- The effect of absorbing resins on substrate concentration and enantiomeric excess in yeast reduction
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The correlation between the enantiomeric excess (e.e.) of the (S)-(+)-ethyl-3-hydroxybutanoate 2, obtained in the baker's yeast reduction of ethyl acetoacetate 1, and the concentration of the substrates in the fermentation mixture has been studied by the use of two different techniques (absorbing resins and organic solvents) The presence of resins undoubtedly influences the enantiomeric excess of the product.
- D'Arrigo, Paola,Fantoni, Giuseppe Pedrocchi,Servi, Stefano,Strini, Alberto
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- Einfache Umwandlung von (-)-(R)-3-Hydroxybuttersaeure in das (+)-(S)-Enantiomere und dessen Lacton (-)-(S)-4-Methyloxethan-2-on
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Condensation of (R)-3-hydroxybutanoic acid (1) with ethyl orthoacetate gives a 2-ethoxy-substituted 1,3-dioxanone 2 which is thermally labile: at ca. 100 deg C, two competing processes commence, one leading to ethyl (R)-3-acetoxybutanoate (3), the other one - with complete inversion of configuration - to the (S)-4-methyloxetan-2-one (4) and ethyl acetate.These can be readily separated by fractional distillation.Thus, enantiomerically pure (S)-3-hydroxybutanoic acid (ent-1) and l-2-alkyl-3-hydroxybutanoic acid derivatives (such as 6 and 8) become available from the biopolymer PHB, the precursor to the acid 1.
- Griesbeck, Axel,Seebach, Dieter
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- The use of liquefied petroleum gas (LPG) as a solvent for yeast reactions
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The yeast mediated reduction of ethyl acetoacetate to ethyl (S)-3-hydroxy butyrate proceeds with good yield and high enantioselectivity in liquefied petroleum gas (LPG). It was found that slightly more water (2 ml/g yeast) and more yeast (1.6 g/mmol substrate) were required to effect complete conversion than was the case with more conventional organic solvents, such as petroleum spirit.
- Johns, Melanie K.,Smallridge, Andrew J.,Trewhella, Maurie A.
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- The effect of particle size and ligand configuration on the asymmetric catalytic properties of proline-functionalized Pt-nanoparticles
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The effect of particle size on the asymmetric catalytic properties of supported ligand-functionalized nanoparticles (NPs) was investigated for the first time and found to alter significantly the activity but surprisingly not the stereoselectivity. These results suggest that the stereoselectivity of these complex systems is primarily determined by the ligand-reactant interaction, whereas the activity is determined by the particle size.
- Schrader, Imke,Neumann, Sarah,Himstedt, Rieke,Zana, Alessandro,Warneke, Jonas,Kunz, Sebastian
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- Enantio-differentiating hydrogenation of alkyl 3-oxobutanoates over tartaric acid-modified Ni catalyst: Enthalpy-entropy compensation effect as a tool for elucidating mechanistic features
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The enantio-differentiating hydrogenations of a series of alkyl 3-oxobutanoates were carried out at the temperatures ranging from 333 to 393 K over the (R,R)-tartaric acid-modified Ni catalyst prepared from commercially available Ni powder to achieve high enantiomeric excesses of 91-94%. It was demonstrated that the enantio-selectivity was not a simple function of the reaction temperature, being enhanced in the low temperature region to reach a maximum at 363–373 K and then decreased at higher temperatures. Nevertheless, all the differential enthalpies and entropies of activation calculated from the enantiomer ratios in the low and high temperature regions compensated with each other, indicating the same enantio-differentiation mechanism over the entire temperature range. A plausible enantio-differentiation mechanism explaining the effects of hydrogenation temperature on the enantio-selectivity is proposed.
- Osawa, Tsutomu,Wakasugi, Masahiro,Kizawa, Tomoko,Borovkov, Victor,Inoue, Yoshihisa
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- A simple enantioselective synthesis of γ-valerolactone
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The readily available biopolymer, poly-(R)-3-hydroxybutyrate was converted to (R)-(+)-γ-valerolactone in 32% overall yield in a simple 4 stage procedure.
- O'Neill,Lindell,Simpson,Willis
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- On the microbial reduction of ethyl α-methylacetoacetate
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In the present work several microorganisms were screened in the reduction of methyl and ethyl acetoacetates. Good to excellent ees were obtained with up to quantitative substrate conversions. These microorganisms were also tested in the reduction of ethyl α-methylacetoacetate with good des and excellent ees. It was noticed that Kluyveromyces marxianus and Trichoderma harzianum were found to lead to products of opposite configuration with the use of methyl or ethyl acetoacetates, which is a very unusual finding.
- Ramos, Aline de Souza,Ribeiro, Joyce Benzaquem,Vazquez, Leonardo,Fiaux, Sorele Batista,Leite, Selma Gomes Ferreira,Cruz, Renata de Andrade,Ramos, Maria da Conceicao Klaus V.,Neto, Francisco Radler de Aquino,Antunes, Octavio A.C.
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- Whole-cell biocatalysis in deep-eutectic-solvents/aqueous mixtures
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Whole-cell biocatalysis with the use of baker's yeast is demonstrated in different mixtures of water with deep eutectic solvents (DESs; choline chloride/glycerol, 1:2 mol/mol). Enantioselective ketone reduction is observed for long reaction times (>200 h), which suggests that the whole cells remain stable in these neoteric solvents. By changing the proportion of the DES added, a complete inversion of enantioselectivity is observed, from approximately 95 % enantiomeric excess (ee) (S) in pure water to approximately 95 % ee (R) in the pure DES. Presumably, some (S)-oxidoreductases present in baker's yeast are inhibited by DESs. DESpicably good: Whole-cell biocatalysis with the use of baker's yeast is demonstrated in different mixtures of water with deep eutectic solvents (DESs). Enantioselective ketone reduction is observed for long reaction times (>200 h), which suggests that the whole cells remain stable in these neoteric solvents. By changing the proportion of the DES added, a complete inversion of enantioselectivity is observed.
- Maugeri, Zaira,Dominguez De Maria, Pablo
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- Formation of the (R)- and (S)-Enantiomers of Ethyl 3-Hydroxybutanoate and of 1-(1,3-Dithian-2-yl)-2-hydroxypropane by Microbial Reduction
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The (R) and (S) enantiomers of 3-hydroxybutanoate and 1-(1,3-dithian-2-yl)-2-hydroxypropane are obtained from ethyl 3-oxobutanoate (1a) and 1-(1,3-dithian-2-yl)-2-oxopropane (1b), respectively, using growing cultures from different strains of Geotrichum candidum and Aspergillus niger.
- Bernardi, Rosanna,Cardillo, Rosanna,Ghiringhelli, Dario
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- Note on Biotransformations with Halobacterium halobium: Reduction of Ethyl 3-Oxobutanoate and Hydrolysis of Ethyl 3-Hydroxybutanoate. Cooperative Effects of Reductase and Hydrolase
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The archaebacterium Halobacterium halobium, growing in saturated NaCl solution, is tested for its ability to achieve biotransformations.We found that this microorganism does accept only a small veriety of compounds as substrates.Ethyl acetoacetate (1) is reduced to ethyl (S)-3-hydroxybutanoate (2) of optical purity of 40-76 percent, but in low chemical yields.The reduction is accompanied by hydrolysis of the hydroxy-ester to 3-hydroxybutanoic acid (3).Hydrolysis of rac-ester 2 by Halobacterium halobium gives (R)-2 of optical purity of up to 88 percent, depending upon reaction time, together with the almost racemic hydroxy-acid 3, both in low chemical yields.Hopes that the 'extremist' Halobacterium halobium would be able to effect unique conversions were not fulfilled.
- Ehrler, Juerg von,Seebach, Dieter
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- β-Ketoester reduction by baker's yeast immobilized in calcium alginate: An examination of pH effects on enantiospecificity
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Enantiospecificity of the reduction process and product yields in the reduction of ethyl benzoylacetate by baker's yeast immobilized in calcium aliginate beads depend strongly on the pH of the medium, and under optimum conditions products with high yields (80-85%) and high optical purity (e.e. 90-99%) can be obtained.
- Bhalerao,Chandraprakash,Babu,Fadnavis
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- Triptycene-Based Chiral and meso-N-Heterocyclic Carbene Ligands and Metal Complexes
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Based on 1-amino-4-hydroxy-triptycene, new saturated and unsaturated triptycene-NHC (N-heterocyclic carbene) ligands were synthesized from glyoxal-derived diimines. The respective carbenes were converted into metal complexes [(NHC)MX] (M=Cu, Ag, Au; X=Cl, Br) and [(NHC)MCl(cod)] (M=Rh, Ir; cod=1,5-cyclooctadiene) in good yields. The new azolium salts and metal complexes suffer from limited solubility in common organic solvents. Consequently, the introduction of solubilizing groups (such as 2-ethylhexyl or 1-hexyl by O-alkylation) is essential to render the complexes soluble. The triptycene unit infers special steric properties onto the metal complexes that enable the steric shielding of selected areas close to the metal center. Next, chiral and meso-triptycene based N-heterocyclic carbene ligands were prepared. The key step in the synthesis of the chiral ligand is the Buchwald–Hartwig amination of 1-bromo-4-butoxy-triptycene with (1S,2S)-1,2-diphenyl-1,2-diaminoethane, followed by cyclization to the azolinium salt with HC(OEt)3. The analogous reaction with meso-1,2-diphenyl-1,2-diaminoethane provides the respective meso-azolinium salt. Both the chiral and meso-azolinium salts were converted into metal complexes including [(NHC)AuCl], [(NHC)RhCl(cod)], [(NHC)IrCl(cod)], and [(NHC)PdCl(allyl)]. An in situ prepared chiral copper complex was tested in the enantioselective borylation of α,β-unsaturated esters and found to give an excellent enantiomeric ratio (er close to 90:10).
- Savka, Roman,Bergmann, Marvin,Kanai, Yuki,Foro, Sabine,Plenio, Herbert
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- A straightforward and modular synthesis of enantiopure C2- and C1-symmetrical 2,2″-phosphino-1,1″-biferrocenes
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A new practical and highly flexible synthesis of enantiopure C2- and C1-symmetrical 2,2″-phosphino-1,1″-biferrocenes is presented. The structural properties of two of their PdCl2 complexes and preliminary Ru-catalysed hydrogenations using the biferrocene ligands, giving anantioselectivities of up to 82%, are described.
- Xiao, Li,Mereiter, Kurt,Spindler, Felix,Weissensteiner, Walter
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- Synthesis of the fungus metabolite cladosin C
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Cladosin C is one of the few known enaminotetramic acids, isolated from extracts of the deep sea fungus Cladosporium sphaerospermum. It was synthesised in ten steps and 14% overall yield by a late-stage amination of the corresponding 3-acyltetramic acid. This was obtained by a Dieckmann condensation of an N-β-ketoacylaminoester derived from dehydrovalinate and the thioester-terminated side chain containing the stereogenic centre which stemmed from poly-(R)-3-hydroxybutyrate.
- Linder, David,Schobert, Rainer
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- 41. Production of (+)-(S)-Ethyl 3-Hydroxybutyrate and (-)-(R)-Ethyl 3-Hydroxybutyrate by Microbial Reduction of Ethyl Acetoacetate
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The production of (S)-ethyl 3-hydroxybutirate (2) from ethyl acetoacetate (1) in higher yields and with higher optical purity than with the usual procedures was achieved by continuous addition of the substrate 1 and sucrose to an aerated suspension of bakers' yeast.The microbial reduction of 1 by the fungus Geotrichum candidum LINK yields - for the first time - the antipode 3.
- Wipf, Beat,Kupfer, Ernts,Bertazzi, Roberto,Lauenberger, Hans Georg Wilhelm
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- Synthesis of BINAP ligands with imidazole tags for highly enantioselective Ru-catalyzed asymmetric hydrogenation of β-keto esters in ionic liquid systems
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The imidazole-tagged BINAP ligands were synthesized and used for Ru-catalyzed asymmetric hydrogenation of β-keto esters in ionic liquid (IL) systems. The Ru-BINAP catalysts with the imidazolium tags show high catalytic activity and enantioselectivity, which closely parallel the performance of unmodified BINAP. The catalyst recycling experiments using [bmim]Tf 2N/MeOH system demonstrated that introducing imidazolium moieties to the BINAP backbone can effectively enhance the affinity of the Ru-catalysts to the IL, reduce Ru leaching and improve catalysts stability, and after several cycles no significant loss of activity and enantioselectivity was observed.
- Jin, Xin,Kong, Fang-Fang,Yang, Zhi-Qiang,Cui, Fei-Fei
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- Rhizopus arrhizus mediated asymmetric reduction of alkyl 3-oxobutanoates
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t-Butyl 3-oxobutanoate gives the hydroxyester in ~68% yield and 99% ee. Alkyl 3-oxobutanoates (alkyl: methyl, ethyl, allyl, isobutyl, t-butyl) were reduced enantioselectively to the corresponding (S)-alcohols by the fungus Rhizopus arrhizus and other Rhizopus sp. The best result obtained was with t-butyl 3-oxobutanoate, which was reduced by R. arrhizus with 99% enantiomeric excess and ~68% isolated yield.
- Salvi, Neeta A.,Chattopadhyay, Subrata
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- Study on effects of modification conditions of powdered nickel-cobalt catalysts on enantioselectivity of hydrogenation of ethyl acetoacetate
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An effect of modification conditions of powdered nickel-cobalt catalysts on enantioselectivity of hydrogenation of ethyl acetoacetate has been studied. Addition of NaBr to the modifying solution of RR-(+)-tartaric acid does not improve enantioselectivity of the catalyst. When the Ni-Co catalysts are modified with amino acids, the best results are obtained with L-β-plienylalanine (17% ee).
- Zubareva,Dorokhin,Klabunovskii
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- Non-linear effects in ruthenium-catalysed asymmetric hydrogenation with atropisomeric diphosphanes
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A strong positive nonlinear effect (asymmetric amplification) was found to take place during asymmetric hydrogenations using chiral atropisomeric diphosphane-ruthenium catalysts. As an example, at atmospheric pressure the use of 50% ee BINAP to prepare [(binap)Ru(Br)2] give rise to a hydrogenated product with 91% ee. The influence of temperature and hydrogen pressure on this effect are presented. These nonlinear effects can be explained on the basis of a hydrogenation mechanism in which diastereomeric dimers as pre- catalytic species are present.
- Girard, Christian,Genet, Jean-Pierre,Bulliard, Michel
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- Enantioselective catalytic asymmetric hydrogenation of ethyl acetoacetate in room temperature ionic liquids
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Ethyl acetoacetate was chosen to evaluate the efficiency of hydrosoluble derivatives of 4,4′- and 5,5′-diamBINAP in enantioselective catalytic asymmetric hydrogenation in various room temperature ionic liquids (RTILs). Complete conversion and good selectivity were obtained. Recycling by simple extraction with pentane was also possible.
- Berthod, Mikael,Joerger, Jean-Michel,Mignani, Gerard,Vaultier, Michel,Lemaire, Marc
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- Unexpected talaroenamine derivatives and an undescribed polyester from the fungus Talaromyces stipitatus ATCC10500
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Chemical investigation of the fungus Talaromyces stipitatus ATCC 10500, whose genome has been sequenced, led to the isolation of four undescribed talaroenamines B-E along with the known talaroenamine A. Their structures were elucidated on the basis of spectroscopic studies including mass spectrometry, extensive 2D NMR and electronic circular dichroism (ECD). Interestingly, talaroenamine A had previously been isolated from the strain of T. stipitatus Δtrop C, a strain knocked out for the gene encoding a non-heme Fe(II)-dependent dioxygenase catalyzing the oxidative ring expansion leading to the tropolone, but never from a wild-type strain. All talaroenamines were evaluated for their antiplasmodial activity and Talaroenamine D exhibited the best inhibition against the chloroquine-resistant Plasmodium falciparum (FcB1 strain) without noticeable toxicity on HeLa and preadipose cell lines. In the course of the chemical investigation of T. stipitatus, an undescribed polyester was also isolated and its absolute configuration was determined by hydrolysis and transesterification followed by gas chromatography on chiral column.
- Zang, Yi,Genta-Jouve, Grégory,Sun, Tithnara Anthony,Li, Xuwen,Didier, Buisson,Mann, Stéphane,Mouray, Elisabeth,Larsen, Annette K.,Escargueil, Alexandre E.,Nay, Bastien,Prado, Soizic
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- ENHANCED OPTICAL PURITY OF 3-HYDROXYESTERS OBTAINED BY BAKER'S YEAST REDUCTION OF 3-KETOESTERS
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Fermenting Baker's yeast, enclosed in a dialysis tube, reduces efficiently 3-ketoesters added to the surrounding subtonic solution, to the corresponding 3-hydroxyesters in good yield (45-55percent) and enhanced optical purity (ee 96-97percent)
- Spiliotis, Vassilis,Papahatjis, Demetris,Ragoussis, Nikitas
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- 107. Preparative Asymmetric Reduction of 3-Ketobutyrate and -valerate by Suspended Cells of Thermophilic Bacteria (Thermoanaerobium brockii) in Ordinary Laboratory Equipment
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The thermophilic and anaerobic bacteria specified in the title are isolated on a 0.8 kg scale by tangential flow filtration and centrifugation from a 300-l bioreactor.The microorganisms are stored in a freezer (-20 deg) and used, analogously to baker's yeast, for asymmetric reductions.Thus, ethyl 3-ketovalerate (4.3 g/l (H2O) is converted in 40 percent yield to (S)-3-hydroxyvalerate (6), with an enantiomeric excess of 93 percent (24 h at 72 deg).
- Seebach, Dieter,Giovannini, Fabio,Lamatsch, Bernd
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- The Yeast Mediated Reduction of Ethyl acetoacetate in Petroleum Ether
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Ethyl acetoacetate is smoothly reduced with high selectivity and good yield to (S)-ethyl 3-hydroxybutyrate using freeze-dried yeast in petroleum ether.
- Jayasinghe, Leonard Y.,Smallridge, Andrew J.,Trewhella, Maurie A.
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- Single-Point Mutant Inverts the Stereoselectivity of a Carbonyl Reductase toward β-Ketoesters with Enhanced Activity
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Enzyme stereoselectivity control is still a major challenge. To gain insight into the molecular basis of enzyme stereo-recognition and expand the source of antiPrelog carbonyl reductase toward β-ketoesters, rational enzyme design aiming at stereoselectivity inversion was performed. The designed variant Q139G switched the enzyme stereoselectivity toward β-ketoesters from Prelog to antiPrelog, providing corresponding alcohols in high enantiomeric purity (89.1–99.1 % ee). More importantly, the well-known trade-off between stereoselectivity and activity was not found. Q139G exhibited higher catalytic activity than the wildtype enzyme, the enhancement of the catalytic efficiency (kcat/Km) varied from 1.1- to 27.1-fold. Interestingly, the mutant Q139G did not lead to reversed stereoselectivity toward aromatic ketones. Analysis of enzyme–substrate complexes showed that the structural flexibility of β-ketoesters and a newly formed cave together facilitated the formation of the antiPrelog-preferred conformation. In contrast, the relatively large and rigid structure of the aromatic ketones prevents them from forming the antiPrelog-preferred conformation.
- Li, Aipeng,Wang, Ting,Tian, Qing,Yang, Xiaohong,Yin, Dongming,Qin, Yong,Zhang, Lianbing
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p. 6283 - 6294
(2021/03/16)
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- Effect of organic solvents on asymmetric reduction of β-keto esters using cyanobacterium Synechocystis sp. PCC 6803
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The asymmetric reduction of tert-butyl 3-oxobutanoate by cyanobacterium Synechocystis sp. PCC 6803 under illumination with red LED light at 25 °C for 24 h afforded the corresponding (R)-β-hydroxy ester in 79% enantiomeric excess (ee) (81% yield), while the addition of toluene (1% (v/v)) to the system gave the corresponding (S)-β-hydroxy ester in >99% ee (87% yield). Organic solvents such as chloroform, benzene, ethylbenzene, cyclohexane, and methylcyclohexane showed similar effects and afforded the corresponding (S)-β-hydroxy ester in >99% ee. However, polar organic solvents, such as DMSO, THF, and ethanol, as well as dodecane—a hydrophobic solvent with a straight long-chain—did not exhibit such effects.
- Tanaka, Shusei,Kojima, Hideo,Takeda, Satomi,Yamanaka, Rio,Takemura, Tetsuo
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supporting information
(2021/07/25)
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- PROCESS OF SYNTHESIZING AND PURIFYING (3R)-HYDROXYBUTYL (3R)-HYDROXYBUTANOATE
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A process for synthesizing (R)-3 -hy droxybutyl (R)-3 -hy droxybutanoate from ethyl (R)-3-hydroxybutanoate and (R)-l,3-butanediol, as well a process for synthesizing (R)-3-hy droxybutyl (R)-3-hy droxybutanoate from (R)-3-hydroxybutyric acid and (R)-l,3-butanediol. Also provided are processes for isolating (R)-3-hy droxybutyl (R)-3-hy droxybutanoate, including from a fermentation broth.
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Page/Page column 0531
(2021/11/20)
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- SYNTHESIS OF 3-HYDROXYBUTYRYL 3-HYDROXYBUTYRATE AND RELATED COMPOUNDS
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In various embodiments methods of preparing hydroxybutyryl 3-hydroxybutyrate and related compounds are provided along with methods of use thereof.
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Paragraph 0308; 0317
(2021/04/02)
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- Asymmetric visible-light photobiocatalytic reduction of β-keto esters utilizing the cofactor recycling system in Synechocystis sp. PCC 6803
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The asymmetric reduction of β-keto esters employing a wild-type strain of cyanobacterium Synechocystis sp. PCC 6803 under illumination of red LED light at 25 °C for 24 h was evaluated. As a result, the corresponding (R)-β-hydroxy esters were obtained as major products. The R-selectivity was shown to increase for bulkier substrates. Moreover, it was also found that the R-selectivity increased with decreasing substrate concentrations. This can be explained by the assumption that the Km value of the R-selective reductase is smaller than that of the S-selective enzyme involved in the reaction. Additionally, it was demonstrated that the R-selective reductase required the light-dependent production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) for effective reaction; however, the S-selective variant did not. Overall, cyanobacterium was employed as a sustainable photobiocatalyst proliferating under illumination of light, while utilizing inorganic salts and atmospheric carbon dioxide (CO2). Employing the whole-cell system allowed for the preparation of industrially-important chiral compounds, such as optically active β-hydroxy esters.
- Tanaka, Shusei,Kojima, Hideo,Takeda, Satomi,Yamanaka, Rio,Takemura, Tetsuo
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supporting information
(2020/05/08)
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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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- 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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- Significantly enhancing the biocatalytic synthesis of chiral alcohols by semi-rationally engineering an anti-Prelog carbonyl reductase from Acetobacter sp. CCTCC M209061
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Chiral alcohols and their derivatives are vital building blocks to synthesize pharmaceutical drugs and high-valued chemicals. Wild-type carbonyl reductase AcCR from Acetobacter sp. has ideal enantioselectivity toward 11 prochiral substrates (e.e.>99%) but poor activity. In this work, a semi-rational engineering was performed to enhance the activity of AcCR. Fortunately, three positive double-mutants (mut-E144A/G152 L, mut-G152 L/Y189 N, and mut-I147 V/G152 L) with specific activity 17–61 folds higher than that of enzyme without modified were achieved. Kinetic studies suggested that the catalytic efficiencies (kcat/Km) of these mutants were also well enhanced. Finally, these modified mut-AcCRs were successfully applied in asymmetric reductions of 11 structurally diverse prochiral substrates (200 mM) with excellent product yields (76.8%–99.1%) and enantiomeric excess (e.e.>99%), which provides an alternative strategy for efficient synthesis of chiral alcohols for pharmaceuticals industry with ideal yield and enantioselectivity.
- Wei, Ping,Guo, Ze-Wang,Wu, Xiao-Ling,Liang, Shan,Ou, Xiao-Yang,Xu, Pei,Zong, Min-Hua,Yang, Ji-Guo,Lou, Wen-Yong
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- Homochiral Metal-Organic Cage for Gas Chromatographic Separations
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Metal-organic cages (MOCs) as a new type of porous material with well-defined cavities were extensively pursued because of their relative ease of synthesis and their potential applications in host-guest chemistry, molecular recognition, separation, catalysis, gas storage, and drug delivery. Here, we first reported that a homochiral MOC [Zn3L2] is explored to fabricate [Zn3L2] coated capillary column for high-resolution gas chromatographic separation of a wide range of analytes, including n-alkanes, polycyclic aromatic hydrocarbons, and positional isomers, especially for racemates. Various kinds of racemates such as alcohols, diols, epoxides, ethers, halohydrocarbons, and esters were separated with good enantioselectivity and reproducibility on the [Zn3L2] coated capillary column. The fabricated [Zn3L2] coated capillary column exhibited significant chiral recognition complementary to that of a commercial β-DEX 120 column and our recently reported homochiral porous organic cage CC3-R coated column. The results show that the homochiral MOCs will be very attractive as a new type of chiral selector in separation science.
- Xie, Sheng-Ming,Fu, Nan,Li, Li,Yuan, Bao-Yan,Zhang, Jun-Hui,Li, Yan-Xia,Yuan, Li-Ming
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p. 9182 - 9188
(2018/07/21)
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- METHOD FOR ISOLATING R-ISOMER OF 3 HYDROXY BUTYRIC ACID ESTER
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PROBLEM TO BE SOLVED: To provide a method for isolating R-isomer of 3-hydroxy butyric acid ester in order to enhance the optical purity of the R-isomer of 3-hydroxy butyric acid ester. SOLUTION: There is provided a method for isolating R-isomer of 3-hydroxy butyric acid ester including: an acylation step A of chemically acylating the hydroxy group at the 3-position of the 3-hydroxy butyric acid ester containing R-isomer and S-isomer; a deacylation step B of deacylating an acylated product of the R-isomer of 3-hydroxy butyric acid ester with lipase to produce the R-isomer of 3-hydroxy butyric acid ester; and a distillation step C of isolating the R-isomer of 3-hydroxy butyric acid ester from an acylated product of the S-isomer of 3-hydroxy butyric acid ester by distillation. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2019,JPOandINPIT
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Paragraph 0059
(2018/12/05)
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- Highly Chemoselective Deprotection of the 2,2,2-Trichloroethoxycarbonyl (Troc) Protecting Group
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Nonreducing, pH-neutral conditions for the selective cleavage of the 2,2,2-trichloroethoxycarbonyl (Troc) protecting group are reported. Using trimethyltin hydroxide in 1,2-dichloroethane, Troc-protected alcohols, thiols, and amines can be selectively unmasked in the presence of various functionalities that are incompatible with the reducing conditions traditionally used to remove the Troc group. This mild deprotection protocol tolerates a variety of other hydrolytically sensitive and acid/base-sensitive moieties as well.
- Trost, Barry M.,Kalnmals, Christopher A.,Tracy, Jacob S.,Bai, Wen-Ju
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supporting information
p. 8043 - 8046
(2019/01/04)
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- Efficient synthesis of the ketone body ester (R)-3-hydroxybutyryl-(R)-3-hydroxybutyrate and its (S,S) enantiomer
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The ketone body ester (R)-3-hydroxybutyryl-(R)-3-hydroxybutyrate and its (S,S) enantiomer were prepared in a short, operationally simple synthetic sequence from racemic β-butyrolactone. Enantioselective hydrolysis of β-butyrolactone with immobilized Candida antarctica lipase-B (CAL-B) results in (R)-β-butyrolactone and (S)-β-hydroxybutyric acid, which are easily converted to (R) or (S)-ethyl-3-hydroxybutyrate and reduced to (R) or (S)-1,3 butanediol. Either enantiomer of ethyl-3-hydroxybutyrate and 1,3 butanediol are then coupled, again using CAL-B, to produce the ketone body ester product. This is an efficient, scalable, atom-economic, chromatography-free, and low cost synthetic method to produce the ketone body esters.
- Budin, Noah,Higgins, Erin,DiBernardo, Anthony,Raab, Cassidy,Li, Chun,Ulrich, Scott
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p. 560 - 564
(2018/07/25)
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- Functional characterization of salt-tolerant microbial esterase WDEst17 and its use in the generation of optically pure ethyl (R)-3-hydroxybutyrate
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The two enantiomers of ethyl 3-hydroxybutyrate are important intermediates for the synthesis of a great variety of valuable chiral drugs. The preparation of chiral drug intermediates through kinetic resolution reactions catalyzed by esterases/lipases has been demonstrated to be an efficient and environmentally friendly method. We previously functionally characterized microbial esterase PHE21 and used PHE21 as a biocatalyst to generate optically pure ethyl (S)-3-hydroxybutyrate. Herein, we also functionally characterized one novel salt-tolerant microbial esterase WDEst17 from the genome of Dactylosporangium aurantiacum subsp. Hamdenensis NRRL 18085. Esterase WDEst17 was further developed as an efficient biocatalyst to generate (R)-3-hydroxybutyrate, an important chiral drug intermediate, with the enantiomeric excess being 99% and the conversion rate being 65.05%, respectively, after process optimization. Notably, the enantio-selectivity of esterase WDEst17 was opposite than that of esterase PHE21. The identification of esterases WDEst17 and PHE21 through genome mining of microorganisms provides useful biocatalysts for the preparation of valuable chiral drug intermediates.
- Wang, Yilong,Xu, Yongkai,Zhang, Yun,Sun, Aijun,Hu, Yunfeng
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p. 769 - 776
(2018/03/29)
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- Synthesis of an advanced intermediate enroute to thiomarinol antibiotics
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A stereoselective synthesis of the C1-C14 fragment of thiomarinols is disclosed. The key steps include the stereoselective preparation of an allylic sulfide via a chloro sulfide by 1,2-asymmetric induction, ring-closing metathesis reaction, Kirmse-Doyle reaction for the preparation of a γ,δ-unsaturated ester, Nozaki-Hiyama-Kishi coupling and Julia-Kocienski olefination reaction. Substrate controlled asymmetric induction has been advantageously employed for the creation of stereogenic centers. Noyori transfer hydrogenation and asymmetric hydrogenation reactions have been utilized for the creation of carbinol stereocenters.
- Raghavan, Sadagopan,Ravi, Anil
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p. 2814 - 2823
(2017/04/14)
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- Identification of a Robust Carbonyl Reductase for Diastereoselectively Building syn-3,5-Dihydroxy Hexanoate: A Bulky Side Chain of Atorvastatin
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t-Butyl-6-cyano-(3R,5R)-dihydroxyhexanoate is an advanced chiral precursor for the synthesis of the side chain pharmacophore of cholesterol-lowering drug atorvastatin. Herein, a robust carbonyl reductase (LbCR) was newly identified from Lactobacillus brevis, which displays high activity and excellent diastereoselectivity toward bulky t-butyl 6-cyano-(5R)-hydroxy-3-oxo-hexanoate (7). The engineered Escherichia coli cells harboring LbCR and glucose dehydrogenase (for cofactor regeneration) were employed as biocatalysts for the asymmetric reduction of substrate 7. As a result, as much as 300 g L-1 of water-insoluble substrate was completely converted to the corresponding chiral diol with >99.5% de in a space-time yield of 351 g L-1 d-1, indicating a great potential of LbCR for practical synthesis of the very bulky and bi-chiral 3,5-dihydroxy carboxylate side chain of best-selling statin drugs.
- Gong, Xu-Min,Zheng, Gao-Wei,Liu, You-Yan,Xu, Jian-He
-
supporting information
p. 1349 - 1354
(2017/09/23)
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- Synthesis process of (R)-3-hydroxybutyric acid and salts thereof
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The invention discloses a synthesis process for preparing (R)-3-hydroxybutyric acid and sodium salt, potassium salt, magnesium salt and calcium salt thereof. The process includes steps: adding 3-oxobutanoate and a ruthenium complex catalyst into organic solvent according to a mole ratio of 1:0.0005-0.005, and reacting at 20-80 DEG C for 12-24h under a hydrogen pressure of 1-20bar to obtain (R)-3-hydroxybutyrate; dissolving (R)-3-hydroxybutyrate into water, and subjecting to reaction with sodium hydroxide, potassium hydroxide or calcium hydroxide for 2-12h at a low temperature to obtain sodium salt, potassium salt, magnesium salt and calcium salt of (R)-3-hydroxybutyric acid; subjecting water solution of (R)-3-sodium hydroxybutyrate to 732 cation exchange resin treatment to remove sodium ions to obtain (R)-3-hydroxybutyric acid; subjecting (R)-3-hydroxybutyric acid to reaction with magnesium hydroxide to obtain (R)-3-magnesium hydroxybutyrate. Ee values of (R)-3-hydroxybutyric acid and sodium salt, potassium salt, magnesium salt and calcium salt thereof reach 90% or above. The method has advantages of low environment pollution, low cost and easiness in aftertreatment.
- -
-
Paragraph 0039; 0040; 0041
(2017/10/07)
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- Cobalt carbonyl ionic liquids based on the 1,1,3,3-tetra-alkylguanidine cation: Novel, highly efficient, and reusable catalysts for the carbonylation of epoxides
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A series of novel cobalt carbonyl ionic liquids based on 1,1,3,3-tetra-alkyl-guanidine, such as [1,1-dimethyl-3,3-diethylguanidinium][Co(CO)4] (3a), [1,1-dimethyl-3,3-dibutylguanidinium][Co(CO)4] (3b), [1,1-dimethyl-3,3-tetramethyleneguanidinium][Co(CO)4] (3c), and [1,1-dimethyl-3,3-pentamethyleneguanidinium] [Co(CO)4] (3d), were synthesized in good yields and were also characterized using infrared spectroscopy, ultraviolet-visible spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, 13C NMR spectroscopy, high–resolution mass spectrometry, differential scanning calorimetry, and thermogravimetric analysis. The four compounds exhibited high thermal and chemical stability. In addition, the catalytic performance of these compounds was investigated in the carbonylation of epoxides, with 3a exhibiting the best catalytic activity without the aid of a base as the additive. The catalyst could be reused at least six times without significant decreases of the selectivity or conversion rate. Moreover, the catalyst system exhibited good tolerance with terminal epoxides bearing alkyl, alkenyl, aryl, alkoxy, and chloromethyl functional groups.
- Zhang, Wei,Han, Feng,Tong, Jin,Xia, Chungu,Liu, Jianhua
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p. 805 - 812
(2017/05/29)
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- A formal total synthesis of anti-Helicobacter pylori agent (+)-spirolaxine methyl ether
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A convergent, formal enantioselective synthesis of anti-Helicobacter pylori agent, (+)-spirolaxine methyl ether 2 has been achieved in high enantiomeric purity starting from commercially available 1,5-pentanediol. The strategy mainly comprises of the Noyori's asymmetric reduction and Brown allylation/Cu-catalyzed lactonization as the key step for the construction of key chiral intermediates, spiroketal 3 and phthalide fragment 4.
- Gadakh, Sunita K.,Sudalai, Arumugam
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supporting information
p. 25 - 28
(2015/12/23)
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- Application of homochiral alkylated organic cages as chiral stationary phases for molecular separations by capillary gas chromatography
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Molecular organic cage compounds have attracted considerable attention due to their potential applications in gas storage, catalysis, chemical sensing, molecular separations, etc. In this study, a homochiral pentyl cage compound was synthesized from a condensation reaction of (S,S)-1,2-pentyl-1,2-diaminoethane and 1,3,5-triformylbenzene. The imine-linked pentyl cage diluted with a polysiloxane (OV-1701) was explored as a novel stationary phase for high-resolution gas chromatographic separation of organic compounds. Some positional isomers were baseline separated on the pentyl cage-coated capillary column. In particular, various types of enantiomers including chiral alcohols, esters, ethers and epoxides can be resolved without derivatization on the pentyl cage-coated capillary column. The reproducibility of the pentyl cage-coated capillary column for separation was investigated using nitrochlorobenzene and styrene oxide as analytes. The results indicate that the column has good stability and separation reproducibility after being repeatedly used. This work demonstrates that molecular organic cage compounds could become a novel class of chiral separation media in the near future.
- Xie, Shengming,Zhang, Junhui,Fu, Nan,Wang, Bangjin,Hu, Cong,Yuan, Liming
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- Asymmetric hydrogenation by RuCl2(R-Binap)(dmf)n encapsulated in silica-based nanoreactors
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The Noyori catalyst RuCl2(R-Binap)(dmf)n has been successfully encapsulated in C-FDU-12 by using the active chlorosilane Ph2Cl2Si as the silylating agent. 31P-NMR results show that there is no strong interaction between the molecular catalyst and the solid support, thus the encapsulated molecular catalyst could move freely in the nanoreactor during the catalytic process. The solid catalyst exhibits high activity and enantioselectivity for the asymmetric hydrogenation of a series of β-keto esters due to the preserved intrinsic properties of RuCl2(R-Binap)(dmf)n encapsulated in the nanoreactor. The solid catalyst could be recycled by simple filtration and be reused at least four times.
- Peng, Juan,Wang, Xuefeng,Zhang, Xiaoming,Bai, Shiyang,Zhao, Yaopeng,Li, Can,Yang, Qihua
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p. 666 - 672
(2015/02/19)
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- A highly efficient designer cell for enantioselective reduction of ketones
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A designer cell, surf-crs-gdh, coexpressing carbonyl reductase (crs) and glucose dehydrogenase (gdh) on the cell surface has been constructed and its enzyme activities are compared with those of the corresponding cell, cyto-crs-gdh, coexpressing crs and gdh in cytosol. For various ketones, surf-crs-gdh exhibited 48- to 265-fold higher crs activity per unit protein compared to cyto-crs-gdh.
- Srivastava, Gautam,Pal, Mohan,Kaur, Suneet,Jolly, Ravinder S.
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p. 105 - 108
(2015/02/19)
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- Conjugated microporous polymers with chiral BINAP ligand built-in as efficient catalysts for asymmetric hydrogenation
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A series of chiral conjugated microporous polymers (CMPs) based on the chiral (R)-BINAP ligand (BINAP-CMPs) were synthesized with tunable BET surface areas. These solid catalysts show high activities and enantioselectivities for the asymmetric hydrogenation of β-keto esters after coordination with ruthenium species. Moreover, CMPs can realize spatial isolation. Through preventing the formation of dimers and trimers, BINAP-CMPs show much higher activity than BINAP for the Ir-catalyzed asymmetric hydrogenation of quinaldine.
- Wang, Xu,Lu, Sheng-Mei,Li, Jun,Liu, Yan,Li, Can
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p. 2585 - 2589
(2015/05/13)
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- ORGANOCATALYTIC PROCESS FOR ASYMMETRIC SYNTHESIS OF DECANOLIDES
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The present invention discloses organocatalytic process for asymmetric synthesis of highly enantioselective decanolide compounds in high yield with >99% ee. Further, the present invention disclose cost effective, improved organocatalytic process for asymmetric synthesis of highly enantioselective decanolides compounds from non-chiral, cheap, easily available raw materials.
- -
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Paragraph 0106; 0139; 0140; 0141
(2015/08/04)
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- Asymmetric synthesis of optically active methyl-2-benzamido-methyl-3-hydroxy-butyrate by robust short-chain alcohol dehydrogenases from Burkholderia gladioli
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Three short-chain alcohol dehydrogenases from Burkholderia gladioli were discovered for their great potential in the dynamic kinetic asymmetric transformation of methyl 2-benzamido-methyl-3-oxobutanoate, and their screening against varied organic solvents and substrates. This is the first report of recombinant enzymes capable of achieving this reaction with the highest enantio- and diastereo-selectivity.
- Chen, Xiang,Liu, Zhi-Qiang,Huang, Jian-Feng,Lin, Chao-Ping,Zheng, Yu-Guo
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p. 12328 - 12331
(2015/07/27)
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- Cloning, expression and enzymatic characterization of an aldo-keto reductase from Candida albicans XP1463
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An aldo-keto reductase encoding gene caakr was cloned from Candida albicans XP1463 (CCTCC M 2014382), and heterologously expressed in Escherichia coli. The aldo-keto reductase CaAKR is NADH-dependent with a molecular weight of approximately 38.6 kDal including a His6-Tag. It is active and stable at 30°C and pH 7.0. The maximal reaction rate (Vmax), apparent Michaelis-Menten constant (Km) and catalytic constant (kcat) for t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate ((R)-1a) were 11.50 mmol/L min, 1.91 mmol/L and 218.50 min-1. Besides atorvastatin's chiral synthon t-butyl 6-cyano-(3R,5R)- dihydroxy hexanoate ((R,R)-1b), it can synthesize N,N-2-dimethyl-(3S)-hydroxy-3-(2-thienyl)-1-propanine ((S)-9b) and methyl 1-[E]-2-[3-[3-[2-(7-chloro-2-quinoliny) ethenyl] phenyl]-(3S)-hydroxy propy] benzoate ((S)-10b), the chiral intermediates of duloxetine and montelukast, displaying potential applications in pharmaceutical industry. 2015 Elsevier B.V. All rights reserved.
- Wang, Ya-Jun,Liu, Xiao-Qing,Luo, Xi,Liu, Zhi-Qiang,Zheng, Yu-Guo
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- Chiral spiro-pyridylamidophosphine ligand compound, synthesis method therefor and application thereof
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The present invention relates to a chiral spiro-pyridylamidophosphine ligand compound, synthesis method therefor and application thereof. The chiral spiro-pyridylamidophosphine compound is a compound having a structure of Formula (I), a racemate or optical isomer thereof, or a catalytically acceptable salt thereof, and is mainly characterized by having a chiral spiro-dihydro-indene skeleton in its structure. The chiral spiro-pyridylamidophosphine compound may be synthesized with optical active 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene or substituted 7-diaryl/alkylphosphino-7′-amino-1,1′-spiro-dihydro-indene having a spiro-skeleton as chiral starting material. The chiral spiro-pyridylamidophosphine compound may be used as a chiral ligand in asymmetric hydrogenation of a carbonyl compound catalyzed by iridium, in which the reaction activity is very high, the amount of the catalyst may be 0.0001 mol %, and the enantioselectivity of the reaction is up to 99.9% ee.
- -
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Page/Page column 17; 18-20
(2015/03/03)
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- Efficient synthesis of an ε-hydroxy ester in a space-time yield of 1580 g L-1 d-1 by a newly identified reductase RhCR
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A new NADH-dependent carbonyl reductase RhCR capable of efficiently reducing the ε-ketoester ethyl 8-chloro-6-oxooctanoate (ECOO) to give ethyl (S)-8-chloro-6-hydroxyoctanoate [(S)-ECHO], an important chiral precursor for the synthesis of (R)-α-lipoic acid, was identified from Rhodococcus sp. ECU1014. Using recombinant Escherichia coli cells expressing RhCR and glucose dehydrogenase used for the regeneration of cofactor, 440 g L-1 (2 M) of ECOO were stoichiometrically converted to (S)-ECHO in a space-time yield of 1580 g L-1 d-1 without the external addition of any expensive cofactor.
- Chen, Rui-Jie,Zheng, Gao-Wei,Ni, Yan,Zeng, Bu-Bing,Xu, Jian-He
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p. 1501 - 1504
(2015/02/02)
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- ORGANOCATALYTIC PROCESS FOR ASYMMETRIC SYNTHESIS OF DECANOLIDES
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The present invention discloses organocatalytic process for asymmetric synthesis of highly enantioselective decanolide compounds in high yield with > 99% ee. Further, the present invention disclose cost effective, improved organocatalytic process for asymmetric synthesis of highly enantioselective decanolides compounds from non-chiral, cheap, easily available raw materials.
- -
-
Paragraph 00059
(2014/03/26)
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- Enhanced enantioselectivity in the heterogeneous catalytic hydrogenation of acetoacetate esters into the corresponding 3-hydroxybutyrates using commercial nickel powder
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Heterogeneous catalytic hydrogenation of acetoacetic acid esters over tartaric acid/NaBr-modified Ni powder was determined to be a critical function of the steric bulk of the ester moiety to afford quantitatively 3-hydroxybutyrate in 94% enantiomeric excess when ethyl and i-butyl esters are used, providing a facile route to optically active 3-hydroxybutyrates.
- Osawa, Tsutomu,Kizawa, Tomoko,Ikeda, Shinji,Kitamura, Takayuki,Inoue, Yoshihisa,Borovkov, Victor
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p. 1630 - 1633
(2015/01/09)
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- PROCESS FOR PRODUCING (R)-3-HYDROXYBUTYL (R)-3-HYDROXYBUTYRATE
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A process for the production of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate comprising: i) contacting poly-(R)-3-hydroxybutyrate with an alcohol to transesterify the poly-(R)-3-hydroxybutyrate under transesterification conditions to produce an ester of (R)-3-hydroxybutyrate and the alcohol; ii) separating the product of step i) into a first and second portion and reducing the first portion of the (R) 3-hydroxybutyrate ester to form (R)-1,3-butanediol; and iii) contacting under transesterification conditions the (R)-1,3-butanediol from step ii) with the second portion of the transesterified ester to produce (R)-3-hydroxybutyl-(R)-hydroxybutanoate.
- -
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Page/Page column 6; 7
(2014/09/29)
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- Heterogeneous versus homogeneous copper(II) catalysis in enantioselective conjugate-addition reactions of boron in water
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We have developed CuII-catalyzed enantioselective conjugate-addition reactions of boron to α,β-unsaturated carbonyl compounds and α,β,γ,δ-unsaturated carbonyl compounds in water. In contrast to the previously reported CuI catalysis that required organic solvents, chiral CuII catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)2 with chiral ligand L1; cat. 2: Cu(OH)2 and acetic acid with ligand L1; and cat. 3: Cu(OAc)2 with ligand L1. Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β-unsaturated carbonyl compounds and an α,β-unsaturated nitrile compound, including acyclic and cyclic α,β-unsaturated ketones, acyclic and cyclic β,β- disubstituted enones, acyclic and cyclic α,β-unsaturated esters (including their β,β-disubstituted forms), and acyclic α,β-unsaturated amides (including their β,β-disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43 200 h-1) for an asymmetric conjugate-addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ, δ-unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4-Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ-unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ-unsaturated carbonyl compounds with compound 2, whereas 1,4-addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6-addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate-addition reactions in water were investigated and we propose stereochemical models that are supported by X-ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover. Copyright
- Kitanosono, Taku,Xu, Pengyu,Kobayashi, Shu
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supporting information
p. 179 - 188
(2014/01/06)
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- CHIRAL SPIRO-PYRIDYLAMIDOPHOSPHINE LIGAND COMPOUND, SYNTHESIS METHOD THEREFOR AND APPLICATION THEREOF
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The present invention relates to a chiral spiro-pyridylamidophosphine ligand compound, synthesis method therefor and application thereof. The chiral spiro-pyridylamidophosphine compound is a compound having a structure of Formula (I), a racemate or optical isomer thereof, or a catalytically acceptable salt thereof, and is mainly characterized by having a chiral spiro-dihydro-indene skeleton in its structure. The chiral spiro-pyridylamidophosphine compound may be synthesized with optical active 7-diaryl/alkylphosphino-7'-amino-1,1'-spiro-dihydro-indene or substituted 7-diaryl/alkylphosphino-7'-amino-1,1'-spiro-dihydro-indene having a spiro-skeleton as chiral starting material. The chiral spiro-pyridylamidophosphine compound may be used as a chiral ligand in asymmetric hydrogenation of a carbonyl compound catalyzed by iridium, in which the reaction activity is very high, the amount of the catalyst may be 0.0001 mol%, and the enantioselectivity of the reaction is up to 99.9%ee.
- -
-
Paragraph 0059; 0060
(2013/10/08)
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- Total syntheses and biological reassessment of lactimidomycin, isomigrastatin and congener glutarimide antibiotics
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Lactimidomycin (1) was described in the literature as an exquisitely potent cell migration inhibitor. Encouraged by this claim, we developed a concise and scalable synthesis of this bipartite glutarimide-macrolide antibiotic, which relies on the power of ring-closing alkyne metathesis (RCAM) for the formation of the unusually strained 12-membered head group. Subsequent deliberate digression from the successful path to 1 also brought the sister compound isomigrastatin (2) as well as a series of non-natural analogues of these macrolides into reach. A careful biological re-evaluation of this compound collection showed 1 and progeny to be potently cytotoxic against a panel of cancer cell lines, even after one day of compound exposure; therefore any potentially specific effects on tumor cell migration were indistinguishable from the acute effect of cell death. No significant cell migration inhibition was observed at sub-toxic doses. Although these findings cannot be reconciled with some reports in the literature, they are in accord with the notion that lactimidomycin is primarily a ribosome-binder able to effectively halt protein biosynthesis at the translation stage. On the contrary! Alkyne metathesis powered a synthesis-driven (re)evaluation of bipartite glutarimide antibiotics, including lactimidomycin and isomigrastatin, which feature highly strained polyunsaturated macrolide head groups. Rather than being potent cell migration inhibitors as previously claimed, lactimidomycin and progeny were found to be acutely cytotoxic, causing cell death before any specific interference with cell motility could set in. Copyright
- Micoine, Kévin,Persich, Peter,Llaveria, Josep,Lam, My-Hanh,Maderna, Andreas,Loganzo, Frank,Fürstner, Alois
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p. 7370 - 7383
(2013/07/25)
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- Improved method for immobilization of a chiral complex on PTA/alumina for asymmetric hydrogenation of a β-ketoester
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Ru-BINAP was immobilized on alumina using the well-known Augustine method with heteropoly acid (HPA) as the anchoring agent ("Augustine catalyst"). The supported catalyst was tested in a high-pressure reaction such as asymmetric hydrogenation of methyl acetoacetate (MAA). Since the activity of the supported catalyst was significantly lower than that of the homogeneous catalyst, the solvent used in preparing PTA/Al2O 3 was changed from ethanol to a solution of HCl. The modified supported catalyst ("modified Augustine catalyst") exhibited higher conversion, better selectivity, and improved enantioselectivity compared with the catalyst prepared by the Augustine method. The modified Augustine catalyst also produced β-hydroxyesters with good yield and enantioselectivity in asymmetric hydrogenation of various β-ketoester derivatives. The modified Augustine catalyst was examined by FT-IR, XRD, NH3-TPD, and ICP-AES, which revealed the existence of strong acid sites formed by HPA with a Keggin structure. These results were attributed to the effect of enhanced acidity on the modified Augustine catalyst.
- Ahn, Sung-Hyun,Choi, Moo-Seok,Im, Jun-Seop,Sheikh, Rizwan,Park, Yeung-Ho
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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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- Synthesis and Suzuki-Miyaura cross-coupling of enantioenriched secondary potassium β-trifluoroboratoamides: Catalytic, asymmetric conjugate addition of bisboronic acid and tetrakis(dimethylamino)diboron to α,β- unsaturated carbonyl compounds
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Enantioenriched potassium β-trifluoroboratoamides have been synthesized via an asymmetric, copper-catalyzed 1,4-addition of tetrahydroxydiboron (BBA) and tetrakis(dimethylamino)-diboron to α,β-Unsaturated amides. These dibora reagents provide access to the desired organotri-fluoroborates using effective and atom economical sources of boron. The copper-catalyzed β-boration is extended to α,β- Unsaturated ketones and esters. The desired potassium organotrifluoroborates are synthesized with yields up to 92% and enantiomeric ratios up to 98:2. The enantioenriched potassium btrifluoroboratoamides are successfully cross-coupled with an array of aryl and heteroaryl chlorides in high yield with complete stereochemical fidelity as the transmetalation proceeds through an SE2 mechanism via an open transition state.
- Molander, Gary A.,Wisniewski, Steven R.,Hosseini-Sarvaria, Mona
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p. 3037 - 3057
(2014/03/21)
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- Enantioselective catalysis with a chiral, phosphane-containing PMO material
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A novel bistriethoxysilyl-BINAP monomer was prepared and co-condensed with a biphenylene-bridged siloxane precursor in the presence of surfactant templates to give periodic mesoporous organosilicas (PMOs) functionalized with BINAP. Complexation of ruthenium followed by asymmetric catalytic hydrogenation and asymmetric transfer hydrogenation were carried out, and demonstrated that high levels of activity and selectivity are achievable with the chiral material.
- Seki, Tomohiro,McEleney, Kevin,Crudden, Cathleen M.
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scheme or table
p. 6369 - 6371
(2012/08/14)
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- Mesoporous cross-linked polymer copolymerized with chiral BINAP ligand coordinated to a ruthenium species as an efficient heterogeneous catalyst for asymmetric hydrogenation
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We report here a successful preparation of a heterogeneous chiral catalyst from copolymerization of mesoporous cross-linked polymer with chiral BINAP ligands, followed by coordination of the BINAP with a ruthenium species, which exhibits high activity, excellent enantioselectivity, and extraordinary recyclability in asymmetric hydrogenation.
- Sun, Qi,Meng, Xiangju,Xiao, Feng-Shou,Liu, Xiao,Zhang, Xiaoming,Yang, Yan,Yang, Qihua
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supporting information
p. 10505 - 10507,3
(2020/09/02)
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- Preparation of chiral secondary boronic esters via copper-catalyzed enantioselective conjugate reduction of β-boronyl-β-alkyl α,β-unsaturated esters
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A new methodology involving the copper(I)-catalyzed enantioselective conjugate reduction of β-boronyl-β-alkyl enoates was developed. Various chiral secondary boronate derivatives can be accessed in excellent yields and good to high levels of enantioselectivity through this efficient copper-catalyzed process using polymethylhydrosiloxane (PMHS) as hydride source.
- Ding, Jinyue,Hall, Dennis G.
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p. 3428 - 3434
(2012/06/04)
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- Efficient reduction of ethyl 2-oxo-4-phenylbutyrate at 620 ?l -1 by a bacterial reductase with broad substrate spectrum
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A β-ketoacyl-ACP reductase (FabG) gene from Bacillus sp. ECU0013 was heterologously overexpressed in Escherichia coli and the encoded protein was purified to homogeneity. The recombinant reductase could reduce a broad spectrum of prochiral ketones including aromatic ketones and keto esters and showed the highest activity in the asymmetric reduction of ethyl 2-oxo-4-phenylbutyrate (OPBE). Using E. coli cells coexpressing both FabG and glucose dehydrogenase (GDH) genes, as much as 620 ?L-1 of OPBE was almost stoichiometrically converted to ethyl (S)-2-hydroxy-4-phenylbutyrate [(S)-HPBE] with excellent (>99%) enantiomeric excess. More importantly, the process could be performed smoothly without external addition of an expensive cofactor as usually done and could be scaled up very easily. All these positive features demonstrate the applicability of this reductase for the large-scale production of optically active α-hydroxy acids/esters.
- Ni, Yan,Li, Chun-Xiu,Zhang, Jie,Shen, Nai-Dong,Bornscheuer, Uwe T.,Xu, Jian-He
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supporting information; experimental part
p. 1213 - 1217
(2011/07/09)
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- Enantioselective hydrogenation of α-ketoesters over alkaloid-modified platinum nanowires
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A green process for enantioselective hydrogenation of α-ketoesters over cinchona alkaloid-modified platinum (Pt) nanowires has been developed. Pt nanowires with a diameter of ~1 nm were successfully synthesized, and used for the asymmetric hydrogenation of α-ketoesters in the presence of cinchona alkaloids under a low pressure at room temperature in water. Quantitative yields and excellent enantioselectivity of up to 78% were achieved. The catalyst along with the modifier was recycled multiple times without any significant loss in activity or selectivity. To our knowledge, such a catalyst system is unprecedented for asymmetric hydrogenation of α-ketoesters. The Royal Society of Chemistry.
- Erathodiyil, Nandanan,Gu, Hongwei,Shao, Huilin,Jiang, Jiang,Ying, Jackie Y.
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experimental part
p. 3070 - 3074
(2011/12/16)
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- Novel anti-Prelog stereospecific carbonyl reductases from Candida parapsilosis for asymmetric reduction of prochiral ketones
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The application of biocatalysis to the synthesis of chiral molecules is one of the greenest technologies for the replacement of chemical routes due to its environmentally benign reaction conditions and unparalleled chemo-, regio- and stereoselectivities. We have been interested in searching for carbonyl reductase enzymes and assessing their substrate specificity and stereoselectivity. We now report a gene cluster identified in Candida parapsilosis that consists of four open reading frames including three putative stereospecific carbonyl reductases (scr1, scr2, and scr3) and an alcohol dehydrogenase (cpadh). These newly identified three stereospecific carbonyl reductases (SCRs) showed high catalytic activities for producing (S)-1-phenyl-1,2-ethanediol from 2-hydroxyacetophenone with NADPH as the coenzyme. Together with CPADH, all four enzymes from this cluster are carbonyl reductases with novel anti-Prelog stereoselectivity. SCR1 and SCR3 exhibited distinct specificities to acetophenone derivatives and chloro-substituted 2-hydroxyacetophenones, and especially very high activities towards ethyl 4-chloro-3-oxobutyrate, a β-ketoester with important pharmaceutical potential. Our study also showed that genomic mining is a powerful tool for the discovery of new enzymes.
- Nie, Yao,Xiao, Rong,Xu, Yan,Montelione, Gaetano T.
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experimental part
p. 4070 - 4078
(2011/07/08)
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