- 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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- Characterization of a robust glucose 1-dehydrogenase, SyGDH, and its application in NADPH regeneration for the asymmetric reduction of haloketone by a carbonyl reductase in organic solvent/buffer system
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To realize coenzyme regeneration in the reduction of haloketones, a codon-optimized gene Sygdh encoding glucose 1-dehydrogenase (SyGDH) was synthesized based on the putative GDH gene sequence (Ta0897) in Thermoplasma acidophilum genomic DNA, and expressed in E. coli BL21(DE3). Recombinant SyGDH was purified to homogeneity by affinity chromatography with the specific activity of 86.3 U/mg protein towards D-glucose at the optimum pH and temperature of 7.5 and 40 °C. It was highly stable in a pH range of 4.5–8.0 and at 60 °C or below, and resistant to various organic solvents. The Km and catalytic efficiency (kcat/Km) of SyGDH towards NADP+ were 0.67 mM and 104.0 mM?1 s?1, respectively, while those towards NAD+ were 157.9 mM and 0.64 mM?1 s?1, suggesting that it preferred NADP+ as coenzyme to NAD+. Additionally, using whole cells of E. coli/Sygdh-Sys1, coexpressing SyGDH and carbonyl reductase (SyS1), as the biocatalyst, the asymmetric reduction of 60 mM m-chlorophenacyl chloride coupled with the regeneration of NADPH in situ was conducted in DMSO/phosphate buffer (2:8, v/v) system, producing (R)-2-chloro-1-(3-chlorophenyl)ethanol with over 99.9% eep and 99.2% yield. Similarly, the reduction of 40 mM α-bromoacetophenone in n-hexane/buffer (6:4, v/v) biphasic system produced (S)-2-bromo-1-phenylethanol with over 99.9% eep and 98.3% yield.
- Hu, Die,Wen, Zheng,Li, Chuang,Hu, Bochun,Zhang, Ting,Li, Jianfang,Wu, Minchen
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- Efficient synthesis of (R)-2-chloro-1-(3-chlorophenyl)ethanol by permeabilized whole cells of candida ontarioensis
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(R)-2-Chloro-1-(3-chlorophenyl)ethanol is a key pharmaceutical intermediate in the synthesis of β3-adrenoceptor receptor (β;3-AR) agonists. The asymmetric reduction of 2-chloro-1-(3-chlorophenyl)ethanone to (R)-2-chloro-1-(3-chlorophenyl)ethanol catalyzed by resting cells of Candida ontarioensis was studied. At a substrate concentration of 10 g/L, the microbial cells showed excellent catalytic activity under the optimum reaction conditions, giving the product in 99.9% ee and 99.0% yield. After cetyltrimethylammonium bromide-pretreatment, the activity of permeabilized Candida ontarioensis cells was increased by more than 2-fold and the product could be produced over the significantly shortened reaction period of 24 h in 99.9% ee and 97.5%yield at a substrate concentration of 30 g/L. This work provides a practical approach for the efficient preparation of the important chiral intermediate (R)-2-chloro-1-(3-chlorophenyl) ethanol.
- Ni, Ye,Zhang, Beihua,Sun, Zhihao
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experimental part
p. 681 - 687
(2012/08/08)
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- Preparation of (R)-2-chloro-1-(m-chlorophenyl)ethanol by Lipozyme TL IM-catalyzed second resolution
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(R)-2-Chloro-1-(m-chlorophenyl)ethanol, a precursor of (R)-3-chlorostyrene oxide which is the key chiral intermediate for the preparation of several β3-adrenergic receptor agonists was prepared in 40% yield and 99% ee by the Lipozyme TL IM-catalyzed second resolution of the corresponding racemate in the presence of vinyl acetate.
- Xia, Shi Wen,Lin, Hui,Chen, Yong Zheng
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p. 289 - 292
(2012/05/05)
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- Novel 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase
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A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.
- Wittman, Mark D.,Balasubramanian, Balu,Stoffan, Karen,Velaparthi, Upender,Liu, Pieying,Krishnanathan, Subramaniam,Carboni, Joan,Li, Aixin,Greer, Ann,Attar, Ricardo,Gottardis, Marco,Chang, Chiehying,Jacobson, Bruce,Sun, Yax,Hansel, Steven,Zoeckler, Mary,Vyas, Dolatrai M.
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p. 974 - 977
(2007/10/03)
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- Enzymatic ketone reduction: mapping the substrate profile of a short-chain alcohol dehydrogenase (YMR226c) from Saccharomyces cerevisiae
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A short-chain alcohol dehydrogenase (YMR226c) from Saccharomyces cerevisiae was cloned and expressed in Escherichia coli, and the encoded protein was purified. The activity and enantioselectivity of this recombinant enzyme were evaluated with a series of ketones. The alcohol dehydrogenase (YMR226c) was found to effectively catalyze the enantioselective reductions of aryl-substituted acetophenones, α-chloroacetophenones, aliphatic ketones, and α- and β-ketoesters. While the enantioselectivity for the reduction of β-ketoesters was moderate, the acetophenone derivatives, aromatic α-ketoesters, some substituted α-chloroacetophenones, and aliphatic ketones were reduced to the corresponding chiral alcohols with excellent enantioselectivity. The enantiopreference of this enzyme generally followed Prelog's rule for the simple ketones. The ester functionality played some role in determining the enzyme's enantiopreference for the reduction of α- and β-ketoesters. The present study serves as a valuable guidance for the future applications of this versatile biocatalyst.
- Yang, Yan,Zhu, Dunming,Piegat, Timothy J.,Hua, Ling
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p. 1799 - 1803
(2008/02/12)
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- Asymmetric hydrogenation of α-chloro aromatic ketones catalyzed by η6-arene/TsDPEN-ruthenium(II) complexes
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(Chemical Equation Presented) Asymmetric hydrogenation of various α-chloro aromatic ketones with Ru(OTf)(TsDPEN)(η6-arene) (TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) produces the chiral chlorohydrins in up to 98% ee. This reac
- Ohkuma, Takeshi,Tsutsumi, Kunihiko,Utsumi, Noriyuki,Arai, Noriyoshi,Noyori, Ryoji,Murata, Kunihiko
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p. 255 - 257
(2007/10/03)
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- METHOD FOR PRODUCING SINGLE ENANTIOMER EPOXIDES BY THE ADH REDUCTION OF ALPHA-LEAVING GROUP-SUBSTITUTED KETONES AND CYCLISATION
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The invention relates to a method for producing single enantiomer epoxides by reducing a-leaving group-substituted ketones with (R)- or (S)-selective alcohol dehydrogenases in the presence of a cofactor and optionally a suitable system for regenerating the oxidised cofactor, to produce the corresponding single enantiomer alcohols and subsequently, by means of cyclisation induced by a base, the corresponding single enantiomer epoxides (EQUATION 1 ), wherein in EQUATION 1 LG may stand for F, CI, Br, I, OSO2Ar, OSO2CH3, OSO2R or OP(O)OR2, and R1, R2 and R3, independently of one another, stand for hydrogen, a branched or unbranched, optionally substituted C1-C2O- alkyl radical, symbolise an optionally randomly substituted C3-C10- cycloalkyl or alkenyl radical or a randomly substituted carbo- or heterocyclic aryl radical, or corresponds to a radical from the group CO2R, CONR2, COSR, CS2R, C(NH)NR2, CN, CHaI3, ArO, ArS, RO, RS, CHO, OH, NHR, NR2, Cl, F, Br, I or SiR3.
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Page/Page column 8
(2008/06/13)
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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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- Purification and characterization of a yeast carbonyl reductase for synthesis of optically active (R)-styrene oxide derivatives
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Optically active styrene oxide derivatives are versatile chiral building blocks. Stereoselective reduction of phenacyl halide to chiral 2-halo-1-phenylethanol is the key reaction of the most economical synthetic route. Rhodotorula glutinis var. dairenensis IFO415 was discovered on screening as a potent microorganism reducing a phenacyl halide to the (R)-form of the corresponding alcohol. An NADPH-dependent carbonyl reductase was purified to homogeneity through four steps from this strain. The relative molecular mass of the enzyme was estimated to be 40,000 on gel filtration and 30,000 on SDS-polyacrylamide gel electrophoresis. This enzyme reduced a broad range of carbonyl compounds in addition to phenacyl halides. Some properties of the enzyme and preparation of a chiral styrene oxide using the crude enzyme are reported herein.
- Kizaki, Noriyuki,Sawa, Ikuo,Yano, Miho,Yasohara, Yoshihiko,Hasegawa, Junzo
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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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- A tandem enzyme reaction to produce optically active halohydrins, epoxides and diols
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The recombinant halohydrin dehalogenase from Agrobacterium radiobacter AD1 was used to obtain enantiomerically pure halohydrins and epoxides by kinetic resolution. By adding an excess of the recombinant epoxide hydrolase from the same organism the reversible conversion was drawn to completion. Halohydrins such as (S)-2,3-dichloro-1-propanol (E>100) and (S)-2-chloro-1-phenylethanol (E=73) were obtained with an enantiomeric excess of higher than 99%. This is a novel biocatalytic route for obtaining enantiomerically pure aromatic halohydrins and epoxides.
- Lutje Spelberg, Jeffrey H.,Van Hylckama Vlieg, Johan E. T.,Bosma, Tjibbe,Kellogg, Richard M.,Janssen, Dick B.
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p. 2863 - 2870
(2007/10/03)
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- Alternative synthesis of the chiral atypical β-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation
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We have developed an alternative synthesis of the atypical β-adrenergic phenylethanolaminotetraline agonist SR58611A. Two key intermediates have been synthesised involving enantioselective hydrogenation of an aminoketone and an enamide providing the corre
- Devocelle, Marc,Mortreux, Andre,Agbossou, Francine,Dormoy, Jean-Robert
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p. 4551 - 4554
(2007/10/03)
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