- Semirational Design of Fluoroacetate Dehalogenase RPA1163 for Kinetic Resolution of α-Fluorocarboxylic Acids on a Gram Scale
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Here the synthetic utility of fluoroacetate dehalogenase RPA1163 is explored for the production of enantiomerically pure (R)-α-fluorocarboxylic acids and (R)-α-hydroxylcarboxylic acids via kinetic resolution of racemic α-fluorocarboxylic acids. While wild-type (WT) RPA1163 shows high thermostability and fairly wide substrate scope, many interesting yet poorly or moderately accepted substrates exist. In order to solve this problem and to develop upscaled production, in silico calculations and semirational mutagenesis were employed. Residue W185 was engineered to alanine, serine, threonine, or asparagine. The two best mutants, W185N and W185T, showed significantly improved performance in the reactions of these substrates, while in silico calculations shed light on the origin of these improvements. Finally, 10 α-fluorocarboxylic acids and 10 α-hydroxycarboxylic acids were prepared on a gram scale via kinetic resolution enabled by WT, W185T, or W185N. This work expands the biocatalytic toolbox and allows a deep insight into the fluoroacetate dehalogenase catalyzed C-F cleavage mechanism.
- Chen, Bo,Li, Min,Li, Yanwei,Ma, Ming,Tian, Shaixiao,Tong, Wei,Wang, Jian-Bo,Xu, Guangyu,Yue, Yue,Zhang, Hongxia
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p. 3143 - 3151
(2020/03/23)
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- Kinetic Resolution of Allylic Alcohol with Chiral BINOL-Based Alkoxides: A Combination of Experimental and Theoretical Studies
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The development and characterization of enantioselective catalytic kinetic resolution of allylic alcohols through asymmetric isomerization with chiral BINOL derivatives-based alkoxides as bifunctional Br?nsted base catalysts were described in the study. A number of chiral BINOL derivatives-based alkoxides were synthesized, and their structure-enantioselectivity correlation study in asymmetric isomerization identified a promising chiral Br?nsted base catalyst, which afforded various chiral secondary allylic alcohols (ee up to 99%, S factor up to >200). In the mechanistic study, alkoxide species were identified as active species and the phenol group of BINOL largely affected the high reactivity and enantioselectivity via hydrogen bonding between the chiral Br?nsted base catalyst and substrates. The strategy is the first successful synthesis strategy of various chiral secondary allylic alcohols through enantioselective transition-metal-free base-catalyzed isomerization. The applicability of the strategy had been demonstrated by the synthesis of the bioactive natural product (+)-veraguensin.
- Liu, Yidong,Liu, Song,Li, Dongmei,Zhang, Nan,Peng, Lei,Ao, Jun,Song, Choong Eui,Lan, Yu,Yan, Hailong
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supporting information
p. 1150 - 1159
(2019/01/11)
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- Highly Efficient Deracemization of Racemic 2-Hydroxy Acids in a Three-Enzyme Co-Expression System Using a Novel Ketoacid Reductase
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Enantiopure 2-hydroxy acids (2-HAs) are important intermediates for the synthesis of pharmaceuticals and fine chemicals. Deracemization of racemic 2-HAs into the corresponding single enantiomers represents an economical and highly efficient approach for synthesizing chiral 2-HAs in industry. In this work, a novel ketoacid reductase from Leuconostoc lactis (LlKAR) with higher activity and substrate tolerance towards aromatic α-ketoacids was discovered by genome mining, and then its enzymatic properties were characterized. Accordingly, an engineered Escherichia coli (HADH-LlKAR-GDH) co-expressing 2-hydroxyacid dehydrogenase, LlKAR, and glucose dehydrogenase was constructed for efficient deracemization of racemic 2-HAs. Most of the racemic 2-HAs were deracemized to their (R)-isomers at high yields and enantiomeric purity. In the case of racemic 2-chloromandelic acid, as much as 300 mM of substrate was completely transformed into the optically pure (R)-2-chloromandelic acid (> 99% enantiomeric excess) with a high productivity of 83.8 g L?1 day?1 without addition of exogenous cofactor, which make this novel whole-cell biocatalyst more promising and competitive in practical application.
- Xue, Ya-Ping,Wang, Chuang,Wang, Di-Chen,Liu, Zhi-Qiang,Zheng, Yu-Guo
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- 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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- Solid phase behavior in the chiral systems of various 2-hydroxy-2-phenylacetic acid (mandelic acid) derivatives
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The solid phase behavior of a series of monosubstituted F-, Cl-, Br-, I-, and CH3- and two 2,4-halogen-disubstituted 2-hydroxy-2-phenylacetic acid (mandelic acid) derivatives was investigated. The study includes detailed information about melting temperature, melting enthalpy, X-ray diffraction data, as well as selected binary phase diagrams of the respective chiral systems. Aside from the known metastable conglomerate 2-chloromandelic acid, evidence for two more metastable conglomerates was found.
- Von Langermann, Jan,Temmel, Erik,Seidel-Morgenstern, Andreas,Lorenz, Heike
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p. 721 - 728
(2015/03/30)
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- Kinetic resolution of mandelate esters via stereoselective acylation catalyzed by lipase PS-30
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By using lipase PS-30 as catalyst, the kinetic resolution of a series of racemic mandelate esters has been achieved via stereoselective acylation. The value of kinetic enantiomeric ratio (E) reached up to 197.5. Substituent effect is briefly discussed.
- Chen, Peiran,Yang, Wenhong
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supporting information
p. 2290 - 2294
(2014/04/17)
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- Relationships between the racemic structures of substituted mandelic acids containing 8- and 10-membered hydrogen bonded dimer rings
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The structures of 27 monosubstituted mandelic acids, including several of their polymorphs, plus unsubstituted mandelic acid itself (two polymorphs) are investigated for structural similarity. The results, presented pictorially as a structural relationship plot, show that rather more structures are built up from the carboxyl-chain hydroxyl hydrogen bonded dimer than from the conventional carboxylic acid dimer. The results show how all the structures are related and, based on the two types of dimer, the degree of similarity that they possess. Some structures with Z′ > 1 contain both sorts of dimers and there are many examples of isostructural sets within the structures so far determined. We also present an example where analysing similarity in related families of structures highlights a structure that should be present and which has indeed then proceeded to be synthesised and determined.
- Coles,Ellis,Leung,Sarson,Threlfall,Tizzard
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p. 10816 - 10823
(2015/02/19)
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- One-pot, single-step deracemization of 2-hydroxyacids by tandem biocatalytic oxidation and reduction
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A facile and efficient one-pot, single-step method for deracemizing a broad range of 2-hydroxyacids to (R)-2-hydroxyacids was established by combination of resting cells of an (S)-hydroxyacid dehydrogenase-producing microorganism and an (R)-ketoacid reductase-producing microorganism.
- Xue, Ya-Ping,Zheng, Yu-Guo,Zhang, Ya-Qin,Sun, Jing-Lei,Liu, Zhi-Qiang,Shen, Yin-Chu
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supporting information
p. 10706 - 10708
(2013/11/06)
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- Robust enzymatic resolution of 3-fluoromandelic acid with lipase PS supported on celite
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The resolution of different mandelic acids using the lipase PS Amano SD enzyme is described. By supporting the lyophilized enzyme over Celite, both the activity and the stability of lipase PS in organic media were significantly improved, enabling the robust resolution scale-up of 3-fluoromandelic acid. The methodology was extended to produce a range of optically pure (R)-mandelic acids, avoiding tedious extractions or chromatography.
- Mendiola, Javier,Garcia-Cerrada, Susana,De Frutos, Oscar,De La Puente, Maria Luz
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experimental part
p. 1312 - 1316
(2012/10/18)
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- Highly enantioselective hydrogenation of aryl vinyl ketones to allylic alcohols catalyzed by the tol-binap/Dmapen ruthenium(II) complex
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(Chemical Equation Presented) Binap catalyst doesn't dmapen expectations: In basified 2-propanol, [RuCl2{(S)-tol-binap}{(R)-dmapen}] (1, see picture, Ar=4-CH3C6H4) catalyzes the highly enantioselective hydrogenation of a series of aryl vinyl ketones and affords the allylic alcohols in high yields with up to 98% ee. Formation of the saturated ketones and alcohols is suppressed with triphenylphosphine when necessary.
- Arai, Noriyoshi,Azuma, Keita,Nii, Noriyuki,Ohkuma, Takeshi
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supporting information; experimental part
p. 7457 - 7460
(2009/03/12)
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- Method for producing optically active cyanohydrins and their corresponding acids
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The invention relates to a method for producing optically active cyanohydrins and the corresponding α-hydroxy-carboxylic acids, starting from an aldehyde, hydrogen cyanide and an optically active vanadyl-salen catalyst, whereby the reaction mixture is reacted at a temperature of between 0 and 60° C. Between 0.8 and 10 equivalents of hydrogen cyanide and between 0.0001 and 0.05 equivalents of vanadyl-salen catalyst in relation to the aldehyde, (concentration of between 0.5 and 4 mol/litre solvent), are preferably used. After said reaction the optically active cyanohydrin or after an acid hydrolysis the corresponding optically active α-hydroxycarboxylic acid can be isolated with a surplus of enantiomers. The vanadium catalyst used in the invention contains a salen ligand, whereby the ratio salen ligand: vanadium (IV) in the catalyst ranges between 1.4:1 and 10:1.
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- Phenylsulfonyl-1,3-dihydro-2h-indole-2-one derivatives, their preparation and their therapeutic use
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The invention relates to compounds of formula: and also to the salts thereof with mineral or organic acids, and the solvates and/or hydrates thereof, with affinity for and selectivity towards the arginine-vasopressin V1b receptors and/or for the ocytocin receptors and, furthermore, for certain compounds, affinity for the V1a receptors. The invention also relates to the process for preparing them, to the intermediate compounds of formula (IV) that are useful for preparing them, to pharmaceutical compositions containing them and to their use for preparing medicinal products.
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Page/Page column 20
(2010/02/08)
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- Process for preparing optically active cyanohydrins and secondary products
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The present invention relates to a process for preparing optically active cyanohydrins of the formula (II), by reacting an aldehyde of the formula (I) with HCN in a water-immiscible organic solvent in the presence of water, in the absence or presence of a buffer, in the presence of a (R)-hydroxynitrile lyase, where X, Y and Z in formula (II) have the same meaning as in formula (I), independently of each other are identical or different and are H, F, Cl, Br, I, OH, O(C1-C4-alkyl), OCOCH3, NHCOCH3, NO2 or C1-C4-alkyl.
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- Selective ET(A) antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives
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The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ETA receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ETA antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC50 59 nM, rat aortic ET(A)). Optimization of 13a led to the identification of 27b, which exhibited an IC50 of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 μmol/kg) and was duly proposed and accepted as a development candidate.
- Astles, Peter C.,Brown, Thomas J.,Halley, Frank,Handscombe, Caroline M.,Harris, Neil V.,Majid, Tahir N.,McCarthy, Clive,McLay, Lain M.,Morley, Andrew,Porter, Barry,Roach, Alan G.,Sargent, Carol,Smith, Christopher,Walsh, Roger J. A.
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p. 900 - 910
(2007/10/03)
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- Structures of Racemic Monofluoro-Substituted Mandelic Acids, Their Relation to the Thermochemical Properties and an Analysis of Short Intermolecular Fluorine-Carbon Contacts
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The structures of the three monofluoro-substituted mandelic acids (C8H7FO3, Mr=170.14) have been determined from low-temperature X-ray diffraction data . o-Fluoromandelic acid, monoclinic, P21/c, a=8.4238 (12), b=5.4766 (7), c=15.959 (2) Angstroem, β=95.962 (11)o, V=732.3 (3) Angstroem3, Z=4, Dx=1.543 g cm-3, μ=11.25 cm-1, F(000)=352, R=0.040 for 1357 contributing reflections, m.p. 388.3 (5) K. m-Fluoromandelic acid (metastable modification), monoclinic, P21/a, a=10.8657 (14), b=9.2663 (10), c=15.722 (2) Angstroem, β=107.474 (10)o, V=1509.9 (6) Angstroem3, Z=8, Dx=1.497 g cm-3, μ=10.92 cm-1, F(000)=704, R=0.048 for 2977 contributing reflections, m.p. 368.4 (5) K. p-Fluoromandelic acid, orthorhombic, Pbca, a=9.4685 (9), b=16.497 (2), c=9.7677 (8) Angstroem, V=1525.7 (5) Angstroem3, Z=8, Dx=1.481 g cm-3, μ=10.80 cm-1, F(000)=704, R=0.042 for 1489 contributing reflections, m.p. 408.9 (5) K.The results obtained from the structure determination are related to their physico-chemical properties examined by differential scanning calorimetry (DSC).The DSC measurements showed that m-fluoromandelic acid is prepared as a metastable modification.The distortions of the angles of the benzene rings observed in the three acids are identical, within experimental error, to those predicted from the sum of the substituent effects.Hydrogen bonds are important for the crystal packing in all these structures, and in addition very short distances are observed in the ortho- and para-substituted acids between the F atom and the C atom of the carboxylic acid group.Semi-empirical calculations indicated that these short distances correspond to attractive electrostatic interactions.The carbon-fluorine interactions were also elucidated by a search in the Cambridge Structural Database. m-Fluoromandelic acid has the lowest melting enthalpy and entropy.This is consistent with the lack of C...F interactions and the presence of two molecules per asymmetric unit in this compound.The ortho and para acids which have similar intermolecular interactions have similar melting enthalpies and entropies, which are higher than those observed in m-fluoromandelic acid.
- Larsen, Sine,Marthi, Katalin
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p. 373 - 381
(2007/10/02)
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- 7-α-Amino-substituted acylamino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acids
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Certain 7-acylamido-3-(1-carboxy-loweralkyl-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acids and their salts and easily hydrolyzed esters of the 4-carboxyl group were synthesized and found to be potent antibacterial agents which exhibited good aqueous solubility. In a preferred embodiment the 7-substituent was 2'-aminomethylphenylacetamido.
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- 7-(D-α-Hydroxy-2-arylacetamido)-3-(2-carboxyalkyl-2,3-dihydro-s-triazolo-[4,3-b]pyridazin-3-on-6-ylthiomethyl)-3-cephem-4-carboxylic acids and derivatives
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7-(D-α-Hydroxy-2-arylacetamido)-3-(2-carboxyalkyl-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on-6-ylthiomethyl)-3-cephem-4-carboxylic acids and derivatives containing blocking groups on the α-hydroxy group and their nontoxic, pharmaceutically acceptable salts are valuable as antibacterial agents and are particularly valuable as therapeutic agents in poultry and in animals, including man, in the treatment of infectious diseases caused by many Gram-positive and Gram-negative bacteria. A preferred compound is 7-(D-mandelamido)-3-(2-carboxyalkyl-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on-6-ylthiomethyl)-3-cephem-4-carboxylic acid.
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- 7-(D-α-Hydroxy-2-arylacetamido)-3-(tetrazolo-[4,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acids
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7-(D-α-Hydroxy-2-arylacetamido)-3-(tetrazolo-[4,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acids and their nontoxic, pharmaceutically acceptable salts are valuable as antibacterial agents and are particularly valuable as therapeutic agents in poultry and animals, including man, in the treatment of infectious diseases caused by many Gram-positive and Gram-negative bacteria.
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