- 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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- Esterification of (RS)-Ibuprofen by native and commercial lipases in a two-phase system containing ionic liquids
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Four commercially available lipases and two native lipases from Aspergillus niger AC-54 and Aspergillus terreus AC-430 were used for the resolution of (RS)-Ibuprofen in systems containing the ionic liquids [BMIM][PF6] and [BMIM][BF4]. The lipases showed higher conversion in a two-phase system using [BMIM][PF6] and isooctane compared to that in pure isooctane. Although the best enzyme was a commercially available lipase from Candida rugosa (E = 8.5), another native lipase, produced in our laboratory, from A. niger gave better enantioselectivity (E = 4.6) than the other lipases tested (E = 1.9-3.3.). After thorough optimization of several reaction conditions (type and ratios of isooctane/ionic liquid, amount of enzyme, and reaction time), the E-value of A. niger lipase (15% w/v) could be duplicated (E = 9.2) in a solvent system composed of [BMIM][PF6] and isooctane (1:1) after 96 h of reaction.
- Contesini, Fabiano Jares,de Oliveira Carvalho, Patricia
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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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- Highly effective and recyclable dendritic BINAP ligands for asymmetric hydrogenation
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A series of dendritic BINAP ligands have been synthesised and their ruthenium complexes used as catalysts in asymmetric hydrogenation.
- Fan, Qing-Hua,Chen, Yong-Ming,Chen, Xiao-Min,Jiang, Da-Zhi,Xi, Fu,Chan, Albert S. C.
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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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- Encapsulation of biologicals within silicate, siloxane, and hybrid sol- gel polymers: An efficient and generic approach
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The sol-gel encapsulation of labile biological materials with catalytic and recognition functions within robust polymer matrices remains a challenging task, despite the considerable research that has been focused on this field. Herein, we describe a new class of precursors, based around polyol silicates and polyol siloxanes, especially those derived from glycerol, that addresses problems faced with traditional bioencapsulation protocols. Poly(glyceryl silicate) (PGS) was prepared and employed for sol- gel bioentrapment, in an approach distinguished by a high biocompatibility and mild encapsulation conditions, and which enables the reproducible and efficient confinement of proteins and cells inside silica. The methodology was extended to metallosilicate, alkylsiloxane, functionalized siloxane, and composite sol-gels, thereby allowing the fabrication of a physicochemically diverse range of bio-doped polymers. The hybrid materials display activities approaching those of the free biologicals, together with the high stabilities and robustness that characterize sol-gel bioceramics. Indeed, the bioencapsulates performed better than those fabricated from tetramethoxysilane, poly(methyl silicate) or alcohol-free poly(silicic acid), even when the latter were doped with glycerol. The activity enhancements appear to derive at least in part from the unusual microstructure of PGS sol- gels, in particular their high porosity, although the underlying mechanisms are unclear. Differences in precursor hydrolysis/condensation; development of gel structure, biological-matrix interactions, precursor toxicity, and pore collapse probably all contribute to the observed efficiency of the PGS materials. The performances of the encapsulates are compared with conventional sol-biogels and other immobilizates, in representative biocatalyst, biosensor, and biodiagnostic applications.
- Gill, Iqbal,Ballesteros, Antonio
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- Resolution of (R,S)-ibuprofen catalyzed by immobilized Novozym40086 in organic phase
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The enantioselective esterification of ibuprofen catalyzed by Novozym40086 was successfully conducted in organic solvent. Removing-water reagent was added into the reaction mixture to remove water produced in the esterification. The effects of temperature, n-hexanol concentration, ibuprofen concentration, and loading of enzymes were investigated. Under the condition of equilibrium, the thermodynamic equilibrium constant (K) of 7.697 and enantioselectivity (E) of 8.512 were obtained. The esterification reaction achieved its equilibrium in approximately 30?hours with conversion of 56% and eeS of 93.78%. The predicted values of X and eeS were 67.90% and 95.60%, respectively. The experimental value is approximately equal to the theoretical value, which indicates the feasibility of ideal models.
- Yuan, Xin,Wang, Lujun,Liu, Guangyong,Dai, Guilin,Tang, Kewen
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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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- Facile conversion of racemic ibuprofen to (S)-ibuprofen
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The methyl ester of ibuprofen was quantitatively formed by Fischer esterification and converted into (S)-ibuprofen in 94% yield with an ee of 94% under dynamic kinetic resolution conditions at pH 9.8, using Candida rugosa lipase, and 20% DMSO. The (R)-methyl ibuprofen ester was observed to racemize by chiral HPLC without the Candida rugosa lipase present. The rates of in situ racemization and enzymatic hydrolysis for the dynamic kinetic resolution were determined to be 0.026 ± 0.004 and 0.053 ± 0.004 h-1, respectively. The rate of enzymatic hydrolysis when no DMSO was present was twice as fast but no racemization occurred. A facile purification of enriched (S)-ibuprofen was developed. Overall, 88% of racemic ibuprofen by weight was converted into (S)-ibuprofen with an ee of 99.7%.
- Chavez-Flores, David,Salvador, James M.
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- New soluble bifunctional polymeric chiral ligands for enantioselectively catalytic reactions
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Two new soluble bifunctional polymeric ligands (R,R)-4 and (R,R)-5 have been prepared via the direct condensation reaction of (R)-3,3′-diformyl-1,1′-bi-2-naphthol (R)-1 with (R)-5,5′-diamino BINAP (R)-2 and with (R)-5,5′-diamino BINAPO (R)-3, respectively. The different types of catalytic centers, BINOL and BINAP or BINAPO, were alternatively organized in a regular chiral polymer chain. Both polymeric ligands were found to be effective in the addition of diethylzinc to benzaldehyde either in the presence or in the absence of Ti(OPri)4 with different enantioselectivities. (R,R)-4/Ti(IV) catalyst, which showed similar efficiency to the parent catalyst BINOL/Ti(IV), was more enantioselective than (R,R)-5/Ti(IV). (R,R)-4 was also found to be highly effective in the Ru(II)-catalyzed asymmetric hydrogenation of 2-arylacrylic acids. The results demonstrated that the use of the co-polymer catalyst rather than a mixture of monomer catalysts not only simplified the recycling of the catalyst, but also improved the enantioselectivity and/or the activity in some cases.
- Fan, Qing-Hua,Liu, Guo-Hua,Deng, Guo-Jun,Chen, Xiao-Min,Chan, Albert S.C.
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- A novel system consisting of easily recyclable dendritic Ru-BINAP catalyst for asymmetric hydrogenation
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Dendritic Ru-BINAP catalysts functionalized with alkyl chain at the periphery together with organic binary solvent system that exhibited phase separation induced by addition of a little water have been employed for asymmetric hydrogenation, leading to high catalytic activity and en-antioselectivity as well as facile catalyst recycling.
- Deng, Guo-Jun,Fan, Qing-Hua,Chen, Xiao-Min,Liua, Dong-Sheng,Chan, Albert S. C.
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- Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens
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We report a stereoselective conversion of terminal alkynes to α-chiral carboxylic acids using a nickel-catalyzed domino hydrocarboxylation-transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti-inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.
- Fu, Kaiyue,Ma, Yu,Sun, Yaxin,Tang, Bo,Yang, Guang,Yang, Peng,Yue, Jieyu,Zhang, Li,Zhou, Jianrong Steve
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- 2,2′-Bipyridine-α,α′-trifluoromethyl-diol ligand: Synthesis and application in the asymmetric Et2Zn alkylation of aldehydes
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A chiral 2,2′-bipyridine ligand (1) bearing α,α′-trifluoromethyl-alcohols at 6,6′-positions was designed in five steps affording either the R,R or S,S enantiomer with excellent stereoselectivities, i.e. 97% de, >99% ee and >99.5% de, >99.5% ee, respectively. The key step for reaching high levels of stereoselectivity was demonstrated to be the resolution of the α-CF3-alcohol using (S)-ibuprofen as the resolving agent. An initial application for the 2,2′-bipyridine-α,α′-CF3-diol ligand was highlighted in the ZnII-catalyzed asymmetric ethylation reaction of aromatic, heteroaromatic, and aliphatic aldehydes. Synergistic electron deficiency and steric hindrance properties of the newly developed ligand afforded the corresponding alcohols in good to excellent yields (up to 99%) and enantioselectivities (up to 95% ee). As observed from single crystal diffraction analysis, the complexation of the 2,2′-bipyridine-α,α′-CF3-diol ligand generates an unusual hexacoordinated ZnII.
- Lauzon, Samuel,Ollevier, Thierry
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p. 11025 - 11028
(2021/11/03)
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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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- Palladium-Catalyzed Asymmetric Markovnikov Hydroxycarbonylation and Hydroalkoxycarbonylation of Vinyl Arenes: Synthesis of 2-Arylpropanoic Acids
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Asymmetric hydroxycarbonylation is one of the most fundamental yet challenging methods for the synthesis of carboxylic acids. Herein, we reported the development of a palladium-catalyzed highly enantioselective Markovnikov hydroxycarbonylation of vinyl arenes with CO and water. A monodentate phosphoramidite ligand L6 plays vital role in the reaction. The reaction tolerates a range of functional groups, and provides a facile and atom-economical approach to an array of 2-arylpropanoic acids including several commonly used non-steroidal anti-inflammatory drugs. The catalytic system has also enabled an asymmetric Markovnikov hydroalkoxycarbonylation of vinyl arenes with alcohols to afford 2-arylpropanates. Mechanistic investigations suggested that the hydropalladation is irreversible and is the regio- and enantiodetermining step, while hydrolysis/alcoholysis is probably the rate-limiting step.
- Guan, Zheng-Hui,Ren, Zhi-Hui,Wang, Yuan,Yang, Hui-Yi,Yao, Ya-Hong,Zou, Xian-Jin
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supporting information
p. 23117 - 23122
(2021/09/18)
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- Asymmetric Markovnikov Hydroaminocarbonylation of Alkenes Enabled by Palladium-Monodentate Phosphoramidite Catalysis
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A palladium-catalyzed asymmetric Markovnikov hydroaminocarbonylation of alkenes with anilines has been developed for the atom-economical synthesis of 2-substituted propanamides bearing an α-stereocenter. A novel phosphoramidite ligand L16 was discovered which exhibited very high reactivity and selectivity in the reaction. This asymmetric Markovnikov hydroaminocarbonylation employs readily available starting materials and tolerates a wide range of functional groups, thus providing a facile and straightforward method for the regio- and enantioselective synthesis of 2-substituted propanamides under ambient conditions. Mechanistic studies revealed that the reaction proceeds through a palladium hydride pathway.
- Yao, Ya-Hong,Yang, Hui-Yi,Chen, Ming,Wu, Fei,Xu, Xing-Xing,Guan, Zheng-Hui
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supporting information
p. 85 - 91
(2021/01/12)
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- Deracemizing α-Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis-Silyl Ketene Acetals with Water or Methanol
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We report a highly enantioselective catalytic protonation of bis-silyl ketene acetals. Our method delivers α-branched carboxylic acids, including nonsteroidal anti-inflammatory arylpropionic acids such as Ibuprofen, in high enantiomeric purity and high yields. The process can be incorporated in an overall deracemization of α-branched carboxylic acids, involving a double deprotonation and silylation followed by the catalytic asymmetric protonation.
- Mandrelli, Francesca,Blond, Aurélie,James, Thomas,Kim, Hyejin,List, Benjamin
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p. 11479 - 11482
(2019/07/18)
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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; 1000-1001
(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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- Asymmetric Hydrocyanation of Alkenes without HCN
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A general and efficient rhodium-catalyzed asymmetric cyanide-free hydrocyanation of alkenes has been developed. Based on the asymmetric hydroformylation/condensation/aza-Cope elimination sequences, a broad scope of substrates including mono-substituted, 1,2-, and 1,1-disubstituted alkenes (involving natural product R- and S-limonene) were employed, and a series of valuable chiral nitriles are prepared with high yields (up to 95 %) and enantioselectivities (up to 98 % ee). Notably, the critical factor to achieve high enantioseletivies is the addition of catalytic amount of benzoic acid. This novel methodology provides an efficient and concise synthetic route to the intermediate of vildagliptin and anagliptin.
- Li, Xiuxiu,You, Cai,Yang, Jiaxin,Li, Shuailong,Zhang, Dequan,Lv, Hui,Zhang, Xumu
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p. 10928 - 10931
(2019/07/15)
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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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- 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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- 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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- 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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- Organocatalytic Enantioselective Decarboxylative Protonation Reaction of Meldrum's Acid Derivatives under PTC Conditions
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An original organocatalyzed enantioselective protonation sequence of a transient quaternary ammonium enolate species has been developed by starting from readily available disubstituted Meldrum's acid derivatives and phenols. Under phase-transfer-catalytic (PTC) conditions, chiral nonracemic 2-aryl propionic ester derivatives were obtained in good isolated yields with enantioselectivities up to 70 % ee. The usefulness of the approach was demonstrated by the synthesis of enantioenriched (S)-ibuprofen.
- Legros, Fabien,Martzel, Thomas,Brière, Jean-Fran?ois,Oudeyer, Sylvain,Levacher, Vincent
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supporting information
p. 1975 - 1983
(2018/05/15)
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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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- Method for synthesizing arylpropionic acid-like nonsteroidal antiinflammatory agent
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The invention discloses a method for synthesizing an arylpropionic acid-like nonsteroidal antiinflammatory agent. The method comprises that an aryl acetonitrile compound as a substrate, an amine borane complex and N, N-dimethylformamide as a solvent undergo a methylation reaction under basic conditions to produce an aryl propionitrile compound, and the aryl propionitrile compound is hydrolyzed under strong basic conditions to form the arylpropionic acid-like nonsteroidal antiinflammatory agent. The method creatively uses the amine borane complex and N, N-dimethylformamide as methylation reagents so that bis-methylation and large toxicity caused by the traditional methylation reagents such as methyl iodide and dimethyl sulfate are avoided. The method is simple and is easy to operate. The arylpropionic acid-like nonsteroidal antiinflammatory agent has a high yield and high purity. Compared with the existing method using a metal catalyst system, the method utilizes anon-metallic system so that the use of transition metals is avoided. The method provides a novel approach for preventing metal residues in synthetic drugs.
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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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- Synthesis method of photoactive 2-aryl propionic acid and derivatives thereof
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The invention provides a synthesis method of photoactive 2-aryl propionic acid and derivatives thereof. The method comprises the following steps: with metal palladium salt and a chiral diphosphine ligand as catalysts, enabling the easily available aryl alkene to react with phenyl formate or carbon monoxide and phenol to obtain photoactive 2-aryl phenyl propionate; and performing hydrolysis or aminolysis to obtain photoactive 2-aryl propionic acid and derivatives thereof. The synthesis method has the advantages of mild reaction conditions, simple steps and easiness in operation; and the maximum enantiomer excess value (ee value) of the obtained photoactive 2-aryl propionic acid and derivatives thereof can reach 95%.
- -
-
Paragraph 0122; 0123; 0124; 0125; 0126
(2017/03/25)
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- Highly Regio- and Enantioselective Copper-Catalyzed Reductive Hydroxymethylation of Styrenes and 1,3-Dienes with CO2
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Herein, we report a highly regio- and enantioselective copper-catalyzed reductive hydroxymethylation of styrenes and 1,3-dienes with 1 atm of CO2. Diverse important chiral homobenzylic alcohols were readily prepared from styrenes. Moreover, a variety of 1,3-dienes also were converted to chiral homoallylic alcohols with high yields and excellent regio-, enantio-, and Z/E-selectivities. The utility of this transformation was demonstrated by a broad range of styrenes and 1,3-dienes, facile product modification, and synthesis of bioactive compounds (R)-(-)-curcumene and (S)-(+)-ibuprofen. Mechanistic studies demonstrated the carboxylation of phenylethylcopper complexes with CO2 as one key step.
- Gui, Yong-Yuan,Hu, Naifu,Chen, Xiao-Wang,Liao, Li-Li,Ju, Tao,Ye, Jian-Heng,Zhang, Zhen,Li, Jing,Yu, Da-Gang
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p. 17011 - 17014
(2017/12/06)
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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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- Asymmetric Hydrogenation of α-Substituted Acrylic Acids Catalyzed by a Ruthenocenyl Phosphino-oxazoline-Ruthenium Complex
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Asymmetric hydrogenation of various α-substituted acrylic acids was carried out using RuPHOX-Ru as a chiral catalyst under 5 bar H2, affording the corresponding chiral α-substituted propanic acids in up to 99% yield and 99.9% ee. The reaction could be performed on a gram-scale with a relatively low catalyst loading (up to 5000 S/C), and the resulting product (97%, 99.3% ee) can be used as a key intermediate to construct bioactive chiral molecules. The asymmetric protocol was successfully applied to an asymmetric synthesis of dihydroartemisinic acid, a key intermediate required for the industrial synthesis of the antimalarial drug artemisinin.
- Li, Jing,Shen, Jiefeng,Xia, Chao,Wang, Yanzhao,Liu, Delong,Zhang, Wanbin
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p. 2122 - 2125
(2016/06/01)
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- Ferrocenyl chiral bisphosphorus ligands for highly enantioselective asymmetric hydrogenation via noncovalent ion pair interaction
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A new class of ferrocenyl chiral bisphosphorus ligand, Wudaphos, was developed, and exhibits excellent ee and activity (ee up to 99%, TON up to 20000) for the asymmetric hydrogenation of both 2-aryl and 2-alkyl acrylic acids through ion pair noncovalent interaction under base free and mild reaction conditions. Well-known anti-inflammatory drugs such as naproxen and ibuprofen together with the intermediate for the preparation of Roche ester and some bioactive compounds were also efficiently obtained with excellent ee. Control experiments were conducted and revealed that the ion pair noncovalent interaction and chain length played important roles.
- Chen, Caiyou,Wang, Heng,Zhang, Zhefan,Jin, Shicheng,Wen, Songwei,Ji, Jianjian,Chung, Lung Wa,Dong, Xiu-Qin,Zhang, Xumu
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p. 6669 - 6673
(2016/10/31)
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- Palladium-Catalyzed Highly Regio- and Enantioselective Hydroesterification of Aryl Olefins with Phenyl Formate
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An effective Pd-catalyzed regio- and enantioselective hydroesterification of aryl olefins with phenyl formate is described. A variety of phenyl 2-arylpropanoates can be obtained in good yields with high b/l ratios and ee's without using toxic CO gas.
- Li, Jingfu,Chang, Wenju,Ren, Wenlong,Dai, Jie,Shi, Yian
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supporting information
p. 5456 - 5459
(2016/11/17)
-
- 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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- Asymmetric cross-coupling of racemic α-bromo esters with aryl Grignard reagents catalyzed by cyclopropane-based bisoxazolines cobalt complexes
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Four new cyclopropane-based bisoxazolines were synthesized and applied to cobalt-catalyzed cross-coupling reactions between racemic α-bromo esters and aryl Grignard reagents. The reaction afforded a series of chiral α-arylalkanoic esters with high yields and good enantioselectivities (up to 93% yield, 92:8 er). This research focuses on the cross-coupling between racemic α-bromopropanoate and p-isobutylphenyl Grignard reagent's which provides ibuprofen ester efficiently. Furthermore, ibuprofen ester 7e was transformed into (S)-ibuprofen (99:1 er) via hydrolysis and recrystallization.
- Liu, Feipeng,Bian, Qinghua,Mao, Jianyou,Gao, Zidong,Liu, Dan,Liu, Shikuo,Wang, Xueyang,Wang, Yu,Wang, Min,Zhong, Jiangchun
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p. 663 - 669
(2016/07/11)
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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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- Chiral diphosphine ligand in asymmetric hydrogenation thereof and related application of the catalyst in the reaction (by machine translation)
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The invention discloses a chiral diphosphine ligand based on ferrocene skeleton in asymmetric hydrogenation thereof and related application of the catalyst in the reaction. This kind of novel chiral diphosphine ligand has as the general formula I The structure of the shown, wherein R 1 can be is methyl, phenyl, tert-butyl, hydroxy, etc.. R 2 can be ethyl, phenyl, cyclohexyl, methyl phenyl, tert-butyl, 3,5-dimethyl phenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-butyl-4-methoxybenzene, 2,6-dimethoxyphenyl, 2,6-dimethyl phenyl, anthryl. At the same time, two phosphine atom bridged between the can is phenyl, naphthyl, alkyl or the like. At the same time, this invention has disclosed this kind of novel chiral diphosphine ligand synthesis and in preparation of chiral pharmaceutical ibuprofen and a naproxen, and the like. (by machine translation)
- -
-
Paragraph 0104; 0108; 0109
(2016/10/09)
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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
-
supporting information
p. 41 - 45
(2015/03/03)
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- Iridium-Catalyzed Enantioselective Hydrogenation of β,β-Disubstituted Nitroalkenes
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A highly efficient, iridium-catalyzed, enantioselective hydrogenation of β,β-disubstituted nitroalkenes has been developed. Using a complex consisting of iridium and (S,S)-f-spiroPhos as the catalyst, a variety of β,β-disubstituted nitroalkenes were successfully hydrogenated to the corresponding chiral nitroalkanes with excellent enantioselectivities (up to 98% ee) and high turnover numbers (TON=1000).
- Liu, Man,Kong, Duanyang,Li, Meina,Zi, Guofu,Hou, Guohua
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p. 3875 - 3879
(2016/01/25)
-
- 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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- Iron-Catalyzed Enantioselective Cross-Coupling Reactions of α-Chloroesters with Aryl Grignard Reagents
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The first iron-catalyzed enantioselective cross-coupling reaction between an organometallic compound and an organic electrophile is reported. Synthetically versatile racemic α-chloro- and α-bromoalkanoates were coupled with aryl Grignard reagents in the presence of catalytic amounts of an iron salt and a chiral bisphosphine ligand, giving the products in high yields with acceptable and synthetically useful enantioselectivities (er up to 91:9). The produced α-arylalkanoates were readily converted to the corresponding α-arylalkanoic acids with high optical enrichment (er up to >99:1) via simple deprotections/recrystallizations. The results of radical probe experiments are consistent with a mechanism that involves the formation of an alkyl radical intermediate, which undergoes subsequent enantioconvergent arylation in an intermolecular manner. The developed asymmetric coupling offers not only facile and practical access to various chiral α-arylalkanoic acid derivatives, which are of significant pharmaceutical importance, but also a basis of controlling enantioselectivity in an iron-catalyzed organometallic transformation. (Chemical Equation Presented).
- Jin, Masayoshi,Adak, Laksmikanta,Nakamura, Masaharu
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supporting information
p. 7128 - 7134
(2015/06/25)
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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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- 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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-
- 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 0065-0067
(2014/07/22)
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- Laccase-Mediator System for Alcohol Oxidation to Carbonyls or Carboxylic Acids: Toward a Sustainable Synthesis of Profens
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By combining two green and efficient catalysts, such as the commercially available enzyme laccase from Trametes versicolor and the stable free radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), the oxidation in water of some primary alcohols to the corresponding carboxylic acids or aldehydes and of selected secondary alcohols to ketones can be accomplished. The range of applicability of bio-oxidation is widened by applying the optimized protocol to the oxidation of enantiomerically pure 2-arylpropanols (profenols) into the corresponding 2-arylpropionic acids (profens), in high yields and with complete retention of configuration.
- Galletti, Paola,Pori, Matteo,Funiciello, Federica,Soldati, Roberto,Ballardini, Alberto,Giacomini, Daria
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p. 2684 - 2689
(2016/12/23)
-
- Synthesis and evaluation of antioxidant-S-(+)-ibuprofen hybrids as gastro sparing NSAIDs
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Ibuprofen is one of the most popular NSAIDs for the last three decades but also known for its gastrointestinal side effects similar to other NSAIDs. To overcome this problem, we have designed and synthesized ibuprofen - antioxidant (thymol, guaiacol, eugenol, and menthol) hybrids (6-13) with and without spacer as gastro sparing agents. The hybrids have been found to be chemically stable, biolabile and exhibited retention of anti-inflammatory and analgesic activity with significant reduced ulcerogenicity as compared to the ibuprofen and ibuprofen + antioxidant physical mixture. The absence of ulcerogenicity may be attributed to antioxidants and improved physicochemical properties of these hybrid molecules.
- Chandiran, Senthil,Vyas, Sandeep,Sharma, Neetika,Sharma, Manu
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p. 1006 - 1016
(2014/01/06)
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- Ni-catalyzed direct carboxylation of benzyl halides with CO2
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A novel Ni-catalyzed carboxylation of benzyl halides with CO2 has been developed. The described carboxylation reaction proceeds under mild conditions (atmospheric CO2 pressure) at room temperature. Unlike other routes for similar means, our method does not require well-defined and sensitive organometallic reagents and thus is a user-friendly and operationally simple protocol for assembling phenylacetic acids.
- León, Thierry,Correa, Arkaitz,Martin, Ruben
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supporting information
p. 1221 - 1224
(2013/03/14)
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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
-
-
- Laboratory evolution of enantiocomplementary Candida antarctica lipase B mutants with broad substrate scope
-
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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p. 1872 - 1881
(2013/08/24)
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- Enantioselective nickel-catalyzed hydrocyanation of vinylarenes using chiral phosphine-phosphite ligands and TMS-CN as a source of HCN
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Anti-headache chemistry: In the presence of a tailored modular P,P ligand the nickel-catalyzed addition of HCN, generated in situ from TMS-CN, to styrene derivatives proceeds with an unprecedented level of stereocontrol (up to 97 % ee) to give 2-aryl-acetonitriles, for example, the depicted precursor of Ibuprofen. Copyright
- Falk, Anna,Goederz, Anna-Lena,Schmalz, Hans-Guenther
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supporting information
p. 1576 - 1580
(2013/03/13)
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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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