- Deracemization through photochemical E/Z isomerization of enamines
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Catalytic deracemization of a-branched aldehydes is a direct strategy to construct enantiopure a-tertiary carbonyls, which are essential to pharmaceutical applications. Here, we report a photochemical E/Z isomerization strategy for the deracemization of a-branched aldehydes by using simple aminocatalysts and readily available photosensitizers. A variety of racemic a-branched aldehydes could be directly transformed into either enantiomer with high selectivity. Rapid photodynamic E/Z isomerization and highly stereospecific iminium/enamine tautomerization are two key factors that underlie the enantioenrichment. This study presents a distinctive photochemical E/Z isomerization strategy for externally tuning enamine catalysis.
- Huang, Mouxin,Luo, Sanzhong,Pan, Tianrun,Zhang, Long
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p. 869 - 874
(2022/03/07)
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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
-
supporting information
p. 23117 - 23122
(2021/09/18)
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- Visible-light photoredox-catalyzed selective carboxylation of C(sp3)?F bonds with CO2
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It is highly attractive and challenging to utilize carbon dioxide (CO2), because of its inertness, as a nontoxic and sustainable C1 source in the synthesis of valuable compounds. Here, we report a novel selective carboxylation of C(sp3)?F bonds with CO2 via visible-light photoredox catalysis. A variety of mono-, di-, and trifluoroalkylarenes as well as α,α-difluorocarboxylic esters and amides undergo such reactions to give important aryl acetic acids and α-fluorocarboxylic acids, including several drugs and analogs, under mild conditions. Notably, mechanistic studies and DFT calculations demonstrate the dual role of CO2 as an electron carrier and electrophile during this transformation. The fluorinated substrates would undergo single-electron reduction by electron-rich CO2 radical anions, which are generated in situ from CO2 via sequential hydride-transfer reduction and hydrogen-atom-transfer processes. We anticipate our finding to be a starting point for more challenging CO2 utilization with inert substrates, including lignin and other biomass.
- Bo, Zhi-Yu,Chen, Lin,Gao, Tian-Yu,Jing, Ke,Lan, Yu,Liu, Shi-Han,Luo, Shu-Ping,Yan, Si-Shun,Yu, Bo,Yu, Da-Gang
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supporting information
p. 3099 - 3113
(2021/11/16)
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- Alpha-alkylphenylacetic acid compound with high optical activity as well as preparation method and application thereof
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The invention discloses an alpha-alkylphenylacetic acid compound with high optical activity as well as a preparation method and application of the alpha-alkylphenylacetic acid compound. The preparation method comprises the following steps: mixing an aryl alkyl substituted malonic acid monoester substrate and a sulfonamide organic catalyst derived from chiral cyclohexylenediamine according to a molar ratio of 1: (0.01-0.30) in an organic solvent, and reacting for 2-48 hours at the temperature of 20-50 DEG C to obtain the alpha-alkylphenylacetic acid compound. The alpha-alkylphenylacetic acid compound can be used for preparing non-steroidal anti-inflammatory drugs, analgesics and central nervous excitants. The preparation method has the advantages of simple operation, mild conditions, almostno by-product, easily available catalyst and high enantioselectivity, and the reaction product can be used for synthesizing medical intermediates with important biological activity through simple conversion.
- -
-
Paragraph 0060-0063
(2020/09/16)
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- Exploration of New Biomass-Derived Solvents: Application to Carboxylation Reactions
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A range of hitherto unexplored biomass-derived chemicals have been evaluated as new sustainable solvents for a large variety of CO2-based carboxylation reactions. Known biomass-derived solvents (biosolvents) are also included in the study and the results are compared with commonly used solvents for the reactions. Biosolvents can be efficiently applied in a variety of carboxylation reactions, such as Cu-catalyzed carboxylation of organoboranes and organoboronates, metal-catalyzed hydrocarboxylation, borocarboxylation, and other related reactions. For many of these reactions, the use of biosolvents provides comparable or better yields than the commonly used solvents. The best biosolvents identified are the so far unexplored candidates isosorbide dimethyl ether, acetaldehyde diethyl acetal, rose oxide, and eucalyptol, alongside the known biosolvent 2-methyltetrahydrofuran. This strategy was used for the synthesis of the commercial drugs Fenoprofen and Flurbiprofen.
- Gevorgyan, Ashot,Hopmann, Kathrin H.,Bayer, Annette
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p. 2080 - 2088
(2020/02/20)
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- Synthesis of pharmaceutical drugs from cardanol derived from cashew nut shell liquid
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Cardanol from cashew nut shell liquid extracted from cashew nut shells was successfully converted into various useful pharmaceutical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene. 3-Vinylphenol, the key intermediate for the synthesis of these drugs, was synthesised from cardanol by ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis. The metathesis reaction worked very well using DCM, but the greener solvent, 2-methyl tetrahydrofuran, also gave very similar results. Hydroxyamination of 3-vinylphenol with an iron porphyrin catalyst afforded norfenefrine in over 70% yield. Methylation and ethylation of norfenefrine afforded rac-phenylephrine and etilefrine respectively. A sequence of C-O coupling, isomerising metathesis and selective methoxycarbonylation afforded fenoprofene in good yield. A comparison of the routes described in this paper with some standard literature syntheses of 3-vinylphenol and of the drug molecules shows significant environmental advantages in terms of precursors, yields, number of steps, conditions and the use of catalysts. The Atom Economy of our processes is generally similar or significantly superior to those of the literature processes mainly because the side products produced during synthesis of 3-vinylphenol (1-octeme, 1,4-cyclohexadiene and propene) are easily separable and of commercial value, especially as they are bio-derived. The E Factor for the production of 2-vinylphenol by our process is also very low compared with those of previously reported syntheses.
- Shi, Yiping,Kamer, Paul C. J.,Cole-Hamilton, David J.
-
supporting information
p. 1043 - 1053
(2019/03/12)
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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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supporting information
p. 11479 - 11482
(2019/07/18)
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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
-
supporting information
p. 1128 - 1131
(2019/01/28)
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- Palladium-Catalyzed α-Arylation of Carboxylic Acids and Secondary Amides via a Traceless Protecting Strategy
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A novel traceless protecting strategy is presented for the long-standing challenge of conducting the palladium-catalyzed α-arylation of carboxylic aids and secondary amides with aryl halides. Both of the presented coupling processes occur with a variety of carboxylic acids and amides and with a variety of aryl bromides containing a broad range of functional groups, including base-sensitive functionality like acyl, alkoxycarbonyl, nitro, cyano, and even hydroxyl groups. Five commercial drugs were prepared through this method in one step in 81-96% yield. Gram-scale synthesis of medication Naproxen and Flurbiprofen with low palladium loading further highlights the practical value of this method.
- He, Zhi-Tao,Hartwig, John F.
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supporting information
p. 11749 - 11753
(2019/08/26)
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- Photocarboxylation of Benzylic C-H Bonds
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The carboxylation of sp3-hybridized C-H bonds with CO2 is a challenging transformation. Herein, we report a visible-light-mediated carboxylation of benzylic C-H bonds with CO2 into 2-arylpropionic acids under metal-free conditions. Photo-oxidized triisopropylsilanethiol was used as the hydrogen atom transfer catalyst to afford a benzylic radical that accepts an electron from the reduced form of 2,3,4,6-tetra(9H-carbazol-9-yl)-5-(1-phenylethyl)benzonitrile generated in situ. The resulting benzylic carbanion reacts with CO2 to generate the corresponding carboxylic acid after protonation. The reaction proceeded without the addition of any sacrificial electron donor, electron acceptor or stoichiometric additives. Moderate to good yields of the desired products were obtained in a broad substrate scope. Several drugs were successfully synthesized using the novel strategy.
- Meng, Qing-Yuan,Schirmer, Tobias E.,Berger, Anna Lucia,Donabauer, Karsten,K?nig, Burkhard
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p. 11393 - 11397
(2019/08/20)
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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.
- -
-
Paragraph 0037-0040
(2017/10/27)
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- Selective aryne formation via Grob fragmentation from the [2+2] cycloadducts of 3-triflyloxyarynes
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A chemoselective ring-opening protocol of the formal [2+2] cycloadducts of 3-triflyloxyarynes was developed to generate 2,3-aryne intermediate via Grob fragmentation. A variety of 1,3-di- and 1, 2, 3-trisubstituted arenes could be readily accessed through this [2+2] cycloaddition-2,3-aryne formation sequence. The regioselectivity in these transformations originates from the steric repulsion of the aliphatic chain.
- Shi, Jiarong,Xu, Hai,Qiu, Dachuan,He, Jia,Li, Yang
-
supporting information
p. 623 - 626
(2017/05/15)
-
- Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
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The enantioselective potential of two polysaccharide-based chiral stationary phases for analysis of chiral structurally diverse biologically active compounds was evaluated in supercritical fluid chromatography using a set of 52 analytes. The chiral selectors immobilized on 2.5?μm silica particles were tris-(3,5-dimethylphenylcarmabate) derivatives of cellulose or amylose. The influence of the polysaccharide backbone, different organic modifiers, and different mobile phase additives on retention and enantioseparation was monitored. Conditions for fast baseline enantioseparation were found for the majority of the compounds. The success rate of baseline and partial enantioseparation with cellulose-based chiral stationary phase was 51.9% and 15.4%, respectively. Using amylose-based chiral stationary phase we obtained 76.9% of baseline enantioseparations and 9.6% of partial enantioseparations of the tested compounds. The best results on cellulose-based chiral stationary phase were achieved particularly with propane-2-ol and a mixture of isopropylamine and trifluoroacetic acid as organic modifier and additive to CO2, respectively. Methanol and basic additive isopropylamine were preferred on amylose-based chiral stationary phase. The complementary enantioselectivity of the cellulose- and amylose-based chiral stationary phases allows separation of the majority of the tested structurally different compounds. Separation systems were found to be directly applicable for analyses of biologically active compounds of interest.
- Kucerova, Gabriela,Kalikova, Kveta,Tesarova, Eva
-
supporting information
p. 239 - 246
(2017/05/29)
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- Site-Selective Catalytic Carboxylation of Unsaturated Hydrocarbons with CO2 and Water
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A catalytic protocol that reliably predicts and controls the site-selective incorporation of CO2 to a wide range of unsaturated hydrocarbons utilizing water as formal hydride source is described. This platform unlocks an opportunity to catalytically repurpose three abundant, orthogonal feedstocks under mild conditions.
- Gaydou, Morgane,Moragas, Toni,Juliá-Hernández, Francisco,Martin, Ruben
-
supporting information
p. 12161 - 12164
(2017/09/12)
-
- 2-ARYL-ZINC-PROPIONATE CATALYST AND PREPARATION METHOD AND USE THEREOF
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The present invention belongs to the technical field of chemical catalysts, and particularly relates to a zinc 2-arylpropionate catalyst, a preparation method therefor and use thereof The structural formula of the zinc 2-arylpropionate catalyst of the present invention is one of the following structures. The catalyst can be used for homogeneous catalysis of a 1,2-aryl rearrangement reaction of α-haloarylketal, and especially for synthesis of high yield and environmentally friendly 2-arylpropanonic acid non-steroidal anti-inflammatory analgesic drugs, such as, ibuprofen, ketoprofen, loxoprofen, flurbiprofen, fenoprofen, or naproxen and the like.
- -
-
Paragraph 0023
(2016/11/28)
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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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- 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)
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- COMPOSITIONS AND METHODS FOR SUBSTRATE-SELECTIVE INHIBITION OF ENDOCANNABINOID OXYGENATION
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Methods for selectively inhibiting endocannabinoid oxygenation but not arachidonic acid oxygenation. In some embodiments, the methods include contacting a COX-2 polypeptide with an effective amount of a substrate-selective COX-2 inhibitor. Also provided are methods for elevating a local endogenous cannabinoid concentrations; methods of reducing depletion of an endogenous cannabinoid; methods for inducing analgesia; methods of providing anxiolytic therapy; methods for providing anti-depressant therapy; and compositions for performing the disclosed methods.
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Page/Page column 62-63
(2014/02/15)
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- Separating agent for optical isomers
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A separating agent for optical isomers that uses a polysaccharide derivative provided by replacing all or a portion of the hydrogen atoms on the hydroxyl groups present in a polysaccharide with two specific atomic groups that act on optical isomers targeted for separation in an optical resolution, wherein the sum of the average introduction ratios of specific terminal substituents in these atomic groups is greater than 3.0 per monosaccharide unit.
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Page/Page column 5-6
(2014/10/29)
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- Cobalt-bisoxazoline-catalyzed asymmetric kumada cross-coupling of racemic α-bromo esters with aryl grignard reagents
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The first cobalt-catalyzed asymmetric Kumada cross-coupling with high enantioselectivity has been developed. The reaction affords a unique strategy for the enantioselective arylation of α-bromo esters catalyzed by a cobalt-bisoxazoline complex. A variety of chiral α-arylalkanoic esters were prepared in excellent enantioselectivity and yield (up to 97% ee and 96% yield). The arylated products were transformed into α-arylcarboxylic acids and primary alcohols without erosion of ee. The new enantioenriched α-arylpropionic esters synthesized herein are potentially useful in the development of nonsteroidal anti-inflammatory drugs. This method was conducted on gram-scale and applied to the synthesis of highly enantioenriched (S)-fenoprofen and (S)-ar-turmerone.
- Mao, Jianyou,Liu, Feipeng,Wang, Min,Wu, Lin,Zheng, Bing,Liu, Shangzhong,Zhong, Jiangchun,Bian, Qinghua,Walsh, Patrick J.
-
supporting information
p. 17662 - 17668
(2015/02/02)
-
- 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.
-
supporting information
p. 1872 - 1881
(2013/08/24)
-
- 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.
-
supporting information
p. 759 - 763
(2012/10/29)
-
- Highly enantioselective direct alkylation of arylacetic acids with chiral lithium amides as traceless auxiliaries
-
A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.
- Stivala, Craig E.,Zakarian, Armen
-
supporting information; experimental part
p. 11936 - 11939
(2011/09/19)
-
- One-step oxidation of 2-arylpropanols to 2-arylpropionic acids: Improving sustainability in the synthesis of profens
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Three oxidation procedures were evaluated for the synthesis of optically pure 2-arylpropionic acids. Efficient, mild, and eco-friendly conditions were obtained with the system comprising TEMPO, NaClO, and NaClO2. Thus a series of profens were obtained in good to excellent yields. Georg Thieme Verlag Stuttgart New York.
- Galletti, Paola,Pori, Matteo,Giacomini, Daria
-
experimental part
p. 2644 - 2648
(2010/11/18)
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- Chemoenzymatic synthesis of (2S)-2-arylpropanols through a dynamic kinetic resolution of 2-arylpropanals with alcohol dehydrogenases
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We applied Horse Liver Alcohol Dehydrogenase (HLADH) to the enantioselective synthesis of six (2S)-2-arylpropanols, useful intermediates in the synthesis of Profens. The influence of substrate structure and reaction conditions on yields and enantioselectivity were investigated. The high yields and high enantioselectivity towards the (S)-enantiomer obtained in the bioreduction of 2-arylpropionic aldehydes, clearly indicate the achievement of a DKR process through a combination of an enzyme-catalyzed kinetic reduction with a chemical base-catalyzed racemization of the unreacted aldehydes. The racemization step is represented by the keto-enol equilibrium of the aldehyde and can be controlled by modulating pH and reaction conditions.
- Galletti, Paola,Emer, Enrico,Gucciardo, Gabriele,Quintavalla, Arianna,Pori, Matteo,Giacomini, Daria
-
supporting information; experimental part
p. 4117 - 4123
(2010/10/03)
-
- 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 15-16
(2010/09/18)
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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
-
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
-
experimental part
p. 5666 - 5669
(2010/11/18)
-
- Iterative saturation mutagenesis accelerates laboratory evolution of enzyme stereoselectivity: Rigorous comparison with traditional methods
-
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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- 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
-
supporting information; experimental part
p. 11629 - 11641
(2010/10/04)
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- (R,S)-azolides as novel substrates for lipase-catalyzed hydrolytic resolution in organic solvents
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Azolides, that is, N-acylazoles, as versatile acylation reagents are well characterized in the literature, in which the azole structure can not only act as a better leaving group but also make the carbonyl carbon more electrophilic and susceptible to nucleophilic attack. It is therefore desirable to combine this unique property and lipase resolution ability in the development of a new resolution process for preparing optically pure carboxylic acids. With the Candida antarctica lipase B (CALB)-catalyzed hydrolysis of (R,S)-N- profenylazoles in organic solvents as the model system, (R,S)-N-profenyl-l,2,4- triazoles instead of their corresponding ester analogues were exploited as the best substrates for preparing optically pure profens, i.e., 2-arylpropionic acids. The structure-reactivity correlations for the (R,S)-azolides in water-saturated methyl tert-butyl ether (MTBE) at 45°C coupled with a thorough kinetic analysis were further employed for elucidating the rate-limiting formation of a tetrahedral adduct without C-N bond breaking or with moderate C-N bond breaking concerted with C-O bond formation in the acylation step. The advantages of easy substrate preparation, high enzyme reactivity and enantioselectivity, and easy recovery of the product and remaining substrate by aqueous extraction demonstrate the potential of using (R,S)-azolides as novel substrates for the enzymatic resolution process.
- Wang, Pei-Yun,Chen, Ying-Ju,Wu, An-Chi,Lin, Yi-Sheng,Kao, Min-Fang,Chen, Jin-Ru,Ciou, Jyun-Fen,Tsai, Shau-Wei
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supporting information; scheme or table
p. 2333 - 2341
(2009/12/27)
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- NEW CHIRAL STATIONARY PHASES FOR CHROMATOGRAPHY BASED ON AROMATIC ALLYL AMINES
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New chiral stationary phases (CSPs) based on chiral selectors covalently bound on a solid support were prepared. Chiral selectors were obtained from enantiomerically pure aromatic amines and 3,5-dinitrobenzoic acid and then linked to the support surface through the allylic double bond. Such obtained materials allow enantioseparation of racemates or enantiomerically enriched compounds. These chiral stationary phases can be used as fillings in chromatographic columns for enantiomer separation of naproxen type drugs and other similar non-steroidal anti-inflammatory drugs (NSAID) by means of high performance liquid chromatography on both the analytical and preparative scale.
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Page/Page column 18-19
(2009/10/22)
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- Catalytic asymmetric synthesis using feedstocks: An enantioselective route to 2-arylpropionic acids and 1-arylethyl amines via hydrovinylation of vinyl arenes
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A three-step procedure for the synthesis of 2-arylpropionic acids (profens) from vinyl arenes in nearly enantiomerically pure form has been developed. Excellent yields (>97%), regioselectivities (>99%), and enantioselectivities (>97% ee) for the desired branched products were obtained in the asymmetric hydrovinylation reactions of vinyl arenes, and the products from these reactions were transformed into 2-arylpropionic acids via oxidative degradation. Subsequent Curtius or Schmidt rearrangements of these acids provided highly valued 1-arylethyl amines, including a prototypical primary amine with an α-chiral tertiary N-alkyl group, in very good yields.
- Smith, Craig R.,Babu, T.V. Rajan
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experimental part
p. 3066 - 3072
(2009/08/08)
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- Kinetic resolution of racemic carboxylic acids using achiral alcohols by the promotion of benzoic anhydrides and tetramisole derivatives: Production of chiral nonsteroidal anti-inflammatory drugs and their esters
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A variety of optically active carboxylic esters were produced by kinetic resolution of racemic carboxylic acids by using achiral alcohols, benzoic anhydrides, and Birman's tetramisole-type catalysts. Bis(α-naphthyl) methanol is a very effective reagent for producing the corresponding esters with high ee values in the presence of 4-methoxybenzoic anhydride (PMBA) as the coupling reagent by promotion of benzotetramisole derivatives (BTM, α-Np-BTM, and β-Np-BTM). This protocol directly provides chiral carboxylic esters from free carboxylic acids and achiral alcohols by utilizing a transacylation process to generate the mixed anhydrides from the acid components with benzoic anhydride derivatives in the presence of chiral catalysts. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Shiina, Isamu,Nakata, Kenya,Onda, Yu-Suke
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experimental part
p. 5887 - 5890
(2009/05/27)
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- Electrosynthesis of 2-arylpropionic acids from α-methylbenzyl chlorides and carbon dioxide by [Co(Salen)]
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The electrochemical synthesis of the 2-arylpropionic acid group of nonsteroidal anti-inflammatory agents such as ibuprofen, naproxen, indoprofen, biprofen, cicloprofen, and fenoprofen has been carried out in dimethylformamide (DMF) containing tetra-n-butylammonium perchlorate (nBu4NClO 4) by electrochemical carboxylation of α-methylbenzyl chlorides catalyzed by a schiff-base complex [Co(salen)] in an undivided cell equipped with a platinum cathode and magnesium anode under constant current density of 10 mA/cm2 in good yields. Cyclic voltammetric studies have also been carried out to investigate the mechanism by which [Co(salen)] catalyzes the cathodic reaction of α-methylbenzyl chlorides in presence of CO 2 by taking α-phenylethylchloride as the model compound. Copyright Taylor & Francis, Inc.
- Damodar,Krishna Mohan,Khaja Lateef,Jayarama Reddy
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p. 1143 - 1150
(2007/10/03)
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- Highly Diastereoselective Conjugate Addition to Alkylidene Bis(Sulfoxides): Asymmetric Synthesis of (+)-erythro-Roccellic Acid
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Facial stereocontrol is possible in Michael additions of nucleophiles (Nu) to alkylidene bis(sulfoxides), which proceed via nonchelated (A) or chelated (B) intermediates depending on the addition of an appropriate Lewis acid (LA). This intriguing reactivi
- Brebion, Franck,Delouvrie, Benedicte,Najera, Francisco,Fensterbank, Louis,Malacria, Max,Vaissermann, Jacqueline
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p. 5342 - 5345
(2007/10/03)
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- Meta, para and ortho double exo nucleophilic additions of trimethylsilylester enolates derived from saturated and unsaturated carboxylic acids to tricarbonylchromium complexes of aryl ethers: dearomatizing cyclization to lactones
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Potassium enolates derived from saturated and unsaturated bis(trimethylsilyl) ketene acetals react with tricarbonylchromium complexes of anisole and diphenylether to give, in addition to α-arylcarboxylic acids, the mono addutcts, lactones, arising from a double exo nucleophilic addition. The latter were not observed in the case of benzenetricarbonylchromium. The intermediate dienol ethers could be isolated and fully characterized by X-ray crystallography. The influenece of the nature of the substituents on the ketene acetals, of the nature of the oxidant, and of the nature of the ester enolates on the course of the reaction has been established and will be discussed.
- Rudler, Henri,Comte, Virginie,Garrier, Eva,Bellassoued, Moncef,Chelain, Evelyne,Vaissermann, Jaqueline
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p. 284 - 298
(2007/10/03)
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- Stereocontrolled ring-opening of some enantiomerically enriched epoxy ketones and epoxy alcohols using trimethylaluminium: Synthesis of (S)-2-arylpropanoic acids
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Poly-(D)-leucine-catalysed epoxidation of chalcone furnished epoxide (+)-6; treatment of this epoxide with trimethylaluminium followed by zinc borohydride reduction and oxidative cleavage furnished (S)-2-phenylpropanoic acid 11. In a complementary sequence epoxy ketones (-)-6 and 25 were converted into (S)-2-phenylpropanoic acid and (S)-fenoprofen 5 respectively by reduction with zinc borohydride, reaction with trimethylaluminium and oxidative cleavage. Similarly epoxy ketones (-)-6, 21 and 28 were treated with methylmagnesium iodide, trimethylaluminium and the resultant alcohols subjected to oxidative cleavage to afford (S)-2-phenylpropanoic acid (from the first two substrates) and (S)-naproxen 1.
- Carde, Lydia,Davies, D. Huw,Roberts, Stanley M.
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p. 2455 - 2463
(2007/10/03)
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- Unexpected formation of 3,3a,4,7a-tetrahydrobenzofuran-2,5-dione as well as arene carboxylic acids upon formal double exo nucleophilic addition of R1R2C-COO- to anisolechromium tricarbonyl complexes
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Bis(trimethylsily)ketene acetals of the general structure 2 (R1 = H,Me,R2 = Me,Et,Pr(i),CMe = CH2) react at -78°C in the presence of Bu(t)OK with a series of arenechromium tricarbonyl complexes 3 to give as expected, after oxidation with I2 followed by silica gel chromatography, arylcarboxylic acids 7. In the case of anisolechromium tricarbonyl 8, besides the m-methoxyarylcarboxylic acids, tetrahydrobenzofuran-2,5-diones 11, are formed as the result of a double nucleophilic addition.
- Bellassoued, Moncef,Chelain, Evelyne,Collot, Jerome,Rudler, Henri,Vaissermann, Jacqueline
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p. 187 - 188
(2007/10/03)
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- PaaSicats: Powerful catalysts for asymmetric epoxidation of enones. Novel syntheses of α-arylpropanoic acids including (S)-fenoprofen
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Application of the recently developed silica-adsorbed polyleucine catalysts to the enantioselective epoxidation of two enones is reported. Treatment of these epoxides with trimethylaluminium in moist dichloromethane generates the α-hydroxy-β-methylketones, with inversion of configuration. Diastereoselective reduction of the ketone moiety followed by oxidative cleavage generates α-arylpropanoic acids.
- Carde, Lydia,Davies, Huw,Geller, Thomas P.,Roberts, Stanley M.
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p. 5421 - 5424
(2007/10/03)
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- An efficient synthesis of fenoprofen, an important antiinflammatory agent
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A simple and practical synthesis of (+/-)-fenoprofen, a well-known non-steroidal antiinflammatory agent, from the commercially available m-phenoxybenzaldehyde has been described.
- Sonawane, H. R.,Nanjundiah, B. S.,Nazeruddin, G. M.
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p. 705 - 706
(2007/10/02)
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- Enzymatic enantioselective ester hydrolysis by carboxylesterase NP
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The enzymatic hydrolysis of a series of carboxylic esters by carboxylesterase NP has been investigated in order to determine the scope and limitations of this enzyme. 2-Substituted propionates were hydrolyzed with high enantioselectivity when an aromatic moiety was part of the 2-substituent.Enantioselective hydrolysis could be accomplished with several 2-arypropionates, 2-(aryloxy)propionates and N-arylalanine esters.The propionate esters yielded propionic acids as (S) enantiomers, whereas the alanine esters yielded the (R) enantiomers.Without a 2-aryl substituent, the enzymatic hydrolysis of the propionates occurred at a lower rate without acceptable enantioselectivity.In addition to 2-substituted propionates, only a few other esters were hydrolyzed with high enantioselectivity by carboxylesterase NP, such as some prochiral disubstituted malonates. 1-Phenylethylacetate was the only substrate with chirality in the alcohol part of the ester that was found to be hydrolyzed enantioselectively.Carboxylesterase NP proved to be a powerful enzyme for kinetic resolution of propionate esters with an aromatic ring containing a 2-substituent.
- Smeets, J. W. H.,Kieboom, A. P. G.
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p. 490 - 495
(2007/10/02)
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- Process for the preparation of α-arylalkanoic acids
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α-Arylalkanoic acids are prepared by a method comprising the step of reacting an alkylaromatic compound corresponding to the desired α-arylalkanoic acid with a new metallation reagent solution. The reagent comprises the reaction product of alkyllithium or aryllithium and about two to five molar equivalents of potassium tert-alkoxide in a trialkylamine solvent.
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- The Reaction of Chiral Nucleophiles with Organomanganese Arene Complexes
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The reaction of the enolate derived from chiral N-acyloxazolidinone (1) and organomanganese arene complexes (2) gives η5-dienyl complexes (3) which can be converted into chiral 2-arylpropionic acids by cleavage of the chiral auxiliary and oxidation of the η5-dienyl moiety.
- Miles, William H.,Smiley, Patricia M.,Brinkman, Herbert R.
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p. 1897 - 1899
(2007/10/02)
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- Process for preparing hetero aryl and aryl alkanoic acids
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An aqueous solution comprising an alkali hydroxide, an aryl or a hetero aryl amine, substituted in ortho position by an alkanoic group and in para position by an inductive electron withdrawing atom or group, and an alkali nitrite is reacted with a mineral acid and hypophosphorous acid in an aqueous medium to afford an aryl and a heteroaryl alkanoic acid substituted in meta position by an electron withdrawing atom or group.
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- Manufacture of optically active α-arylalkanoic acids and precursors thereof
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This invention concerns a new process of preparing optically active α-arylalkanoic acids and their precursors. These α-arylalkanoic acids, esters, amides, nitriles, oxazolines and metal salts are stereoselectively prepared by forming the metal or metal halide of the corresponding acid, ester, amide, oxazoline, nitrile, or metal salt and treating the compound so prepared with an aryl halide in the presence of a chiral (optically active) transition metal catalyst of the formula (LL*)QZT wherein Q is a transition metal selected from palladium and nickel; Z and T are independently halogen; and LL* is a chiral tertiary diphosphine compound capable of acting as a bidentate ligand with Q to form a 5-membered ring, optionally in the presence of a dipolar aprotic solvent or mixtures thereof, for a time sufficient to form the corresponding optically active α-arylalkanoic acid, ester, amide, nitrile, oxazoline or metal salt, and optionally concomitantly or sequentially hydrolyzing any ester, amide, nitrile, oxazoline or metal salt formed to the corresponding optically active α-arylalkanoic acid. The process optionally further includes removal of halogen atom from the aromatic portion of the α-arylalkanoic acid. The process optionally includes subsequent formation of the pharmaceutically acceptable salts and esters of the optionally active α-arylalkanoic acid. This is a simple process for the preparation of the described optically active α-arylalkanoic acids. These compounds are useful as pharmaceutical (e.g., anti-inflammatory) agents.
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- ELECTROSYNTHESIS OF CARBOXYLIC ACIDS FROM ORGANIC HALIDES AND CARBON DIOXIDE
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The electrocarboxylation of a large variety of organic halides is achieved in simple and mild conditions in diaphragm-less cells.
- Sock, Oumar,Troupel, Michel,Perichon, Jacques
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p. 1509 - 1512
(2007/10/02)
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- Stereoselective inversion of (R)-fenoprofen to (S)-fenoprofen in humans
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The concentrations of the (R)- and (S)-enantiomers of fenoprofen (α-methyl-3-phenoxy-benzeneacetic acid) were measured in plasma and urine of volunteers after oral administration of the (R,S)-racemate. In addition, urinary concentrations of the (R)- and (S)-4'-hydroxy metabolite of fenoprofen, the major metabolite, were measured. The (R)-enantiomer of fenoprofen was stereoselectively inverted to (S)-fenoprofen, which was the major isomeric form found in plasma and urine. A potency comparison of the enantiomers in vitro showed the (S)-isomer to be 35 times more active than the (R)-isomer in inhibiting the fatty acid cyclo-oxygenase pathway from human platelets. In vivo, the similar pharmacological potency of the two enantiomers previously observed in experimental animals may have been due to the rapid inversion of the (R)- to (S)-isomer.
- Rubin,Knadler,Ho,Bechtol,Wolen
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- Manufacture of alpha-arylalkanoic acids and precursors
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α-Arylalkanoic acids or esters, orthoesters or amides thereof are prepared by forming an α-hydroxy ketal or thioketal of an aryl alkyl ketone, activating the α-hydroxy substituent with an esterifying agent to form the corresponding ketal or thioketal ester substrate, wherein the ester group is sufficiently labile to non-catalytically disassociate from the substrate in a protic or dipolar, aprotic solvent, maintaining the ester substrate in contact with the protic or dipolar, aprotic solvent or mixtures thereof for a time sufficient to form the corresponding α-arylakanoic acid or ester, orthoester or amide thereof, and optionally concomitantly or sequentially hydrolyzing any ester, orthoester or amide formed to the corresponding α-arylalkanoic acid.
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- Derivatives of antiphlogistically effective carboxylic acids, their preparation and medicinal use
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Compounds of Formula I STR1 wherein R1 is the residue of an antiphlogistically effective carboxylic acid of the formula R1 COOH, n is an integer 1, 2, or 3, and X is oxygen, sulfur, or optionally alkylated nitrogen have valuable antiinflammatory activity.
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