- Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway
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Cardiac hypertrophy is a common adaptive response to a variety of stimuli, but prolonged hypertrophy leads to heart failure. Hence, discovery of agents treating cardiac hypertrophy is urgently needed. In the present study, we investigated the effects of QF84139, a newly synthesized pyrazine derivative, on cardiac hypertrophy and the underlying mechanisms. In neonatal rat cardiomyocytes (NRCMs), pretreatment with QF84139 (1–10 μM) concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation, increased ANP protein level and enlarged cardiomyocytes. In adult male mice, administration of QF84139 (5–90 mg·kg?1·d?1, i.p., for 2 weeks) dose-dependently reversed transverse aortic constriction (TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size, left ventricular mass, heart weights, and reactivation of fetal genes. We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKIIδ, ERK1/2, AKT, PKCε, and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice. In NRCMs, QF84139 did not show additive effects with metformin on the AMPK activation, whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2. In AMPKα2-deficient mice, the anti-hypertrophic effect of QF84139 was also vanished. These results demonstrate that QF84139 attenuates the PE- and TAC-induced cardiac hypertrophy via activating the AMPK signaling. This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy.
- Li, Xu-xia,Zhang, Peng,Yang, Yang,Wang, Jing-jing,Zheng, Yan-jun,Tan, Ji-liang,Liu, Shen-yan,Yan, Yong-ming,Zhang, You-yi,Cheng, Yong-xian,Yang, Huang-tian
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- Catalytic Asymmetric Darzens-Type Epoxidation of Diazoesters: Highly Enantioselective Synthesis of Trisubstituted Epoxides
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Highly enantioselective Darzens-type epoxidation of diazoesters with glyoxal derivatives was accomplished using a chiral boron–Lewis acid catalyst, which facilitated asymmetric synthesis of trisubstituted α,β-epoxy esters. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in high yield (up to 99 %) with excellent enantio- and diastereoselectivity (up to >99 % ee and >20:1 dr, respectively). The synthetic potential of this method was illustrated by conversion of the products to various compounds such as epoxy γ-butyrolactone, tertiary β-hydroxy ketone and epoxy diester.
- Nam, Dong Guk,Shim, Su Yong,Jeong, Hye-Min,Ryu, Do Hyun
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supporting information
p. 22236 - 22240
(2021/09/13)
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- Visible-Light-Promoted Photocatalyst-Free Hydroacylation and Diacylation of Alkenes Tuned by NiCl2·DME
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Herein, we describe a visible light-promoted hydroacylation strategy that facilitates the preparation of ketones from alkenes and 4-acyl-1,4-dihydropyridines via an acyl radical addition and hydrogen atom transfer pathway under photocatalyst-free conditions. The efficiency was highlighted by wide substrate scope, good to high yields, successful scale-up experiments, and expedient preparation of highly functionalized ketone derivatives. In addition, this protocol allows for the synthesis of 1,4-dicarbonyl compounds through alkene diacylation in the presence of NiCl2·DME.
- Zhao, Xinxin,Li, Bing,Xia, Wujiong
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supporting information
p. 1056 - 1061
(2020/02/15)
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- Visible-Light-Induced Regioselective Dicarbonylation of Indolizines with Oxoaldehydes via Direct C-H Functionalization
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A metal-free system for regioselective dehydrogenative cross-couplings between indolizines and oxoaldehydes catalyzed by visible light under mild conditions has been described. As an atom economical and eco-friendly protocol, the reaction proceeds in good yields using inexpensive, readily available visible-light sources and the environmentally friendly oxidant oxygen. Various valuable 1,2-dicarbonyl derivatives attached to an indolizine core were easily accessed by the direct dicarbonylation of the sp2 C-H bond.
- Teng, Lili,Liu, Xiang,Guo, Pengfeng,Yu, Yue,Cao, Hua
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supporting information
p. 3841 - 3845
(2020/05/08)
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- Antiproliferative Activity of 2-Aroyland 2-Heteroyl-1,1,3,3-Tetracyanoprop-2-en-1-ides
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The influence of previously synthesized 2-aroyl-1,1,3,3-tetracyanoprop-2-en-1-ides on the growth of conditionally normal and tumor cells was studied in continuation of a search for new anticancer drugs. Cytotoxicities of the compounds were studied with respect to human tumor cell lines from the ATCC. All compounds were ineffective against melanoma and lung and ovary cancer cell lines and exhibited moderate activity in the other cases. The tested compounds exhibited highly selective effects because they were safe for conditionally normal skin fibroblasts.
- Kayukov, Ya. S.,Mar’yasov, M. A.,Nasakin, O. E.
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- Asymmetric Conjugate Addition of α-Cyanoketones to Benzoyl Acrylonitrile Derivatives Using a Diaminomethylenemalononitrile Organocatalyst
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A diaminomethylenemalononitrile (DMM) organocatalyst was used to efficiently promote asymmetric conjugate addition of various α-cyanoketones to benzoyl acrylonitrile derivatives. The corresponding 1,5-dicarbonyl compounds containing vicinal tertiary and quaternary stereogenic centers are versatile synthetic intermediates and were obtained in good yields and with excellent enantioselectivities (up to 96% ee). The present study describes the first successful examples of asymmetric conjugate addition reactions of α-cyanoketones with benzoyl acrylonitriles. In addition, the DMM organocatalyst can be recovered and reused up to five times without significant loss of either catalytic activity or enantioselectivity.
- Akutsu, Hiroshi,Nakashima, Kosuke,Kanetsuna, Yuta,Kawada, Masahiro,Hirashima, Shin-Ichi,Miura, Tsuyoshi
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p. 3874 - 3880
(2020/10/06)
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- Stereocontrolled Synthesis of 1,4-Dicarbonyl Compounds by Photochemical Organocatalytic Acyl Radical Addition to Enals
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We report a visible-light-mediated organocatalytic strategy for the enantioselective acyl radical conjugate addition to enals, leading to valuable 1,4-dicarbonyl compounds. The process capitalizes upon the excited-state reactivity of 4-acyl-1,4-dihydropyridines that, upon visible-light absorption, can trigger the generation of acyl radicals. By means of a chiral amine catalyst, iminium ion activation of enals ensures a stereoselective radical trap. We also demonstrate how the combination of this acylation process with a second catalyst-controlled bond-forming event allows to selectively access the full matrix of all possible stereoisomers of the resulting 2,3-substituted 1,4-dicarbonyl products.
- Goti, Giulio,Bieszczad, Bartosz,Vega-Pe?aloza, Alberto,Melchiorre, Paolo
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supporting information
p. 1213 - 1217
(2019/01/04)
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- Cardiac hypertrophy-resistant drug, and preparation method and use thereof
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The invention provides a cardiac hypertrophy-resistant drug, and a preparation method and a use thereof, and concretely discloses a compound represented by formula A, or a pharmaceutically acceptablesalt, an enantiomer, a diastereomer, a tautomer, a solvate, a polymorph or a prodrug thereof, and a preparation method and a pharmaceutical use of the compound. All groups in the formula A are as defined in the description. The compound has the advantages of good cardiac hypertrophy prevention or treatment effect and good development and application prospects.
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Paragraph 0165; 0176; 0177
(2019/07/04)
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- Modular Synthesis of Di- A nd Trisubstituted Imidazoles from Ketones and Aldehydes: A Route to Kinase Inhibitors
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A one-pot and modular approach to the synthesis of 2,4(5)-disubstituted imidazoles was developed based on ketone oxidation, employing catalytic HBr and DMSO, followed by imidazole condensation with aldehydes. This methodology afforded twenty-nine disubstituted NH-imidazoles (23%-85% yield). A three-step synthesis of 20 kinase inhibitors was achieved by employing this oxidation-condensation protocol, followed by bromination and Suzuki coupling in the imidazole ring to yield trisubstituted NH-imidazoles (23%-69%, three steps). This approach was also employed in the synthesis of known inhibitor GSK3037619A.
- De Toledo, Ian,Grigolo, Thiago A.,Bennett, James M.,Elkins, Jonathan M.,Pilli, Ronaldo A.
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p. 14187 - 14201
(2019/10/16)
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- Oxidative C-C Bond Cleavage for the Synthesis of Aryl Carboxylic Acids from Aryl Alkyl Ketones
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A metal-free and one-pot two-step synthesis of aryl carboxylic acids from aryl alkyl ketones has been achieved. The reactions were performed with iodine as the catalyst, DMSO and TBHP as the oxidants. Under the optimal reaction conditions, a number of aryl alkyl ketones could be converted into their corresponding aryl carboxylic acids in good to excellent yields (up to 94%).
- Xu, Liang,Wang, Shengpeng,Chen, Bajin,Li, Meichao,Hu, Xinquan,Hu, Baoxiang,Jin, Liqun,Sun, Nan,Shen, Zhenlu
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supporting information
p. 1505 - 1509
(2018/05/25)
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- Enantioselective Cyanosilylation of α,α-Dialkoxy Ketones by Using Phosphine-Thiourea Dual-Reagent Catalysis
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The first highly enantioselective cyanosilylation of α,α-dialkoxy ketones enabled by a dual-reagent catalysis has been developed. With the combination of a chiral bifunctional phosphine-thiourea and methyl acrylate, the key organophosphorus zwitterion intermediate was generated in situ as a novel Lewis base, which catalyzed the enantioselective cyanosilylation reaction in excellent yields (up to 99 %) with good-to-excellent enantioselectivities (up to 94 % ee).
- Yu, Qi-Wen,Wu, Lu-Ping,Kang, Tian-Chen,Xie, Jin,Sha, Feng,Wu, Xin-Yan
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supporting information
p. 3992 - 3996
(2018/07/31)
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- Visible-light assisted one-pot preparation of aryl glyoxals from acetoarylones via in-situ arylacyl bromides formation: Selenium-free approach to acetoarylones oxidation
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A novel visible-light (blue LEDs: hν?=?425?±?15?nm) photocatalyzed one-pot method for the synthesis of electronically diverse aryl glyoxals in good to excellent yields from acetoarylones and green regents such as air, vitamin C and dioxane dibromide has been described. In addition, an application of the current methodology has been demonstrated for the oxidation of monoamine oxidase-B inhibitors, i.e., 1-(4-((4-fluorobenzyl)oxy)phenyl)ethanone and 1-(3-((4-chlorobenzyl)oxy)phenyl)ethanone. This finding may serves as a valuable alternative to the traditional acetoarylones oxidation reactions conducted using selenium dioxide a harmful and unselective reagent known to simultaneously oxidize allylic, benzylic, [sbnd]CH3and so on.
- Natarajan, Palani,Manjeet,Kumar, Naveen,Devi, Sapna,Mer, Kalyani
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supporting information
p. 658 - 662
(2017/01/25)
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- Trisubstituted Imidazoles with a Rigidized Hinge Binding Motif Act As Single Digit nM Inhibitors of Clinically Relevant EGFR L858R/T790M and L858R/T790M/C797S Mutants: An Example of Target Hopping
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The high genomic instability of non-small cell lung cancer tumors leads to the rapid development of resistance against promising EGFR tyrosine kinase inhibitors (TKIs). A recently detected triple mutation compromises the activity of the gold standard third-generation EGFR inhibitors. We have prepared a set of trisubstituted imidazoles with a rigidized 7-azaindole hinge binding motif as a new structural class of EGFR inhibitors by a target hopping approach from p38α MAPK inhibitor templates. On the basis of an iterative approach of docking, compound preparation, biological testing, and SAR interpretation, robust and flexible synthetic routes were established. As a result, we report two reversible inhibitors 11d and 11e of the clinically challenging triple mutant L858R/T790M/C797S with IC50 values in the low nanomolar range. Furthermore, we developed a kinome selective irreversible inhibitor 45a with an IC50 value of 1 nM against the EGFR L858R/T790M double mutant. Target binding kinetics and metabolic stability data are included. These potent mutant EGFR inhibitors may serve as a basis for the development of structurally novel EGFR probes, tools, or candidates.
- Juchum, Michael,Günther, Marcel,D?ring, Eva,Sievers-Engler, Adrian,L?mmerhofer, Michael,Laufer, Stefan
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supporting information
p. 4636 - 4656
(2017/06/13)
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- Experimental and Theoretical Studies on Iron-Promoted Oxidative Annulation of Arylglyoxal with Alkyne: Unusual Addition and Migration on the Aryl Ring
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An Fe(III)-promoted oxidative annulation reaction was developed for the synthesis of 1,2-naphthoquinones. A variety of substituted arylglyoxals and internal alkynes undergo the transformation in the presence of FeCl3 at room temperature to afford the 1,2-naphthoquinone products in good yields in a short reaction time. Interestingly, the products show unusual pseudomigration of the substituent on the arene ring of arylglyoxals. A possible mechanism involving Fe(III)-promoted formation of a vinyl cation from arylglyoxal and alkyne, electrophilic addition of the vinyl cation to the ipso carbon of the aryl group to give a spiral intermediate, and then migration of the keto carbon to the ortho carbon was proposed as key steps and verified using quantum mechanics.
- Hung, Chen-Hsun,Gandeepan, Parthasarathy,Cheng, Lin-Chieh,Chen, Liang-Yu,Cheng, Mu-Jeng,Cheng, Chien-Hong
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supporting information
p. 17015 - 17021
(2017/12/06)
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- Synthesis and X-ray Characterization of Alkali Metal 2-Acyl-1,1,3,3-tetracyanopropenides
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A novel route for synthesis of 2-acyl-1,1,3,3-tetracyanopropenides (ATCN) salts in high yields and excellent purities starting from readily available methyl ketones, malononitrile, bromine, and alkali metal acetates is reported. The starting aryl(heteroaryl) methyl ketones were oxidized to the corresponding α-ketoaldehydes by new a DMSO-NaBr-H2SO4 oxidation system in yields up to 90% within a short reaction time of 8-10 min. The subsequent stages of ATCN preparation are realized in aqueous media without use of any toxic solvents, in accordance with principle 5 of "green chemistry". Lithium, sodium, potassium, rubidium, and cesium 2-benzoyl-1,1,3,3-tetracyanopropenides were characterized by X-ray diffraction analysis. These salts show a good potential for synthesis of five- and six-membered heterocycles and may serve as potentially useful ligands in coordination and supramolecular chemistry.
- Karpov, Sergey V.,Grigor'Ev, Arthur A.,Kayukov, Yakov S.,Karpova, Irina V.,Nasakin, Oleg E.,Tafeenko, Victor A.
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p. 6402 - 6408
(2016/08/16)
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- Synthesis of 2-aroyl-(4 or 5)-aryl-1H-imidazoles and 2-hydroxy-3,6-diaryl- pyrazines via a cascade process
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The synthesis of (4 or 5)-aryl-2-aroyl-1H-imidazoles and 2-hydroxy-3,6-diarylpyrazines from aryl methyl ketones via a cascade process of DMSO-HBr oxidation and Debus reaction was investigated. Owing to the simple starting materials, mild conditions, easy operation, high bioactivity of imidazole and pyrazine derivatives, this protocol has great potential in medicinal chemistry.
- Liu, Cong,Dai, Rong J.,Yao, Guo W.,Deng, Yu L.
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p. 146 - 163
(2014/04/17)
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- Design and synthesis of 2-acylbenzothiazoles via in situ cross-trapping strategy from benzothiazoles with aryl ketones
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An I2/KOH synergistically promoted direct ring-opening aroylation of benzothiazoles with aryl ketones has been discovered. Aryl ketones were seen to act as carbonyl sources to construct 2-acylbenzothiazoles. This reaction could provide an example for the convergent integration of self-labor domino sequences based on an in situ cross-trapping strategy.
- Gao, Qinghe,Wu, Xia,Jia, Fengcheng,Liu, Meicai,Zhu, Yanping,Cai, Qun,Wu, Anxin
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p. 2792 - 2797
(2013/04/24)
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- Oxidation of aryl and heteroaryl methyl ketone to aryl and heteroarylglyoxals by using CuCl2-DMSO
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The oxidation of aryl methyl ketone and heteroaryl methyl ketone to arylglyoxals and heteroaryl glyoxal respectively has been carried out by using the cheap and easily available, non toxic, Lewis acid CuCl2 in DMSO solvent at 70-80°C within 1-2 hr. The reaction can be performed in air without loss of variety of oxidisable fuctional group like phenolic OH, hetroaryl ring, aryl substituted methyl, halo, nitro group, etc.
- Lokhande, Pradeep D.,Waghmare, Smita R.,Gaikwad, Harsh,Hankare
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p. 300 - 305
(2013/05/08)
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- Structural and antimicrobial studies of some newly synthesized mixed ligand complexes of CoII, NiII, CuIIand Zn II
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Four new mixed ligand complexes of CoII, NiII, CuII and ZnII with 2-furylglyoxal-2-amino thiophenol (FGATP) and diphenyl amine-2-hydroxy-2?-carboxylic acid (DPHC) were synthesized and characterized by their melting point determination of recrystallised samples, running TLC for single spot, elemental analyses, molar conductance, magnetic measurements, IR, 1H NMR and UV spectral data. All the synthesized compounds were screened for antimicrobial activities against two bacteria, Escherichia coli (gram -ve) and Staphylococcus aureus (gram +ve), and two fungi, Aspergillus niger and Aspergillus flavus. Metal complexes exhibit several fold increase in their antimicrobial activity in comparison to that of the constituting ligand fragments as determined by Serial Dilution Method.
- Sharma,Giri,Kumar
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experimental part
p. 421 - 424
(2012/04/10)
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- SUBSTITUTED PYRAZINYL AMIDE COMPOUNDS AS MODULATORS OF THE HISTAMINE H3 RECEPTOR
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Certain substituted pyrazinyl amide compounds are histamine H3 receptor modulators useful in the treatment of histamine H3 receptor-mediated diseases.
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Page/Page column 8-9
(2009/05/28)
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- Enantioselective cyanosilylation of α,α-dialkoxy ketones catalyzed by proline-derived in-situ-prepared N-oxide as bifunctional organocatalyst
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Bifunctional N,N′-dioxide catalysts have been developed for highly enantioselective cyanosilylation of α,α-dialkoxy ketones. This process, catalyzed by in-situ-prepared proline-derived N,N′-dioxide 2b, produced the corresponding cyanohydrin trimethylsilyl ethers in excellent yields (up to 99%) with high enantioselectivities (up to 93% ee). A reasonable mechanism was proposed according to the observation of the linear effect, 1H NMR spectra, isolated cyanohydrin, and the roles of the NH and N-oxide moieties of the catalyst.
- Qin, Bo,Liu, Xiaohua,Shi, Jian,Zheng, Ke,Zhao, Haitao,Feng, Xiaoming
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p. 2374 - 2378
(2007/10/03)
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- Catalytic asymmetric allylation of aldehydes using the chiral (salen)chromium(III) complexes
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The enantioselective addition of allylstannanes to glyoxylates and glyoxals, as well as simple aromatic and aliphatic aldehydes, catalyzed by chiral (salen)Cr(III) complexes, has been studied. The reaction proceeded smoothly for the reactive 2-oxoaldehydes and allyltributyltin in the presence of small amounts (1-2 mol %) of (salen)Cr(III)BF4 (1b) under mild, undemanding conditions. However, in the case of other simple aldehydes, the use of high-pressure conditions is required to obtain good yields. Classic chromium catalyst 1b, easily prepared from the commercially available chloride complex 1a, affords homoallylic alcohols usually in good yield and with enantiomeric purity of 50-79% ee. The stereochemical results are rationalized on the basis of the proposed model.
- Kwiatkowski, Piotr,Cha?adaj, Wojciech,Jurczak, Janusz
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p. 5116 - 5125
(2007/10/03)
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- 6-(1-ACYL-1-HYDROXYMETHYL)PENICILLANIC ACID DERIVATIVES
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6-(1-Acyl-1-hydroxymethyl)penicillanic acid derivatives are useful as antibacterials and/or beta-lactamase inhibitors.
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- Structure-activity Relationship of Herbicidal 2,3-Dicyano-5-Substituted Pyrazines
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Sixty six 2,3-dicyano-5-substituted pyrazines were synthesized and their herbicidal activities against barnyard grass were measured in pot tests to clarify the relationship between chemical structure and activity.The activity of 59 derivatives was related parabolically to the hydrophobic substituent parameter at the 5-position of the pyrazine ring.
- Nakamura, Akira,Ataka, Toshiei,Segawa, Hirozo,Takeuchi, Yasutomo,Takematsu, Tetsuo
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p. 1555 - 1560
(2007/10/02)
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