- Exploiting Cofactor Versatility to Convert a FAD-Dependent Baeyer–Villiger Monooxygenase into a Ketoreductase
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Cyclohexanone monooxygenases (CHMOs) show very high catalytic specificity for natural Baeyer–Villiger (BV) reactions and promiscuous reduction reactions have not been reported to date. Wild-type CHMO from Acinetobacter sp. NCIMB 9871 was found to possess an innate, promiscuous ability to reduce an aromatic α-keto ester, but with poor yield and stereoselectivity. Structure-guided, site-directed mutagenesis drastically improved the catalytic carbonyl-reduction activity (yield up to 99 %) and stereoselectivity (ee up to 99 %), thereby converting this CHMO into a ketoreductase, which can reduce a range of differently substituted aromatic α-keto esters. The improved, promiscuous reduction activity of the mutant enzyme in comparison to the wild-type enzyme results from a decrease in the distance between the carbonyl moiety of the substrate and the hydrogen atom on N5 of the reduced flavin adenine dinucleotide (FAD) cofactor, as confirmed using docking and molecular dynamics simulations.
- Xu, Jian,Peng, Yongzhen,Wang, Zhiguo,Hu, Yujing,Fan, Jiajie,Zheng, He,Lin, Xianfu,Wu, Qi
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supporting information
p. 14499 - 14503
(2019/09/17)
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- Boron-Catalyzed O-H Bond Insertion of α-Aryl α-Diazoesters in Water
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A catalytic, metal-free O-H bond insertion of α-diazoesters in water in the presence of B(C6F5)3·nH2O (2 mol %) was developed, affording a series of α-hydroxyesters in good to excellent yields. The reaction features easy operation and wide substrate scope, and importantly, no metal is needed as compared with the conventional methods. Significantly, this approach further expands the applications of B(C6F5)3 under water-tolerant conditions.
- San, Htet Htet,Wang, Shi-Jun,Jiang, Min,Tang, Xiang-Ying
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p. 4672 - 4676
(2018/08/09)
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- Endothelin antagonists benzene oxygen benzene acetic acids and its preparation method and application
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The invention provides a phenoxy phenylacetic acid endothelin antagonist shown in a formula (I) or a pharmaceutically acceptable salt thereof, and also provides a preparation method of the benzene oxygen phenylacetic acid endothelin antagonist or the pharmaceutically acceptable salt thereof, and an application thereof in preparation of a medicament for treating cardiovascular and cerebrovascular diseases, tumors, diabetes mellitus, nephrosis, asthma or hyperthyroidism.
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- Asymmetric catalytic arylation of ethyl glyoxylate using organoboron reagents and Rh(i)-phosphane and phosphane-phosphite catalysts
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Herein we report the first application of Rh(i)-phosphane and phosphane-phosphite catalysts in the enantioselective catalytic arylation of ethyl glyoxylate with organoboron reagents, providing access to ethyl mandelate derivatives in high yield (up to 99%) and moderate to very good enantioselectivities (up to 75% ee). Commercial phosphane ligands, such as (R)-MonoPhos and (R)-Phanephos were tested, as well as non-commercial (R,R)-TADDOL-derived phosphane-phosphite ligands. Those ligands containing bulky substituents in the ortho-and para-positions of the chiral phosphite moiety were found to be the most selective.
- Marques, Carolina Silva,Dindaroglu, Mehmet,Schmalz, Hans-Guenther,Burke, Anthony J.
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p. 6035 - 6041
(2014/01/23)
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- Iron-catalyzed hydrogenation for the in situ regeneration of an NAD(P)H model: Biomimetic reduction of α-Keto-/α-iminoesters
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Two irons for a smoother finish: An NAD(P)H model was regenerated readily in situ by iron-catalyzed reduction with molecular hydrogen. The subsequent biomimetic reduction of α-keto-/ α-iminoesters proceeded smoothly in the presence of an iron-based Lewis acid (LA) to provide α-hydroxyesters and amino acid esters in good to excellent yields (see scheme; NAD(P) +=nicotinamide adenine dinucleotide (phosphate), TM=transition metal). Copyright
- Lu, Liang-Qiu,Li, Yuehui,Junge, Kathrin,Beller, Matthias
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supporting information
p. 8382 - 8386
(2013/09/02)
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- Suzuki-Miyaura coupling reaction of boronic acids and ethyl glyoxylate: Synthetic access to mandelate derivatives
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The palladium-catalyzed coupling reaction of arylboronic acids with ethyl glyoxylate provides a straightforward method for the synthesis of mandelic esters. Pd2(dba)3·CHCl3 in combination with 2-di-tert-butylphosphanylbiphenyl as the catalytic system and Cs 2CO3 as the base were used. The reaction tolerates a wide range of functionalized boronic acids. Mandelic esters were isolated in good-to-excellent yields with a variety of neutral, slightly electron-rich, and slightly electron-poor substituents. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Francesco, Irene Notar,Wagner, Alain,Colobert, Francoise
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supporting information; experimental part
p. 5692 - 5695
(2009/05/31)
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- Reliable and versatile synthesis of 2-aryl-substituted cinnamic acid esters
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2-Aryl-substituted phosphono acetates can be readily synthesized by a four-step sequence from the respective arenes. Succeeding Horner-Wadsworth- Emmons olefinations provide stereoselectively the 2-aryl cinnamic acid esters even when sensitive moieties are involved. Georg Thieme Verlag Stuttgart.
- Ianni, Alen,Waldvogel, Siegfried R.
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p. 2103 - 2112
(2008/02/02)
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- Reduction of activated carbonyl groups by alkyl phosphines: Formation of α-hydroxy esters and ketones
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Reduction of activated carbonyl groups such as α-keto esters, benzils, 1,2-cyclohexanedione, and α-ketophosphonates by alkyl phosphines afforded the corresponding α-hydroxy esters or ketones in good to excellent yields in THF at room temperature. The mechanism of the proton transfer and intramolecular hydrolysis has been studied on the basis of deuterium and 18O labeling experiments. The Royal Society of Chemistry 2006.
- Zhang, Wen,Shi, Min
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p. 1218 - 1220
(2008/02/03)
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- Mechanism and scope of salen bifunctional catalysts in asymmetric aldehyde and α-ketoester alkylation
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Metal complexes of C2-symmetric Lewis acid/Lewis base salen ligands provide bifunctional activation resulting in rapid rates in the enantioselective addition of diethylzinc to aldehydes (up to 92% ee). Further experiments probed the reactivity of the individual Lewis acid and Lewis base components of the catalyst and established that both moieties are essential for asymmetric catalysis. These catalysts are also effective in the asymmetric addition of diethylzinc to α-ketoesters. This finding is significant because α-ketoesters alone serve as their own ligands to accelerate racemic 1,2-carbonyl addition of Et2Zn and racemic carbonyl reduction. The latter proceeds via a metalloene pathway, and often accounts for the predominant product. Singular Lewis acid catalysts do not accelerate enantioselective 1,2-addition over these two competing paths. The bifunctional amino salen catalysts, however, rapidly provide enantioenriched 1,2-addition products in excellent yield, complete chemoselectivity, and good enantioselectivity (up to 88% ee). A library of the bifunctional amino salens was synthesized and evaluated in this reaction. The utility of the α-ketoester method has been demonstrated in the synthesis of an opiate antagonist.
- Fennie, Michael W.,DiMauro, Erin F.,O'Brien, Erin M.,Annamalai, Venkatachalam,Kozlowski, Marisa C.
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p. 6249 - 6265
(2007/10/03)
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- Perfluorosulfonylmethide compounds; use thereof for carbon-carbon bond formation
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Free perfluorosulfonylmethide compounds and metal salts thereof show strong catalytic activity in carbon-carbon bond formation reactions, in amounts as low as 0.1 mole %. Fluorous media may be used, especially biphasic fluorous media enabling ready recycling of the catalyst. The formula thereof is: M[C(SO2R1)3?(m+q)(SO2R2)m(SO2R3)q]xwhere M is H, Sc, Y, La, Ce, Pr, Nd, Sm Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Zr, Hf, Th, Nb, Ta, U, Bi, Al, Ga, In or Tl, x is the common oxidation state of a said metal M, R1, R2and R3are perfluorinated or polyfluoronated hydrocarbon, ether or amine moieties or mixtures thereof and m+q=0, 1, 2 or 3 (m and q being zero or integers).
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Page column 12-13
(2010/02/06)
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- Development of bifunctional salen catalysts: Rapid, chemoselective alkylations of α-ketoesters
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Lewis acid-Lewis base salen complexes have been identified as highly efficient catalysts for the addition of dialkylzincs to α-ketoesters. In contrast to aldehydes or ketones, the reaction between diethylzinc and α-ketoesters is significant in the absence of catalyst. In the presence of catalyst, the reaction rate is increased over 100-fold relative to the background. Furthermore, the reduction product, which is a major coproduct with other catalysts, is not observed with these bifunctional salens. As a result, high yields of the addition products can be obtained (57-99%). Both the Lewis acid and Lewis base portions of the catalyst are critical to the reactivity and selectivity. The two separate portions of the catalyst have been shown to function in a cooperative manner. Copyright
- DiMauro, Erin F.,Kozlowski, Marisa C.
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p. 12668 - 12669
(2007/10/03)
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- YCL3-catalyzed highly selective conversion of arylglyoxal to α-aryl- α-hydroxyacetic ester: Dramatic influence of base
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Yttrium chloride catalyzed reaction of arylglyoxal and alcohol resulted in highly selective formation of α-aryl-α-hydroxyacetic ester under the influence of an added base (triethylamine, pyridine, piperidine) and afforded acetal in the absence of the base. The possible role of the additive (base) is discussed.
- Likhar, Pravin R.,Bandyopadhyay, Ananda K.
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p. 538 - 540
(2007/10/03)
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- How does organic structure determine organic reactivity? Nucleophilic substitution and alkene-forming elimination reactions of α-carbonyl and α-thiocarbonyl substituted benzyl derivatives
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The effect of α-(N,N-dimethylcarbamoyl) and α-(N,N-dimethylthiocarbamoyl) substituents on the rate constants for partitioning of α-substituted 1-(4-methoxyphenyl)ethyl carbocations between nucleophilic addition of 50:50 (v:v) MeOH/H20 (k(s), s-1) and deprotonation by this solvent (k(e), s-1) have been investigated. The data show that these α-amide and α-thioamide substituents result in 80-fold and ≤ 30000-fold decreases, respectively, in k(s) for capture of the 4-methoxybenzyl carbocation by solvent, but that they lead to much smaller changes in k(e), for deprotonation of the corresponding α-substituted 1-(4-methoxyphenyl)ethyl carbocations by solvent. The large effect of the α-thioamide substituent on the partitioning of α-substituted 1-phenylethyl carbocations between formation of the products of solvolysis and elimination is therefore due primarily to the effect of this α-substituent on k(s), for capture of the carbocation by solvent. The results of experimental and computational studies are consistent with the conclusion that the relative magnitude of the rate constants k(s) and k(e) for partitioning of α-substituted 1-phenylethyl carbocations is strongly controlled by the relative thermodynamic stabilities of the neutral products of these reactions.
- Richard, John P.,Lin, Shrong-Shi,Buccigross, Jeanne M.,Amyes, Tina L.
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p. 12603 - 12613
(2007/10/03)
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- The Effects of α-Substituents on the Kinetic and Thermodynamic Stability of 4-Methoxybenzyl Carbocations: Carbocation Lifetimes That Are Independent of Their Thermodynamic Stability
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The following new rate constants for reaction of α-substituted 4-methoxybenzyl carbocations, 4-MeOC6H4CR1(R2)(1+), with a solvent of 50:50 (v/v) trifluoroethanol/water at 25 deg C and ionic strength 0.50 (NaClO4) are reported: 4-MeOC6H4CH(OMe)(1+), Ks = 2.2E7 s-1; 4-MeOC6H4CH(N3)(1+), ks = 3.3E5 s-1; 4-MeOC6H4C(CH3)2(1+), ks = 1.3E7 s-1; 4-MeOC6H4CH(CO2Et)(1+), ks = 1.4E7 s-1; 4-MeOC6H4CCH3(CF3)(1+), ks = 2.5E7 s-1.The values of ks for reaction of 4-MeOC6H4CR1(R2)(1+) with 50:50 (v/v) trifluoroethanol/water are nearly independent of very large changes in the thermodynamic stability of these carbocations caused by the addition of a wide range of electron-withdrawing or electron-donating groups at the α-position.In the most extreme case, the change from an α-methoxy to two α-(trifluoromethyl) substituents leads to a 23 kcal/mol thermodynamic destabilization of 4-MeOC6H4CR1(R2)(1+) relative to the neutral azide ion adducts but a 5-fold decrease in its reactivity toward solvent.The data show that the effects of α-substituents on the kinetic stability of 4-MeOC6H4CR1(R2)(1+) are complex and do not parallel the thermodynamic stability of these carbocations.The results are explained by consideration of the polar and resonance effects of the α-substituents on both the thermodynamic driving force and the intrinsic barrier for capture of the carbocations by solvent.These reactions are a new example of the consequences of the "principle of nonperfect synchronization".
- Amyes, Tina L.,Stevens, Ishmael W.,Richard, John P.
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p. 6057 - 6066
(2007/10/02)
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- Generation and determination of the lifetime of an α-carbonyl substituted carbocation
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The α-carboxyethyl-4-methoxybenzyl carbocation reacts with a solvent of 50:50 (v:v) trifluoroethanol/water with a rate constant k(s) = 1.4 x 107 s-1, which is 14-fold slower than the capture of the unsubstituted 4-methoxybenzyl carbo
- Richard,Amyes,Stevens
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p. 4255 - 4258
(2007/10/02)
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- Diphenylsilane Reduction of C=O and C=N Bearing Electron-Withdrawing Group in the Presence of Aluminium(III) Chloride
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Several α-keto esters and methyl N-p-tolylsulfonyl-2-aryl-2-iminoacetates were reduced to the corresponding α-hydroxy esters and methyl N-p-tolylsulfonyl-2-arylglycinates in high yields by a combination of aluminium(III) chloride and diphenylsilane under operating conditions in which diphenylsilane was added to the pre-formed substrate-aluminium(III) chloride complex in dichloromethane and the mixture stirred.The case of an exactly equivalent amount of aluminium(III) chloride as the substrate resulted in good results.
- Hojo, Makoto,Hojo, Masahiro,Inoue, Yoshihiko,Tanimoto, Shigeo
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p. 2588 - 2592
(2007/10/02)
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