- The effect of SDE on the separation of diastereomeric salts: A case study for the resolution of mandelic acid derivatives with Pregabalin
-
A resolution method has been elaborated for mandelic acid and 2-chloromandelic acid applying the (R)-(-)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin) as the resolving agent. The formation of the corresponding diastereomers was kinetically controlled. This observation was rationalized by the behavior of enantiomeric mixtures of mandelic acid, 2-chloromandelic acid, and 3-(aminomethyl)-5-methylhexanoic acid. It was found that the eutectic composition of Pregabalin influenced the diastereomeric excess of the diastereomers formed under kinetic control.
- Szeleczky, Zsolt,Bagi, Péter,Pálovics, Emese,Fogassy, Elemér
-
-
Read Online
- One-pot, single-step deracemization of 2-hydroxyacids by tandem biocatalytic oxidation and reduction
-
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
-
-
Read Online
- Enantioseparation of chiral mandelic acid derivatives by supercritical fluid chromatography
-
Mandelic acid and its derivatives are important chiral analogs which are widely used in the pharmaceutical synthetic industry. The present study investigated the enantiomeric separation of six mandelic acids (mandelic acid, 2-chloromandelic acid, 3-chloromandelic acid, 4-chloromandelic acid, 4-bromomandelic acid, 4-methoxymandelic acid) on the Chiralpak AD-3 column by supercritical fluid chromatography. The influences of volume fraction of trifluoroacetic acid, type and percentage of modifier, column temperature, and backpressure on the separation efficiency were investigated. And the enantiomer elution order was determined. The results show that, for a given modifier, the retention factor, the separation factor, and the separation resolution decreased gradually with increasing the volume ratio of the modifier. At the same volume ratio of modifier, the retention factor of the mandelic acid and its derivatives increased in the order of methanol, ethanol, and isopropanol, except 3-chloromandelic acid. The separation factor and the separation resolution decreased with the increase of column temperature (below the temperature limit). The backpressure affected the enantioseparation process: As the backpressure increased, a corresponding decrease in retention factor was observed. Under the same chiral column conditions, the SFC method exhibited faster and more efficient separation with better enantioselectivity than the HPLC method.
- Ding, Jiawei,Zhang, Ming,Dai, Huixue,Lin, Chunmian
-
-
Read Online
- The phase behavior and crystallization of 2-chloromandelic acid: The crystal structure of the pure enantiomer and the behavior of its metastable conglomerate
-
Crystallization of racemic 2-chloromandelic acid yields a metastable conglomerate in addition to a more stable racemic compound. The crystal structure of the pure enantiomer is reported and the relative stability of the racemic compound and conglomerate was determined at both room temperature and the melting point. Crystallizations from melt and solution are shown to offer potential crystallization pathways to the conglomerate, provided crystallization of the racemic compound can be avoided.
- Lorenz, Heike,Von Langermann, Jan,Sadiq, Ghazla,Seaon, Colin C.,Davey, Roger J.,Seidel-Morgenstern, Andreas
-
-
Read Online
- Efficient production of (R)-o-chloromandelic acid by recombinant escherichia coli cells harboring nitrilase from burkholderia cenocepacia J2315
-
A solvent engineering approach and an extended fed-batch reaction mode were introduced to increase the activity and enantioselectivity and alleviate the substrate inhibition of nitrilase BCJ2315 from Burkholderia cenocepacia J2315 toward o-chloromandelonitrile. Among the seven water-miscible organic solvents tested, ethanol (30%, v/v) demonstrated the highest reaction conversion (55.7%) and enantioselectivity (enantiomeric excess, 98.2% ee) compared with those of the control [which did not contain any organic solvent (13% and 89.2%, respectively)] and was thus chosen as the suitable cosolvent. In the extended fed-batch reaction mode, o-chloromandelonitrile (solubilized in ethanol, 5 M) was continuously fed into the reaction mixture containing ethanol as cosolvent (20%, v/v) to ensure an optimal reaction rate by adjusting the feeding rate and simultaneously increasing the enantioselectivity due to the increased concentration of ethanol. Finally, a maximum of 415 mM of product was produced with an enantiomeric excess value of 97.6% ee. The hydrolysis process was easily scaled up to 2 L, demonstrating that the described biocatalytic process was rationally designed and could be applied further on an industrial scale.
- Wang, Hualei,Sun, Huihui,Gao, Wenyuan,Wei, Dongzhi
-
-
Read Online
- β-Cyclodextrin-teba: A new catalyst system for selective synthesis of α-hydroxyacids
-
The presence of β-cyclodextrin (β-CD) and triethylbenzyl ammonium chloride (TEBA) favors the one-pot reaction of aromatic aldehydes, chloroform and sodium hydroxide to give α- hydroxyarylacetic acids in 81% ~ 89% yields.
- Zhou,Yuan,Xie
-
-
Read Online
- Efficient preparation of (R)-2-chloromandelic acid via a recycle process of resolution
-
Efficient preparation of (R)-2-chloromandelic acid (R)-1 based on a recycle process of resolution is described. In the process, the desired (R)-1 was obtained by coordination-mediated resolution with D-O,O′-di-(p-toluoyl)-tartaric acid in the presence of Ca2+. Meanwhile, the undesired (S)-1 could be racemized in the presence of sodium hydroxide and the product was suitable for further resolution. A carbanion mechanism for the racemization of (S)-1 is proposed.
- Hu, Yu,Wu, Chang,Wu, Xue-Ying,Li, Shao-Lei,Sun, Xiao-Xia,Tang, Ze-Biao
-
-
Read Online
- Biocatalytic racemization of aliphatic, arylaliphatic, and aromatic α-hydroxycarboxylic acids
-
Biocatalytic racemization of a range of aliphatic, (aryl)aliphatic, and aromatic α-hydroxycarboxylic acids was accomplished by using whole resting cells of a range of Lactobacillus spp. The mild (physiological) reaction conditions ensured an essentially "clean" isomerization in the absence of side reactions, such as elimination or decomposition. Whereas straight-chain aliphatic 2-hydroxy-carboxylic acids were racemized with excellent rates (up to 85% relative to lactate), steric hindrance was observed for branched-chain analogues. Good rates were observed for aryl-alkyl derivatives, such as 3-phenyllactic acid (up to 59%) and 4-phenyl-2-hydroxybutanoic acid (up to 47%). In addition, also mandelate and its o-chloro analogue were accepted at a fair rate (45%). This biocatalytic racemization represents an important tool for the deracemization of a number of pharmaceutically important building blocks.
- Glueck, Silvia M.,Pirker, Monika,Nestl, Bettina M.,Ueberbacher, Barbara T.,Larissegger-Schnell, Barbara,Csar, Katrin,Hauer, Bernhard,Stuermer, Rainer,Kroutil, Wolfgang,Faber, Kurt
-
-
Read Online
- Design of nitrilases with superior activity and enantioselectivity towards sterically hindered nitrile by protein engineering
-
Abstract The enantioselective hydrolysis of ortho-chloromandelonitrile with nitrilase is one of the most attractive approaches to prepare (R)-ortho-chloromandelic acid. To date, efforts to develop this nitrilase-mediated process were plagued by either insufficient eep (enantiomeric excess of product) or low activity due to the steric hindrance from the ortho-substituted substrate. To improve the nitrilase potential for producing (R)-ortho-chloromandelic acid, an enhancement of both activity and enantioselectivity towards sterically hindered nitriles would be highly desirable. Molecular docking of the (R)-ortho-chloromandelonitrile into the active site of wild-type 2A6 nitrilase (nitA) allowed the identification of proximal nitA active site residues. Several residues (52, 132, 189 and 190) were selected as targets for single and double point mutation to improve nitA activity and enantioselectivity towards ortho-chloromandelonitrile. Targeted mutagenesis yielded several nitA variants with superior activity and enantioselectivity. The best mutant T132A/F189T exhibited a 4.37-fold higher specific activity (7.39 U/mg) towards ortho-chloromandelonitrile than the wild-type nitA. More importantly, the enantioselectivity (E) was improved from 17.34 to >200, resulting in a highly enantiopure product. Molecular docking experiments further support the enhanced activity and enantioselectivity shown experimentally and the structural effects of this amino acid substitution on the active site of nitA are provided. The amino acids at sites 189 and 132 determine the activity and enantioselectivity towards ortho-chloromandelonitrile. With mutant T132A/F189T as a catalyst, a maximum of 450 mM of (R)-ortho-chloromandelic acid was produced with a 90% conversion and >99% eep within 3 h. This is the first time that a high productivity of (R)-ortho-chloromandelic acid of up to 671.76 g L-1d-1 using a nitrilase-mediated approach is reported. The engineered T132A/F189T variant represents a promising and competitive biocatalyst for practical application in synthesizing (R)-ortho-chloromandelic acid.
- Xue, Ya-Ping,Shi, Cheng-Ci,Xu, Zhe,Jiao, Biao,Liu, Zhi-Qiang,Huang, Jian-Feng,Zheng, Yu-Guo,Shen, Yin-Chu
-
-
Read Online
- Improved apparent enantioselectivity of a hydrolase by sequential hydrolysis and racemization
-
Further improvement of the enantioselectivity of hydrolases with moderate enantioselectivity is of important significance to fulfill the requirement in industrial application. Herein, a strategy based on sequential hydrolysis and racemization was adopted, using esterase BioH from Escherichia coli as an example. After coupling with a mandelate racemase, the E value of esterase BioH toward methyl (S)-o-chloromandelate was enhanced from 73 to 162, demonstrating the effectiveness of this strategy.
- Gu, Jiali,Ye, Lidan,Guo, Fei,Lv, Xiaomei,Lu, Wenqiang,Yu, Hongwei
-
-
Read Online
- Enzymatic Hydrocyanation of a Sterically Hindered Aldehyde. Optimization of a Chemoenzymatic Procedure for (R)-2-Chloromandelic Acid
-
The asymmetric synthesis of (R)-o-chloromandelic acid, a key intermediate for the anti-thrombotic agent clopidogrel, via the almond meal catalyzed hydrocyanation of 2-chlorobenzaldehyde and subsequent acidic hydrolysis was developed into an industrially viable procedure. The use of a minimum amount of water consistent with enzyme activity and a slow feed of the reactants were the keys to obtaining (R)-2-chloromandelonitrile in a high (98%) yield and satisfactory (90%) enantiomeric excess. Acidic hydrolysis of the nitrile followed by crystallization from toluene afforded enantiopure (ee > 99%) (R)-2-chloromandelic acid.
- Van Langen, Luuk M.,Van Rantwijk, Fred,Sheldon, Roger A.
-
-
Read Online
- Semirational Design of Fluoroacetate Dehalogenase RPA1163 for Kinetic Resolution of α-Fluorocarboxylic Acids on a Gram Scale
-
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
-
-
Read Online
- Reaction of carboxylic acids with diethyl phosphorocyanidate; a novel synthesis of homologated α-hydroxycarboxylic acids from carboxylic acids
-
Carboxylic acids react with 2 equivalents of diethyl phosphorocyanidate in the presence of triethylamine to give dicyanophosphates in good yields; these dicyanophosphates can be hydrolyzed easily to give homologated α- hydroxycarboxylic acids.
- Mizuno, Masanori,Shioiri, Takayuki
-
-
Read Online
- Resolution of halogenated mandelic acids through enantiospecific co-crystallization with levetiracetam
-
The resolution of halogenated mandelic acids using levetiracetam (LEV) as a resolving agent via forming enantiospecific co-crystal was presented. Five halogenated mandelic acids, 2-chloromandelic acid (2-ClMA), 3-chloromandelic acid (3-ClMA), 4-chloromandelic acid (4-ClMA), 4-bromomandelic acid (4-BrMA), and 4-fluoromandelic acid (4-FMA), were selected as racemic compounds. The effects of the equilibrium time, molar ratio of the resolving agent to racemate, amount of solvent, and crystallization temperature on resolution performance were investigated. Under the optimal conditions, the resolution efficiency reached up to 94% and the enantiomeric excess (%e.e.) of (R)-3-chloromandelic acid was 63%e.e. All five halogenated mandelic acids of interest in this study can be successfully separated by LEV via forming enantiospecific co-crystal, but the resolution performance is significantly different. The results showed that LEV selectively co-crystallized with S enantiomers of 2-ClMA, 3-ClMA, 4-ClMA, and 4-BrMA, while it co-crystallized with R enantiomers of 4-FMA. This indicates that the position and type of substituents of racemic compounds not only affect the co-crystal configuration, but also greatly affect the efficiency of co-crystal resolution.
- Peng, Yangfeng,Wang, Jie
-
-
- Photocatalytic Carbinol Cation/Anion Umpolung: Direct Addition of Aromatic Aldehydes and Ketones to Carbon Dioxide
-
We have developed a new photocatalytic umpolung reaction of carbonyl compounds to generate anionic carbinol synthons. Aromatic aldehydes or ketones reacted with carbon dioxide in the presence of an iridium photocatalyst and 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzimidazole (DMBI) as a reductant under visible-light irradiation to furnish the corresponding α-hydroxycarboxylic acids through nucleophilic addition of the resulting carbinol anions to electrophilic carbon dioxide.
- Okumura, Shintaro,Uozumi, Yasuhiro
-
supporting information
p. 7194 - 7198
(2021/09/22)
-
- Oxalyl-CoA Decarboxylase Enables Nucleophilic One-Carbon Extension of Aldehydes to Chiral α-Hydroxy Acids
-
The synthesis of complex molecules from simple, renewable carbon units is the goal of a sustainable economy. Here we explored the biocatalytic potential of the thiamine-diphosphate-dependent (ThDP) oxalyl-CoA decarboxylase (OXC)/2-hydroxyacyl-CoA lyase (HACL) superfamily that naturally catalyzes the shortening of acyl-CoA thioester substrates through the release of the C1-unit formyl-CoA. We show that the OXC/HACL superfamily contains promiscuous members that can be reversed to perform nucleophilic C1-extensions of various aldehydes to yield the corresponding 2-hydroxyacyl-CoA thioesters. We improved the catalytic properties of Methylorubrum extorquens OXC by rational enzyme engineering and combined it with two newly described enzymes—a specific oxalyl-CoA synthetase and a 2-hydroxyacyl-CoA thioesterase. This enzymatic cascade enabled continuous conversion of oxalate and aromatic aldehydes into valuable (S)-α-hydroxy acids with enantiomeric excess up to 99 %.
- Burgener, Simon,Cortina, Ni?a Socorro,Erb, Tobias J.
-
supporting information
p. 5526 - 5530
(2020/02/20)
-
- Method for preparing alpha-hydroxy acid
-
The invention relates to the technical field of organic chemical asymmetric hydrogenation, specifically to a method for catalyzing an asymmetric hydrogenation alpha-ketonic acid compound to prepare achiral alpha-hydroxy acid compound. The method is simple in synthesis route, high in conversion rate and high in ee value.
- -
-
Paragraph 0072-0079
(2019/05/28)
-
- Characterization of a new nitrilase from Hoeflea phototrophica DFL-43 for a two-step one-pot synthesis of (S)-β-amino acids
-
A nitrilase from Hoeflea phototrophica DFL-43 (HpN) demonstrating excellent catalytic activity towards benzoylacetonitrile was identified from a nitrilase tool-box, which was developed previously in our laboratory for (R)-o-chloromandelic acid synthesis from o-chloromandelonitrile. The HpN was overexpressed in Escherichia coli BL21 (DE3), purified to homogeneity by nickel column affinity chromatography, and its biochemical properties were studied. The HpN was very stable at 30–40?°C, and highly active over a wide range of pH values (pH 6.0–10.0). In addition, the HpN could tolerate against several hydrophilic organic solvents. Steady-state kinetics indicated that HpN was highly active towards benzoylacetonitrile, giving a KM of 4.2?mM and a kcat of 170?s?1, the latter of which is ca. fivefold higher than the highest record reported so far. A cascade reaction for the synthesis of optically pure (S)-β-phenylalanine from benzoylacetonitrile was developed by coupling HpN with an ω-transaminase from Polaromonas sp. JS666 in toluene-water biphasic reaction system using β-alanine as an amino donor. Various (S)-β-amino acids could be produced from benzoylacetonitrile derivatives with moderate to high conversions (73–99%) and excellent enantioselectivity (> 99% ee). These results are significantly advantageous over previous studies, indicating a great potential of this cascade reaction for the practical synthesis of (S)-β-phenylalanine in the future.
- Zhang, Zhi-Jun,Cai, Rui-Feng,Xu, Jian-He
-
p. 6047 - 6056
(2018/05/15)
-
- Highly Efficient Deracemization of Racemic 2-Hydroxy Acids in a Three-Enzyme Co-Expression System Using a Novel Ketoacid Reductase
-
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
-
-
- Preparation and reactions of certain racemic and optically active cyanohydrins derived from 2-chlorobenzaldehyde, 4-fluorobenzaldehyde, benzo[d][1,3]-dioxole-5-carbaldehyde and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. Antimicrobial and in vitro antitumor evaluation of the products
-
THE CHEMOENZYMATIC reaction of selected aldehydes, namely 2-chlorobenzaldehyde (1a), 4-fluorobenzaldehyde (1b), benzo[d][1,3]dioxole-5-carbaldehyde (1c) and/or 2,3-dihydrobenzo [b] [1,4] dioxine-6-carbaldehyde (1d) with hydrogen cyanide in presence of (R)-oxynitrilase (R)-Pa HNL [EC 4.1.2.10] from almonds, as a chiral catalyst, gave the optically active cyanohydrin enantiomers ( R)-2a-c, respectively. Acetone cyanohydrin (3), was also used, as a transcyanating agent, to give the same products. The racemic cyanohydrins (R,S)-2a-d have been synthesized, as well, by treating compounds 1a-d with aqueous potassium cyanide solution in presence of a saturated solution of sodium metabisulphite (Na2S2O5). The optical purity of cyanohydrins (R)-2a-c was determined through their derivatization with (S)-naproxen chloride (S)-5 to the respective diastereomers (R,2S)-6a-c which were obtained in diastereomeric excess (de) values up to 93 % (1H NMR). Heating compounds (R)-2a,b and / or their racemic analogues (R,S)-2a-c with concentrated hydrochloric acid gave the respective α-hydroxycarboxylic acids 7a-c. Moreover, reduction of cyanohydrins (R,S)-2b,c under different conditions resulted in a hydrodecyanation giving the respective primary alcohols 8a,b. Structures and configurations of the new compounds were confirmed with compatible elementary microanalyses and spectroscopic (IR, 1H NMR, 13C NMR, MS and single crystal X-ray crystallography) measurements. The antimicrobial activity of derivatives 6a-d against four bacterial species (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) and two fungi (Aspergillus flavus and Candida albicans) were undertaken. Moreover, compounds (R,2S)-6b, (R,2S)(S,2S)-6b and (R,2S)-6c were screened for their in virto antitumor activity against three human solid cancer cell lines (HCT 116, HepG2 and MCF-7). In general, the tested compounds were found inactive or showed weak activities in comparison with the standard drugs.
- Yosef, Hisham Abdallah A.,Elmasry,Ibrahim, Nabila M.,Ismael, Eman H. I.,Mahran
-
p. 301 - 328
(2017/06/08)
-
- Enzymatic Resolution by a d-Lactate Oxidase Catalyzed Reaction for (S)-2-Hydroxycarboxylic Acids
-
Oxidase-catalyzed kinetic resolution is important for the production of enantiopure 2-hydroxycarboxylic acids (2-HAs), which are versatile building blocks for the synthesis of many significant compounds. However, in contrast to that of (R)-2-HAs, the production of (S)-2-HA is challenging because of the lack of related oxidases. Herein, suitable enzymes were screened systematically through the analysis of numerous putative d-lactate oxidase sequences and identification of several required properties. Finally, a d-lactate oxidase from Gluconobacter oxydans 621H with advantageous characteristics, such as good solubility, broad substrate spectrum, and high stereoselectivity, was selected to resolve 2-HAs into (S)-2-HAs. A variety of (S)-2-HAs was produced successfully using this d-lactate oxidase with excellent enantiomeric excess values (>99 %). The presented screening criteria and approach for target biocatalysis suggested a guideline for the production of optically active chemicals such as (S)-2-HAs.
- Sheng, Binbin,Xu, Jing,Ge, Yongsheng,Zhang, Shuo,Wang, Danqi,Gao, Chao,Ma, Cuiqing,Xu, Ping
-
p. 2630 - 2633
(2016/08/30)
-
- Asymmetric hydrogenation reaction of alpha-ketoacids compound
-
The invention relates to the technical field of organic chemistry, especially to an asymmetric hydrogenation reaction of an alpha-ketoacids compound. The asymmetric hydrogenation reaction comprises a scheme shown in the description. In the scheme, R1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, C1-C6 alkyl, or aralkyl; a substituent group is C1-C6 alkyl, C1-C6 alkoxy, or halogen; and the number of the substituent group is 1-3. In the scheme, M is a chiral spiro-pyridylamino phosphine ligand iridium complex having a structure shown in the description. In the structure, R is hydrogen, 3-methyl, 4-tBu, or 6-methyl.
- -
-
Paragraph 0031; 0032; 0033; 0037; 0043
(2016/10/10)
-
- An efficient enzymatic aminolysis for kinetic resolution of aromatic α-hydroxyl acid in non-aqueous media
-
A new and highly efficient enzymatic aminolysis approach for kinetic resolution of aromatic α-hydroxy acid in non-aqueous media has been developed. The corresponding α-hydroxyl acid ester was employed as the substrate, and commercially available Candida antarctica lipase B is used as the biocatalyst, anhydrous ammonia is the resolving agent. Reactions can be proceeded smoothly in organic solvent at ambient temperatures. High concentration of substrate is allowed due to the application of organic media and the products are obtained in yields of up to 49% with ee values of up to 99%, and with E value of >300, representing an appealing and promising protocol for large-scale preparations.
- Chen, Shan,Liu, Fuyan,Zhang, Kuan,Huang, Hansheng,Wang, Huani,Zhou, Jiaying,Zhang, Jing,Gong, Yiwei,Zhang, Dela,Chen, Yiping,Lin, Chang,Wang, Bo
-
supporting information
p. 5312 - 5314
(2016/11/16)
-
- Solid phase behavior in the chiral systems of various 2-hydroxy-2-phenylacetic acid (mandelic acid) derivatives
-
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
-
p. 721 - 728
(2015/03/30)
-
- Nitrilases
-
The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition, methods of designing new nitrilases and methods of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
- -
-
Paragraph 0351; 0352
(2015/09/22)
-
- Nitrilases, nucleic acids encoding them and methods for making and using them
-
The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition methods of designing new nitrilases and method of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
- -
-
Page/Page column 70; 71; 74-79
(2016/01/09)
-
- Kinetic resolution of mandelate esters via stereoselective acylation catalyzed by lipase PS-30
-
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
-
supporting information
p. 2290 - 2294
(2014/04/17)
-
- Relationships between the racemic structures of substituted mandelic acids containing 8- and 10-membered hydrogen bonded dimer rings
-
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
-
p. 10816 - 10823
(2015/02/19)
-
- Direct asymmetric hydrogenation of α-keto acids by using the highly efficient chiral spiro iridium catalysts
-
A new efficient and highly enantioselective direct asymmetric hydrogenation of α-keto acids employing the Ir/SpiroPAP catalyst under mild reaction conditions has been developed. This method might be feasible for the preparation of a series of chiral α-hydroxy acids on a large scale.
- Yan, Pu-Cha,Xie, Jian-Hua,Zhang, Xiang-Dong,Chen, Kang,Li, Yuan-Qiang,Zhou, Qi-Lin,Che, Da-Qing
-
p. 15987 - 15990
(2015/02/19)
-
- Increased catalyst productivity in α-hydroxy acids resolution by esterase mutation and substrate modification
-
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
-
p. 1026 - 1031
(2014/04/03)
-
- Carboxylation with CO2 via brook rearrangement: Preparation of α-hydroxy acid derivatives
-
In the presence of CsF, a wide range of α-substituted α-siloxy silanes were carboxylated under a CO2 atmosphere (1 atm) via Brook rearrangement. A variety of α-substituents including aryl, alkenyl, and alkyl groups were tolerated to afford α-hydroxy acids in moderate-to-high yields. One-pot synthesis from aldehydes using PhMe2SiLi and CO 2 was also possible, providing α-hydroxy acids without the isolation of an α-hydroxy silane.
- Mita, Tsuyoshi,Higuchi, Yuki,Sato, Yoshihiro
-
supporting information
p. 14 - 17
(2014/01/23)
-
- Amberlyst A-26: An efficient and reusable heterogeneous catalyst for a one-pot oxidation-Cannizarro reaction
-
Amberlyst A-26 catalyses the efficient synthesis of α-hydroxy- arylacetic acids from aryl methyl ketones in the presence of SeO2. After simple separation, the catalyst does not lose its activity and can be reused without significant loss in activity for at least four cycles.
- Shen, Ming-Gui,Shang, Shi-Bin,Song, Zhan-Qian,Wang, Dan,Rao, Xiao-Ping,Gao, Hong,Liu, He
-
-
- Diastereomeric resolution of racemic o-chloromandelic acid
-
The separation of rac-o-chloromandelic acid 1 with enantiopure aryloxypropylamine via diastereomeric salt formation was investigated. (R)-o-chloromandelic acid (R)-1, a key intermediate for the antithrombotic agent clopidogrel, was obtained in 65% yield a
- Wang, Pei,Zhang, En,Zhao, Peng,Ren, Qing-Hua,Guan, Yuan-Yuan,Liu, Hong-Min
-
p. 1013 - 1017
(2013/02/22)
-
- [Ru(phgly)2(binap)]/Li2CO3: A Highly Active, Robust, and Enantioselective Catalyst for the Cyanosilylation of Aldehydes
-
The right combination: A series of aromatic, heteroaromatic, aliphatic, and α,β-unsaturated aldehydes can be converted into the desired silylated cyanohydrins by reaction with (CH3)3SiCN and a catalyst system consisting of the combination of a chiral ruthenium complex and Li2CO3 (see scheme). The reaction is highly enantioselective and affords the R products with up to 98% ee within 24 h at a substrate-tocatalyst ratio of 10000:1. (Chemical Equation Presented).
- Kurono, Nobuhito,Arai, Kenta,Uemura, Masato,Ohkuma, Takeshi
-
supporting information; experimental part
p. 6643 - 6646
(2009/03/12)
-
- CeCl3·7H2O: An effective additive in ru-catalyzed enantioselective hydrogenation of aromatic α-ketoesters
-
(Chemical Equation Presented) In the presence of catalytic amounts of CeCl3·7H2O, [RuCl(benzene)(S)-SunPhos]Cl is a highly effective catalyst for the asymmetric hydrogenation of aromatic α-ketoesters. A variety of ethyl α-hydroxy-α-arylacetates have been prepared in up to 98.3% ee with a TON up to 10 000. Challenging aromatic α-ketoesters with ortho substituents are also hydrogenated with high enantioselectivities. The addition of CeCl3·7H2O not only improves the enantioselectivity but also enhances the stability of the catalyst. The ratio of CeCl3·7H2O to [RuCl(benzene)(S)-SunPhos]Cl plays an important role in the hydrogenation reaction with a large substrate/catalyst ratio.
- Meng, Qinghua,Sun, Yanhui,Ratovelomanana-Vidal, Virginie,Genet, Jean Pierre,Zhang, Zhaoguo
-
p. 3842 - 3847
(2008/09/21)
-
- An R-selective hydroxynitrile lyase from Arabidopsis thaliana with an α/β-hydrolase fold
-
Folding and selectivity: The noncyanogenic plant Arabidopsis thaliana contains a new hydroxynitrile lyase, which was cloned and characterized. This enzyme is readily available form a recombinant source, has a broad range of substrates, and enantioselectively transforms aliphatic and aromatic aldehydes as well as ketones into the corresponding R-cyanohydrins. (Chemical Equation Presented).
- Andexer, Jennifer,Von Langermann, Jan,Mell, Annett,Bocola, Marco,Kragl, Udo,Eggert, Thorsten,Pohl, Martina
-
p. 8679 - 8681
(2008/09/18)
-
- THE METHOD OF MAKING OPTICALLY ACTIVE 2-CHLOROMANDELIC ACID ESTERS AND 2-CHLOROMANDELIC ACIDS BY ENZYMATIC METHOD
-
The present invention relates to process for the preparation of optically active 2-chloromandelic acid esters represented by the general formula 2 and optically active 2-chloromandelic acids represented by the general formula 2 which are used intensively as important chiral intermediates. In more detail, this invention relates to the process for preparing optically active 2-chloromandelic acid esters and optically active 2-chloromandelic acids by stereospecific hydrolysis of racemic 2-chloromandelic acid ester using lipases or lipase-producing microorganisms in the aqeous phase or organic phase including aqeous solvent. The method of making optically active 2-chloromandelic aicd esters and their acids is usful in the practical process because production of seperation of compounds with high optical purity are easy.
- -
-
Page/Page column 4-5
(2008/06/13)
-
- OPTICALLY ACTIVE MIXTURES COMPRISING VANADYL-SALEN COMPLEXES
-
The invention relates to mixtures comprising vanadyl-salen complexes with 10 to 99.9 wt.% of a compound of formula VOm(Salen)n (I), with m ? n and m 1-C10 alkyl, or a group O(C1-C4 alkyl), or F, Cl, Br or I, an optionally substituted aryl group or -(CH2)m-, where m = a whole number between 1 and 8 and n in formula (I) is a whole number ≥ 2.
- -
-
-
- Optically active catalysts
-
An optically active catalyst containing a salen ligand of formula (II) and vanadium at oxidation stage (IV), wherein the groups R, R′ and R″ of the salen ligand independently of one another represent hydrogen, branched or unbranched C1-C10 alkyl groups or an O(C1-C4-alkyl) group or F, Cl, Br or I, an optionally substituted aryl group, or —(CH2)m— whereby m represents a whole number ranging between 1 and 8 and the catalyst contains between 1.4 and 10 equivalents of a salen ligand for an equivalent of vanadium (IV).
- -
-
-
- METHOD FOR PRODUCING CHIRAL alpha HYDROXYCARBOXYLIC CRYSTALLINE ACIDS
-
The invention relates to a method for producing chiral alpha-hydroxycarboxylic crystalline acids consisting in transforming cyanhydrins (R) or (S) into alpha-hydroxycarboxylic acids (R) or (S), respectively by enzymatic hydrolysis in the presence of Rhodococcus erythropolis NCIMB 11540.
- -
-
Page/Page column 11-12
(2008/06/13)
-
- Method for producing optically active mandelic acid derivatives
-
The present invention provides a method for enzymatically producing optically active mandelic acid derivatives. An optically active mandelic acid derivative (shown as Formula II) is produced by reacting a culture or cell body of a microorganism, or processed products thereof, with a phenylglyoxylic acid derivative, and then recovering the obtained optically active mandelic acid derivative, wherein the microorganism has the ability to stereo-selectively reduce the phenylglyoxylic acid derivative. An optically active mandelic acid obtained according to the present invention is useful as an intermediate for the synthesis of pharmaceuticals and agricultural chemicals.
- -
-
Page column 16
(2008/06/13)
-
- Method for producing optically active cyanohydrins and their corresponding acids
-
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.
- -
-
-
- OPTICALLY ACTIVE MANDELIC ACID AND ITS DERIVATIVE, AND METHOD FOR CRYSTALLIZATION THEREOF
-
A method of crystallizing optically active mandelic acids characterized in that it comprises adding alkali to an aqueous solution comprising optically active mandelic acids and mineral acid for partial neutralization, and then crystallizing the optically active mandelic acids from the aforementioned aqueous solution.
- -
-
-
- METHOD FOR THE PRODUCTION OF OPTICALLY-ACTIVE CYANOHYDRINS AND THE CORRESPONDING MANDELIC ACIDS
-
The invention relates to a method for the production of optically-active cyanohydrins and the corresponding α-hydroxycarboxylic acids, from an aldehyde, a CN source and an optically-active vanadyl-salen catalyst in a biphasic liquid/liquid system, whereby the reaction mixture is reacted at a temperature of 0 to 60 °C. 0.8 to 10 equivalents of cyanide and 0.000005 to 0.05 equivalents of vanadyl-salen catalyst, based on the aldehyde (concentration 0.5 to 4 mol/Liter of solvent) are used. After the reaction the optically-active cyanohydrin, or the corresponding optically-active α-hydroxycarboxylic acid from acid hydrolysis, can be isolated with good enantiomeric excess. The vanadyl-salen catalyst used comprises a salen ligand, whereby the ratio of salen ligand: vanadium (IV) in the catalyst lies in the range 1.4: 1 to 10: 1.
- -
-
-
- Method for producing alpha-hydroxycarboxylic acid
-
The present invention relates to: a method for producing α-hydroxycarboxylic acid, which comprises hydrolyzing cyanohydrin in the presence of a hydrocarbon solvent; a method for producing optically active α-hydroxycarboxylic acid, which comprises: producing optically active cyanohydrin by performing a reaction between a carbonyl compound and hydrogen cyanide, using a solvent comprising at least one organic solvent selected from a group consisting of an alcoholic solvent, an ester solvent, an ethereal solvent and a carboxylic solvent; removing said organic solvent from said reaction solvent; and hydrolyzing the remaining reaction mixture without isolating optically active cyanohydrin; a method for producing optically active α-hydroxycarboxylic acid, which comprises hydrolyzing optically active cyanohydrin, using at most 10 equivalents of mineral acid relative to said optically active cyanohydrin under the condition that maximum temperature when reacting is 90° C. or less; and a method for producing optically active crystalline α-hydroxycarboxylic acid, which comprises crystallizing optically active α-hydroxycarboxylic acid in an aqueous solution.
- -
-
-
- An enzyme library approach to biocatalysis: Development of nitrilases for enantioselective production of carboxylic acid derivatives
-
The discovery, from Nature, of a large and diverse set of nitrilases is reported. The utility of this nitrilase library for identifying enzymes that catalyze efficient production of valuable hydroxy carboxylic acid derivatives is demonstrated. Unprecedented enantioselectivity and substrate scope are highlighted for three newly discovered and distinct nitrilases. For example, a wide array of (R)-mandelic acid derivatives and analogues were produced with high rates, yields, and enantiomeric excesses (95-99% ee). We also have found nitrilases that provide direct access to (S)-phenyllactic acid and other aryllactic acid derivatives, again with high yields and enantioselectivities. Finally, different nitrilases have been discovered that catalyze enantiotopic hydrolysis of 3-hydroxyglutaronitrile to afford either enantiomer of 4-cyano-3-hydroxybutyric acid with high enantiomeric excesses (>95% ee). The first enzymes are reported that effect this transformation to furnish the (R)-4-cyano-3-hydroxybutyric acid which is a precursor to the blockbuster drug Lipitor. Copyright
- DeSantis, Grace,Zhu, Zuolin,Greenberg, William A.,Wong, Kelvin,Chaplin, Jenny,Hanson, Sarah R.,Farwell, Bob,Nicholson, Lawrence W.,Rand, Cynthia L.,Weiner, David P.,Robertson, Dan E.,Burk, Mark J.
-
p. 9024 - 9025
(2007/10/03)
-
- Process for preparing optically active cyanohydrins and secondary products
-
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.
- -
-
-
- PROCESS FOR PRODUCING OPTICALLY ACTIVE AMINOALCOHOL
-
An industrially advantageous process for producing optically active 4-amino-2-methylbutane-1-ol which is useful as an intermediate in synthesizing optically active medicines and pesticides. Racemic 4-amino-2-methylbutane-1-ol is treated with an optically active organic acid. The diastereomeric salt thus obtained is crystallized out and subjected to solid-liquid separation to give optically active 4-amino-2-methylbutane-1-ol. The diastereomeric salt of optically active 4-amino-2-methylbutane-1-ol with an optically active reagent for optical resolution is decomposed by bringing into contact with a solvent and an alkali and subjected to solid-liquid separation, thereby recovering the optically active 4-amino-2-methylbutane-1-ol from the filtrate. Further, the filtration residue containing the alkali salt of the reagent for optical resolution obtained by the solid-liquid separation is brought into contact with a solvent and an acid. Then the reagent for optical resolution thus crystallized out is subjected to solid-liquid separation and recovered.
- -
-
-
- Process for the preparation of optically and chemically highly pure (R) - or (S) -alpha- hydroxycarboxylic acids
-
Process for the preparation of optically highly pure (R)— and (S)—α-hydroxycarboxylic acids, in which either isolated, impure (R)— and (S)—α-hydroxycarboxylic acids prepared by acidic hydrolysis of the (R)— and (S)—cyanohydrins obtained by enzyme-catalyzed addition of a cyanide group donor to the corresponding aldehydes or ketones are recrystallized in an aromatic hydrocarbon, optionally in the presence of a cosolvent, and optically highly pure (R)— and (S)—α-hydroxycarboxylic acids having an optical purity of over 98%ee are obtained or the hydrolysis solution obtained by acidic hydrolysis of the (R)— and (S)—cyanohydrins is treated directly with an aromatic hydrocarbon, optionally in combination with a cosolvent, and is then extracted at hydrolysis temperature, whereupon after cooling of the organic phase the corresponding chemically and optically highly pure (R)— and (S)—α-hydroxycarboxylic acids having an optical purity of over 98%ee crystallize out.
- -
-
-
- Selective ET(A) antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives
-
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.
-
p. 900 - 910
(2007/10/03)
-
