- O 2-(N -Hydroxy(methoxy)-2-ethanesulfonamido) protected diazen-1-ium-1,2-diolates: Nitric oxide release via a base-induced β-elimination cleavage
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O2-(Ethanesulfohydroxamic acid) and O2-(N-methoxy-2- ethanesulfonylamido) diazen-1-ium-1,2-diolates (4-7), a novel type of O 2-(protected) diazeniumdiolate, were synthesized using a key thioacetate oxidation reaction. Nitr
- Huang, Zhangjian,Knaus, Edward E.
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- Reshaping the active pocket of esterase Est816 for resolution of economically important racemates
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Bacterial esterases are potential biocatalysts for the production of optically pure compounds. However, the substrate promiscuity and chiral selectivity of esterases usually have a negative correlation, which limits their commercial value. Herein, an efficient and versatile esterase (Est816) was identified as a promising catalyst for the hydrolysis of a wide range of economically important substrates with low enantioselectivity. We rationally designed several variants with up to 11-fold increased catalytic efficiency towards ethyl 2-arylpropionates, mostly retaining the initial substrate scope and enantioselectivity. These variants provided a dramatic increase in efficiency for biocatalytic applications. Based on the best variant Est816-M1, several variants with higher or inverted enantioselectivity were designed through careful analysis of the structural information and molecular docking. Two stereoselectively complementary mutants, Est816-M3 and Est816-M4, successfully overcame and even reversed the low enantioselectivity, and several 2-arylpropionic acid derivatives with highEvalues were obtained. Our results offer potential industrial biocatalysts for the preparation of structurally diverse chiral carboxylic acids and further lay the foundation for improving the catalytic efficiency and enantioselectivity of esterases.
- Fan, Xinjiong,Fu, Yao,Liu, Xiaolong,Zhao, Meng
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p. 6126 - 6133
(2021/09/28)
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- Bidentate phosphine-phosphine oxide ligand and intermediate, preparation method and application thereof
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The invention discloses a bidentate phosphine-phosphine oxide ligand and an intermediate, a preparation method and application thereof. The phosphine oxide compound is shown as a formula I and/or ent-I. The phosphine oxide compound is used as a metal ligand and is applied to Suzuki-Miyaura coupling reaction so that generation of self-coupled by-products is avoided, and an alpha-aryl carbonyl compound is obtained; and the dosages of the ligand and the metal catalyst are less.
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Paragraph 0431-0434
(2020/11/10)
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- Homochiral Metal-Organic Frameworks for Enantioselective Separations in Liquid Chromatography
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Selective separation of enantiomers is a substantial challenge for the pharmaceutical industry. Chromatography on chiral stationary phases is the standard method, but at a very high cost for industrial-scale purification due to the high cost of the chiral stationary phases. Typically, these materials are poorly robust, expensive to manufacture, and often too specific for a single desired substrate, lacking desirable versatility across different chiral analytes. Here, we disclose a porous, robust homochiral metal-organic framework (MOF), TAMOF-1, built from copper(II) and an affordable linker prepared from natural l-histidine. TAMOF-1 has shown to be able to separate a variety of model racemic mixtures, including drugs, in a wide range of solvents of different polarity, outperforming several commercial chiral columns for HPLC separations. Although not exploited in the present article, it is worthy to mention that the preparation of this new material is scalable to the multikilogram scale, opening unprecedented possibilities for low-energy chiral separation at the industrial scale.
- Corella-Ochoa, M. Nieves,Tapia, Jesús B.,Rubin, Heather N.,Lillo, Vanesa,González-Cobos, Jesús,Nú?ez-Rico, José Luis,Balestra, Salvador R.G.,Almora-Barrios, Neyvis,Lledós, Marina,Gu?ll-Bara, Arnau,Cabezas-Giménez, Juanjo,Escudero-Adán, Eduardo C.,Vidal-Ferran, Anton,Calero, Sofiá,Reynolds, Melissa,Martí-Gastaldo, Carlos,Galán-Mascarós, José Ramón
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p. 14306 - 14316
(2019/10/11)
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- Preparation and characterization of a new open-tubular capillary column for enantioseparation by capillary electrochromatography
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In order to use the enantioseparation capability of cationic cyclodextrin and to combine the advantages of capillary electrochromatography (CEC) with open-tubular (OT) column, in this study, a new OT-CEC, coated with cationic cyclodextrin (1-allylimidazolium-β-cyclodextrin [AI-β-CD]) as chiral stationary phase (CSP), was prepared and applied for enantioseparation. Synthesized AI-β-CD was characterized by infrared (IR) spectrometry and mass spectrometry (MS). The preparation conditions for the AI-β-CD-coated column were optimized with the orthogonal experiment design L9(34). The column prepared was characterized by scanning electron microscopy (SEM) and elemental analysis (EA). The results showed that the thickness of stationary phase in the inner surface of the AI-β-CD-coated columns was about 0.2 to 0.5?μm. The AI-β-CD content in stationary phase based on the EA was approximately 2.77?mmol·m?2. The AI-β-CD-coated columns could separate all 14 chiral compounds (histidine, lysine, arginine, glutamate, aspartic acid, cysteine, serine, valine, isoleucine, phenylalanine, salbutamol, atenolol, ibuprofen, and napropamide) successfully in the study and exhibit excellent reproducibility and stability. We propose that the column, coated with AI-β-CD, has a great potential for enantioseparation in OT-CEC.
- Li, Yingjie,Tang, Yimin,Qin, Shili,Li, Xue,Dai, Qiang,Gao, Lidi
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p. 283 - 292
(2019/02/05)
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- Colistin sulfate chiral stationary phase for the enantioselective separation of pharmaceuticals using organic polymer monolithic capillary chromatography ?
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A new functionalized polymer monolithic capillary with a macrocyclic antibiotic, namely colistin sulfate, as chiral selector was prepared via the copolymerization of binary monomer mixtures consisting of glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) in porogenic solvents namely 1-propanol and 1,4-butanediol, in the presence of azobisiso-butyronitrile (AIBN) as initiator and colistin sulfate. The prepared capillaries were investigated for the enantioselective nano-LC separation of a group of racemic pharmaceuticals, namely, α- and β-blockers, anti-inflammatory drugs, antifungal drugs, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, antihistaminics, anticancer drugs, and antiarrhythmic drugs. Acceptable separation was achieved for many drugs using reversed phase chromatographic conditions with no separation achieved under normal phase conditions. Colistin sulfate appears to be useful addition to the available macrocyclic antibiotic chiral phases used in liquid chromatography.
- Fouad, Ali,Shaykoon, Montaser Sh.A.,Ibrahim, Samy M.,El-Adl, Sobhy M.,Ghanem, Ashraf
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- Palladium-Catalyzed Enantioselective Thiocarbonylation of Styrenes
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A highly enantioselective thiocarbonylation of styrenes with CO and thiols has been achieved by Pd catalysis, providing highly enantioenriched thioesters in good to excellent yields. Key to the successful execution of this reaction is the use of a chiral sulfoxide-(P-dialkyl)-phosphine (SOP) ligands. This thiocarbonylation proceeds smoothly under mild reaction conditions (1 atm CO and 0 °C) and displays broad substrate scope. Also demonstrated is that this transformation can be conducted using surrogates of CO, greatly increasing the safety aspects of running the reaction. The generality and utility of the method is manifested by its application to the synthetic transformations of thioester products and the direct acylation of cysteine-containing dipeptides. A primary mechanism was investigated and a plausible catalytic cycle was proposed.
- Wang, Xihong,Wang, Bing,Yin, Xuemei,Yu, Wangzhi,Liao, Yang,Ye, Jialin,Wang, Min,Hu, Lianrui,Liao, Jian
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supporting information
p. 12264 - 12270
(2019/08/01)
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- Method for synthesizing thioester compounds through olefin insert carbonyl sulfide esterification (by machine translation)
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The invention belongs to the field, and belongs to the field of chemical synthesis. The invention specifically relates to a method for synthesizing chiral or non-chiral thioester compounds through palladium-catalyzed olefin carbonyl sulfide esterification
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Paragraph 0146-0147; 0151-0152
(2019/10/01)
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- Method for synthesizing alkyne through catalytic asymmetric cross coupling (by machine translation)
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The invention belongs to the field of, asymmetric synthesis, and discloses a method for catalyzing asymmetric cross- coupling to synthesize: an alkyne, and the L method comprises, the following steps, of A: preparing B a cuprous, salt and C a: ligand; preparing a catalyst; adding a base; reacting the compound with the compound with the compound; and reacting the compound with the compound. Of these, one of them, X is selected from the group consisting of, R halogens. 1 Optionally substituted heteroarylsulfonylcyanamide groups selected from the, group consisting, of optionally substituted, phenyl groups In-flight vehicle, R6 Trialkyl silyl groups or alkyl radicals, R2 Cycloalkyl radicals optionally substituted with an, optionally substituted alkyl, (CH radical2 )n R4 Multi,layer chain, n＝0-10,R saw blade4 A group selected, from, the group consisting of phenyl, alkenyl, aralkynyls, noonyloxy,and, noonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylphenyl disiloxy-radicals. R3 A ligand, selected from hydrogen or any of the functional groups, is selected from the group consisting of, hydrogen and any L other functional group. The method, R disclosed by the, A invention has the, advantages of good catalytic, R ’ effect, wide application range. and high catalytic efficiency, and the, method disclosed by the, invention has the. advantages of good catalytic effect, wide application range and high catalytic efficiency. (by machine translation)
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Paragraph 0983; 0997-0999
(2020/01/12)
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- Synthesis of Chiral Esters via Asymmetric Wolff Rearrangement Reaction
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The first asymmetric Wolff rearrangement reaction that directly converts α-diazoketones into broadly useful chiral α,α-disubstituted carboxylic esters with high enantioselectivities (up to 97.5:2.5 er) is reported. The cascade reaction proceeds through the seamless combination of visible-light-induced formation of the ketene intermediate and asymmetric ketene esterification using a readily available benzotetramisole-type catalyst.
- Meng, Jing,Ding, Wei-Wei,Han, Zhi-Yong
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p. 9801 - 9805
(2019/10/16)
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- Enantioselective Palladium-Catalyzed Cross-Coupling of α-Bromo Carboxamides and Aryl Boronic Acids
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We herein report an enantioselective palladium-catalyzed cross-coupling between α-bromo carboxamides and aryl boronic acids, generating a series of chiral α-aryl carboxamides in good yields and excellent enantioselectivities. The development of a chiral P,P=O ligand was critical in overcoming the second transmetalation issue and allows the first asymmetric palladium-catalyzed coupling of α-bromo carbonyl compounds.
- Li, Bowen,Li, Tiejun,Aliyu, Muinat A.,Li, Zhen Hua,Tang, Wenjun
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supporting information
p. 11355 - 11359
(2019/07/12)
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- A Chemoselective α-Oxytriflation Enables the Direct Asymmetric Arylation of Amides
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Until recently, the direct oxidative oxysulfonylation of carbonyl compounds was limited to ketones. Here, we report the first direct oxytriflation of simple, non-activated amides. Amide umpolung with triflic anhydride and pyridine-N-oxide in the absence of external nucleophiles directly leads to the formation of reactive α-triflates in a single step, which provides a platform for the deployment of valuable downstream α-functionalization reactions. The utility of this method was demonstrated by in situ clean conversion to their corresponding bromides, as desirable starting materials for nickel-catalyzed deracemizing enantioselective arylation. This approach not only enables a telescoped asymmetric arylation of unsubstituted amides but also extends its scope because of the broad chemoselectivity and functional group tolerance of the method. Amides bearing a functional group in α-position are found in many natural products and drugs. The direct α-functionalization of amides is one of the most popular approaches to access these moieties. Classically, the α-functionalization of amides has been dominated by enolate chemistry; however, carboxamides are among the least C-H acidic carbonyl derivatives, and the presence of further carbonyl or carboxyl groups (such as esters and ketones) is therefore not usually tolerated. Here, we report the first direct α-oxytriflation of simple, non-activated amides using triflic anhydride and pyridine-N-oxide in the absence of external nucleophiles, which provides a platform for the deployment of valuable downstream α-functionalization reactions. The utility of this method was demonstrated by in situ clean conversion to the corresponding bromides, which are valuable starting materials for nickel-catalyzed deracemizing enantioselective arylation. A direct and chemoselective α-oxytriflation of simple and non-activated amides has been developed. This approach provides a platform for the development of valuable downstream α-functionalization reactions of amides. Furthermore, the combination of α-oxytriflation of amides and nickel-catalyzed Suzuki reaction provides an efficient approach for direct asymmetric α-arylation of simple amides.
- Li, Jing,Berger, Martin,Zawodny, Wojciech,Simaan, Marwan,Maulide, Nuno
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supporting information
p. 1883 - 1891
(2019/07/08)
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- Nickel-catalyzed Enantioselective Hydroarylation and Hydroalkenylation of Styrenes
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We have developed a Ni-catalyzed enantioselective hydroarylation of styrenes with arylboronic acids using MeOH as the hydrogen source, providing an efficient method to access 1,1-diarylalkanes, which are essential structural units in many biologically active compounds. In addition, Ni-catalyzed enantioselective hydrovinylation of styrenes with vinylboronic acids is also realized with good yields and enantioselectivities. The synthetic utility was demonstrated by the efficient synthesis of (R)-(-)-ibuprofen.
- Chen, Yue-Gang,Shuai, Bin,Xu, Xue-Tao,Li, Yi-Qian,Yang, Qi-Liang,Qiu, Hui,Zhang, Kun,Fang, Ping,Mei, Tian-Sheng
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supporting information
p. 3395 - 3399
(2019/03/07)
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- Iron-catalysed enantioselective Suzuki-Miyaura coupling of racemic alkyl bromides
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The first iron-catalysed enantioselective Suzuki-Miyaura coupling reaction has been developed. In the presence of catalytic amounts of FeCl2 and (R,R)-QuinoxP?, lithium arylborates are cross-coupled with tert-butyl α-bromopropionate in an enantioconvergent manner, enabling facile access to various optically active α-arylpropionic acids including several nonsteroidal anti-inflammatory drugs (NSAIDs) of commercial importance. (R,R)-QuinoxP? is specifically able to induce chirality when compared to analogous P-chiral ligands that give racemic products, highlighting the critical importance of transmetalation in the present asymmetric cross-coupling system.
- Iwamoto, Takahiro,Okuzono, Chiemi,Adak, Laksmikanta,Jin, Masayoshi,Nakamura, Masaharu
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supporting information
p. 1128 - 1131
(2019/01/28)
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- A CRYSTALLINE METAL ORGANIC FRAMEWORK
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The present invention relates to a crystalline metal organic framework which comprises repeating units of formula (RR)-(IA)or (SS)-(IA)or (RS)-(IA) or (SR)-(IA); or alternatively of formula (RR)-(IB) or (SS)-(IB) or (RS)-(IB) or (SR)-(IB) and acomposition containing it. It also relates to processes for their preparation and theiruses as a separation agent and as a catalyst.
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Page/Page column 44-45
(2018/05/16)
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- Cellulose type chiral stationary phase based on reduced graphene oxide@silica gel for the enantiomer separation of chiral compounds
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The graphene oxide (GO) was covalently coupled to the surfaces of silica gel (SiO2) microspheres by amide bond to get the graphene oxide@silica gel (GO@SiO2). Then, the GO@SiO2 was reduced with hydrazine to the reduced graphene oxide@silica gel (rGO@SiO2), and the cellulose derivatives were physically coated on the surfaces of rGO@SiO2 to prepare a chiral stationary phase (CSP) for high performance liquid chromatography. Under the optimum experimental conditions, eight benzene-enriched enantiomers were separated completely, and the resolution of trans-stilbene oxide perfectly reached 4.83. Compared with the blank column of non-bonded rGO, the separation performance is better on the new CSP, which is due to the existence of rGO to produce special retention interaction with analytes, such as π-π stacking, hydrophobic effect, π-π electron-donor–acceptor interaction, and hydrogen bonding. Therefore, the obtained CSP shows special selectivity for benzene-enriched enantiomers, improves separation selectivity and efficiency, and rGO plays a synergistic effect with cellulose derivatives on enantioseparation.
- Li, Yuanyuan,Li, Qiang,Zhu, Nan,Gao, Zhuxian,Ma, Yulong
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p. 996 - 1004
(2018/07/29)
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- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
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A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
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p. 1067 - 1078
(2018/08/01)
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- Biocatalytic Parallel Interconnected Dynamic Asymmetric Disproportionation of α-Substituted Aldehydes: Atom-Efficient Access to Enantiopure (S)-Profens and Profenols
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The biocatalytic asymmetric disproportionation of aldehydes catalyzed by horse liver alcohol dehydrogenase (HLADH) was assessed in detail on a series of racemic 2-arylpropanals. Statistical optimization by means of design of experiments (DoE) allowed the identification of critical interdependencies between several reaction parameters and revealed a specific experimental window for reaching an ′optimal compromise′ in the reaction outcome. The biocatalytic system could be applied to a variety of 2-arylpropanals and granted access in a redox-neutral manner to enantioenriched (S)-profens and profenols following a parallel interconnected dynamic asymmetric transformation (PIDAT). The reaction can be performed in aqueous buffer at ambient conditions, does not rely on a sacrificial co-substrate, and requires only catalytic amounts of cofactor and a single enzyme. The high atom-efficiency was exemplified by the conversion of 75 mM of rac-2-phenylpropanal with 0.03 mol% of HLADH in the presence of ～0.013 eq. of oxidized nicotinamide adenine dinucleotide (NAD+), yielding 28.1 mM of (S)-2-phenylpropanol in 96% ee and 26.5 mM of (S)-2-phenylpropionic acid in 89% ee, in 73% overall conversion. Isolated yield of 62% was obtained on 100 mg-scale, with intact enantiopurities. (Figure presented.).
- Tassano, Erika,Faber, Kurt,Hall, Mélanie
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p. 2742 - 2751
(2018/07/29)
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- Neutral iridium catalysts with chiral phosphine-carboxy ligands for asymmetric hydrogenation of unsaturated carboxylic acids
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We developed neutral iridium catalysts with chiral spiro phosphine-carboxy ligands (SpiroCAP) for asymmetric hydrogenation of unsaturated carboxylic acids. Different from the cationic Crabtree-type catalysts, the iridium catalysts with chiral spiro phosphine-carboxy ligands are neutral and do not require the use of a tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF?) counterion, which is necessary for stabilizing cationic Crabtree-type catalysts. Another advantage of the neutral iridium catalysts is that they have high stability and have a long lifetime in air. The new iridium catalysts with chiral spiro phosphine-carboxy ligands exhibit unprecedented high enantioselectivity (up to 99.4% ee) in the asymmetric hydrogenations of various unsaturated carboxylic acids, particularly for 3-alkyl-3-methylenepropionic acids, which are challenging substrates for other chiral catalysts.
- Yang, Shuang,Che, Wen,Wu, Hui-Ling,Zhu, Shou-Fei,Zhou, Qi-Lin
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p. 1977 - 1980
(2017/03/09)
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- Ultrafast chiral separations for high throughput enantiopurity analysis
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Recent developments in fast chromatographic enantioseparations now make high throughput analysis of enantiopurity on the order of a few seconds achievable. Nevertheless, routine chromatographic determinations of enantiopurity to support stereochemical investigations in pharmaceutical research and development, synthetic chemistry and bioanalysis are still typically performed on the 5-20 min timescale, with many practitioners believing that sub-minute enantioseparations are not representative of the molecules encountered in day to day research. In this study we develop ultrafast chromatographic enantioseparations for a variety of pharmaceutically-related drugs and intermediates, showing that sub-minute resolutions are now possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed phase liquid chromatography (RP-LC). Examples are provided illustrating how such methods can be routinely developed and used for ultrafast high throughput analysis to support enantioselective synthesis investigations.
- Barhate, Chandan L.,Joyce, Leo A.,Makarov, Alexey A.,Zawatzky, Kerstin,Bernardoni, Frank,Schafer, Wes A.,Armstrong, Daniel W.,Welch, Christopher J.,Regalado, Erik L.
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supporting information
p. 509 - 512
(2017/01/13)
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- Enantioselective analysis of ibuprofen enantiomers in mice plasma and tissues by high-performance liquid chromatography with fluorescence detection: Application to a pharmacokinetic study
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A direct fluorometric high-performance liquid chromatography (HPLC) method was developed and validated for the analysis of ibuprofen enantiomers in mouse plasma (100?μl) and tissues (brain, liver, kidneys) using liquid–liquid extraction and 4-tertbutylphenoxyacetic acid as an internal standard. Separation of enantiomers was accomplished in a Chiracel OJ-H chiral column based on cellulose tris(4-methylbenzoate) coated on 5?μm silica-gel, 250 x 4.6?mm at 22?°C with a mobile phase composed of n-hexane, 2-propanol, and trifluoroacetic acid that were delivered in gradient elution at a flow rate of 1?ml min?1. A fluorometric detector was set at: λexcit. = 220?nm and λemis. = 290?nm. Method validation included the evaluation of the selectivity, linearity, lower limit of quantification (LLOQ), within-run and between-run precision and accuracy. The LLOQ for the two enantiomers was 0.125 μg ml?1 in plasma, 0.09?μg g?1 in brain, and 0.25?μg g?1 in for liver and kidney homogenates. The calibration curves showed good linearity in the ranges of each enantiomers: from 0.125 to 35?μg ml?1 for plasma, 0.09–1.44?μg g?1 for brain, and 0.25–20?μg g?1 for liver and kidney homogenates. The method was successfully applied to a pharmacokinetic study of ibuprofen enantiomers in mice treated i.v. with 10?mg kg?1 of racemate.
- Przejczowska-Pomierny, Katarzyna,W?odyka, Monika,Cios, Agnieszka,Wyska, El?bieta
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p. 500 - 511
(2017/08/26)
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- Novel iridium complex of spirophosphine-carboxylic acid, preparation method and application thereof
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The invention relates to an iridium complex of spirophosphine-carboxylic acid, a preparation method and application thereof. The iridium complex of spirophosphine-carboxylic acid is a compound with a structure shown as formula (I), wherein n=0-3; and the values of R1, R2, R3, R4, R5, R6 and R7 are defined as claim 1. Substituted 7-carboxyl-7'-diarylphosphino-1, 1'-spirobiindane is taken as the ligand to from carboxylic acid anion under the action of alkali, and then complexation with an iridium precursor is carried out to obtain different iridium/spirophosphine-carboxylic acid complexes. The iridium complex of spirophosphine-carboxylic acid provided by the invention can catalyze the asymmetric hydrogenation reaction of a variety of unsaturated carboxylic acids, and show high activity and enantioselectivity, thus having good industrialization prospects. (formula (I)).
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Paragraph 0081-0084; 0086
(2017/05/20)
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- Efficient resolution of profen ethyl ester racemates by engineered Yarrowia lipolytica Lip2p lipase
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Enzyme-catalyzed enantiomer discrimination is still a great challenge for the development of industrial pharmaceutical processes. For the resolution of ibuprofen, naproxen and ketoprofen racemates, three major anti-inflammatory drugs, only lipases from Candida rugosa present a high selectivity if solvent and surfactant use is discarded. However, their catalytic activities are too low. In the present work, we demonstrate that the lipase Lip2p from the yeast Yarrowia lipolytica has a higher catalytic activity than C. rugosa lipases to hydrolyze the ethyl esters of ibuprofen, naproxen and ketoprofen, but its selectivity is not sufficient [E?=?52 (S); 11 (S) and 1.5 (R) respectively]. The enantioselectivity was further improved by site-directed mutagenesis, targeted at the substrate binding site and guided by molecular modelling studies. By investigating the binding modes of the (R)- and (S)-enantiomers in the active site, two amino acid residues located in the hydrophobic substrate binding site of the lipase, namely residues 232 and 235, were identified as crucial for enantiomer discrimination and enzyme activity. The (S) enantioselectivity of Lip2p towards ethyl ibuprofen esters was rendered infinite (E???300) by replacing V232 by an A or C residue. Substitution of V235 by C, M, S, or T amino acids led to a great increase in the (S)-enantioselectivity (E???300) towards naproxen ethyl ester. Finally, the variant V232F enabled the efficient kinetic resolution of ethyl ketoprofen ester enantiomers [(R)-enantiopreference; E???300]. In addition to the increase in selectivity, a remarkable increase in velocity by 2.6, 2.7 and 2.5?times, respectively, was found for ibuprofen, naproxen and ketoprofen ethyl esters.
- Gérard, Doriane,Guéroult, Marc,Casas-Godoy, Leticia,Condoret, Jean-Stéphane,André, Isabelle,Marty, Alain,Duquesne, Sophie
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p. 433 - 441
(2017/03/24)
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- Stereoselective Ketone Rearrangements with Hypervalent Iodine Reagents
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The first stereoselective version of an iodine(III)-mediated rearrangement of arylketones in the presence of orthoesters is described. The reaction products, α-arylated esters, are very useful intermediates in the synthesis of bioactive compounds such as ibuprofen. With chiral lactic acid-based iodine(III) reagents product selectivities of up to 73 % ee have been achieved.
- Malmedy, Florence,Wirth, Thomas
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supporting information
p. 16072 - 16077
(2016/10/30)
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- Enzymatic hydrolytic resolution of racemic ibuprofen ethyl ester using an ionic liquid as cosolvent
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The aim of this study was to develop an ionic liquid (IL) system for the enzymatic resolution of racemic ibuprofen ethyl ester to produce (S)-ibuprofen. Nineteen ILs were selected for use in buffer systems to investigate the effects of ILs as cosolvents for the production of (S)-ibuprofen using thermostable esterase (EST10) from Thermotoga maritima. Analysis of the catalytic efficiency and conformation of EST10 showed that [OmPy][BF4] was the best medium for the EST10-catalyzed production of (S)-ibuprofen. The maximum degree of conversion degree (47.4%), enantiomeric excess of (S)-ibuprofen (96.6%) and enantiomeric ratio of EST10 (177.0) were achieved with an EST10 concentration of 15 mg/mL, racemic ibuprofen ethyl ester concentration of 150 mM, at 75°C, with a reaction time of 10 h. The reaction time needed to achieve the highest yield of (S)-ibuprofen was decreased from 24 h to 10 h. These results are relevant to the proposed application of ILs as solvents for the EST10-catalyzed production of (S)-ibuprofen.
- Wei, Tao,Yang, Kunpeng,Bai, Bing,Zang, Jie,Yu, Xuan,Mao, Duobin
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- One pot three-component reaction for covalent immobilization of enzymes: Application of immobilized lipases for kinetic resolution of: Rac -ibuprofen
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This paper presents a novel strategy for the simple immobilization of biomolecules on epoxy-functionalized supports via a one-pot three component reaction. Lipase B from Candida antarctica (CALB) and Rhizomucor miehei lipase (RML) as model enzymes were immobilized on epoxy-functionalized silica and mesoporous silica nanoparticles (SBA-15). Investigation of the mechanism of this reaction confirmed the participation of three functional groups including carboxylic acid groups from the enzyme surface, epoxy groups from the support and isocyanide from the reaction medium. The results revealed very rapid immobilization of 10 and 40 mg of RML on 1 gr of the supports shortly after 30 minutes of incubation. The loading capacity of the supports was also dramatically improved with the maximum loading of 158 mg of CALB and 77 mg of RML on SBA-15 and silica, respectively. Silica-epoxy-RML showed an enantiomeric excess (ee) of 92% and an E-value of 29.9 in the enantioselective esterification of (R,S)-ibuprofen.
- Mohammadi, Mehdi,Gandomkar, Somayyeh,Habibi, Zohreh,Yousefi, Maryam
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p. 52838 - 52849
(2016/06/14)
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- Easily accessible TADDOL-derived bisphosphonite ligands: Synthesis and application in the asymmetric hydroformylation of vinylarenes
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The synthesis of chiral bidentate bisphosphonite ligands based on the TADDOL motif from readily available starting materials has been developed. Taking advantage of the modular nature of the building blocks, a diverse ligand library has been prepared. Their catalytic potential has been evaluated in the asymmetric hydroformylation of styrene and derivatives. These catalysts showed high activity and provided the aldehydes in high enantiomeric purity.
- Allmendinger, Simon,Kinuta, Hirotaka,Breit, Bernhard
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supporting information
p. 41 - 45
(2015/03/03)
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- Reversed-phase high-performance liquid chromatographic separation of some 2-arylpropionic acids using vancomycin as chiral stationary phase
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Abstract A rapid, sensitive and reproducible HPLC method has been developed for enantioseparation of six non-steroidal anti-inflammatory drugs, which are acidic compounds: carprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen and ketoprofen. The effects of the mobile phase composition on retention times and resolutions of the analytes were studied. A column based on vancomycin immobilized by reductive amination to aldehyde functionalised silica was prepared in house and used. The prepared sorbent shows a great stability and selectivity over a range of pH (4-6), and the separation was carried out using the mobile phase composed of a mixture of 40% of methanol in ammonium nitrate buffer (50 mM) at pH 5.0. Another mobile phase consisted of 50% of methanol in phosphate buffer (5A mM) at pH 5.0 was also prepared and tested. The two mobile phases are the optimum conditions obtained. All experiments were conducted at flow rate 0.6 ml/min, using a UV detector wavelength at λ = 254 nm.
- Bouchair, Nabila,Righezza, Michel,Hamdi, Abderrezak
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p. 921 - 928
(2015/05/05)
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- Synthesis of tertiary and quaternary amine derivatives from wood resin as chiral NMR solvating agents
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Chiral tertiary and quaternary amine solvating agents for NMR spectroscopy were synthesized from the wood resin derivative (+)-dehydroabietylamine (2). The resolution of enantiomers of model compounds [Mosher's acid (3) and its n-Bu4N salt (4)] (guests) by (+)-dehydroabietyl-N,N-dimethylmethanamine (5) and its ten different ammonium salts (hosts) was studied. The best results with 3 were obtained using 5 while with 4 the best enantiomeric resolution was obtained using (+)-dehydroabietyl-N,N-dimethylmethanaminium bis(trifluoromethane-sulfonimide) (6). The compounds 5 and 6 showed a 1:1 complexation behaviour between the host and guest. The capability of 5 and 6 to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu4N salts in enantiomeric excess (ee) determinations was demonstrated. A modification of the RES-TOCSY NMR pulse sequence is described, allowing the enhancement of enantiomeric discrimination when the resolution of multiplets is insufficient.
- Laaksonen, Tiina,Heikkinen, Sami,W?h?l?, Kristiina
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supporting information
p. 20873 - 20886
(2015/12/23)
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- Engineered hydrophobic pocket of (S)-selective arylmalonate decarboxylase variant by simultaneous saturation mutagenesis to improve catalytic performance
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A bacterial arylmalonate decarboxylase (AMDase) catalyzes asymmetric decarboxylation of unnatural arylmalonates to produce optically pure (R)-arylcarboxylates without the addition of cofactors. Previously, we designed an AMDase variant G74C/C188S that displays totally inverted enantioselectivity. However, the variant showed a 20,000-fold reduction in activity compared with the wild-type AMDase. Further studies have demonstrated that iterative saturation mutagenesis targeting the active site residues in a hydrophobic pocket of G74C/C188S leads to considerable improvement in activity where all positive variants harbor only hydrophobic substitutions. In this study, simultaneous saturation mutagenesis with a restricted set of amino acids at each position was applied to further heighten the activity of the (S)-selective AMDase variant toward α-methyl-α-phenylmalonate. The best variant (V43I/G74C/A125P/V156L/M159L/C188G) showed 9,500-fold greater catalytic efficiency kcat/Km than that of G74C/C188S. Notably, a high level of decarboxylation of α-(4-isobutylphenyl)-α-methylmalonate by the sextuple variant produced optically pure (S)-ibuprofen, an analgesic compound which showed 2.5-fold greater activity than the (R)-selective wild-type AMDase.
- Yoshida, Shosuke,Enoki, Junichi,Kourist, Robert,Miyamoto, Kenji
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p. 1965 - 1971
(2015/11/24)
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- SPIROBENZYLAMINE-PHOSPHINE, PREPARATION METHOD THEREFOR AND USE THEREOF
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The present invention relates to a spirobenzylamine-phosphine, preparation method therefor and use thereof. The compound has a structure represented by formula (I), wherein n=0 to 3; R1, R2, R3, R4, R5, R6, R7, R8 and R9 having a value as defined in claim 1. Starting from the substituted 7-trifluoromesyloxy-7'-diarylphosphino-1, 1'-spiro-dihydroindene, the compound is synthesized in a two-step or three-step reactions. The new spirobenzylamine-phosphine is complexed with an iridium precursor and is subjected to ion exchange, to give an Iridium/spirobenzylamine-phosphine complex comprising various anions. The spiro benzyl amine-phosphine/Iridium complex according to the present invention may be used for catalyzing asymmetry hydrogenation of a variety of alpha-substituted acrylic acids, has high activity and enantio-selectivity, and has a good prospect of industrialization.
- -
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Paragraph 0057; 0058
(2014/07/22)
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- Spirobenzylamine-Phosphine, Preparation Method Therefor And Use Thereof
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The present invention relates to a spirobenzylamine-phosphine, preparation method therefor and use thereof. The compound has a structure represented by formula (I), wherein n=0 to 3; R1, R2, R3, R4, R5, R6, R7, R8 and R9 having a value as defined in claim 1. Starting from the substituted 7-trifluoromesyloxy-7′-diarylphosphino-1,1′-spiro-dihydroindene, the compound is synthesized in a two-step or three-step reactions. The new spirobenzylamine-phosphine is complexed with an iridium precursor and is subjected to ion exchange, to give an Iridium/spirobenzylamine-phosphine complex comprising various anions. The spiro benzyl amine-phosphine/Iridium complex according to the present invention may be used for catalyzing asymmetry hydrogenation of a variety of alpha-substituted acrylic acids, has high activity and enantio-selectivity, and has a good prospect of industrialization.
- -
-
Paragraph 0065; 0066; 0067
(2014/07/22)
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- High pressure CO2-controlled reactors: Enzymatic chiral resolution in emulsions
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In this work we have reported the formulation of a CO2-based micelle stabilized by nontoxic TMN series surfactants. Enantioselection of racemic ibuprofen catalyzed by Candida antarctica lipase B (CALB) was used as a model reaction. The effect of reactive parameters, such as temperature, pH, pressure, and water content on reactive environment and conversion has been discussed. For the resolution of racemic ibuprofen in CO2-based micelles, the enzymatic activity reached a high level at 45 °C, with pressure 250 bar, pH 7.4, and water to surfactant ratio W0 25. In addition, the relatively long-chain length in TMN-10 could help the esterification and trans-esterification processes, which resulted in an efficient reaction rate in a CO2-based micelle system. Enzymatic catalysis has been conducted in a CO2-based system rather than in the conventional media to make the enzyme reaction greener. The better resolution efficiency in high pressure CO2-based micelles could be achieved within a relatively short period of time compared with other traditional reactive systems. The Royal Society of Chemistry 2014.
- Shang, Wenting,Zhang, Xiaogang,Yang, Xiaoxi,Zhang, Shujuan
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p. 24083 - 24088
(2014/06/24)
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- Enantioselective resolution of racemic ibuprofen esters using different lipases immobilized on octyl sepharose
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Here we report the stereoselective hydrolysis of racemic esters catalyzed by Candida rugosa lipase (CRL) and Rhizopus oryzae lipase (ROL) immobilized on octyl-sepharose via physical adsorption. Hydrophobic immobilization caused to almost six fold hyperactivation with 229.2 and 81.3 U/mg enzyme for immobilized CRL and ROL, respectively (13.2 and 48.75 U/mg for corresponding free enzyme). Based on the preliminary results, CRL was chosen for further investigation. The performance and yield of the reaction were evaluated as a function of the critical reaction parameters such as temperature, enzyme to substrate ratio and organic co-solvent. An increase in the temperature resulted to decrease in enantioselectivity of hydrolysis reaction. The hydrolysis reactions were carried out in presence of two organic solvents; n-hexane and isooctane. Generally n-hexane was a better co-solvent compared to isooctane. High enantioselective hydrolysis of the racemic esters (yielding S(+) ibuprofen; ee ≤ 95%) can be achieved using the immobilized CRL. Among various esters the kinetic resolution of ibuprofen butyl ester yielded the best results (E value 70 and 74; conversion 14.6 and 8.9 in n-hexane and isooctane, respectively). The immobilized derivatives were re-used in four cycles and showed little decrease in enantiomeric excess of (S)-ibuprofen. 96.7 eep and conversion 14.6 in first cycle reached to 90.5 eep and conversion 11.3 in the forth cycle.
- Yousefi, Maryam,Mohammadi, Mehdi,Habibi, Zohreh
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- Predictability of enantiomeric chromatographic behavior on various chiral stationary phases using typical reversed phase modeling software
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Pharmaceutical companies worldwide tend to apply chiral chromatographic separation techniques in their mass production strategy rather than asymmetric synthesis. The present work aims to investigate the predictability of chromatographic behavior of enantiomers using DryLab HPLC method development software, which is typically used to predict the effect of changing various chromatographic parameters on resolution in the reversed phase mode. Three different types of chiral stationary phases were tested for predictability: macrocyclic antibiotics-based columns (Chirobiotic V and T), polysaccharide-based chiral column (Chiralpak AD-RH), and protein-based chiral column (Ultron ES-OVM). Preliminary basic runs were implemented, then exported to DryLab after peak tracking was accomplished. Prediction of the effect of % organic mobile phase on separation was possible for separations on Chirobiotic V for several probes: racemic propranolol with 97.80% accuracy; mixture of racemates of propranolol and terbutaline sulphate, as well as, racemates of propranolol and salbutamol sulphate with average 90.46% accuracy for the effect of percent organic mobile phase and average 98.39% for the effect of pH; and racemic warfarin with 93.45% accuracy for the effect of percent organic mobile phase and average 99.64% for the effect of pH. It can be concluded that Chirobiotic V reversed phase retention mechanism follows the solvophobic theory. 2013 Wiley Periodicals, Inc.
- Wagdy, Hebatallah A.,Hanafi, Rasha S.,El-Nashar, Rasha M.,Aboul-Enein, Hassan Y.
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p. 506 - 513
(2013/09/12)
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- Characterization of a new thermophilic and acid tolerant esterase from Thermotoga maritima capable of hydrolytic resolution of racemic ketoprofen ethyl ester
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A gene coding for a putative thermostable esterase (Tm1160) from the hyperthermophilic bacterium Thermotoga maritima was cloned and expressed in Escherichia coli. The purified enzyme displayed optimal activity at 70 °C and had a half-life of 60 min at 90 °C. It was stable over a range of pHs from 5.0 to 7.5 with an optimum around 5.0-5.5. The enzyme was found to have high acid tolerance and maintained about 50% of its activity even after 60 min of treatment at pH 4.5 and 70 °C. Furthermore, the enzyme exhibited the highest specific activity with p-nitrophenyl butyrate (318 ± 7 s -1 mM-1). Under native conditions, Tm1160 forms a ～74 kDa dimer in solution. In addition, the esterase Tm1160 could enantioselectively hydrolyze the racemic ketoprofen ethyl ester and with an enantiomeric excess (eep) of 91.4% at a conversion of 41.1%, which makes it as a promising biocatalyst for the chiral resolution of (S)-ketoprofen.
- Wei, Tao,Feng, Shengxue,Mao, Duobin,Yu, Xuan,Du, Congcong,Wang, Xihua
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- Laboratory evolution of enantiocomplementary Candida antarctica lipase B mutants with broad substrate scope
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Candida antarctica lipase B (CALB) is a robust and easily expressed enzyme used widely in academic and industrial laboratories with many different kinds of applications. In fine chemicals production, examples include acylating kinetic resolution of racemic secondary alcohols and amines as well as desymmetrization of prochiral diols (or the reverse hydrolytic reactions). However, in the case of hydrolytic kinetic resolution of esters or esterifying kinetic resolution of acids in which chirality resides in the carboxylic acid part of the substrate, rate and stereoselectivity are generally poor. In the present study, directed evolution based on iterative saturation mutagenesis was applied to solve the latter problem. Mutants with highly improved activity and enantioselectivity relative to wild-type CALB were evolved for the hydrolytic kinetic resolution of p-nitrophenyl 2-phenylpropanoate, with the selectivity factor increasing from E = 1.2 (S) to E = 72 (S) or reverting to E = 42 (R) on an optional basis. Surprisingly, point mutations both in the acyl and alcohol pockets of CALB proved to be necessary. Some of the evolved CALB mutants are also efficient biocatalysts in the kinetic resolution of other chiral esters without performing new mutagenesis experiments. Another noteworthy result concerns the finding that enantiocomplementary CALB mutants for α-substituted carboxylic acid esters also show stereocomplementarity in the hydrolytic kinetic resolution of esters derived from chiral secondary alcohols. Insight into the source of stereoselectivity was gained by molecular dynamics simulations and docking experiments.
- Wu, Qi,Soni, Pankaj,Reetz, Manfred T.
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supporting information
p. 1872 - 1881
(2013/08/24)
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- Enantioselective hydrogenation of α-substituted acrylic acids catalyzed by iridium complexes with chiral spiro aminophosphine ligands
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Highly active: Iridium complexes with chiral spiro aminophosphine ligands were synthesized and applied as catalysts for the asymmetric hydrogenation of α-substituted acrylic acids (see scheme). The complexes were highly active catalysts, showing turnover frequencies of up to 6000 h-1, and catalyst loadings could be reduced to 0.01 mol %. Copyright
- Zhu, Shou-Fei,Yu, Yan-Bo,Li, Shen,Wang, Li-Xin,Zhou, Qi-Lin
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scheme or table
p. 8872 - 8875
(2012/10/08)
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- Design and synthesis of Janus-type chiral dendritic diphosphanes and their applications in asymmetric hydrogenation
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A series of chiral diphosphane-functionalized Janus dendrimers (up to 16 BINAP units) have been readily synthesized by using liquid-phase organic synthesis with the third-generation Frechet-type poly(aryl ether) dendron as the soluble support. The resulting dendritic ligands were purified by simple solvent precipitation without the need for chromatographic separation at the end of reaction. Complete functionalization of the dendrimers with BINAP moieties was confirmed by 1H NMR, MALDI-TOF mass spectroscopy, and elemental analyses. Their ruthenium complexes were applied to the asymmetric hydrogenation of 2-arylacrylic acids. It was found that only slightly lower enantioselectivities were achieved than the corresponding small-molecular Ru catalyst. Interestingly, a clear increase in activity of the dendritic catalysts was observed on going to the higher generations. In addition, the third-generation catalyst could be recycled without significant loss of catalytic activity or enantioselectivity before the fifth catalytic run. A new kind of easily available Janus dendritic diphosphane ligand has been synthesized and their metal complexes were applied to the asymmetric hydrogenation of 2-arylacrylic acids. Interestingly, a clear increase in activity of the dendritic catalysts was observed on going to the higher generations. Furthermore, the third-generation catalyst could be recycled at least five times. Copyright
- Liu, Ji,Feng, Yu,Ma, Baode,He, Yan-Mei,Fan, Qing-Hua
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supporting information
p. 6737 - 6744
(2013/01/15)
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- Substrate-selective inhibition of cyclooxygenase-2: Development and evaluation of achiral profen probes
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Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.
- Windsor, Matthew A.,Hermanson, Daniel J.,Kingsley, Philip J.,Xu, Shu,Crews, Brenda C.,Ho, Winnie,Keenan, Catherine M.,Banerjee, Surajit,Sharkey, Keith A.,Marnett, Lawrence J.
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supporting information
p. 759 - 763
(2012/10/29)
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- SPIRO PHOSPHORUS-OXAZOLINE, SYNTHESIS AND USE THEREOF
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The present invention belongs to a spiro phosphine-oxazoline and preparation method and application thereof, particularly, publishes a novel spiro phosphine-oxazoline and the preparation method of its iridium complex. The substituted 7-diaryl phosphino-7'-carboxy-1,1'-Lo-dihydro-indene is used as the starting raw material to synthesize the novel spiro phosphine-oxazoline of the present invention through a two-step reaction. The novel spiro phosphine-oxazoline and the iridium precursor are complexed to become a complex, and then through ion exchange, an iridium/phosphine spiro-oxazoline complex with different anions can be obtained. The present invention overcomes the shortcomings of the existing technology. The cheap readily available amino alcohol is used as the raw material to synthesize the novel spiro phosphine-oxazoline, on the fourth position of the oxazoline ring of which there is no substituent. The iridium complex of this novel spiro phosphine-oxazoline can catalyze the asymmetric hydrogenation of α-substituted acrylic acid, and shows very high activity and enantioselectivity, therefore has a vey high research value and an industrialization prospect.
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Page/Page column 10
(2011/02/17)
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- Synthesis of chiral disulfides: Potential reagents for enantioselective sulfurization
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Synthesis of chiral phosphorothioates for use as antisense oligonucleotides might benefit from the use of chiral disulfides. This paper reports the synthesis of chiral analogs of phenylacetyl disulfide and of 5-methyl-3H-1,2,4-dithiazol-3-one from the same set of 2-arylalkanoic acids. The X-ray crystal structures of the disulfides derived from (R) and [S]-2-phenylpropanoic acid establish the stereochemistry and the helicity of these materials, and density functional theory calculations suggest that the high specific rotations can be due to preferred retention of this helicity in solution. Chiral HPLC showed that the final products were formed with enantiomeric purities from 86.1% to >99.9%.
- Mukhlall, Joshua A.,Noll, Bruce C.,Hersh, William H.
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body text
p. 199 - 212
(2012/01/06)
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- Chiral separation by a pseudo membrane in a triple-laminar flow with a microfluidic contactor
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A split personality: The first simultaneous reaction/separation of chiral compounds in a continuous process in an inorganic polymer-chip device affords the rapid and continuous separation of chiral compounds. Selective esterification of (S)-ibuprofen by lipase in organic mediums was followed by transportation of the (S)-ibuprofen ester through an ionic liquid as a pseudo-membrane and finalized by hydrolytic recovery in the aqueous layer.
- Yoon, Tae-Ho,Hong, Lan-Young,Kim, Dong-Pyo
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scheme or table
p. 1015 - 1018
(2011/10/31)
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- High-performance liquid chromatography separation of enantiomers of mandelic acid and its analogs on a chiral stationary phase
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The enantiomers of mandelic acid and its analogs have been chromatographically separated on a chiral stationary phase (CSP) derived from 4-(3,5-dinitrobenzamido) tetrahydrophenanthrene. The rationale of separations of these compounds is discussed with respect to the method development for determining enantiomeric purity and possibility of obtaining enantiomerically pure materials by high-pressure liquid chromatography. The relationship of analyte structure to the extent of enantiomeric separation has been examined and separation factors (a) are presented for various groups of structurally related compounds. Chiral recognition models have been suggested to account for the observed separations. These models provide mechanistic insights into the chiral recognition process.
- Aneja, Ritu,Luthra, Pratibha Mehta,Ahuja, Satinder
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experimental part
p. 479 - 485
(2010/08/20)
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- Synthesis of dendrimer-type chiral stationary phases based on the selector of (1S,2R)-(+)-2-amino-1,2-diphenylethanol derivate and their enantioseparation evaluation by HPLC
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In our recent work, a series of dendritic chiral stationary phases (CSPs) were synthesized, in which the chiral selector was L-2-(p-toluenesulfonamido)-3- phenylpropionyl chloride (selector I), and the CSP derived from three-generation dendrimer showed the best separation ability. To further investigate the influence of the structures of dendrimer and chiral selector on enantioseparation ability, in this work, another series CSPs (CSPs 1-4) were prepared by immobilizing (1S,2R)-1,2-diphenyl-2-(3-phenylureido)ethyl 4-isocyanatophenylcarbamate (selector II) on one- to four-generation dendrimers that were prepared in previous work. CSPs 1 and 4 demonstrated the equivalent enantioseparation ability. CSPs 2 and 3 showed the best and poorest enantioseparation ability respectively. Basically, these two series of CSPs exhibited the equivalent enantioseparation ability although the chiral selectors were different. Considering the enantioseparation ability of the CSP derived from aminated silica gel and selector II is much better than that of the one derived from aminated silica gel and selector I, it is believed that the dendrimer conformation essentially impacts enantioseparation.
- He, Bao-Jiang,Yin, Chuan-Qi,Li, Shi-Rong,Bai, Zheng-Wu
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experimental part
p. 69 - 76
(2010/09/09)
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- Enantioselective partitioning of racemic ibuprofen in a biphasic recognition chiral extraction system
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Enantioselective partitioning of ibuprofen enantiomers in a biphasic recognition chiral extraction system was studied. A combination of hydrophobic L-isobutyl tartrate in organic phase and hydrophilic β-cyclodextrin derivative in aqueous phase is necessary to establish a biphasic recognition chiral extraction system. The studies performed involve an enantioselective extraction in a biphasic system, where ibuprofen enantiomers form four complexes with the β-cyclodextrin derivative in aqueous phase and the D(L)-isobutyl tartrate in organic phase, respectively. In these biphasic resolutions, the types and the concentrations of the extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. Good enantioselectivities for ibuprofen enantiomers were obtained at pH≤2.5 and a ratio of 2:1 of [L-isobutyl tartrate] to [HP-β-CD]. Biphasic recognition chiral extraction is of strong chiral separation ability, and may be very helpful to optimize the extraction systems and realize the large-scale production of enantiomers.
- Tang, Kewen,Song, Litao,Pan, Yang,Jiang, Xinyu,Miao, Jiabing
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scheme or table
p. 119 - 124
(2010/11/17)
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- An effective kinetic resolution of racemic α-arylpropanoic acids, α-arylbutanoic acids, and β-substituted-α-arylpropanoic acids with bis(9-phenanthryl)methanol as a new achiral nucleophile in the asymmetric esterification using carboxylic anhydrides and the acyl-transfer catalyst
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A general method for the kinetic resolution of racemic α-arylalkanoic acids with achiral alcohols is described. It was determined that bis(9-phenanthryl)methanol is a suitable nucleophile which reacts with the intermediary mixed anhydrides generated from aromatic anhydrides with α-arylpropanoic acids or β-substituted-α-arylpropanoic acids in the presence of (+)-benzotetramisole to produce the corresponding optically active esters with high ee's under very mild conditions.
- Nakata, Kenya,Onda, Yu-Suke,Ono, Keisuke,Shiina, Isamu
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scheme or table
p. 5666 - 5669
(2010/11/18)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE ESTER AND METHOD FOR PRODUCING OPTICALLY ACTIVE CARBOXYLIC ACID
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Disclosed is a method for producing an optically active ester by highly selectively esterifying one enantiomer of a racemic carboxylic acid, while producing an optically active carboxylic acid which is the other enantiomer. An optically active ester is produced while producing an optically active carboxylic acid at the same time by reacting a racemic carboxylic acid with a specific alcohol or phenol derivative in the presence of benzoic anhydride or a derivative thereof and a catalyst such as tetramisole or benzotetramisole, thereby selectively esterifying one enantiomer of the racemic carboxylic acid.
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Page/Page column 11-12
(2010/09/18)
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- Kinetic resolution of racemic α-arylalkanoic acids with achiral alcohols via the asymmetric esterification using carboxylic anhydrides and acyl-transfer catalysts
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A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic α-substituted carboxylic acids using achiral alcohols, aromatic or aliphatic carboxylic anhydrides, and chiral acyl-transfer catalysts. The combination of 4-methoxybenzoic anhydride (PMBA) or pivalic anhydride with the modified benzotetramisole-type catalyst ((S)-β-Np-BTM) is the most effective for promotion of the enantioselective coupling reaction between racemic carboxylic acids and a novel nucleophile, bis(α-naphthyl) methanol, to give the corresponding esters with high ees. This protocol was successfully applied to the production of nonracemic nonsteroidal anti-inflammatory drugs from racemic compounds utilizing the transacylation process to generate the mixed anhydrides from the acid components with the suitable carboxylic anhydrides.
- Shiina, Isamu,Nakata, Kenya,Ono, Keisuke,Onda, Yu-Suke,Itagaki, Makoto
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supporting information; experimental part
p. 11629 - 11641
(2010/10/04)
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- Iterative saturation mutagenesis accelerates laboratory evolution of enzyme stereoselectivity: Rigorous comparison with traditional methods
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Efficacy in laboratory evolution of enzymes is currently a pressing issue, making comparative studies of different methods and strategies mandatory. Recent reports indicate that iterative saturation mutagenesis (ISM) provides a means to accelerate directed evolution of stereoselectivity and thermostability, but statistically meaningful comparisons with other methods have not been documented to date. In the present study, the efficacy of ISM has been rigorously tested by applying it to the previously most systematically studied enzyme in directed evolution, the lipase from Pseudomonas aeruginosa as a catalyst in the stereoselective hydrolytic kinetic resolution of a chiral ester. Upon screening only 10 000 transformants, unprecedented enantioselectivity was achieved (E = 594). ISM proves to be considerably more efficient than all previous systematic efforts utilizing error-prone polymerase chain reaction at different mutation rates, saturation mutagenesis at hot spots, and/or DNA shuffling, pronounced positive epistatic effects being the underlying reason.
- Reetz, Manfred T.,Prasad, Shreenath,Carballeira, Jose D.,Gumulya, Yosephine,Bocola, Marco
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experimental part
p. 9144 - 9152
(2010/08/21)
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