- The Synthesis of Chiral α-Aryl α-Hydroxy Carboxylic Acids via RuPHOX-Ru Catalyzed Asymmetric Hydrogenation
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A ruthenocenyl phosphino-oxazoline-ruthenium complex (RuPHOX?Ru) catalyzed asymmetric hydrogenation of α-aryl keto acids has been successfully developed, affording the corresponding chiral α-aryl α-hydroxy carboxylic acids in high yields and with up to 97% ee. The reaction could be performed on a gram scale with a relatively low catalyst loading (up to 5000 S/C) and the resulting products can be transformed to several chiral building blocks, biologically active compounds and chiral drugs. (Figure presented.).
- Guo, Huan,Li, Jing,Liu, Delong,Zhang, Wanbin
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p. 3665 - 3673
(2017/09/11)
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- Penipyridones A-F, Pyridone Alkaloids from Penicillium funiculosum
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Six new pyridone alkaloids, named penipyridones A-F (1-6), were isolated from the fermentation broth of an Antarctic moss-derived fungus, Penicillium funiculosum GWT2-24. Their structures were elucidated from extensive NMR and MS data. Although they possess the same major chromophore and some of them presented almost mirror ECD spectra, their absolute configurations were found to be uniformly S, as evidenced by X-ray single-crystal diffraction analysis, stereocontrolled total synthesis, and chemical conversions. TDDFT-ECD calculations of compounds 3 and 6 revealed that subtle conformational changes are responsible for the significantly different ECD curves. None of the compounds were cytotoxic (IC50 > 50 μM), while compounds 1, 2, 5, and 7 elicited lipid-lowering activity in HepG2 hepatocytes.
- Zhou, Haibo,Li, Liyuan,Wu, Chongming,Kurtán, Tibor,Mándi, Attila,Liu, Yankai,Gu, Qianqun,Zhu, Tianjiao,Guo, Peng,Li, Dehai
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p. 1783 - 1790
(2016/08/02)
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- Increased catalyst productivity in α-hydroxy acids resolution by esterase mutation and substrate modification
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Optically pure α-hydroxy acids and their derivatives are versatile chiral building blocks in the pharmaceutical industry. In this study, the potential of a recombinant Pseudomonas putida esterase (rPPE01) for the enzymatic resolution of α-acetoxy acids was significantly improved by combinatorial engineering of both the biocatalyst and substrate. Semirational design based on homologous modeling and molecular docking provided a single-point variant, W187H, whose kcat/KM for sodium 2-acetoxy-2-(2′-chlorophenyl)acetate (Ac-CPA-Na) was increased 100-fold, from 0.0611 to 6.20 mM-1 s-1, while retaining its excellent enantioselectivity and broad substrate spectrum. Biocatalyst deactivation under the operating conditions was decreased by using the potassium salt of Ac-CPA instead of Ac-CPA-Na. With 0.5 g L-1 of lyophilized cells containing rPPE01-W187H, 500 mM (R,S)-Ac-CPA-K was selectively deacylated with 49.9% conversion within 15 h, giving satisfactory enantiomeric excesses (ee) for both the S product (>99% ee) and the remaining R substrate (98.7% ee). Consequently, the amount of (S)-2-hydroxy-2-(2′-chlorophenyl)acetate prepared per unit weight of lyophilized cells was improved by a factor of 18.9 compared with the original productivity of the wild-type esterase. Further enzymatic resolution of other important hydroxy acids at the 100 mL scale demonstrated that the rPPE01-W187H-based bioprocess is versatile and practical for the large-scale preparation of chiral α-hydroxy acids.
- Ma, Bao-Di,Kong, Xu-Dong,Yu, Hui-Lei,Zhang, Zhi-Jun,Dou, Shuai,Xu, Yan-Peng,Ni, Yan,Xu, Jian-He
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p. 1026 - 1031
(2014/04/03)
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- Stereochemically probing the photo-favorskii rearrangement: A mechanistic investigation
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Using model (R)-2-acetyl-2-phenyl acetate esters of (S)- or (R)-α-substituted-p-hydroxybutyrophenones (S,R)-12a and (R,R)-12b, we have shown that a highly efficient photo-Favorskii rearrangement proceeds through a series of intermediates to form racemic rearrangement products. The stereogenic methine on the photoproduct, rac-2-(p-hydroxyphenyl)propanoic acid (rac-9), is formed by closure of a phenoxy-allyloxy intermediate 17 collapsing to a cyclopropanone, the Favorskii intermediate 18. These results quantify the intermediacy of a racemized triplet biradical 316 on the major rearrangement pathway elusively to the intermediate 18. Thus, intersystem crossing from the triplet biradical surface to the ground state generates a planar zwitterion prior to formation of a Favorskii cyclopropanone that retains no memory of its stereochemical origin. These results parallel the mechanism of Dewar and Bordwell for the ground state formation of cyclopropanone 3 that proceeds through an oxyallyl zwitterionic intermediate. The results are not consistent with the stereospecific SN2 ground state Favorskii mechanism observed by Stork, House, and Bernetti. Interconversion of the diastereomeric starting esters of (S,R)-12a and (R,R)-12b during photolysis did not occur, thus ruling out leaving group return prior to rearrangement.
- Givens, Richard S.,Rubina, Marina,Stensrud, Kenneth F.
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p. 1709 - 1717
(2013/03/28)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 51
(2010/12/31)
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- Highly enantioselective hydrolysis of phenyl-1,2-ethanediol cyclic carbonates by newly isolated Bacillus sp. ECU0015
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A bacterial strain (No. ECU0015), which catalyzes the hydrolysis of phenyl-1,2-ethanediol cyclic carbonates (4-phenyl-1,3-dioxolan-2-one, 1) to (S)-1-phenyl-1,2-ethanediol (2) with high enantioselectivity, was newly isolated from soil samples utilizing the cyclic carbonate as sole carbon and energy source. The bacterium was later identified as Bacillus species by its 16S rDNA sequence and phylogenetic analysis. The optimal reaction temperature and pH for the asymmetric hydrolysis of 1 using whole cells were 35 °C and pH 7.3, respectively. Partial bio-oxidation of the produced (R)-diol was observed, resulting in an increase in the eep (enantiomeric excess of product) of the main product (S)-diol. Under the improved reaction condition, the target product (S)-diol was prepared in gram scale, affording an excellent ee p (>99%) with a moderate yield (27.8%) as compared to the maximum theoretical yield of 50% for kinetic resolution. This strain of Bacillus sp. also displayed fairly good activity and enantioselectivity towards some other compounds tested, such as 2-acetoxy-2-phenylacetic acid (3) and its derivatives.
- Chang, Lei,Ouyang, Li-Ming,Xu, Yi,Pan, Jiang,Xu, Jian-He
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experimental part
p. 95 - 100
(2011/01/03)
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- Development of new HPLC chiral stationary phases based on native and derivatized cyclofructans
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An unusual class of chiral selectors, cyclofructans, is introduced for the first time as bonded chiral stationary phases. Compared to native cyclofructans (CFs), which have rather limited capabilities as chiral selectors, aliphatic-and aromatic-functionalized CF6s possess unique and very different enantiomeric selectivities. Indeed, they are shown to separate a very broad range of racemic compounds. In particular, aliphatic-derivatized CF6s with a low substitution degree baseline separate all tested chiral primary amines. It appears that partial derivatization on the CF6 molecule disrupts the molecular internal hydrogen bonding, thereby making the core of the molecule more accessible. In contrast, highly aromaticfunctionalized CF6 stationary phases lose most of the enantioselective capabilities toward primary amines, however they gain broad selectivity for most other types of analytes. This class of stationary phases also demonstrates high "loadability" and therefore has great potential for preparative separations. The variations in enantiomeric selectivity often can be correlated with distinct structural features of the selector. The separations occur predominantly in the presence of organic solvents.
- Sun, Ping,Wang, Chunlei,Breitbach, Zachary S.,Zhang, Ying,Armstrong, Daniel W.
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experimental part
p. 10215 - 10226
(2010/05/01)
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- Lipase activity of Lecitase Ultra: characterization and applications in enantioselective reactions
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The general properties of Lecitase Ultra, a phospholipase manufactured and marketed by Novozymes, Denmark, have been studied after purification by ultrafiltration. The enzyme has a molecular mass of 35 KD, pH-optimum of 8.5, and appears to possess a single active site which exhibits both the lipase and phospholipase activities that increase in the presence of Ca2+ and Mg2+ ions. The enzyme is inhibited by heavy metal ions and surfactants, and does not accept p-nitrophenyl acetate and glycerol triacetate. Substrates, such as glycerol tributyrate and p-nitrophenyl palmitate, esters of N-acetyl-α-amino acids and α-hydroxy acids are readily accepted. Amino acids with aliphatic residues, such as alanine, isoleucine, and methionine, are hydrolyzed with high enantioselectivity for the l-enantiomer (E >100), but amino acids with aromatic residues such as phenylalanine and phenylglycine, and esters of α-hydroxy acids are hydrolyzed with low enantioselectivity (E = 1-5). Immobilization of the enzyme in a gelatin matrix (gelozyme) leads to a marginal improvement in the enantioselectivity for these substrates. However, a dramatic improvement in enantioselectivity is observed for ethyl 2-hydroxy-4-oxo-4-phenylbutyrate (E value increases from 4.5 to 19.5 with S-selectivity). Similarly, glycidate esters, such as ethyl trans-(±)-3-phenyl glycidate and methyl trans-(±)-3-(4-methoxyphenyl) glycidate, are selectively hydrolyzed with a remarkable selectivity towards the (2S,3R)-enantiomer providing unreacted (2R,3S)-glycidate esters (ee >99%, conversion 52-55%) by the immobilized enzyme.
- Mishra, Mithilesh Kumar,Kumaraguru, Thenkrishnan,Sheelu, Gurrala,Fadnavis, Nitin W.
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experimental part
p. 2854 - 2860
(2010/04/05)
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- Investigations into the parallel kinetic resolution of acetyl mandelic acid
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The resolution of a series of active esters (derived from acetyl mandelic acid) using an equimolar combination of quasi-enantiomeric oxazolidin-2-ones is discussed. The levels of diastereoselectivity and the facial selectivity were found to be dependent on the structural nature of the pro-leaving group.
- Chavda, Sameer,Coulbeck, Elliot,Eames, Jason
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scheme or table
p. 7398 - 7402
(2009/05/27)
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- 2-Hydroxy-1,2,2-triphenylethanone as an efficient photolabile protecting group for carboxylic acids
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The synthesis is reported of 2-hydroxy-1,2,2-triphenylethanone esters of carboxylic acids by the reaction between 2-chloro-1,2,2-triphenylethanone and a carboxylic acid in the presence of silver carbonate and silver tetrafluoroborate. Photolysis of the esters occurs rapidly on irradiation with a medium-pressure mercury lamp through quartz or Pyrex to return the carboxylic acid. The side product of the photolysis is benzo[b]phenanthro[9,10-d]furan, formed through a tandem process involving initial generation of 2,3-diphenylbenzofuran, photochemical cyclisation and re-aromatisation by aerial oxidation.
- Ashraf, M. Arfan,Russell, Alexander G.,Wharton, Christopher W.,Snaith, John S.
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p. 586 - 593
(2007/10/03)
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- Nitrile hydratase activity of a recombinant nitrilase
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Appreciable amounts of amide are formed in the course of nitrile hydrolysis in the presence of recombinant nitrilase from Pseudomonas fluorescens EBC 191, depending on the α-substituent and the reaction conditions. The ratio of the nitrilase and nitrile hydratase activities of the enzyme is profoundly influenced by the electronic and steric properties of the reactant. In general, amide formation increased when the α-substituent was electron-deficient; 2-chloro-2-phenylacetonitrile, for example, afforded 89% amide. We found, moreover, that (R)-mandelo-nitrile was hydrolysed with 11% of amide formation whereas 55% amide was formed from the (S)-enantiomer; a similar effect was found for the O-acetyl derivatives. A mechanism that accomodates our results is proposed.
- Fernandes, Bruno C. M.,Mateo, Cesar,Kiziak, Christoph,Chmura, Andrzej,Wacker, Jan,Van Rantwijk, Fred,Stolz, Andreas,Sheldon, Roger A.
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p. 2597 - 2603
(2007/10/03)
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- Nonracemic α-allenyl carbinols from asymmetric propargylation with the 10-trimethylsilyl-9-borabicyclo[3.3.2]decanes
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(Chemical Equation Presented) The asymmetric propargylboration of aldehydes at -78°C in 98% ee). The reagents 1 are easily prepared in both enantiomeric forms with a simple Grignard procedure and air-stable borinate complexes 2. The ozonolysis of 6 proceeds smoothly through an acylsilane intermediate to give a TMS ester, which is hydrolyzed to the α-hydroxy acid quantitatively with water.
- Hernandez, Eliud,Soderquist, John A.
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p. 5397 - 5400
(2007/10/03)
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- New chiral ligands derived from mandelic acid: Synthesis and application in the asymmetric phenyl transfer reaction to an aromatic aldehyde
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Starting from inexpensive enantiopure (R)- and (S)-mandelic acid, a range of α-hydroxy-2-oxazolines has been prepared. The synthesis involves the condensation of the acid chloride with a vicinal amino alcohol, followed by intramolecular cyclization to form the oxazoline ring. The resulting compounds have been used as ligands in the asymmetric phenyl transfer reaction to 4-chlorobenzaldehyde, employing a mixture of triphenylborane and diethylzinc as the phenyl source. Good yields (up to 76%) and moderate enantioselectivities (up to 35%) have been achieved.
- Bolm, Carsten,Zani, Lorenzo,Rudolph, Jens,Schiffers, Ingo
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p. 2173 - 2180
(2007/10/03)
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- Resolution of Racemic Carboxylic and Sulfonic Acids via D-Xylose Derived New Cyclic Carbamate Reagents (Oxazolidin-2-ones)
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Two new chiral oxazolidin-2-ones have been easily prepared from D-xylose and studied as chiral derivatizing agents (CDA's) for the resolution of racemic carboxylic and sulfonic acids.The resultant diastereomers are readily separated by chromatographic methods and easily hydrolyzed to isolate the resolved materials in high optical purities and to return the CDA's for reuse.
- Koell, Peter,Luetzen, Arne
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- Total synthesis of avermectins Part 2: Enantioselective synthesis of the C10-C25 northern fragment and final steps for the construction of the 22,23-dihydroavermectin B1b aglycone
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The total synthesis of the aglycone of 22,23-dihydroavermectin B1b involves a retrosynthetic two building-blocks approach.A Stille Pd(0) catalyzed cross-coupling reaction is carried out between a northern C10-C25 E-vinylstannane and a southern C1-C9 vinyl iodide.The final steps include successive removal of the carboxyl β-(trimethylsilyl)ethyl protecting group of the intermediate secoester, macrolactonization under Yonemitsu's conditions and removal of the 5-O-TBS protecting group.These last steps have been carried out with the aid of a relay study from commercial Ivermectin; a macrolactone opening reaction of the aglycone in the presence of Ti(OiPr)4 has been developed where the crucial Δ3,4 double bond as well as the configuration at C-2 were totally preserved. - Key words: avermectin / spiroketal / diastereoselection / aldolization / sulfone / homoaldolization / Hoppe reaction / hydrostannylation / palladium Stille coupling / titanium isopropoxide / transesterification / macrolactone / total synthesis
- Ferezou, Jean-Pierre,Julia, Marc,Li, Yun,Liu Lu Wei,Pancrazi, Ange
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p. 428 - 452
(2007/10/02)
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- Design, synthesis and evaluation of D,D-peptidase and beta-lactamase inhibitors: Azapeptides, oxapeptides and related heterocycles
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Reactive molecules susceptible to form stable acyl enzyme intermediates with D,D-peptidases and β-lactamases were designed as potential irreversible inhibitors of Penicillin Sensitive Enzymes (PSEs). The structures examined were a series of azapeptides and oxapeptides, both analogs of the D-Ala-D-Ala substrate, and some heterocycles, such as imidazolidinones and oxazolidinones, both analogs of the β-lactam antibiotics. The various strategies investigated for their synthesis are described and discussed. Some biological results are reported.
- Marchand-Brynaert,Mougenot,Combret,Belotti,Guillot,Ghosez
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p. 455 - 469
(2007/10/02)
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- Preparation of Optically Active 2-Furylcarbinols by Kinetic Resolution Using the Sharpless Reagent and Their Application in Organic Synthesis
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The kinetic resolution of 2-furylcarbinols 1 by the Sharpless reagent proceeds highly efficiently, thus providing a general method for the synthesis of homochiral 1.The reaction can be applied to compounds 1 possessing various types of substituents, although compound 1d, which has a sterically demanding tertiary alkyl group, is a poor substrate.The kinetic resolution of 3-furylcarbinol 3 also proceeds efficiently.Various homochiral 1 thus obtained have been successfully converted into α-alkoxy acids 4 by oxidative cleavage of the furan ring after protection of the hydroxyl group.The compound (R)-1b has been converted into the naturally occuring γ-lactone 5.
- Kusakabe, Masato,Kitano, Yasunori,Kobayashi, Yuichi,Sato, Fumie
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p. 2085 - 2091
(2007/10/02)
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- STEREOCHIMIE DE LA REDUCTION ELECTROCHIMIQUE D'α-CETOAMIDES OPTIQUEMENT ACTIVES I. ELECTROREDUCTION DE LA S(-) N-(α-METHYLBENZYL)BENZOYLFORMAMIDE
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Electrochemical reduction of the title compound has been investigated in hydro-alcoholic medium, at a mercury cathode.Polarographic study shows adsorption of the substrate in very acidic medium (pH 5.5.Controlled potential electrolyses give the corresponding mandelamide in a quasi-quantitative yield; titration of the mixture of the two epimers is achieved by proton NMR at 300 MHz.In very acidic medium, preferential formation of the RS mandelamide is observed (higher optical yield:12.5percent).On the contrary, SS mandelamide is generally the main stereoisomerin acetic or ammoniacal buffer; however, when electroreductions are carried out at very cathodic potentials, again preferential formation of the RS epimer is observed.Stereochemistry of the reduction is explained taking into account conformations of the starting molecule and protonation of the carbanion resulting from a 2 electron reduction.
- Boulmedais, Ali,Jubault, Michel,Tallec, Andre
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p. 610 - 617
(2007/10/02)
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- The Preparation and Absolute Configuration of the Optically Active Forms of the Diastereoisomers of 2-(1-Phenylethyl)amino-1-phenylethanol and Their Use as Chiral Auxiliaries in the Asymmetric Reduction of Acetophenone with Modified Lithium Aluminium Hydrides
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(1S,2S)-(-)-2-(1-Phenylethyl)amino-1-phenylethanol (4b) (α-form) and the (1S,2R)-(+)-diastereoisomer (4f) (β-form) were prepared by lithium aluminium hydride reduction of the optically active amides derived from the appropriate mandelic acids and 1-phenylethylamines.The preparative methods give the absolute stereochemistry.The aminoethanols (4) were used along with the lower alcohols to prepare chirally modified lithium aluminium hydrides which were in turn used to reduce acetophenone.The optical yields varied, giving at best, under low temperature conditions and use of a 25 percent optical yield.
- Garry, Scott W.,Neilson, Douglas G.
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p. 601 - 606
(2007/10/02)
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