- A mechanistic study of the dihydroflavin reductive cleavage of the dihydroflavin-tetrahydronaphthalene epoxide adducts
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Dihydroflavins are facile reducing agents and potent nucleophiles. The dihydroflavin nucleophilic reactivity, as measured by the rate of covalent flavin adduct formation with tetrahydronaphthalene epoxides, is comparable to that of the thiolate anion (Y. T. Lee and J. F. Fisher (1993) J. Org. Chem. 58, 3712). In these reactions there appears subsequent to the nucleophilic cleavage of the epoxide by the dihydroflavin the product corresponding to formal hydride reduction product (at the benzylic carbon) of these epoxides. Thus the reaction of (±)-1a,2,3,7b-tetrahydro-(1aα,2α,3β,7bα)-naphth[1,2-b]oxiren e-2,3-diol (1), (±)-1a,2,3,7b-tetrahydro-(1aα,2β,3α,7bα)-naphth[1,2-b]oxiren e-2,3-diol (2), and (±)-1a,2,3,7b-tetrahydro-(1aα,7bα)-naphth[1,2-b]oxirene (3) in 9:1 (v/v) aqueous Tris buffer-dioxane, at both acidic and neutral pH, with FMNH2 and 1,5-dihydrolumiflavin (LFH2) gave (following covalent flavin-epoxide adduct formation) the products having a methylene group at the benzylic position. The reduction product yield was proportional to the yield of the N(5) flavin-epoxide adduct intermediate, and the rate of the reaction was proportional to the dihydroflavin concentration. These observations are consistent with these reduction products resulting from bimolecular reaction between the dihydroflavin-epoxide adduct and a second molecule of dihydroflavin. (C) 2000 Academic Press.
- Lee,Fisher
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Read Online
- Half-Sandwich Nickel(II) NHC-Picolyl Complexes as Catalysts for the Hydrosilylation of Carbonyl Compounds: Evidence for NHC-Nickel Nanoparticles under Harsh Reaction Conditions
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The cationic [NiCp(Mes-NHC-CH2py]Br complex 2 a was prepared directly by the reaction of nickelocene with 1-(2-picolyl)-3-mesityl-imidazolium bromide (1), and its PF6? derivative 2 b, by subsequent salt metathesis. X-ray diffraction studies and Variable Temperature 1H NMR experiments run with 2 a and 2 b strongly suggest the bidentate coordination of the picolyl-functionalized carbene to the nickel both in the solid state and in solution in both cases. These data suggest the absence of hemilabile behavior of the latter, even in the presence of a coordinating anion. Both complexes show similar activity in aldehyde hydrosilylation, further implying the absence of hemilability of the picolyl-functionalized carbene, and effectively reduce a broad scope of aldehydes in the absence of additive under mild conditions. In the case of ketones, effective hydrosilylation is only observed in the presence of a catalytic amount of potassium t-butoxide at 100 °C. Dynamic light scattering, scanning transmission electron microscopy and X-ray photoelectron spectroscopy show evidence for the involvement of NHC-picolyl-Ni nanoparticles under these conditions.
- Ulm, Franck,Shahane, Saurabh,Truong-Phuoc, Lai,Romero, Thierry,Papaefthimiou, Vasiliki,Chessé, Matthieu,Chetcuti, Michael J.,Pham-Huu, Cuong,Michon, Christophe,Ritleng, Vincent
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supporting information
p. 3074 - 3082
(2021/08/03)
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- Access to both enantiomers of substituted 2-tetralol analogs by a highly enantioselective reductase
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Both (S) and (R) forms of enantiomerically pure 2-tetralols, and their substituted analogs, are fundamental pharmaceutical intermediates. Here, we utilized the wild type and an engineered form of a highly enantioselective acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD) to produce (S)- and (R)-2-tetralols, and their substituted analogs. All mutations targeted residue Trp288, which has been shown to restrict substrate binding, but not play a direct role in catalysis. The wild type produced (S)-alcohols with excellent enantioselectivity, while the engineered forms produced either (S)- or (R)- alcohols, depending on the substituent on the aromatic ring of the substrate, indicating that enantioselectivity can be rationally controlled. As a result, we were able to produce 6-hydroxy-2-tetralol, a potential antifungal drug intermediate, with 98% ee (S) and 81% ee (R) by wild type and Trp288Ser GcAPRD, respectively. To our knowledge, this is the first report of generating chiral 6-hydroxy-2-tetralol by rational enzyme design.
- Koesoema, Afifa Ayu,Matsuda, Tomoko,Standley, Daron M.,T. sriwong, Kotchakorn,Tamura, Mayumi
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supporting information
(2020/02/11)
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- GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with a defect in glyoxylate metabolism, for example a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.
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Paragraph 00681; 00683; 00894
(2021/01/22)
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- A General Regioselective Synthesis of Alcohols by Cobalt-Catalyzed Hydrogenation of Epoxides
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A straightforward methodology for the synthesis of anti-Markovnikov-type alcohols is presented. By using a specific cobalt triphos complex in the presence of Zn(OTf)2 as an additive, the hydrogenation of epoxides proceeds with high yields and selectivities. The described protocol shows a broad substrate scope, including multi-substituted internal and terminal epoxides, as well as a good functional-group tolerance. Various natural-product derivatives, including steroids, terpenoids, and sesquiterpenoids, gave access to the corresponding alcohols in moderate-to-excellent yields.
- Beller, Matthias,Junge, Kathrin,Leischner, Thomas,Li, Wu,Liu, Weiping
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supporting information
p. 11321 - 11324
(2020/05/16)
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- Organic-inorganic nanocrystal reductase to promote green asymmetric synthesis
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An acetophenone reductase from Geotrichum candidum (GcAPRD) was immobilized by the organic-inorganic nanocrystal method. The GcAPRD nanocrystal presented improved stability and recyclability compared with those of the free GcAPRD. Moreover, the GcAPRD nanocrystal reduced broad kinds of ketones with excellent enantioselectivities to produce beneficial chiral alcohols such as (S)-1-(3′,4′-dichlorophenyl)ethanol with >99% yield and >99% ee. The robust and versatile properties of the GcAPRD nanocrystal demonstrated an approach to promote green asymmetric synthesis and sustainable chemistry. This journal is
- Koesoema, Afifa Ayu,Matsuda, Tomoko,Tsriwong, Kotchakorn
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p. 30953 - 30960
(2020/09/11)
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- Method for synthesizing tetrahydronaphthalene-2-alcohol derivative compound
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The invention relates to the technical field of compound preparation, and discloses a method for synthesizing a tetrahydronaphthalene-2-alcohol derivative compound, which comprises the following steps: (1) mixing a compound I with a palladium catalyst, an oxidant and a solvent, and carrying out sealed stirring reaction at 70-130 DEG C for 1-24 hours; carrying out post-treatment on the mixed solution obtained in the step (1) to obtain an intermediate product II; mixing the intermediate product II with a catalyst, acetonitrile and water, replacing air with nitrogen, and carrying out closed stirring reaction at 85-95 DEG C for 1-24 hours; and carrying out post-treatment on the mixed solution obtained in the step (3) to obtain a final product III, namely, the tetrahydronaphthalene-2-alcohol derivative compound. According to the method, intramolecular C (sp3)-H arylation is directly carried out through cross dehydrogenation coupling between inert C (sp3)-H and C (sp2)-H bonds to synthesizea benzopyran-3-alcohol derivative compound, the route is simple, the yield is high, the universality is good, the reaction condition is mild, and the selectivity is high.
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Paragraph 0026; 0032
(2020/07/21)
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- Base-free transfer hydrogenation of aryl-ketones, alkyl-ketones and alkenones catalyzed by an IrIIICp* complex bearing a triazenide ligand functionalized with pyrazole
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An IrIIICp* complex (2) bearing a triazenide ligand functionalized with pyrazole was synthesized and fully characterized by spectroscopic methods and the structure confirmed by X-ray diffraction studies. The catalytic activity of 2 and the control complex 3, which lacks of pyrazole in its structure, was evaluated in the reduction of aryl-ketones, alkyl-ketones, α,β-unsaturated and γ,δ-unsaturated ketones. The catalytic system, using either 2 or 3, exhibited good to excellent selectivity when tested with ketones and alkenones at 90 °C in 2-propanol as hydrogen source under base-free conditions. Reactivity of 2 in 2-propanol and NaH gave a neutral metal hydride (4) while in the absence of base gave two major cationic hydrides species (5 and 6).
- Medrano-Castillo, Layla J.,Collazo-Flores, Miguel á.,Camarena-Díaz, Juan P.,Correa-Ayala, Erick,Chávez, Daniel,Grotjahn, Douglas B.,Rheingold, Arnold L.,Miranda-Soto, Valentín,Parra-Hake, Miguel
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- Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds
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A set of GluN2B NMDA receptor antagonists with conformationally restricted phenylethylamine substructure was prepared and pharmacologically evaluated. The phenylethylamine substructure was embedded in ring expanded 3-benzazocines 4 as well as ring-contracted tetralinamines 6 and indanamines 7. The ligands 4, 6 and 7 were synthesized by reductive alkylation of secondary amine 11, reductive amination of ketones 12 and 16 and nucleophilic substitution of nosylates 14 and 17. The moderate GluN2B affinity of 3-benzazocine 4d (Ki = 32 nM) translated into moderate cytoprotective activity (IC50 = 890 nM) and moderate ion channel inhibition (60% at 10 μM) in two-electrode voltage clamp experiments with GluN1a/GluN2B expressing oocytes. Although some of the tetralinamines 6 and indanamines 7 showed very high GluN2B affinity (e.g. Ki (7f) = 3.2 nM), they could not inhibit glutamate/glycine inducted cytotoxicity. The low cytoprotective activity of 3-benzazocines 4, tetralinamines 6 and indanamines 7 was attributed to the missing OH moiety at the benzene ring and/or in benzylic position. Docking studies showed that the novel GluN2B ligands adopt similar binding poses as Ro 25–6981 with the central H-bond interaction between the protonated amino moiety of the ligands and the carbamoyl moiety of Gln110. However, due to the lack of a second H-bond forming group, the ligands can adopt two binding poses within the ifenprodil binding pocket.
- Bechthold, Elena,Gawaskar, Sandeep,Robaa, Dina,Schepmann, Dirk,Schreiber, Julian A.,Seebohm, Guiscard,Sippl, Wolfgang,Temme, Louisa,Wünsch, Bernhard
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supporting information
(2020/02/18)
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- Efficient Transfer Hydrogenation of Ketones Catalyzed by a Phosphine-Free Cobalt-NHC Complex
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A simple phosphine-free cobalt-NHC pincer complex has been synthesized and utilized for the transfer hydrogenation of ketones with 2-propanol as hydrogen donor. A broad range of ketones varying from aromatic, aliphatic and heterocyclic were effectively reduced to their corresponding alcohols in moderate to excellent yields with good tolerance of functional groups.
- Ibrahim, Jessica Juweriah,Reddy, C. Bal,Fang, Xiaolong,Yang, Yong
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p. 4429 - 4432
(2020/07/04)
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- Insights into the Substrate Promiscuity of Novel Hydroxysteroid Dehydrogenases
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Hydroxysteroid dehydrogenases (HSDHs) are valuable biocatalysts for the regio- and stereoselective modification of steroids, bile acids and other steroid derivatives. In this work, we investigated the substrate promiscuity of this highly selective class of enzymes. In order to reach this goal, a preliminary search of HSDH homologues in in-house or public available (meta)genomes was carried out. Eight novel NAD(H)-dependent HSDHs, showing either 7α-, 7β-, or 12α-HSDH activity, and including, for the first time, enzymes from extremophilic microorganisms, were identified, recombinantly produced, and characterized. Among the novel HSDHs, four highly active (up to 92 U mg?1) NAD(H)-dependent 7β-HSDHs showing negligible similarity towards previously described 7β-HSDHs, were discovered. These enzymes, along with previously characterized HSDHs, were tested as biocatalysts for the stereoselective reduction of a panel of substrates including two α-ketoesters of pharmaceutical interest and selected ketones that partially resemble the structural features of steroids. All the reactions were coupled with a suitable cofactor regeneration system. Regarding the α-ketoesters, nearly all of the tested HSDHs showed a good activity toward the selected substrates, yielding the reduced α-hydroxyester with up to 99% conversions and enantiomeric excesses. On the other hand, only the 7β-HSDHs from Collinsella aerofaciens and Clostridium absonum showed appreciable activity toward more complex ketones, i. e., (±)-trans-1-decalone, but with interesting as well as different selectivity. (Figure presented.).
- Bertuletti, Susanna,Ferrandi, Erica Elisa,Marzorati, Stefano,Vanoni, Marta,Riva, Sergio,Monti, Daniela
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p. 2474 - 2485
(2020/05/06)
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- Chiral (cyclopentadienone)iron complexes with a stereogenic plane as pre-catalysts for the asymmetric hydrogenation of polar double bonds
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In this paper, we describe a small library of easy-to-prepare chiral (cyclopentadienone)iron pre-catalysts for enantioselective C[dbnd]O and C[dbnd]N hydrogenations. Starting from readily accessible achiral materials, six chiral (cyclopentadienone)iron complexes (1a-f) possessing a stereogenic plane were synthesized in racemic form. Based on the screening of pre-catalysts (±)-1a-f in the hydrogenation of ketones and ketimines, we selected two complexes (1a and 1d) for resolution by semipreparative enantioselective HPLC. The absolute configuration of the separated enantiomers of 1a and 1d was assigned by XRD analysis (1a) and by comparison between experimental and DFT-calculated ECD and ORD spectra (1d). The enantiopure pre-catalysts (S)-1a and (R)-1d were tested in the asymmetric hydrogenation of several ketones and ketimines and showed good activity and modest enantioselectivity, the e.e. values ranging from very low to moderate (54%).
- Bai, Xishan,Cettolin, Mattia,Mazzoccanti, Giulia,Pierini, Marco,Piarulli, Umberto,Colombo, Valentina,Dal Corso, Alberto,Pignataro, Luca,Gennari, Cesare
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p. 1415 - 1424
(2019/02/09)
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- GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme glycolate oxidase (GO). Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.
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Paragraph 00723; 00724; 00726; 00936; 00937; 00938
(2019/07/17)
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- Identification of an Esterase Isolated Using Metagenomic Technology which Displays an Unusual Substrate Scope and its Characterisation as an Enantioselective Biocatalyst
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Evaluation of an esterase annotated as 26D isolated from a marine metagenomic library is described. Esterase 26D was found to have a unique substrate scope, including synthetic transformations which could not be readily effected in a synthetically useful manner using commercially available enzymes. Esterase 26D was more selective towards substrates which had larger, more sterically demanding substituents (i. e. iso-propyl or tert-butyl groups) on the β-carbon, which is in contrast to previously tested commercially available enzymes which displayed a preference for substrates with sterically less demanding substituents (e.g. methyl group) at the β-carbon. (Figure presented.).
- Gavin, Declan P.,Murphy, Edel J.,Foley, Aoife M.,Castilla, Ignacio Abreu,Reen, F. Jerry,Woods, David F.,Collins, Stuart G.,O'Gara, Fergal,Maguire, Anita R.
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p. 2466 - 2474
(2019/03/11)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH APJ RECEPTOR ACTIVITY
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This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol "APLNR"). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and/or symptoms and/or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; and (iv) organ failure; (v) diseases, disorders, and conditions associated with infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular non-limiting examples of such diseases, disorders, or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension.
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Page/Page column 142-143
(2019/09/18)
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- Enantioselective Synthesis of Boryl Tetrahydroquinolines via Cu-Catalyzed Hydroboration
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A Cu-catalyzed regio- and enantioselective hydroboration of 1,2-dihydroquinolines with high yields and excellent enantioselectivities (up to 98% ee) was presented. This method could be applied in the asymmetric synthesis of the important intermediates used in the enantioselective synthesis of the potential agent Sumanirole for the treatment of Parkinson's disease and of the potentially interesting positive inotropic agent (S)-903.
- Kong, Duanyang,Han, Suna,Zi, Guofu,Hou, Guohua,Zhang, Jiaxin
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p. 1924 - 1932
(2018/02/23)
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- Asymmetric Transfer Hydrogenation of (Hetero)arylketones with Tethered Rh(III)-N-(p-Tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine Complexes: Scope and Limitations
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A series of new tethered Rh(III)/Cp? complexes containing the N-(p-tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine ligand have been prepared, characterized, and evaluated in the asymmetric transfer hydrogenation (ATH) of a wide range of (hetero)aryl ketones. The reaction was performed under mild conditions with the formic acid/triethylamine (5:2) system as the hydrogen source and provided enantiomerically enriched alcohols with good yields and high to excellent enantioselectivities. Although the nature of the substituents on the phenyl tethering ring did not alter the stereochemical outcome of the reaction, complexes bearing electron-donating groups exhibited a higher catalytic activity than those having electron-withdrawing groups. A scale-up of the ATH of 4-chromanone to the gram scale quantitatively delivered the reduced product with excellent enantioselectivity, demonstrating the potential usefulness of these new complexes.
- Zheng, Long-Sheng,Llopis, Quentin,Echeverria, Pierre-Georges,Férard, Charlène,Guillamot, Gérard,Phansavath, Phannarath,Ratovelomanana-Vidal, Virginie
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p. 5607 - 5615
(2017/06/07)
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- Visible-Light-Mediated Anti-Markovnikov Hydration of Olefins
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Considering that stoichiometric borane and oxidant are required in the classical alkene anti-Markovnikov hydration process, it remains appealing to achieve the transformation in a catalytic protocol. Herein, a visible-light-mediated anti-Markovnikov addition of water to alkenes by using an organic photoredox catalyst in conjunction with a redox-active hydrogen atom donor was developed, which avoided the need for a transition-metal catalyst, stoichiometric borane, as well as oxidant. Both terminal and internal olefins are readily accommodated in this transformation to obtain corresponding primary and secondary alcohols in good yields with single regioselectivity. This procedure can be scaled up to gram scale with a 230 turnover number based on photocatalyst.
- Hu, Xia,Zhang, Guoting,Bu, Faxiang,Lei, Aiwen
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p. 1432 - 1437
(2017/08/09)
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- Selective Catalytic Hydrogenation of Arenols by a Well-Defined Complex of Ruthenium and Phosphorus-Nitrogen PN3-Pincer Ligand Containing a Phenanthroline Backbone
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Selective catalytic hydrogenation of aromatic compounds is extremely challenging using transition-metal catalysts. Hydrogenation of arenols to substituted tetrahydronaphthols or cyclohexanols has been reported only with heterogeneous catalysts. Herein, we demonstrate the selective hydrogenation of arenols to the corresponding tetrahydronaphthols or cyclohexanols catalyzed by a phenanthroline-based PN3-ruthenium pincer catalyst.
- Li, Huaifeng,Wang, Yuan,Lai, Zhiping,Huang, Kuo-Wei
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p. 4446 - 4450
(2017/07/24)
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- Deoxygenation of carbonyl compounds using an alcohol as an efficient reducing agent catalyzed by oxo-rhenium complexes
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This work describes the first methodology for the deoxygenation of carbonyl compounds using an alcohol as a green solvent/reducing agent catalyzed by oxo-rhenium complexes. The system 3-pentanol/ReOCl3(SMe2)(OPPh3) was successfully employed in the deoxygenation of several aryl ketones to the corresponding alkenes and also in the deoxygenation of aryl aldehydes to alkanes with moderate to excellent yields. The catalyst ReOCl3(SMe2)(OPPh3) can also be used in several catalytic cycles with good activity.
- Bernardo, Joana R.,Fernandes, Ana C.
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supporting information
p. 2675 - 2681
(2016/05/24)
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- Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ
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The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.
- Pujala, Brahmam,Agarwal, Anil K.,Middya, Sandip,Banerjee, Monali,Surya, Arjun,Nayak, Anjan K.,Gupta, Ashu,Khare, Sweta,Guguloth, Rambabu,Randive, Nitin A.,Shinde, Bharat U.,Thakur, Anamika,Patel, Dhananjay I.,Raja, Mohd.,Green, Michael J.,Alfaro, Jennifer,Avila, Patricio,Pérez de Arce, Felipe,Almirez, Ramona G.,Kanno, Stacy,Bernales, Sebastián,Hung, David T.,Chakravarty, Sarvajit,McCullagh, Emma,Quinn, Kevin P.,Rai, Roopa,Pham, Son M.
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supporting information
p. 1161 - 1166
(2016/12/16)
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- Asymmetric Transfer Hydrogenation of Ketones with Modified Grubbs Metathesis Catalysts: On the Way to a Tandem Process
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Herein, we report the successful transformation of a 1st generation Grubbs metathesis catalyst into an asymmetric transfer hydrogenation (ATH) catalyst. Upon addition of a chiral amine ligand, an alcohol and a base, the 1st generation Hoveyda-Grubbs catalyst (HG-I) was found to promote the enantioselective reduction of acetophenone to 1-phenylethanol. After optimizing the order of addition and the reaction conditions, the substrate scope was assessed leading to enantiomeric excesses up to 97% ee. NMR experiments were run in order to get information about the in situ-generated ATH catalyst. Furthermore, the possibility to perform olefin metathesis and ketone transfer hydrogenation sequentially in one pot was demonstrated, and the first tandem olefin metathesis-ketone asymmetric transfer hydrogenation was carried out.
- Renom-Carrasco, Marc,Gajewski, Piotr,Pignataro, Luca,De Vries, Johannes G.,Piarulli, Umberto,Gennari, Cesare,Lefort, Laurent
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supporting information
p. 515 - 519
(2016/02/27)
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- Chiral Cyclopentadienone iron complexes for the catalytic asymmetric hydrogenation of ketones
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Three chiral (cyclopentadienone)iron complexes derived from (R)-BINOL (CK1-3) were synthesized and their structures unambiguously confirmed by X-ray analysis (CK3). Under suitable conditions for the in situ conversion into the corresponding (hydroxycyclopentadienyl)iron hydrides (Me3NO, H2), the new chiral complexes were tested in the catalytic asymmetric hydrogenation of ketones, showing moderate to good enantioselectivity. In particular, the complex bearing methoxy substituents at the 3,3-positions of the binaphthyl moiety (CK2) proved remarkably more enantioselective than the unsubstituted one (CK1) and reached the highest level of enantioselectivity (up to 77% ee) ever obtained with chiral (cyclopentadienone)iron complexes. Reducto! Chiral (cyclopentadienone)iron complexes were synthesized and tested, after in situ activation, in the catalytic asymmetric hydrogenation of ketones leading to the highest enantiomeric excesses ever obtained with this type of catalysts.
- Gajewski, Piotr,Renom-Carrasco, Marc,Facchini, Sofia Vailati,Pignataro, Luca,Lefort, Laurent,De Vries, Johannes G.,Ferraccioli, Raffaella,Forni, Alessandra,Piarulli, Umberto,Gennari, Cesare
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supporting information
p. 1887 - 1893
(2015/03/18)
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- Preparation of chiral ligands connected with quaternary ammonium group for recyclable catalytic asymmetric transfer hydrogenation in ionic liquid
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Reuse of chiral ruthenium catalyst in catalytic asymmetric transfer hydrogenation (CATH) has attracted attention from economic and environmental viewpoints, and reactions using ionic liquids (ILs) as solvent are recognized as one of the most useful methods for reuse of the catalyst. We synthesized (1 S,2 S )- N-( p - toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN) derivatives with various ionic moieties, and investigated the effect of their structure with respect to catalytic ability and recyclability in CATH with ILs. Ligand 3a having an imidazolium group showed the best results, and significant differences were observed depending on the structure of the ionic moiety or the length of the alkyl chain connecting the ligand site and the ionic moiety. Among various prochiral ketones used as substrates at various cycles, 3a showed a relatively good result.
- Uchimoto, Hitomi,Tsuji, Tomoko,Kawasaki, Ikuo,Arimitsu, Kenji,Yasui, Hiroyuki,Yamashita, Masayuki,Ohta, Shunsaku,Nishide, Kiyoharu
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p. 200 - 209
(2015/03/18)
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- Synthesis of (R)-BINOL-Derived (Cyclopentadienone)iron Complexes and Their Application in the Catalytic Asymmetric Hydrogenation of Ketones
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A family of chiral (cyclopentadienone)iron complexes, featuring an (R)-BINOL-derived backbone, and their application in the asymmetric hydrogenation of ketones are described. The complexes differ from each other in the substituents at the 3,3′-positions of the binaphthyl residue (H, OH, OR, OCOR, OSO2R) or at the 2,5-positions of the cyclopentadienone ring [trimethylsilyl (TMS) or Ph]. Remarkably, eight precatalysts with different 3,3′-binaphthyl substitution [(R)-1c-1j] were synthesized from a common parent complex [(R)-1b] through direct functional group interconversion reactions of the complexes. The 3,3′-(bis)methoxy-substituted precatalyst (R)-1b gave the best catalytic performance, and its application scope was assessed in the hydrogenation of several ketones. The observed ee values (up to 77%) are much higher than those previously reported for other chiral (cyclopentadienone)iron complexes.
- Gajewski, Piotr,Renom-Carrasco, Marc,Facchini, Sofia Vailati,Pignataro, Luca,Lefort, Laurent,De Vries, Johannes G.,Ferraccioli, Raffaella,Piarulli, Umberto,Gennari, Cesare
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supporting information
p. 5526 - 5536
(2015/09/01)
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- Ansa-Ruthenium(II) Complexes of R2NSO2DPEN-(CH2)n(η6-Aryl) Conjugate Ligands for Asymmetric Transfer Hydrogenation of Aryl Ketones
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New 3rd generation designer ansa-ruthenium(II) complexes featuring N,C-alkylene-tethered N,N-dialkylsulfamoyl-DPEN/η6-arene ligands, exhibited good catalytic performance in the asymmetric transfer hydrogenation (ATH) of various classes of (het)aryl ketones in formic acid/triethylamine mixture. In particular, benzo-fused cyclic ketones furnished 98 to >99.9% ee using a low catalyst loading.
- Ki?ic, Andrea,Stephan, Michel,Mohar, Barbara
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p. 2540 - 2546
(2015/08/18)
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- HETEROCYCLIC COMPOUNDS AND METHODS OF USE
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The present application discloses compounds that are inhibitors of Btk, compounds that are inhibitors of ΡΒΚδ, and compounds that are dual inhibitors of both Btk and PI3Kδ. Also described are methods for synthesizing such inhibitors and methods for using such inhibitors for the treatment of diseases wherein inhibition of Btk and PI3Kδ provides a therapeutic benefit to a patient having the disease.
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Paragraph 0208; 0243
(2015/05/05)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE ALCOHOL
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Provided is an industrially advantageous method for producing optically active alcohols in high yields from ketones of various structures by using an inexpensive chiral catalyst. The method of the present invention for producing optically active alcohols comprises reducing a ketone in the presence of an iridium(III) complex having a chiral prolinamide compound as a ligand. The ketone is preferably a compound represented by formula [I]: (wherein R1 and R2 are different from each other, and each represent an optionally substituted straight or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group, and R1 and R2 may be bound to each other at any appropriate position to form a ring, the ring optionally containing one or more atoms which may be the same or different and are selected from an oxygen atom, an optionally substituted nitrogen atom and a sulfur atom, and optionally being condensed with an aromatic or hetero-aromatic ring).
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Paragraph 0093-0095
(2014/09/17)
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- Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis
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Meropenem, a broad-spectrum parenteral β-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem's short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem.
- Teitelbaum, Aaron M.,Meissner, Anja,Harding, Ryan A.,Wong, Christopher A.,Aldrich, Courtney C.,Remmel, Rory P.
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p. 5605 - 5617
(2013/09/02)
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- A mild and efficient flow procedure for the transfer hydrogenation of ketones and aldehydes using hydrous zirconia
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A flow chemistry Meerwein-Ponndorf-Verley (MPV) reduction procedure using partially hydrated zirconium oxide via a machine-assisted approach is reported. The heterogeneous reductive system could be applied to a wide range of functionalized substrates, allowing clean and fast delivery of the alcohol products within a few minutes (6-75 min). In three examples the system was scaled to deliver 50 mmol of product.
- Battilocchio, Claudio,Hawkins, Joel M.,Ley, Steven V.
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supporting information
p. 2278 - 2281
(2013/06/05)
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- Quenched skeletal Ni as the effective catalyst for selective partial hydrogenation of polycyclic aromatic hydrocarbons
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Quenched skeletal Ni is an active and selective catalyst for selective partial hydrogenation of polycyclic aromatic hydrocarbons (PAHs). The molecular structure of PAHs significantly dominate the hydrogenation process and furthermore, the distribution of hydrogenated products.
- Liu, Chengyun,Rong, Zeming,Sun, Zhuohua,Wang, Yong,Du, Wenqiang,Wang, Yue,Lu, Lianhai
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p. 23984 - 23988
(2013/11/19)
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- Tetrahydroxynaphthalene reductase: Catalytic properties of an enzyme involved in reductive asymmetric naphthol dearomatization
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In reduced circumstances: Tetrahydroxynaphthalene reductase shows a broad substrate range including alternate phenolic compounds and cyclic ketones. Structural modeling reveals major enzyme-substrate interactions; C-terminal truncation of the enzyme causes an altered substrate preference, in accordance with stabilization of the substrate by the C-terminal carboxylate (see picture). This effect allows the identification of a homologous enzyme. Copyright
- Schaetzle, Michael A.,Flemming, Stephan,Husain, Syed Masood,Richter, Michael,Guenther, Stefan,Mueller, Michael
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supporting information; experimental part
p. 2643 - 2646
(2012/05/04)
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- Asymmetric hydrosilylation of ketones catalyzed by complexes formed from trans-diaminocyclohexane-based diamines and diethylzinc
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Chiral acyclic and macrocyclic amines derived from trans-1,2- diaminocyclohexane in complexes with diethylzinc efficiently catalyze asymmetric hydrosilylation of aryl-alkyl and aryl-aryl ketones with enantiomeric excess of the product up to 86 %. A trianglamine ligand with a cyclic structure or the presence of an additional coordinating group increases the enantioselectivity of the reaction, in comparison with catalysis by a simple acyclic N,N′-dibenzyl-1,2-diaminocyclohexane ligand. In addition, the effect of the asymmetric activation of the catalyst by a variety of alcohols and diols is studied.
- Gajewy, Jadwiga,Gawronski, Jacek,Kwit, Marcin
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experimental part
p. 1045 - 1054
(2012/09/22)
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- Enantioselective hydrosilylation of aromatic alkenes catalyzed by chiral bis(oxazolinyl)phenyl-rhodium acetate complexes
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Highly efficient and enantioselective hydrosilylation of aromatic alkenes catalyzed by the chiral rhodium acetate complexes with the bis(oxazolinyl)phenyl ligands has been reported that afforded chiral silane derivatives with up to 99% ee. Georg Thieme Ve
- Naito, Tatsuo,Yoneda, Takuma,Ito, Jun-Ichi,Nishiyama, Hisao
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p. 2957 - 2960
(2013/02/22)
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- An unexpected directing effect in the asymmetric transfer hydrogenation of α,α-disubstituted ketones
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α,α-Disubstituted ketones containing an aromatic ring or alkene are reduced in high enantiomeric excess using an asymmetric transfer hydrogenation catalyst. The sense of reduction indicates that the unsaturated region of the ketone adopts a position adjacent to the Ru-bound η6-arene ring in the reduction transition state.
- Soni, Rina,Collinson, John-Michael,Clarkson, Guy C.,Wills, Martin
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supporting information; experimental part
p. 4304 - 4307
(2011/10/11)
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- Screening on the use of Kluyveromyces marxianus CBS 6556 growing cells as enantioselective biocatalysts for ketone reductions
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The versatility of Kluyveromyces marxianus CBS 6556 growing cells in the enantioselective reduction of ketone functionalities to the corresponding alcohols was exploited. In particular, methyl ketones were reduced to (S)-alcohols with ees of up to 96%. Longer chain alkyl ketones afforded, under the same experimental condition, (R)-alcohols with an ee of up to 84%. Interestingly, carbon-carbon double and the triple bonds can also be reduced in the presence of Kluyveromyces marxianus CBS 6556 yeast. A cyclic ketone, such as 2-tetralone, was also quantitatively reduced to its corresponding (S)-alcohol with ee = 76%.
- Vitale, Paola,Perna, Filippo Maria,Perrone, Maria Grazia,Scilimati, Antonio
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experimental part
p. 1985 - 1993
(2012/03/22)
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- Enantioselective reduction of ketones and imines catalyzed by (CN-Box)ReV-oxo complexes
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The development and application of chiral, non-racemic ReV-oxo complexes to the enantioselective reduction of prochiral ketones is described. In addition to the enantioselective reduction of prochiral ketones, we report the application of these complexes to 1) a tandem Meyer-Schuster rearrangement/reduction to access enantioenriched allylic alcohols and 2) the enantioselective reduction of imines.
- Nolin, Kristine A.,Ahn, Richard W.,Kobayashi, Yusuke,Kennedy-Smith, Joshua J.,Toste, F. Dean
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supporting information; experimental part
p. 9555 - 9562
(2010/10/03)
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- Regio- and stereoselective biohydroxylations with a recombinant escherichia coli expressing P450pyr monooxygenase of sphingomonas Sp. HXN-200
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A recombinant Escherichia coli expressing P450pyr monooxygenase of Sphingomonas sp. HXN-200 was developed as a useful biocatalyst for regio- and stereoselective hydroxylations, with no side reaction and easy cell growth. The resting E. coli cells showed an activity of 4.1 U/g cdw and 9.9 U/g cdw for the hydroxylation of N-benzylpyrrolidin-2-one 1 and N-benzyloxycarbonylpyrrolidine 3, respectively, being as active as the wide-type strain. Biohydroxylation of N-benzylpyrrolidin-2-one 1 with the resting cells gave (S)-N-benzyl-4- hydroxypyrrolidin-2-one 2 in >99% ee and 10.8 mM, a 2.6 times increase of product concentration in comparison with the wild-type strain. Biohydroxylation of N-tert-butoxycarbonylpiperidin-2-one 5, N-benzylpiperidine 7 and N-tert-butoxycarbonylazetidine 9 with the E. coli cells afforded the corresponding 4-hydroxypiperidin-2-one 6, 4-hydroxypiperidine 8, and 3-hydroxyazetidine 10 in 14 mM, 17 mM, and 21 mM, respectively. Moreover, hydroxylation of (-)-β-pinene 11 with the recombinant E. coli cells showed excellent regio- and stereoselectivity and gave (1R)-trans-pinocarveol 12 in 82% yield and 4.1 mM, which is over 200 times higher than that obtained with the best biocatalytic system known thus far. The recombinant strain was also able to hydroxylate other types of substrates with unique selectivity: biohydroxylation of norbornane 13 gave exo-norbornaeol 14, with exo/endo selectivity of 95%; tetralin 15 and 6-methoxytetralin 17 were hydroxylated at the non-activated 2-position, for the first time, with regioselectivities of 83-84%. Copyright
- Zhang, Wei,Tang, Weng Lin,Wang, Zunsheng,Li, Zhi
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experimental part
p. 3380 - 3390
(2011/02/23)
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- Gold-catalyzed oxidative coupling reactions with aryltrimethylsilanes
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During continuing studies with a novel oxidative gold oxyarylation reaction, arylsilanes were found to be competent coupling partners, providing further evidence for an intramolecular electrophilic aromatic substitution mechanism. While providing yields complementary to those of the previously described boronic acid methods, the use of trimethylsilanes reduces the observation of homocoupling byproducts and allows for facile intramolecular coupling reactions.
- Brenzovich Jr., William E.,Brazeau, Jean-Francois,Toste, F. Dean
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supporting information; experimental part
p. 4728 - 4731
(2010/12/25)
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- Synthesis and evaluation of dimeric 1,2,3,4-Tetrahydro-naphthalenylamine and Indan-1-ylamine derivatives with mast cell-stabilising and anti-allergic activity
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In a continuation of our studies into 4-Amino-3,4-dihydro-2H-naphthalen-1-ones as novel modulators of allergic and inflammatory phenomena, we have extended our work to include dimeric analogues. Of these derivatives, the most promising activity was seen with tertiary amine 58a, which exhibited potent mast cell-stabilising activity in vitro against a variety of stimuli and also in vivo against passive cutaneous anaphylaxis.
- Barlow, James W.,Walsh, John J.
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experimental part
p. 25 - 37
(2010/03/04)
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- Metal-free catalytic reduction of aldehydes, ketones, aldimines, and ketimines
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The metal-free combination of catalytic amounts of PPh3, B(C6F5)3, and PhSiH3 can efficiently hydrosilylate aldehydes, ketones, aldimines and ketimines to afford the corresponding reduction products in good yields.
- Matsuoka, Hiroaki,Kondo, Kazuhiro
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scheme or table
p. 1314 - 1317
(2011/10/08)
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- Enzymatic resolution of 5-hydroxy- and 8-hydroxy-2-tetralols using immobilized lipases
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(R)-2-Tetralol (R)-2a, (R)-5-hydroxy-2-tetralol (R)-2b and (R)-8-hydroxy-2-tetralol (R)-2c, which are key intermediates in the synthesis of pharmacologically active 2-aminotetralins 3, were prepared in moderate to very high enantiomeric excess (up to 99% ee) by enzymatic resolution of the corresponding racemic butyrates rac-1a, rac-1b and rac-1c, respectively, using lipases immobilized on octyl agarose. This methodology is an alternative to the microbial reduction of 2-tetralones.
- Bonomi, Paolo,Cairoli, Paola,Ubiali, Daniela,Morelli, Carlo F.,Filice, Marco,Nieto, Ines,Pregnolato, Massimo,Manitto, Paolo,Terreni, Marco,Speranza, Giovanna
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experimental part
p. 467 - 472
(2009/09/06)
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- Convenient enantioselective hydrosilylation of ketones catalyzed by zinc-macrocyclic oligoamine complexes
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Chiral macrocyclic tetra- and hexamine macrocycles derived from trans-1,2-diaminocyclohex-ane (DACH) in complexes with diethylzinc efficiently catalyze the asymmetric hydrosilylation of aryl alkyl ketones with enantiomeric excess of the product up to 89%. The cyclic structure of the triangla-mine ligand increases the enantioselectivity of the reaction, in comparison to the catalysis with the acyclic N,N′-dibenzyl-DACH ligand. Density functional theory (DFT) computations on the structures of ligand-zinc complexes and on the structures of these complexes with a coordinated acetophenone mole-cule allow us to rationalize the direction of the asymmetric induction of the hydrosilylation reaction as well as the superiority of the cyclic ligand compared to the acyclic one. This is the first example of asymmetric catalysis for the hydrosilylation reaction of ketones with the use of a readily available, inexpensive, and reusable macrocyclic trianglamine ligand.
- Gajewy, Jadwiga,Kwit, Marcin,Gawronski, Jacek
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experimental part
p. 1055 - 1063
(2009/12/05)
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- Asymmetric hydrogenation of ketones using Ir(III) complexes of N-alkyl-N'-tosyl-1,2-ethanediamine ligands
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The combination of an enantiomerically pure N′-alkylated derivative of N-4-toluenesulfonyl-1,2-diphenylethane-1,2-diamine (TsDPEN) with iridium trichloride results in the formation of a catalyst with high selectivity for ketone hydrogenation. Products with enantiomeric excesses of up to 84% were formed. The best results were obtained using a ligand with an n-alkyl chain and ortho-substituted acetophenone derivatives and other hindered derivatives.
- Martins, José E.D.,Morris, David J.,Wills, Martin
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supporting information; experimental part
p. 688 - 692
(2011/02/27)
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- Rhodium/graphite-catalyzed hydrogenation of carbocyclic and heterocyclic aromatic compounds
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Rhodium on graphite (Rh/Gr, C24Rh) was prepared by reaction of anhydrous rhodium trichloride with potassium graphite (C8K, 3 equivalents) and used as a heterogeneous catalyst for the hydrogenation of carbocyclic and heterocyclic aromatic compounds at room temperature and 1 atm of hydrogen pressure. The effect of substitution on the benzene ring was examined in a variety of derivatives, including those with alkyl, hydroxy, alkoxy, aryloxy, carboxy, amino, nitro, acyl, chloro, or functionalized alkyl groups. Reduction of carbonyl functions of aromatic aldehydes and ketones occurred with complete or partial cleavage of the benzylic C-O bond; this cleavage also occurred in the hydrogenation of benzylic alcohols and esters. Georg Thieme Verlag Stuttgart.
- Falini, Giuseppe,Gualandi, Andrea,Savoia, Diego
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experimental part
p. 2440 - 2446
(2010/02/27)
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- Stereoselective bioreduction of bulky-bulky ketones by a novel ADH from Ralstonia sp.
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(Figure Presented) Ketones with two bulky substituents, named bulky-bulky ketones, as well as less sterically demanding ketones were successfully reduced to the corresponding optically highly enriched alcohols using a novel identified recombinant short-chain alcohol dehydrogenase RasADH from Ralstonia sp. DSM 6428 overexpressed in E. coli.
- Lavandera, Ivan,Kern, Alexander,Ferreira-Silva, Bianca,Glieder, Anton,De Wildeman, Stefaan,Kroutil, Wolfgang
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p. 6003 - 6005
(2008/12/21)
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- One-way biohydrogen transfer for oxidation of sec-alcohols
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(Chemical Equation Presented) Quasi-irreversible oxidation of sec-alcohols was achieved via biocatalytic hydrogen transfer reactions using alcohol dehydrogenases employing selected ketones as hydrogen acceptors, which can only be reduced but not oxidized. Thus, only 1 equiv of oxidant was required instead of a large excess. For the oxidation of both isomers of methylcarbinols a single nonstereoselective short-chain dehydrogenase/reductase from Sphingobium yanoikuyae was identified and overexpressed in E. coli.
- Lavandera, Ivan,Kern, Alexander,Resch, Verena,Ferreira-Silva, Bianca,Glieder, Anton,Fabian, Walter M. F.,De Wildeman, Stefaan,Kroutil, Wolfgang
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supporting information; experimental part
p. 2155 - 2158
(2009/05/27)
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- Asymmetric anti-Prelog reduction of ketones catalysed by Paracoccus pantotrophus and Comamonas sp. cells via hydrogen transfer
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A broad range of ketones including methyl-aryl-, methyl-alkyl-, cyclic and sterically hindered ketones were reduced to the corresponding anti-Prelog alcohols with moderate to excellent stereoselectivities by employing lyophilised cells of Paracoccus pantotrophus DSM 11072 and Comamonas sp. DSM 15091 via hydrogen transfer. The reduction equivalents were provided using 2-propanol as a hydride donor. For instance, acetophenone was reduced to the corresponding (R)-enantiomer with >99% ee.
- Lavandera, Ivan,Hoeller, Brigitte,Kern, Alexander,Ellmer, Ursula,Glieder, Anton,de Wildeman, Stefaan,Kroutil, Wolfgang
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p. 1954 - 1958
(2008/12/22)
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- Synthesis of aryl-containing terpenoids based on 1,4-dihydronaphthalene
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Successive transformations including oxidation of 1,4-dihydronaphthalene into 1,2,3,4-tetrahydronaphthalen-2-one, Reformatskii reaction of the latter with methyl bromoacetate, ozonolysis of the Reformatsky reaction product, and Emmons olefination of the aldehyde group in methyl 3-oxo-5-(2-formylphenyl) pentanate thus formed gave analogs of highly active dienoate juvenoids having an aromatic ring in their molecules.
- Kukovinets,Kislitsyn,Zainullin,Mukhamedzyanova,Galin,Abdullin
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p. 362 - 368
(2008/12/22)
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- Iron(II) chloride-mediated addition of dialkylmagnesium to carbonyl compounds
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Addition reactions to carbonyl compounds with a complex reagent, prepared from organomagnesium and iron(II) chloride, were examined. The reagent works as effective nucleophile to an easily enolizable ketone such as β-tetralone; it also added to keto ester chemoselectively. Copyright
- Sada, Mutsumi,Matsubara, Seijiro
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p. 800 - 801
(2008/12/21)
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