- First total synthesis of three cembrene diterpenoids
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The first total synthesis and three diterpenoids of the cembrane class, is described. And the absolute stereochemistry of these natural products is assigned by synthesis.
- Li, Jing,Lan, Jiong,Liu, Zuosheng,Li, Ying,Li, Yulin
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Read Online
- Investigating the Structure-Reactivity Relationships Between Nicotinamide Coenzyme Biomimetics and Pentaerythritol Tetranitrate Reductase
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Ene reductases (ERs) are attractive biocatalysts in terms of their high enantioselectivity and expanded substrate scope. Recent works have proved that synthetic nicotinamide coenzyme biomimetics (NCBs) can be used as easily accessible alternatives to natural cofactors in ER-catalyzed reactions. However, the structure-reactivity relationships between NCBs and ERs and influence factors are still poorly understood. In this study, a series of C-5 methyl modified NCBs were synthesized and tested in the PETNR-catalyzed asymmetric reductions. The physicochemical properties of these NCBs including electrochemical properties, stability, and kinetic behavior were studied in detail. The results showed that hydrophobic interaction caused by the introduced methyl group contributed to the stabilization of binding conformation in enzyme active site, resulting in comparable catalytic activity with that of NADPH. Molecular dynamics and steered molecular dynamics simulations were further performed to explain the binding mechanism between PETNR and NCBs, which revealed that stable catalytic conformation, appropriate donor-acceptor distance and angle, as well as free dissociation energy are important factors affecting the activity of NCBs. (Figure presented.).
- Tan, Zhuotao,Han, Yaoying,Fu, Yaping,Zhang, Xiaowang,Xu, Mengjiao,Na, Qi,Zhuang, Wei,Qu, Xudong,Ying, Hanjie,Zhu, Chenjie
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p. 103 - 113
(2021/10/07)
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- Zwitterion-induced organic-metal hybrid catalysis in aerobic oxidation
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In many metal catalyses, the traditional strategy of removing chloride ions is to add silver salts via anion exchange to obtain highly active catalysts. Herein, we reported an alternative strategy of removing chloride anions from ruthenium trichloride using an organic [P+-N-] zwitterionic compound via multiple hydrogen bond interactions. The resultant organic-metal hybrid catalytic system has successfully been applied to the aerobic oxidation of alcohols, tetrahydroquinolines, and indolines under mild conditions. The performance of zwitterion is far superior to that of many other common Lewis bases or Br?nsted bases. Mechanistic studies revealed that the zwitterion triggers the dissociation of chloride from ruthenium trichloride via nonclassical hydrogen bond interaction. Preliminary studies show that the zwitterion is applicable to catalytic transfer semi-hydrogenation.
- Hu, Rong-Bin,Lam, Ying-Pong,Ng, Wing-Hin,Wong, Chun-Yuen,Yeung, Ying-Yeung
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p. 3498 - 3506
(2021/04/07)
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- Multicatalytic approach to one-pot stereoselective synthesis of secondary benzylic alcohols
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One-pot procedures bear the potential to rapidly build up molecular complexity without isolation and purification of consecutive intermediates. Here, we report multicatalytic protocols that convert alkenes, unsaturated aliphatic alcohols, and aryl boronic acids into secondary benzylic alcohols with high stereoselectivities (typically >95:5 er) under sequential catalysis that integrates alkene cross-metathesis, isomerization, and nucleophilic addition. Prochiral allylic alcohols can be converted to any stereoisomer of the product with high stereoselectivity (>98:2 er, >20:1 dr).
- Casnati, Alessandra,Lichosyt, Dawid,Lainer, Bruno,Veth, Lukas,Dydio, Pawe?
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supporting information
p. 3502 - 3506
(2021/05/10)
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- Enantioselective Hydrogenation of Endocyclic Enones: the Solution to a Historical Problem?
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The enantioselective hydrogenation of endocyclic enones has been a historical problem for homogeneous catalysis. We herein report an efficient method to reduce endocyclic enones with molecular hydrogen. Catalyzed by a rhodium/Zhaophos complex, a variety of enones with five-, six- or seven-member ring were hydrogenated with high enantioselectivity (92%—99% ee). Excellent chemo- and enantioselectivity demonstrated this method was successfully applied in the enantioselective hydrogenation of citral to produce enantio-enriched citronellal.
- Lang, Qiwei,Yang, Huaxin,Gu, Guoxian,Feng, Qiang,Wen, Jialin,Zhang, Xumu
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supporting information
p. 933 - 936
(2021/03/03)
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- Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors
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Geranylgeranyl diphosphate synthase (GGDPS) inhibitors are of potential therapeutic interest as a consequence of their activity against the bone marrow cancer multiple myeloma. A series of bisphosphonates linked to an isoprenoid tail through an amide linkage has been prepared and tested for the ability to inhibit GGDPS in enzyme and cell-based assays. The amides were designed as analogues to triazole-based GGDPS inhibitors. Several of the new compounds show GGDPS inhibitory activity in both enzyme and cell assays, with potency dependent on chain length and olefin stereochemistry.
- Goetz, Daniel B.,Holstein, Sarah A.,Varney, Michelle L.,Wiemer, David F.
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- Chiral amorphous metal–organic polyhedra used as the stationary phase for high-resolution gas chromatography separations
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Herein, we describe a new chiral amorphous metal–organic polyhedra used as the stationary phase for high-resolution gas chromatography (GC). The chiral stationary phase was coated onto a capillary column via a dynamic coating process and investigated for a variety of compounds. The experimental results showed that the chiral stationary phase exhibits good selectivity for linear alkanes, linear alcohols, polycyclic aromatic hydrocarbons, isomers, and chiral compounds. In addition, the column has the advantages of high column efficiency and short analysis time. The present work indicated that amorphous metal–organic polyhedra have great potential for application as a new type of stationary phase for GC.
- Tang, Bo,Sun, Chenyu,Wang, Wei,Geng, Lina,Sun, Liquan,Luo, Aiqin
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p. 1178 - 1185
(2020/07/09)
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- Preparation method of optically active citronellal (by machine translation)
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The preparation method of the optically active citronellal can significantly improve the catalytic stability, of the optically active transition metal catalyst for homogeneous catalysis to obtain, the optically active citronellal. which is obtained by reacting a transition metal compound with an optically active ligand containing two phosphorus atoms, and, or iron in the substrate material used for the asymmetric hydrogenation reaction . is prepared by reacting a transition metal compound with an optically active ligand containing two phosphorus atoms in the presence of a transition metal catalyst in the preparation method of the optically active citronellal with an asymmetric hydrogenation reaction in the presence of a transition metal catalyst to achieve a higher degree of peripheral speed, ≤6mgKOH/g/of the optically ≤50ppm. active citronellal. (by machine translation)
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Paragraph 0078-0080; 0086-0092; 0098-0113
(2020/03/17)
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- Method for preparing optically active citronellal (by machine translation)
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The invention provides a method, for preparing optically active citronellal by reacting a transition metal catalyst with an asymmetric hydrogenation reaction, to obtain the optically active citronellal, wherein the substrate is neral and/or the vanillic, catalyst is obtained, by controlling the catalytic activity ≤500ppm of the asymmetric hydrogenation reaction substrate and remarkably improving the service life of the catalyst by controlling the asymmetric hydrogenation reaction substrate through oxidation . and ≤10ppm, or the aqueous chlorine, catalyst obtained by reacting the transition metal compound with the optically, active ligand containing .the two phosphorus atoms to obtain the optically active citronellal. (by machine translation)
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Paragraph 0082-0084; 0090-0093; 0109-0111; 0115-0117
(2020/05/05)
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- Iridium-Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols Using MaxPHOX Ligands: Experimental and Theoretical Study
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The asymmetric isomerization of primary allylic alcohols to chiral aldehydes using iridium-catalysts bearing P,N-MaxPHOX ligands has been studied. These catalysts can be fine-tuned as they present three different stereogenic centers to modulate both the reactivity and enantioselectivity of a family of different substrates. The experimental part is supported by a DFT study of the reaction mechanism, which provides new insights into the key steps of this transformation.
- Cabré, Albert,Gar?on, Martí,Gallen, Albert,Grisoni, Lorenzo,Grabulosa, Arnald,Verdaguer, Xavier,Riera, Antoni
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p. 4112 - 4120
(2020/07/04)
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- Method for preparing optically active citronellal, and catalyst used in method
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The invention provides a method for preparing optically active citronellal, and a catalyst for the method. The method comprises: in the presence of a catalyst, asymmetrically hydrogenating citral represented by a formula (I) and/or geranial represented by a formula (II) to prepare optically active R-citronellal represented by a formula (III), wherein the catalyst comprises rhodium as a catalytically active transition metal, a chiral bidentate diphosphine ligand, and basic alumina. According to the present invention, the catalytic stability of an optically active transition metal catalyst for asymmetric hydrogenation of homogeneous catalysis can be significantly improved without introducing of carbon monoxide so as to achieve high turnover number.
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Paragraph 0060-0066; 0071-0072
(2020/04/22)
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- Engineering the enantioselectivity of yeast old yellow enzyme Oye2Y in asymmetric reduction of (E/Z)-citral to (R)-citronellal
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The members of the Old Yellow Enzyme (OYE) family are capable of catalyzing the asymmetric reduction of (E/Z)-citral to (R)-citronellal—a key intermediate in the synthesis of L-menthol. The applications of OYE-mediated biotransformation are usually hampered by its insufficient enantioselectivity and low activity. Here, the (R)-enantioselectivity of Old Yellow Enzyme from Saccharomyces cerevisiae CICC1060 (OYE2y) was enhanced through protein engineering. The single mutations of OYE2y revealed that the sites R330 and P76 could act as the enantioselectivity switch of OYE2y. Site-saturation mutagenesis was conducted to generate all possible replacements for the sites R330 and P76, yielding 17 and five variants with improved (R)-enantioselectivity in the (E/Z)-citral reduction, respectively. Among them, the variants R330H and P76C partly reversed the neral derived enantioselectivity from 32.66% e.e. (S) to 71.92% e.e. (R) and 37.50% e.e. (R), respectively. The docking analysis of OYE2y and its variants revealed that the substitutions R330H and P76C enabled neral to bind with a flipped orientation in the active site and thus reverse the enantioselectivity. Remarkably, the double substitutions of R330H/P76M, P76G/R330H, or P76S/R330H further improved (R)-enantioselectivity to >99% e.e. in the reduction of (E)-citral or (E/Z)-citral. The results demonstrated that it was feasible to alter the enantioselectivity of OYEs through engineering key residue distant from active sites, e.g., R330 in OYE2y.
- Ying, Xiangxian,Yu, Shihua,Huang, Meijuan,Wei, Ran,Meng, Shumin,Cheng, Feng,Yu, Meilan,Ying, Meirong,Zhao, Man,Wang, Zhao
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- P-CHIRAL PHOSPHINE LIGANDS AND USE THEREOF FOR ASYMMETRIC SYNTHESIS
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The present invention relates to chiral compounds with two optically active phosphorus atoms, chiral transition metal catalysts which comprise these compounds as ligands, a process for preparing the P-chiral compounds and processes for asymmetric synthesis using the chiral transition metal catalysts. The present invention specifically relates to a process for preparing an optically active carbonyl compound by asymmetric hydrogenation of a prochiral α,β-unsaturated carbonyl compound with hydrogen in the presence of an optically active transition metal catalyst according to the invention. Yet more specifically, the present invention relates to a process for the asymmetric hydrogenation of citral, and also a process for preparing optically active menthol.
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Paragraph 0924-0928
(2019/07/23)
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- Method for methyl heptanone to synthetize chiral citronellal
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The invention provides a method for methyl heptanone to synthetize chiral citronellal. The method includes the following steps: (1) performing methylenenation reaction on methyl heptanone and an organic tiron so that a 2,6-dimethyl-1,5-heptadiene intermediate with high yield; and (2) performing asymmetric hydroformylation on the heptadiene intermediate under the action of a homogeneous chiral rhodium catalyst so that a chiral citronellal product can be obtained. The main advantages of the method are as follows: the method is novel in synthetic method, a synthetic route is brief, and the chiralcitronellal product can be obtained by only two steps of reaction; the tiron can be used to perform the methylenenation reaction of the methyl heptanone, so that the 2,6-dimethyl-1,5-heptadiene can be obtained with high yield, and therefore, the method is higher than other existing known methods; and the method creatively utilizes the homogeneous chiral rhodium catalyst to realize the asymmetrichydroformylation of the 2,6-dimethyl-1,5-heptadiene, so that the method is high in reaction yield and excellent in stereoselectivity.
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Paragraph 0060-0071
(2019/05/08)
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- Mechanistic Studies on the Organocatalytic α-Chlorination of Aldehydes: The Role and Nature of Off-Cycle Intermediates
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Herein we report the isolation and characterization of aminal intermediates in the organocatalytic α-chlorination of aldehydes. These species are stable covalent ternary adducts of the substrate, the catalyst and the chlorinating reagent. NMR-assisted kinetic studies and isotopic labeling experiments with the isolated intermediate did not support its involvement in downstream stereoselective processes as proposed by Blackmond. By tuning the reactivity of the chlorinating reagent, we were able to suppress the accumulation of rate-limiting off-cycle intermediates. As a result, an efficient and highly enantioselective catalytic system with a broad functional group tolerance was developed.
- Ponath, Sebastian,Menger, Martina,Grothues, Lydia,Weber, Manuela,Lentz, Dieter,Strohmann, Carsten,Christmann, Mathias
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supporting information
p. 11683 - 11687
(2018/09/10)
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- CuH-Catalyzed Asymmetric Reduction of α,β-Unsaturated Carboxylic Acids to β-Chiral Aldehydes
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The copper hydride (CuH)-catalyzed enantioselective reduction of α,β-unsaturated carboxylic acids to saturated aldehydes is reported. This protocol provides a new method to access a variety of β-chiral aldehydes in good yields, with high levels of enantioselectivity and broad functional group tolerance. A reaction pathway involving a ketene intermediate is proposed based on preliminary mechanistic studies and density functional theory calculations.
- Zhou, Yujing,Bandar, Jeffrey S.,Liu, Richard Y.,Buchwald, Stephen L.
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supporting information
p. 606 - 609
(2018/01/26)
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- METHOD FOR SYNTHESIZING OPTICALLY ACTIVE CARBONYL COMPOUNDS
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The present invention relates to a process for the preparation of an optically active carbonyl compound by asymmetric hydrogenation of a prochiral α,β-unsaturated carbonyl compound with hydrogen in the presence of at least one optically active transition metal catalyst that is soluble in the reaction mixture and which has rhodium as catalytically active transition metal and a chiral, bidentate bisphosphine ligand, wherein the reaction mixture during the hydrogenation of the prochiral α,β-unsaturated carbonyl compound additionally comprises at least one compound of the general formula (I): in which R1, R2: are identical or different and are C6- to C10-aryl which is unsubstituted or carries one or more, e.g. 1, 2, 3, 4 or 5, substituents which are selected from C1- to C6-alkyl, C3- to C6-cycloalkyl, C6- to C10-aryl, C1- to C6-alkoxy and amino;Z is a group CHR3R4 or aryl which is unsubstituted or carries one or more, e.g. 1, 2, 3, 4 or 5, substituents which are selected from C1- to C6-alkyl, C3- to C6-cycloalkyl, C6- to C10-aryl, C1- to C6-alkoxy and amino, wherein R3 and R4 are as defined in the claims and the description.
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Paragraph 0199
(2018/03/25)
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- Enantio- A nd regioselective: Ene-reductions using F420H2-dependent enzymes
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In the past decade it has become clear that many microbes harbor enzymes that employ an unusual flavin cofactor, the F420 deazaflavin cofactor. Herein we show that F420-dependent reductases (FDRs) can successfully perform enantio-, regio- A nd chemoselective ene-reductions. For the first time, we have demonstrated that F420H2-driven reductases can be used as biocatalysts for the reduction of α,β-unsaturated ketones and aldehydes with good conversions (>99%) and excellent regioselectivities and enantiomeric excesses (>99% ee). Noteworthily, FDRs typically display an opposite enantioselectivity when compared to the well established FMN-dependent Old Yellow Enzymes (OYEs).
- Mathew, Sam,Trajkovic, Milos,Kumar, Hemant,Nguyen, Quoc-Thai,Fraaije, Marco W.
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supporting information
p. 11208 - 11211
(2018/10/15)
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- A process for preparing optically active aldehyde or ketone method and catalyst preparation method
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The invention provides a method for preparing optically active aldehyde or ketone by asymmetric hydrogenation and a preparation method of a catalyst thereof. The optically active aldehyde or ketone is prepared by using a homogeneous and optically active double transition metal catalyst and a chiral amino acid cocatalyst through asymmetric hydrogenation of alpha, beta-unsaturated aldehyde or ketone. The reaction pressure (absolute pressure) is 0.1-10MPa, preferably 5-8MPa; the reaction temperature is 25-90 DEG C; the catalyst is prepared from chiral multi-coordination phosphine-containing ligands and transition metals; chiral amino acid added to the reaction system serves as a cocatalyst; and the reaction selectivity is 95-99%, the conversion rate can reach 85-99.9%, and the optical purity of the product is 80-99ee%.
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Paragraph 0104; 0105; 0106; 0107-0119
(2017/04/07)
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- A process for preparing optically active aldehyde or ketone method (by machine translation)
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The present invention provides an asymmetric hydrogenation process for preparing optically active aldehyde or ketone of the method. The invention using transition metal catalyst and amino acid ester catalyst, so that the α, β - unsaturated aldehyde or ketone by selective asymmetric hydrogenation and the preparation of optically active aldehyde or ketone, reaction selectivity is greatly improved, the optical purity of the product can be as high as 99ee %. (by machine translation)
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Paragraph 0083; 0084-0086; 0100; 0101; 0104-0106; 0110-0111
(2017/07/19)
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- Method for preparing chiral citronellal through citral catalytic asymmetric hydrogenation
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The invention relates to a method for preparing chiral citronellal through citral catalytic asymmetric hydrogenation in the technical field of chemical engineering. Under the effect of additives such as sodium iodide, tetraoctyl ammonium bromide and phenyltriethylammonium chloride, E-type and/or Z-type citral is catalyzed by chiral rhodium complex and asymmetrically hydrogenated into R or S chiral citronellal. In addition, E-type or Z-type citral can be catalyzed into chiral citronellal of the same required structure by changing chirality of chiral catalysts. Thus, citral of all structures can be completely converted into chiral rhodium of one required structure. The reaction method is mild in condition, easy and convenient to operate, capable of achieving good reaction yield and reaction efficiency and good in application effect.
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Paragraph 0082; 0083; 0084
(2016/10/07)
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- Copper-Catalyzed Enantioselective Conjugate Addition to α,β-Unsaturated Aldehydes with Various Organometallic Reagents
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β-Substituted aldehydes constitute a very important class of compounds found in nature. Synthesis of this motif can be envisioned by C-C bond formation on enals. For this purpose, we report herein the development of enantioselective copper-catalyzed conjugate addition of various organometallic reagents to α,β-unsaturated aldehydes with (R)-H8BINAP, (R)-TolBINAP, and (R)-SEGPHOS as chiral ligands. Three sets of conditions were successfully developed and several enals were used. Reactivity and regio- and enantioselectivities were strongly dependent on reaction conditions and substrates. Good to excellent regio- and enantioselectivities were obtained with zinc reagents R2Zn and aluminum reagents R3Al. However, the asymmetric conjugate addition of Grignard reagents afforded only moderate to good regio- and enantioselectivities.
- Goncalves-Contal, Sylvie,Gremaud, Ludovic,Palais, La?titia,Babel, Lucille,Alexakis, Alexandre
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p. 3301 - 3308
(2016/09/12)
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- A kind of preparation method of the optical active carbonyl compounds (by machine translation)
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The invention discloses a kind of preparation method of the optical active carbonyl compounds, comprising the following steps: in the hand natural amine salt and under the catalysis of a transition metal catalyst, to hydrogen and a catalytic amount of dihydropyridine compound as the hydrogen source, α, β-unsaturated aldehyde or α, β-unsaturated ketone compound for asymmetric catalytic hydrogenation reaction, the obtained optically active carbonyl compounds. Mild reaction conditions of the method, the operation is simple, dihydropyridine compound amount is a catalytic amount, so that the target product is easily separated and purified from the reaction system, at the same time, can realize the recovery and reuse of the metal catalyst, in accordance with economic requirements. (by machine translation)
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Paragraph 0055; 0056; 0057; 0058
(2017/01/02)
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- Gas-liquid segmented flow microfluidics for screening copper/tempo-catalyzed aerobic oxidation of primary alcohols
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Aerobic oxidation using a combination of copper salts and 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) represent useful tools for organic synthesis and several closely related catalyst systems have been reported. To gain further insights, these catalytic systems were evaluated in a gas-liquid segmented flow device. The improvement of oxygen mass transfer has a significant influence on the turnover-limiting step. Hence, an improved catalytic system using copper(II) as copper source was implemented in a microreactor for the safe and efficient oxidation of primary alcohol.
- Vanoye, Laurent,Pablos, Mertxe,De Bellefon, Claude,Favre-Réguillon, Alain
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p. 739 - 746
(2015/03/18)
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- Chiral 3D open-framework material Ni(D-cam)(H2O)2 used as GC stationary phase
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Metal-organic frameworks (MOFs) have been explored for analytical applications because of their outstanding properties such as high surface areas, flexibility and specific structure features, especially for chromatography application in recent years. In this work, a chiral MOF Ni(D-cam)(H 2O)2 with unusual integration of molecular chirality, absolute helicity, and 3-D intrinsic chiral net was chosen as stationary phase to prepare Ni(D-cam)(H2O)2-coated open tubular columns for high-resolution gas chromatographic (GC) separation. Two fused-silica open tubular columns with different inner diameters and lengths, including column A (30 m × 250 μm i.d.) and column B (2 m × 75 μm i.d.), were prepared via a dynamic coating method. The chromatographic properties of the two columns were investigated using n-dodecane as the analyte at 120 °C. The number of theoretical plates (plates/m) of the two metal-organic framework (MOF) columns was 1300 and 2750, respectively. The racemates, isomer and linear alkanes mixture were used as analytes for evaluating the separation properties of Ni(D-cam)(H2O)2-coated open tubular columns. The results showed that the columns offered good separations of isomer and linear alkanes mixture, especially racemates. Chirality 26:27-32, 2013. 2013 Wiley Periodicals, Inc.
- Xie, Shengming,Wang, Bangjin,Zhang, Xinhuan,Zhang, Junhui,Zhang, Mei,Yuan, Liming
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- Metal-organic framework Co(D-cam)1/2(bdc)1/2(tmdpy) for improved enantioseparations on a chiral cyclodextrin stationary phase in gas chromatography
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Initial efforts to combine a chiral metal-organic framework (MOF), Co(D-Cam)1/2(bdc)1/2(tmdpy) (D-Cam=D-camphoric acid, bdc=1,4-benzenedicarboxylic acid, tmdpy=4,4′-trimethylenedipyridine), with peramylated β-cyclodextrins to investigate whether the use of a MOF can enhance enantioseparations on a cyclodextrin stationary phase are reported. Compared with columns of peramylated β-cyclodextrin incorporated in a MOF containing sodium chloride, the column of peramylated β-cyclodextrin+MOF shows excellent selectivity for the recognition of racemates, and higher resolutions are achieved on the peramylated β-cyclodextrin+MOF stationary phase. Experimental results indicate that the use of Co(D-Cam) 1/2(bdc)1/2(tmdpy) can improve enantioseparations on peramylated β-cyclodextrins. This is the first report that chiral MOFs can improve enantioseparations on a chiral stationary phase for chromatography. Copyright
- Liu, Hong,Xie, Sheng-Ming,Ai, Ping,Zhang, Jun-Hui,Zhang, Mei,Yuan, Li-Ming
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p. 1103 - 1108
(2014/11/07)
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- NAD(P)h-independent asymmetric C=C bond reduction catalyzed by ene reductases by using artificial co-substrates as the hydrogen donor
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To develop a nicotinamide-independent single flavoenzyme system for the asymmetric bioreduction of C=C bonds, four types of hydrogen donor, encompassing more than 50 candidates, were investigated. Six highly potent, cheap, and commercially available co-substrates were identified that (under the optimized conditions) resulted in conversions and enantioselectivities comparable with, or even superior to, those obtained with traditional two-enzyme nicotinamide adenine dinucleotide phosphate (NAD(P)H)-recycling systems.
- Winkler, Christoph K.,Clay, Dorina,Entner, Marcello,Plank, Markus,Faber, Kurt
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p. 1403 - 1409
(2014/04/03)
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- Enantioselective rearrangement coupled with water addition: Direct synthesis of enantiomerically pure saturated carboxylic acids from α,β-unsaturated aldehydes
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A novel type of organic synthesis enabling a direct one-pot transformation of α,β-unsaturated aldehydes into saturated carboxylic acids is described. As sole reagent water is required, which is integrated completely in the product. This tandem process proceeds under perfect atom economy, and consists of two coupled redox biotransformations without the need of external co-substrates for cofactor regeneration. The initial reduction of the C=C double bond of an α,β-unsaturated aldehyde is catalyzed by an NADPH-dependent ene reductase, leading to the formation of the saturated aldehyde and NADP+. The aldehyde intermediate is then oxidized to the corresponding carboxylic acid, thus regenerating NADPH for the next catalytic cycle. When using prochiral α,β-unsaturated aldehydes as substrates the corresponding carboxylic acids are formed enantioselectively with up to >99 % ee as demonstrated, e.g., for the transformation of citral to (S)-citronellic acid. Making a splash with citral: The direct one-pot transformation of α,β-unsaturated aldehydes to saturated carboxylic acids using only water proceeds with perfect atom economy. This tandem process involves two redox biotransformations without need of additional external co-substrates for cofactor regeneration. With, for example, citral as prochiral α,β-unsaturated aldehyde, transformation to (S)-citronellic acid proceeds with >99 % conversion and >99 % ee.
- Winkler, Till,Groeger, Harald,Hummel, Werner
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p. 961 - 964
(2014/05/06)
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- Practical one-pot sequence for the asymmetric synthesis of 1,2 diols from primary alcohols
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A practical one-pot three-step sequence is reported for the asymmetric synthesis of α-benzoyloxylated alcohols from primary alcohols. Good overall yields (36-52%) and enantioselectivities (91-94% e.e.) are obtained using a commercial organocatalyst in the key oxylation reaction. A simple modification in the protocol allows the formation of enantioenriched γ-benzoyloxylated α,β-unsaturated ester from alcohol. Synthetic utility has been harnessed to the easy preparation of (-)-γ-octalactone from hexan-1-ol.
- Hermange, Philippe,Portalier, Fran?ois,Thomassigny, Christine,Greck, Christine
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supporting information
p. 1052 - 1055
(2013/04/10)
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- METHOD FOR MANUFACTURING OPTICALLY ACTIVE MENTHOL
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An object of the present invention is to provide a method for manufacturing an optically active menthol having fewer steps, which generates less environmentally polluting waste because a catalytic reaction is involved in all of the steps, and is capable of saving a production cost. The present invention relates to a method for manufacturing an optically active menthol, including the following steps: A-1) asymmetrically hydrogenating at least one of geranial and neral to thereby obtain an optically active citronellal, B-1) conducting a ring-closure reaction of the optically active citronellal in the presence of an acid catalyst to thereby obtain an optically active isopulegol, and C-1) hydrogenating the optically active isopulegol to thereby obtain an optically active menthol.
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Paragraph 0512
(2013/10/07)
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- Enantioselective isomerization of primary allylic alcohols into chiral aldehydes with the tol-binap/dbapen/ruthenium(II) catalyst
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Efficient isomerization: The title reaction was catalyzed by the [RuCl 2{(S)-tol-binap}{(R)-dbapen}]/KOH system in ethanol at 25°C (see scheme). A series of E- and Z-configured aromatic and aliphatic allylic alcohols, including a simple primary alkyl-substituted compound (E)-3-methyl-2-hepten-1-ol, were transformed into the chiral aldehydes with at least 99 % ee. dbapen=2-dibutylamino-1-phenylethylamine, tol-binap=2,2′- bis(di-4-tolylphosphanyl)-1,1′-binaphthyl. Copyright
- Arai, Noriyoshi,Sato, Keisuke,Azuma, Keita,Ohkuma, Takeshi
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supporting information
p. 7500 - 7504
(2013/07/26)
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- Nicotinamide-dependent Ene reductases as alternative biocatalysts for the reduction of activated alkenes
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Four NAD(P)H-dependent non-flavin ene reductases have been investigated for their ability to reduce activated C=C bonds in an asymmetric fashion by using 20 structurally diverse substrates. In comparison with flavin-dependent Old Yellow Enzyme homologues, a higher degree of electronic activation was required, because the best activities were obtained with enals and nitroalkenes rather than enones and carboxylic esters. Although FaEO from Fragaria x ananassa (strawberry) and its homologue SlEO from Solanum lycopersicum (tomato) exhibited a narrow substrate spectrum, progesterone 5β-reductase (At5β-StR) from Arabidopsis thaliana (thale cress) and leukotriene B4 12-hydroxydehydrogenase (LTB4DH/PGR) from Rattus norvegicus (rat) appear to be promising candidates, in particular for the asymmetric bioreduction of open-chain enals, nitroalkenes and α,β-unsaturated γ-butyrolactones. Competing nitro reduction and non-enzymatic Weitz-Scheffer epoxidation were largely suppressed. Electronically activated alkenes have been stereoselectively reduced by using a single-enzyme-cofactor system employing nicotinamide-dependent non-flavin ene reductases. Copyright
- Durchschein, Katharina,Wallner, Silvia,MacHeroux, Peter,Schwab, Wilfried,Winkler, Thorsten,Kreis, Wolfgang,Faber, Kurt
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p. 4963 - 4968
(2013/01/14)
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- A dual catalyst system provides the shortest pathway for l-menthol synthesis
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We have demonstrated that a combination of enantiopure 2- diarylmethylpyrrolidines and heterogeneous Pd/BaSO4 is an efficient catalytic system for the asymmetric hydrogenation of citral, specifically, a mixture of E-citral and Z-citral in any ratio, and that citronellal is obtained with high enantioselectivity. This dual catalyst system provides a new and more economical route to l-menthol.
- Maeda, Hironori,Yamada, Shinya,Itoh, Hisanori,Hori, Yoji
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supporting information; scheme or table
p. 1772 - 1774
(2012/03/09)
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- CATALYST FOR ASYMMETRIC HYDROGENATION AND METHOD FOR MANUFACTURING OPTICALLY ACTIVE CARBONYL COMPOUND USING THE SAME
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The present invention provides a catalyst used for manufacturing an optically active carbonyl compound by selective asymmetric hydrogenation of an α,β-unsaturated carbonyl compound, which is insoluble in a reaction mixture, and a method for manufacturing the corresponding optically active carbonyl compound. Particularly, the invention provides a catalyst for obtaining an optically active citronellal useful as a flavor or fragrance, by selective asymmetric hydrogenation of citral, geranial or neral. The invention relates to a catalyst for asymmetric hydrogenation of an α,β-unsaturated carbonyl compound, which comprises: a powder of at least one metal selected from metals belonging to Group 8 to Group 10 of the Periodic Table, or a metal-supported substance in which the at least one metal is supported on a support; an optically active peptide compound; and an acid, and also relates to a method for manufacturing an optically active carbonyl compound using the same.
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Page/Page column 24-26
(2012/06/16)
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- Highly enantioselective asymmetric isomerization of primary allylic alcohols with an iridium-N,P complex
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Access to chiral aldehydes: The asymmetric isomerization of primary allylic alcohols was studied with a bicyclic phosphine-oxazoline iridium catalyst. This method displays a broad substrate scope and leads to the desired chiral aldehydes with excellent enantioselectivities (see scheme; R1, R 2=Ar or alkyl). Copyright
- Li, Jia-Qi,Peters, Byron,Andersson, Pher G.
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supporting information; experimental part
p. 11143 - 11145
(2011/10/31)
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- A Site-Saturated Mutagenesis Study of Pentaerythritol Tetranitrate Reductase Reveals that Residues 181 and 184 Influence Ligand Binding, Stereochemistry and Reactivity
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We have conducted a site-specific saturation mutagenesis study of H181 and H184 of flavoprotein pentaerythritol tetranitrate reductase (PETN reductase) to probe the role of these residues in substrate binding and catalysis with a variety of α,β-unsaturated alkenes. Single mutations at these residues were sufficient to dramatically increase the enantiopurity of products formed by reduction of 2-phenyl-1-nitropropene. In addition, many mutants exhibited a switch in reactivity to predominantly catalyse nitro reduction, as opposed to C=C reduction. These mutants showed an enhancement in a minor side reaction and formed 2-phenylpropanal oxime from 2-phenyl-1-nitropropene. The multiple binding conformations of hydroxy substituted nitro-olefins in PETN reductase were examined by using both structural and catalytic techniques. These compounds were found to bind in both active and inhibitory complexes; this highlights the plasticity of the active site and the ability of the H181/H184 couple to coordinate with multiple functional groups. These properties demonstrate the potential to use PETN reductase as a scaffold in the development of industrially useful biocatalysts. Divergent evolution: A site-saturation study of PETN reductase was performed at conserved substrate binding residues H181 and H184. These residues were shown to dramatically alter the ratio of alkene versus nitro-group reduction in favour of oxime by-product formation, as summarised in the picture.
- Toogood, Helen S.,Fryszkowska, Anna,Hulley, Martyn,Sakuma, Michiyo,Mansell, David,Stephens, Gill M.,Gardiner, John M.,Scrutton, Nigel S.
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scheme or table
p. 738 - 749
(2012/02/01)
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- Asymmetric bioreduction of alkenes using ene-reductases YersER and KYE1 and effects of organic solvents
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Asymmetric trans-bioreduction of activated alkenes by KYE1 from Kluyveromyces lactis and Yers-ER from Yersinia bercovieri, two ene-reductases from the Old Yellow Enzyme family, showed a broad substrate spectrum with a moderate to excellent degree of stereoselectivity. Both substrate- and enzyme-based stereocontrols were observed to furnish opposite stereoisomeric products. The effects of organic solvents on enzyme activity and stereoselectivity were outlined in this study, where two-phase systems hexane and toluene are shown to sustain bioreduction efficiency even at high organic solvent content.
- Yanto, Yanto,Winkler, Christoph K.,Lohr, Stephanie,Hall, Melanie,Faber, Kurt,Bommarius, Andreas S.
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supporting information; experimental part
p. 2540 - 2543
(2011/06/25)
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- Biocatalysis with thermostable enzymes: Structure and properties of a thermophilic 'ene'-reductase related to old yellow enzyme
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We report the crystal structure of a thermophilic "ene" reductase (TOYE) isolated from Thermoanaerobacter pseudethanolicus E39. The crystal structure reveals a tetrameric enzyme and an active site that is relatively large compared to most other structurally determined and related Old Yellow Enzymes. The enzyme adopts higher order oligomeric states (octamers and dodecamers) in solution, as revealed by sedimentation velocity and multiangle laser light scattering. Bead modelling indicates that the solution structure is consistent with the basic tetrameric structure observed in crystallographic studies and electron microscopy. TOYE is stable at high temperatures (T m > 70°C) and shows increased resistance to denaturation in water-miscible organic solvents compared to the mesophilic Old Yellow Enzyme family member, pentaerythritol tetranitrate reductase. TOYE has typical ene-reductase properties of the Old Yellow Enzyme family. There is currently major interest in using Old Yellow Enzyme family members in the preparative biocatalysis of a number of activated alkenes. The increased stability of TOYE in organic solvents is advantageous for biotransformations in which water-miscible organic solvents and biphasic reaction conditions are required to both deliver novel substrates and minimize product racemisation.
- Adalbjoernsson, Bjoern V.,Toogood, Helen S.,Fryszkowska, Anna,Pudney, Christopher R.,Jowitt, Thomas A.,Leys, David,Scrutton, Nigel S.
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experimental part
p. 197 - 207
(2010/12/19)
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- Towards preparative-scale, biocatalytic alkene reductions
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Simple strategies for using alkene reductase enzymes to produce gram-scale quantities of both (R)- and (S)-citronellal have been developed. The methodology is easily accessible to non-specialist laboratories, allowing alkene reductases to be added to the toolbox of routine synthetic transformations.
- Bougioukou, Despina J.,Walton, Adam Z.,Stewart, Jon D.
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body text
p. 8558 - 8560
(2011/01/03)
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- Focused Directed Evolution of Pentaerythritol Tetranitrate Reductase by Using Automated Anaerobic Kinetic Screening of Site-Saturated Libraries
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This work describes the development of an automated robotic platform for the rapid screening of enzyme variants generated from directed evolution studies of pentraerythritol tetranitrate (PETN) reductase, a target for industrial biocatalysis. By using a 96-well format, near pure enzyme was recovered and was suitable for high throughput kinetic assays; this enabled rapid screening for improved and new activities from libraries of enzyme variants. Initial characterisation of several single site-saturation libraries targeted at active site residues of PETN reductase, are described. Two mutants (T26S and W102F) were shown to have switched in substrate enantiopreference against substrates (E)-2-aryl-1-nitropropene and α-methyl-trans-cinnamaldehyde, respectively, with an increase in ee (62 % (R) for W102F). In addition, the detection of mutants with weak activity against α,β-unsaturated carboxylic acid substrates showed progress in the expansion of the substrate range of PETN reductase. These methods can readily be adapted for rapid evolution of enzyme variants with other oxidoreductase enzymes.
- Hulley, Martyn E.,Toogood, Helen S.,Fryszkowska, Anna,Mansell, David,Stephens, Gill M.,Gardiner, John M.,Scrutton, Nigel S.
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experimental part
p. 2433 - 2447
(2011/07/08)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE, RACEMIC MENTHOL
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The present invention relates to a particularly economic overall method for producing menthol, specifically for producing optically active, essentially enantiomerically and diastereomerically pure L-menthol and racemic menthol, starting from the starting material citral which is available inexpensively on an industrial scale. The method comprises the following steps a.1) catalytic hydrogenation of neral and/or geranial to give citronellal, b.1) cyclization of citronellal to isopulegol in the presence of an acidic catalyst, c.1) purification of isopulegol by crystallization and d.1) catalytic hydrogenation of isopulegol to give menthol.
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Page/Page column 38
(2010/10/19)
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- CATALYST FOR ASYMMETRIC HYDROGENATION
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This invention aims at providing a catalyst for producing an optically active aldehyde or an optically active ketone, which is an optically active carbonyl compound, by carrying out selective asymmetric hydrogenation of an α,β-unsaturated carbonyl compound, particularly a catalyst which is insoluble in a reaction mixture for obtaining optically active citronellal which is useful as a flavor or fragrance, by carrying out selective asymmetric hydrogenation of citral, geranial or neral; and a method for producing a corresponding optically active carbonyl compound. The invention relates to a catalyst for asymmetric hydrogenation of an α,β-unsaturated carbonyl compound, which comprises a powder of at least one metal selected from metals belonging to Group 8 to Group 10 of the Periodic Table, or a metal-supported substance in which at least one metal selected from metals belonging to Group 8 to Group 10 of the Periodic Table is supported on a support, an optically active cyclic nitrogen-containing compound and an acid.
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Page/Page column 59
(2010/12/31)
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- Expanded scope for the iridium-catalyzed asymmetric isomerization of primary allylic alcohols using readily accessible second-generation catalysts
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A second generation of chiral (P,N)-iridium catalysts - readily accessible from inexpensive l-serine - displays expanded scope for the asymmetric isomerization of primary allylic alcohols.
- Mantilli, Luca,Mazet, Clement
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supporting information; experimental part
p. 445 - 447
(2010/04/04)
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- Improved catalysts for the iridium-catalyzed asymmetric isomerization of primary allylic alcohols based on charton analysis
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An improved generation of chiral cationic iridium catalysts for the asymmetric isomerization of primary allylic alcohols is disclosed. The design of these air-stable complexes relied on the preliminary mechanistic information available, and on Charton analyses using two preceding generations of iridium catalysts developed for this highly challenging transformation. Sterically unbiased chiral aldehydes that were not accessible previously have been obtained with high levels of enantioselectivity, thus validating the initial hypothesis regarding the selected ligand-design elements. A rationale for the high enantioselectivities achieved in most cases is also presented. Achieving enantioselectivity: An improved generation of chiral cationic iridium catalysts for the asymmetric isomerization of primary allylic alcohols is disclosed. The design of these air-stable complexes relies on preliminary mechanistic information and on Charton analyses using two preceding generations of iridium catalysts developed for this highly challenging transformation (see figure).
- Mantilli, Luca,Gerard, David,Torche, Sonya,Besnard, Celine,Mazet, Clement
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supporting information; experimental part
p. 12736 - 12745
(2011/02/21)
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- ALUMINIUM COMPLEXES AND USE THEREOF AS A CATALYST IN INTRAMOLECULAR RING CLOSURE REACTIONS
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To provide a process for increasing the proportion of an optical isomer of not only a compound having a closed ring but also a compound not having a closed ring when an optical isomer mixture of a compound having both a formyl group and a double bond capable of causing a carbonyl-ene ring closing reaction in the same molecule is subjected to a ring closing reaction. A process for increasing the proportion of an optical isomer characterized by subjecting an optical isomer mixture of a compound having both a formyl group and a double bond capable of causing a carbonyl-ene ring closing reaction in the same molecule to a ring closing reaction in the presence of a predetermined aluminum complex represented by the general formula: [All(L1)l(L2)m(Lh)n]k.
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Page/Page column 48-49
(2010/08/05)
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- ALUMINIUM COMPLEXES AND USE THEREOF AS A CATALYST IN INTRAMOLECULAR RING CLOSURE REACTIONS
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To provide a process for increasing the proportion of an optical isomer of not only a compound having a closed ring but also a compound not having a closed ring when an optical isomer mixture of a compound having both a formyl group and a double bond capable of causing a carbonyl-ene ring closing reaction in the same molecule is subjected to a ring closing reaction. A process for increasing the proportion of an optical isomer characterized by subjecting an optical isomer mixture of a compound having both a formyl group and a double bond capable of causing a carbonyl-ene ring closing reaction in the same molecule to a ring closing reaction in the presence of a predetermined aluminum complex represented by the general formula: [Al2(L1)n(L2)3-n]m.
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Page/Page column 44-45
(2010/08/05)
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- The substrate spectra of pentaerythritol tetranitrate reductase, morphinone reductase, N-ethylmaleimide reductase and estrogen-binding protein in the asymmetric bioreduction of activated alkenes
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Four flavoproteins from the old yellow enzyme (OYE) family, pentaerythritol tetranitrate (PETNR) reductase, N-ethylmaleimide reductase (NEMR), morphinone reductase (MorR) and estrogen-binding protein (EBP1), exhibited a broad substrate tolerance by accepting conjugated enals, enones, imides, dicarboxylic acids and esters, as well as a nitroalkene and therefore can be employed for the asymmetric bioreduction of carbon-carbon double (C=C) bonds. In particular, morphinone reductase and estrogen-binding protein often showed a complementary stereochemical preference in comparison to that of previously investigated OYES.
- Mueller, Nicole J.,Stueckler, Clemens,Hauer, Bernhard,Baudendistel, Nina,Housden, Hazel,Bruce, Neil C.,Faber, Kurt
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experimental part
p. 387 - 394
(2010/06/11)
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- Characterization of xenobiotic reductase A (XenA): Study of active site residues, substrate spectrum and stability
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Xenobiotic reductase A (XenA) has broad catalytic activity and reduces various α,β-unsaturated and nitro compounds with moderate to excellent stereoselectivity. Single mutants C25G and C25V are able to reduce nitrobenzene, a non-active substrate for the wild type, to produce aniline. Total turnover is dominated by chemical rather than thermal instability. The Royal Society of Chemistry 2010.
- Yanto, Yanto,Yu, Hua-Hsiang,Hall, Melanie,Bommarius, Andreas S.
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scheme or table
p. 8809 - 8811
(2011/02/28)
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- Asymmetric transfer hydrogenation in aqueous media catalyzed by resin-supported peptide having a polyleucine tether
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A resin-supported N-terminal prolyl peptide having a β-turn motif and a polyleucine tether has been developed for the organocatalytic asymmetric transfer hydrogenation under aqueous conditions. Polyleucine accelerated the reaction in a highly enantioselective manner by providing a hydrophobic microenvironment around the prolyl residue. The investigation of catalyst structures indicates that the l-form of polyleucine is essential for both reaction efficiency and enantioselectivity.
- Akagawa, Kengo,Akabane, Hajime,Sakamoto, Seiji,Kudo, Kazuaki
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scheme or table
p. 461 - 466
(2009/09/06)
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- Asymmetrie reduction of activated alkenes by pentaerythritol tetranitrate reductase: Specificity and control of stereochemical outcome by reaction optimisation
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We show that pentaerythritol tetranitrate reductase (PETNR), a member of the 'ene' reductase old yellow enzyme family, catalyses the asymmetric reduction of a variety of industrially relevant activated α,β-unsaturated alkenes including enones, enals, maleimides and nitroalkenes. We have rationalised the broad substrate specificity and stereochemical outcome of these reductions by reference to molecular models of enzyme-substrate complexes based on the crystal complex of the PETNR with 2cyclohexenone 4a. The optical purity of products is variable (49-99% ee), depending on the substrate type and nature of substituents. Generally, high enantioselectivity was observed for reaction products with stereogenic centres at Cβ (>99% ee). However, for the substrates existing in two isomeric forms (e.g., citral 11a or nitroalkenes 18-19a), an enantio-divergent course of the reduction of E/Z-forms may lead to lower enantiopurities of the products. We also demonstrate that the poor optical purity obtained for products with stereogenic centres at Ca is due to non-enzymatic racemisation. In reactions with ketoisophorone 3a we show that product racemisation is prevented through reaction optimisation, specifically by shortening reaction time and through control of solution pH. We suggest this as a general strategy for improved recovery of optically pure products with other biocatalytic conversions where there is potential for product racemisation.
- Fryszkowska, Anna,Toogood, Helen,Sakuma, Michiyo,Gardiner, John M.,Stephens, Gill M.,Scrutton, Nigel S.
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supporting information; experimental part
p. 2976 - 2990
(2010/03/25)
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- Asymmetric bioreduction of C=C bonds using enoate reductases OPR1, OPR3 and YqjM: Enzyme-based stereocontrol
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Three cloned enoate reductases from the "old yellow enzyme" family of flavoproteins were investigated in the asymmetric bioreduction of activated alkenes. 12-Oxophytodienoate reductase isoenzymes OPR1 and OPR3 from Lycopersicon esculentum (tomato), and YqjM from Bacillus subtilis displayed a remarkably broad substrate spectrum by reducing α,β-unsaturated aldehydes, ketones, maleimides and nitroalkenes. The reaction proceeded with absolute chemoselectivity-only the conjugated C=C bond was reduced, while isolated olefins and carbonyl groups remained intact-with excellent stereoselectivities (ees up to >99%). Upon reduction of a nitroalkene, the stereochemical outcome could be determined via choice of the appropriate enzyme (OPR1 versus OPR3 or YqjM), which furnished the corresponding enantiomeric nitroalkanes in excellent ee. Molecular modelling suggests that this "enzyme-based stereocontrol" is caused by subtle differences within the active site geometries.
- Hall, Melanie,Stueckler, Clemens,Ehammer, Heidemarie,Pointner, Eva,Oberdorfer, Gustav,Gruber, Karl,Hauer, Bernard,Stuermer, Rainer,Kroutil, Wolfgang,Macheroux, Peter,Faber, Kurt
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experimental part
p. 411 - 418
(2009/04/10)
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