohexanol

The kinetic bioresolution of 2-nitrocyclohexanol 1 was investigated by screening a range of hydrolases both for enantioselective transesterification and for enantioselective hydrolysis of the corresponding acetate. By appropriate choice of biocatalyst and conditions, both enantiomers of cis and trans 2-nitrocyclohexanol 1 can be accessed in enantiopure form.

ChemInform Abstract: Enantioselective Transesterification Catalysis by Candida antarctica Lipase Immobilized on Superparamagnetic Nanoparticles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enantioselective transesterification catalysis by nanosized serine protease subtilisin Carlsberg particles in tetrahydrofuran

Enzyme catalysis in organic solvents is a powerful tool for stereo-selective synthesis but the enantioselectivity is still hard to predict. To overcome this obstacle, we employed a nanoparticulate formulation of subtilisin Carlsberg (SC) and designed a series of 14 structurally related racemic alcohols. They were employed in the model transesterification reaction with vinyl butyrate and the enantioselectivities were determined. In general, short alcohol side chains led to low enantioselectivties, while larger and bulky side chains caused better discrimination of the enantiomers by the enzyme. With several bulky substrates high enantioselectivities with E>100 were obtained. Computational modeling highlighted that key to high enantioselectivity is the discrimination of the R and S substrates by the sole hydrophobic binding pocket based on their size and bulkiness. While bulky S enantiomer side chains could be accommodated within the binding pocket, bulky R enantiomer side chains could not. However, when also the S enantiomer side chain becomes too large and does not fit into the binding pocket anymore, enantioselectivity accordingly drops.

Synthesis of chiral non-racemic intermediates and Arg-Gly-Asp mimetics by CaLB-catalyzed resolution

The reactivity of both the ester and amine functions present in β-amino esters was tested in order to obtain the synthesis of enantiopure αvβ3 and α5β1 integrin ligands. CaLB successfully catalyzed both the enantioselective transesterification and the N-acylation of racemic β-amino esters, allowing the isolation of intermediates for the preparation of Arg-Gly-Asp (RGD) mimetic compounds. In particular, a CaLB-catalyzed amidation reaction with unprotected p-aminobenzylamine reduced the number of synthetic steps, thus avoiding protection and deprotection of the intermediate compounds. Following this procedure, RGD mimetics were isolated with high yields and enantiomeric purities.

Microreactor with mesoporous silica support layer for lipase catalyzed enantioselective transesterification

Lipase PS was immobilized in mesoporous silica (MPS) thin films inside a borosilicate tube microreactor for use in the enantioselective transesterification of vinyl acetate with (±)-1-phenylethanol. The immobilization was tested for 3D cubic and 2D hexagonal MPS thin films inside microreactors with and without hydrophobic treatment. The hydrophobic treatment enhanced the adsorption amount and the lipase activity for both 3D cubic and 2D hexagonal films. Of these treated films, the 3D cubic structure film exhibited the highest yield (64%) with an enantioselectivity higher than 99% in a continuous flow experiment. The activity of the immobilized lipase PS was well maintained for 36-hour continuous operation. A Ping-Pong Bi Bi kinetic model was employed to interpret the activity of the immobilized lipase PS. The ratios of the maximum velocity to the Ping-Pong constant (i.e., specificity constants) were measured for lipase PS immobilized inside the microreactor and for native lipase PS. The value inside the microreactor was 800 times greater than that of the native lipase PS.

Enantioselective transesterification catalysis by Candida antarctica lipase immobilized on superparamagnetic nanoparticles

Lipase B from Candida antarctica can be directly immobilized onto functionalized superparamagnetic nanoparticles, preserving its enzymatic activity in the enantioselective transesterification of secondary alcohols, with excellent results in terms of enantiomeric discrimination. The immobilized enzyme can be easily recovered with a magnet, allowing its reuse with negligible loss of activity.