- Unmasking the Hidden Carbonyl Group Using Gold(I) Catalysts and Alcohol Dehydrogenases: Design of a Thermodynamically-Driven Cascade toward Optically Active Halohydrins
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A concurrent cascade combining the use of a gold(I) N-heterocyclic carbene (NHC) and an alcohol dehydrogenase (ADH) is disclosed for the synthesis of highly valuable enantiopure halohydrins in an aqueous medium and under mild reaction conditions. The meth
- Escot, Lorena,González-Granda, Sergio,Gotor-Fernández, Vicente,Lavandera, Iván
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p. 2552 - 2560
(2022/02/16)
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- Biocatalytic preparation of a key intermediate of antifungal drugs using an alcohol dehydrogenase with high organic tolerance
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In this study, an alcohol dehydrogenase derived from Lactobacillus kefir (LkADH) was engineered and a simple and practical bioreduction system was developed for the preparation of (R)-2-chloro-1-(2, 4-dichlorophenyl) ethanol ((R)-CDPO), a key intermediate for the synthesis of antifungal drugs. Through active pocket iterative saturation mutagenesis, mutant LkADH-D18 (Y190C/V196L/M206H/D150H) was obtained with high stereoselectivity (99% ee, R vs 87% ee, S) and increased activity (0.44 μmol·min?1·mg?1). LkADH-D18 demonstrated NAD(P)H regeneration capability using a high concentration of isopropanol (IPA) as a co-substrate. Using 40% IPA (v/v), 400 mM of (R)-CDPO (90.1 g·L-1) was obtained via complete substrate conversion using 40 mg·mL?1 LkADH-D18 wet cells. The biocatalytic process catalyzed at constant pH with the cheap co-solvent IPA contributed to improved isolated yield of (R)-CDPO (97%), lower reaction cost, and simpler downstream purification, indicating the potential utility of LkADH-D18 in future industrial applications.
- Yan, Jinrong,Wang, Xiaojing,Li, Fangling,Yang, Lei,Shi, Guixiang,Sun, Weihang,Shao, Lei,Huang, Junhai,Wu, Kai
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supporting information
(2021/10/20)
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- Molecular switch manipulating Prelog priority of an alcohol dehydrogenase toward bulky-bulky ketones
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Structure-guided rational design revealed the molecular switch manipulating the Prelog and anti-Prelog priorities of an NADPH-dependent alcohol dehydrogenase toward prochiral ketones with bulky and similar substituents. Synergistic effects of unconserved residues at 214 and 237 in small and large substrate binding pockets were proven to be vital in governing the stereoselectivity. The ee values of E214Y/S237A and E214C/S237 G toward (4-chlorophenyl)-(pyridin-2-yl)-methanone were 99.3% (R) and 78.8% (S) respectively. Substrate specificity analysis revealed that similar patterns were also found with (4’-chlorophenyl)-phenylmethanone, (4’-bromophenyl)-phenylmethanone and (4’-nitrophenyl)-phenylmethanone. This study provides valuable evidence for understanding the molecular mechanism on enantioselective recognition of prochiral ketones by alcohol dehydrogenase.
- Xu, Guochao,Dai, Wei,Wang, Yue,Zhang, Lu,Sun, Zewen,Zhou, Jieyu,Ni, Ye
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- Efficient Asymmetric Synthesis of Ethyl (S)-4-Chloro-3-hydroxybutyrate Using Alcohol Dehydrogenase SmADH31 with High Tolerance of Substrate and Product in a Monophasic Aqueous System
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Bioreductions catalyzed by alcohol dehydrogenases (ADHs) play an important role in the synthesis of chiral alcohols. However, the synthesis of ethyl (S)-4-chloro-3-hydroxybutyrate [(S)-CHBE], an important drug intermediate, has significant challenges concerning high substrate or product inhibition toward ADHs, which complicates its production. Herein, we evaluated a novel ADH, SmADH31, obtained from the Stenotrophomonas maltophilia genome, which can tolerate extremely high concentrations (6 M) of both substrate and product. The coexpression of SmADH31 and glucose dehydrogenase from Bacillus subtilis in Escherichia coli meant that as much as 660 g L-1 (4.0 M) ethyl 4-chloroacetoacetate was completely converted into (S)-CHBE in a monophasic aqueous system with a >99.9% ee value and a high space-time yield (2664 g L-1 d-1). Molecular dynamics simulation shed light on the high activity and stereoselectivity of SmADH31. Moreover, five other optically pure chiral alcohols were synthesized at high concentrations (100-462 g L-1) as a result of the broad substrate spectrum of SmADH31. All these compounds act as important drug intermediates, demonstrating the industrial potential of SmADH31-mediated bioreductions.
- Chen, Rong,Liu, Qinghai,Wang, Hualei,Wei, Dongzhi,Xie, Youyu,Yang, Zeyu,Ye, Wenjie
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p. 1068 - 1076
(2020/07/06)
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- Deep Eutectic Solvents as Media in Alcohol Dehydrogenase-Catalyzed Reductions of Halogenated Ketones
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The application of deep eutectic solvents (DESs) in biotechnological processes has gained an outstanding relevance, as they can be used as greener media to obtain higher productivities and selectivities. In the present contribution, an eutectic mixture composed of choline chloride (ChCl): glycerol (1 : 2 mol/mol) has been used as a reaction medium in combination with Tris?SO4 50 mM buffer pH 7.5, applied to the alcohol dehydrogenase (ADH)-catalyzed reduction of various carbonyl precursors of chiral halohydrins. These alcohols are key intermediates of biologically active compounds, and hence they are of industrial interest. In the presence of up to 50 % v/v of DES, these biotransformations were achieved up to 300–400 mM of the α-halogenated ketone substrate, getting access to the final compounds with excellent conversions (usually >90 %) and enantiomeric excess (ee >99 %). Among the different ADHs tested, two stereocomplementary enzymes (Lactobacillus brevis ADH and Rhodococcus ruber ADH) afforded the best results, so both alcohol enantiomers could be obtained in all the studied examples. Selected bioreductions were scaled up to 250 mg and 1 g, demonstrating the potential that DESs can offer as media in redox processes for substrates with low solubility in water.
- Ibn Majdoub Hassani, Fatima Zohra,Amzazi, Saaid,Kreit, Joseph,Lavandera, Iván
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p. 832 - 836
(2019/12/24)
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- Efficient asymmetric synthesis of chiral alcohols using high 2-propanol tolerance alcohol dehydrogenase: Sm ADH2 via an environmentally friendly TBCR system
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Alcohol dehydrogenases (ADHs) together with the economical substrate-coupled cofactor regeneration system play a pivotal role in the asymmetric synthesis of chiral alcohols; however, severe challenges concerning the poor tolerance of enzymes to 2-propanol and the adverse effects of the by-product, acetone, limit its applications, causing this strategy to lapse. Herein, a novel ADH gene smadh2 was identified from Stenotrophomonas maltophilia by traditional genome mining technology. The gene was cloned into Escherichia coli cells and then expressed to yield SmADH2. SmADH2 has a broad substrate spectrum and exhibits excellent tolerance and superb activity to 2-propanol even at 10.5 M (80%, v/v) concentration. Moreover, a new thermostatic bubble column reactor (TBCR) system is successfully designed to alleviate the inhibition of the by-product acetone by gas flow and continuously supplement 2-propanol. The organic waste can be simultaneously recovered for the purpose of green synthesis. In the sustainable system, structurally diverse chiral alcohols are synthesised at a high substrate loading (>150 g L-1) without adding external coenzymes. Among these, about 780 g L-1 (6 M) ethyl acetoacetate is completely converted into ethyl (R)-3-hydroxybutyrate in only 2.5 h with 99.9% ee and 7488 g L-1 d-1 space-time yield. Molecular dynamics simulation results shed light on the high catalytic activity toward the substrate. Therefore, the high 2-propanol tolerance SmADH2 with the TBCR system proves to be a potent biocatalytic strategy for the synthesis of chiral alcohols on an industrial scale.
- Yang, Zeyu,Fu, Hengwei,Ye, Wenjie,Xie, Youyu,Liu, Qinghai,Wang, Hualei,Wei, Dongzhi
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- Lipase mediated enzymatic kinetic resolution of phenylethyl halohydrins acetates: A case of study and rationalization
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Racemic phenylethyl halohydrins acetates containing several groups attached to the aromatic ring were resolved via hydrolysis reaction in the presence of lipase B from Candida antarctica (Novozym 435). In all cases, the kinetic resolution was highly selective (E > 200) leading to the corresponding (S)-β-halohydrin with ee > 99 %. However, the time required for an ideal 50 % conversion ranged from 15 min for 2,4-dichlorophenyl chlorohydrin acetate to 216 h for 2-chlorophenyl bromohydrin acetate. Six chlorohydrins and five bromohydrins were evaluated, the latter being less reactive. For the β-brominated substrates, steric hindrance on the aromatic ring played a crucial role, which was not observed for the β-chlorinated derivatives. To shed light on the different reaction rates, docking studies were carried out with all the substrates using MD simulations. The computational data obtained for the β-brominated substrates, based on the parameters analysed such as NAC (near attack conformation), distance between Ser-O and carbonyl-C and oxyanion site stabilization were in agreement with the experimental results. On the other hand, the data obtained for β-chlorinated substrates suggested that physical aspects such as high hydrophobicity or induced change in the conformation of the enzymatic active site are more relevant aspects when compared to steric hindrance effects.
- Fonseca, Thiago de Sousa,Vega, Kimberly Benedetti,da Silva, Marcos Reinaldo,de Oliveira, Maria da Concei??o Ferreira,de Lemos, Telma Leda Gomes,Contente, Martina Letizia,Molinari, Francesco,Cespugli, Marco,Fortuna, Sara,Gardossi, Lucia,de Mattos, Marcos Carlos
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- Fine tuning the enantioselectivity and substrate specificity of alcohol dehydrogenase from Kluyveromyces polysporus by single residue at 237
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Here, S237 was identified to be important in fine tuning the substrate specificity and enantioselectivity of alcohol dehydrogenase from Kluyveromyces polysporus (KpADH). In the reduction of a diaryl ketone, (4-chlorophenyl)-(pyridin-2-yl)-methanone (1a), the highest and lowest enantioselectivity of 96.1% and 27.0% e.e. (R) were obtained with S237A and S237C. Kinetic parameters analysis revealed that S237G, S237A, S237H and S237D displayed improved kcat/Km toward 1a. Various prochiral ketones, including acetophenone, 4-chloroacetophenone and ethyl 2-oxo-4-phenylbutyrate could be asymmetrically reduced by S237C, S237G and S237E with > 99% e.e. This study provides guidance for the application of KpADH in the preparation of chiral secondary alcohols.
- Wang, Yue,Dai, Wei,Liu, Yongmei,Zhang, Zhongwei,Zhou, Jieyu,Xu, Guochao,Ni, Ye
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- Hydroclassified Combinatorial Saturation Mutagenesis: Reshaping Substrate Binding Pockets of KpADH for Enantioselective Reduction of Bulky-Bulky Ketones
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A hydroclassified combinatorial saturation mutagenesis (HCSM) strategy was proposed for reshaping the substrate binding pocket by dividing 20 amino acids into four groups based on their hydrophobicity and size. These smart HCSM libraries could significantly reduce screening effort especially for the simultaneous mutagenesis of three or more residues and lacking high throughput screening methods. Employing HCSM strategy, the stereoselectivity of KpADH, an alcohol dehydrogenase from Kluyveromyces polysporus, was efficiently improved to 99.4% ee. (4-Chlorophenyl)(pyridin-2-yl)methanone (CPMK), generally regarded as a "hard-to-reduce" ketone, was used as a model substrate, and its corresponding chiral alcohol products could be utilized as antihistamine precursors. The best variant 50C10 displayed higher binding affinity and catalytic efficiency toward CPMK with KM/kcat of 59.3 s-1·mM-1, 3.51-fold that of KpADH. Based on MD simulations, increased difference between two binding pockets, enhanced hydrophobicity, and π-π and halogen-alkyl interactions were proposed to favor the enantioselective recognition and substrate binding in 50C10. Substrate spectrum analysis revealed that 50C10 exhibited improved enantioselectivity toward diaryl ketones especially with halo- or other electron-withdrawing groups. As much as 500 mM CPMK could be asymmetrically reduced into chiral diaryl alcohols with ee of 99.4% and a space-time yield of 194 g·L-1·d-1 without addition of external NADP+. This study provides an effective mutagenesis strategy for the protein engineering of substrate specificity and enantioselectivity.
- Xu, Guo-Chao,Wang, Yue,Tang, Ming-Hui,Zhou, Jie-Yu,Zhao, Jing,Han, Rui-Zhi,Ni, Ye
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p. 8336 - 8345
(2018/09/18)
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- Iridium-Catalyzed Asymmetric Hydrogenation of Halogenated Ketones for the Efficient Construction of Chiral Halohydrins
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Iridium-catalyzed asymmetric hydrogenation of prochiral halogenated ketones was successfully developed to prepare various chiral halohydrins with high reactivities and excellent enantioselectivities under basic reaction condition (up to >99% conversion, 99% yield, >99% ee). Moreover, gram-scale experiment was performed well in the presence of just 0.005 mol% (S/C=20 000) Ir/f-amphox catalyst with 99% yield and >99% ee. (Figure presented.).
- Yin, Congcong,Wu, Weilong,Hu, Yang,Tan, Xuefeng,You, Cai,Liu, Yuanhua,Chen, Ziyi,Dong, Xiu-Qin,Zhang, Xumu
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supporting information
p. 2119 - 2124
(2018/04/30)
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- Ultrafast Iron-Catalyzed Reduction of Functionalized Ketones: Highly Enantioselective Synthesis of Halohydrines, Oxaheterocycles, and Aminoalcohols
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A molecularly defined chiral boxmi iron alkyl complex catalyzes the hydroboration of various functionalized ketones and provides the corresponding chiral halohydrines, oxaheterocycles (oxiranes, oxetanes, tetrahydrofurans, and dioxanes) and amino alcohols with excellent enantioselectivities (up to >99 %ee) and conversion efficiencies at low catalyst loadings (as low as 0.5 mol %). Turnover frequencies of greater than 40000 h?1 at ?30 °C highlight the activity of this earth-abundant metal catalyst which tolerates a large number of functional groups.
- Blasius, Clemens K.,Vasilenko, Vladislav,Gade, Lutz H.
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supporting information
p. 10231 - 10235
(2018/07/31)
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- Aqueous biphasic iron-catalyzed asymmetric transfer hydrogenation of aromatic ketones
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For the first time, an iron(ii) catalyst is used in the biphasic asymmetric transfer hydrogenation (ATH) of ketones to enantioenriched alcohols employing water and potassium formate as the proton and hydride source, respectively. The precatalyst [FeCl(CO)(P-NH-N-P)]BF4 (P-NH-N-P = (S,S)-PPh2CH2CH2NHCHPhCHPhNCHCH2PPh2) in the organic phase with the substrate is activated by base to produce a system that rivals the best ruthenium biphasic ATH catalysts in activity but not enantioselectivity. Biorenewable 2-methyltetrahydrofuran as a cosolvent and biodegradable TWEEN80 as a surfactant were added to the reaction mixture to greatly decrease the mass-transfer limitations caused by the biphasic reaction mixture. The enantioselectivity of the reduction was as high as 76% depending on the substitution pattern of the arylketone employed. NMR studies verified the formation of an iron hydride [FeH(CO)(PPh2CH2CH2NHCHPhCHPhNCHCHPPh2)] intermediate as was observed in our 2-propanol-based ATH studies.
- Demmans,Ko,Morris
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p. 88580 - 88587
(2016/09/28)
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- An imidazolium-modified chiral rhodium/diamine-functionalized periodic mesoporous organosilica for asymmetric transfer hydrogenation of α-haloketones and benzils in aqueous medium
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The use of a hydrophobic, imidazolium-functionalized periodic mesoporous organosilica for immobilization of chiral organometallic complexes as a heterogeneous catalyst is highly desirable as this catalyst can greatly promote an aqueous organic transformation due to its hydrophobic function and phase-transfer feature in an aqueous medium. Herein, by utilizing a three-component co-condensation strategy, we conveniently incorporate 1,2-bis(triethoxysilyl)ethane, (R,R)-4-((trimethoxysilyl)ethyl)phenylsulfonyl-1,2-diphenylethylene-diamine and 1,3-bis(3-(triethoxysilyl)propyl)-1H-imidazol-3-ium iodide within its silicate network, which is coordinated with (Cp?RhCl2)2, leading to an imidazolium-modified chiral rhodium/diamine-functionalized periodic mesoporous organosilica. A solid-state carbon spectrum discloses its well-defined chiral rhodium/diamine active species, and its X-ray diffraction; nitrogen adsorption-desorption measurement and transmission electron microscopy images reveal its ordered dimensional-hexagonal mesostructure. As a bifunctional heterogeneous catalyst, this periodic mesoporous organosilica significantly boosts asymmetric transfer hydrogenation of α-haloketones and benzils in water, where the hydrophobic periodic mesoporous organosilica, phase-transfer-featured imidazolium-functionality, and the confined chiral organorhodium catalytic nature are responsible for its catalytic performance. Furthermore, the catalyst can be recovered and recycled seven times without the loss of its catalytic activity, making it an attractive heterogeneous catalyst for asymmetric transfer hydrogenation in an environmentally friendly manner.
- Zhou, Feng,Hu, Xiaoying,Gao, Ming,Cheng, Tanyu,Liu, Guohua
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p. 5651 - 5657
(2016/10/21)
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- Enantioselective bioreductive preparation of chiral halohydrins employing two newly identified stereocomplementary reductases
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Two robust stereocomplementary carbonyl reductases (DhCR and CgCR) were identified through rescreening the carbonyl reductase toolbox. Five reductases were returned through the activity and enantioselectivity assay for α-chloro-1-acetophenone and ethyl 4-chloro-3-oxo-butanate (COBE). Three reductases were stable at elevated substrate loading. Enzymatic characterization revealed that DhCR and CgCR were more thermostable. As much as 330 g COBE in 1 L biphasic reaction mixture was reduced to (S)- and (R)-3-hydroxy-4-chlorobutyrate by DhCR and CgCR (coexpressed with glucose dehydrogenase), with 92.5% and 93.0% yields, >99% ee, and total turnover numbers of 53800 and 108000, respectively. Six other α-halohydrins were asymmetrically reduced to optically pure forms at a substrate loading of 100 g L-1. Our results indicate the potential of these two stereocomplementary reductases in the synthesis of valuable α-halohydrins for pharmaceuticals. This journal is
- Xu, Guo-Chao,Yu, Hui-Lei,Shang, Yue-Peng,Xu, Jian-He
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p. 22703 - 22711
(2015/03/14)
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- Facile access to chiral alcohols with pharmaceutical relevance using a ketoreductase newly mined from Pichia guilliermondii
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Chiral secondary alcohols with additional functional groups are frequently required as important and valuable synthons for pharmaceuticals, agricultural and other fine chemicals. With the advantages of environmentally benign reaction conditions, broad reaction scope, and high stereoselectivity, biocatalytic reduction of prochiral ketones offers significant potential in the synthesis of optically active alcohols. A CmCR homologous carbonyl reductase from Pichia guilliermondii NRRL Y-324 was successfully overexpressed. Substrate profile characterization revealed its broad substrate specificity, covering aryl ketones, aliphatic ketones and ketoesters. Furthermore, a variety of ketone substrates were asymmetrically reduced by the purified enzyme with an additionally NADPH regeneration system. The reduction system exhibited excellent enantioselectivity (>99% ee) in the reduction of all the aromatic ketones and ketoesters, except for 2-bromoacetophenone (93.5% ee). Semi-preparative reduction of six ketones was achieved with high enantioselectivity (>99% ee) and isolation yields (>80%) within 12 h. This study provides a useful guidance for further application of this enzyme in the asymmetric synthesis of chiral alcohol enantiomers. Copyright
- Xu, Guochao,Yu, Huilei,Xu, Jianhe
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p. 349 - 354
(2013/08/22)
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- Asymmetric transfer hydrogenation of prochiral ketones catalyzed by aminosulfonamide-ruthenium complexes in ionic liquid
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Chiral aminosulfonamides containing imidazolium group were used as ligands for the ruthenium(II)-catalyzed asymmetric transfer hydrogenation of prochiral ketones in ionic liquid, affording good to excellent conversions and enantiomeric excesses. The catalytic system could be easily recovered and reused several times. Versita Sp. z o.o.
- Zhou, Zhongqiang,Sun, Yong,Zhang, Aiqing
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experimental part
p. 175 - 179
(2012/04/04)
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- Ruthenium(II)-catalyzed asymmetric transfer hydrogenation of aromatic ketones in water using novel water-soluble chiral monosulfonamide ligands
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Novel water-soluble analogues of Noyori's (R,R)-N-(p-tolylsulfonyl)-1,2- diphenylethyl- enediamine and Knochel's (R,R)-N-(p-tolylsulfonyl)-1,2- diaminocyclohexane, containing an additional quaternary ammonium group, have been synthesized. The ruthenium catalysts prepared in situ by reacting chiral monosulfonamides with [RuCl2(p-cymene)]2 afforded high conversion rates and enantiomeric excess (ee) values in the asymmetric transfer hydrogenation of aromatic ketones in aqueous HCOONa. Furthermore, the catalyst could be easily recovered and reused at least five times without obvious loss of ee value.
- Zhou, Zhongqiang,Ma, Qiong,Sun, Yong,Zhang, Aiqing,Li, Lin
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experimental part
p. 505 - 514
(2011/07/30)
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- Sulfonate Catalyst and Method of Producing Alcohol Compound Using the Same
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A sulfonate catalyst represented by the formula below and a ketone compound are placed in a solvent, and the ketone compound is hydrogenated by mixing in the presence of hydrogen to produce an optically active alcohol.
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Page/Page column 8
(2008/12/07)
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- An investigation into the tether length and substitution pattern of arene-substituted complexes for asymmetric transfer hydrogenation of ketones
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(Figure Presented) A series of Ru(II) catalysts were prepared and tested in the asymmetric transfer hydrogenation of ketones. The catalyst containing a "4-carbon" tether gave the fastest rates of ketone reduction. This is due to both increased rate of reg
- Cheung, Fung K.,Lin, Changxue,Minissi, Franco,Criville, Adriana Lorente,Graham, Mark A.,Fox, David J.,Wills, Martin
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p. 4659 - 4662
(2008/03/12)
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- 'Green' synthesis of important pharmaceutical building blocks: Enzymatic access to enantiomerically pure α-chloroalcohols
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Thirty one recombinant ketoreductase enzymes were screened for the reduction of six α-chloroketones, the precursors of pharmaceutically valuable α-chloroalcohols. Several highly active and enantioselective ketoreductases were found and their applications
- Zhu, Dunming,Mukherjee, Chandrani,Hua, Ling
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p. 3275 - 3278
(2007/10/03)
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- A practical synthesis of optically active aromatic epoxides via asymmetric transfer hydrogenation of α-chlorinated ketones with chiral rhodium-diamine catalyst
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A practical method for the synthesis of optically active aromatic epoxides has been developed via the formation of optically active α-chlorinated alcohols and intramolecular etherification. Optically active alcohols with up to 99% ee can be obtained from
- Hamada, Takayuki,Torii, Takayoshi,Izawa, Kunisuke,Ikariya, Takao
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p. 7411 - 7417
(2007/10/03)
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- Practical synthesis of optically active styrene oxides via reductive transformation of 2-chloroacetophenones with chiral rhodium catalysts
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(equation presented) A practical method for the synthesis of optically active styrene oxides has been developed via formation of optically active 2-chloro-1-phenylethanols generated by reductive transformation of ring-substituted 2-chloroacetophenones. Th
- Hamada, Takayuki,Torii, Takayoshi,Izawa, Kunisuke,Noyori, Ryoji,Ikariya, Takao
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p. 4373 - 4376
(2007/10/03)
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- anti-Prelog microbial reduction of aryl α-halomethyl or α- hydroxymethyl ketones with Geotrichum sp. 38
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Reduction of aryl α-halomethyl ketones 5a-d and 7a-h and α- hydroxymethyl ketones 10a-b by Geotrichum sp. 38 affording mostly the anti- Prelog alcohols was reported and the stereoselectivities of the reductive products were discussed.
- Wei, Zhi-Liang,Li, Zu-Yi,Lin, Guo-Qiang
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p. 13059 - 13072
(2007/10/03)
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- Nucleophilic reactions between cyclic 1,2-sulfites and chloride ions
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When cyclic 1,2-sulfites are ring opened by chloride ion, the chlorohydrins are formed with low regio- and stereo-selectivity. The mechanisms involved in the process were investigated by measuring the stereochemical outcome of the reactions. The results showed that reversible inversion pathways (SN2 reactions) and a retention pathway (SN2i reaction) gave rise to the loss in ee in both the chlorohydrins and in the cyclic 1,2-sulfites. Acta Chemica Scandinavica 1996.
- Nymann, Kirsten,Jensen, Linda,Svendsen, John S.
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p. 832 - 841
(2007/10/03)
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