- Optimization of asymmetric reduction conditions of 1-(benzo [d] [1,3] dioxol-5-yl) ethanone by Lactobacillus fermentum P1 using D-optimal experimental design-based model
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The biocatalytic asymmetric reduction of prochiral ketones is a significant transformation in organic chemistry as chiral carbinols are biologically active molecules and may be used as precursors of many drugs. In this study, the bioreduction of 1-(benzo [d] [1,3] dioxol-5-yl) ethanone for the production of enantiomerically pure (S)-1-(1,3-benzodioxal-5-yl) ethanol was investigated using freeze-dried whole-cell of Lactobacillus fermentum P1 and the reduction conditions was optimized with a D-optimal experimental design-based optimization methodology. This is the first study using this optimization methodology in a biocatalytic asymmetric reduction. Using D-optimal experimental design-based optimization, optimum reaction conditions were predicted as pH 6.20, temperature 30 °C, incubation time 30 h, and agitation speed 193 rpm. For these operating conditions, it was estimated that the product could be obtained with 94% enantiomeric excess (ee) and 95% conversion rate (cr). Besides, the actual ee and cr were found to be 99% tested under optimized reaction conditions. These findings demonstrated that L. fermentum P1 as an effective biocatalyst to obtain (S)-1-(1,3-benzodioxal-5-yl) ethanol and with the D-optimal experimental design-based optimization, this product could be obtained with the 99% ee and 99% cr. Finally, the proposed mathematical optimization technique showed the applicability of the obtained results for asymmetric reduction reactions.
- ?zdemir, Ak?n,Dertli, Enes,?ahin, Engin
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Read Online
- Production of (R)-1-(1,3-benzodioxol-5-yl)ethanol in high enantiomeric purity by Lactobacillus paracasei BD101
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Piperonyl ring is found in a number of naturally occurring compounds and possesses enormous biological activities. There are many studies in the literature with compounds containing a piperonyl ring, but there are very few studies on the synthesis of chiral piperonyl carbinol. The objective of this study was to determine the microbial reduction ability of bacterial strains and to reveal the effects of different physicochemical parameters on this reduction ability. A total of 15 bacterial isolates were screened for their ability to reduce 1-(benzo[d][1,3]dioxol-5-yl) ethanone 1 to its corresponding alcohol. Among these isolates Lactobacillus paracasei BD101 was found to be the most successful biocatalyst to reduce the ketone containing piperonyl ring to the corresponding alcohol. The reaction conditions were systematically optimized for the reducing agent L?paracasei BD101, which showed high enantioselectivity and conversion for the bioreduction. The preparative scale study was performed, and a total of 3.72?g of (R)-1-(1,3-benzodioxol-5-yl) ethanol in high enantiomeric form (>99% enantiomeric excess) was produced in a mild, cheap, and environment-friendly process. This study demonstrates that L?paracasei BD101 can be used as a biocatalyst to obtain chiral carbinol with excellent yield and selectivity.
- ?ahin, Engin
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Read Online
- Indium-Catalyzed Formal Carbon-Halogen Bond Insertion: Synthesis of α-Halo-α,α-disubstituted Esters from Benzylic Halides and Diazo Esters
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One-carbon-unit insertion into carbon-halogen (C-X) bonds accompanied by the formation of a new C-X bond and carbon-chain elongation is a powerful synthetic method of complex organohalides. Herein, we developed an indium trihalide catalyzed formal insertion of diazo esters into a C-X (X = Cl, Br, I) bond. In the present system, the reactions of α-aryl diazo esters with benzylic chlorides, bromides, and iodides yielded α-chloro, α-bromo, and α-iodo esters, respectively.
- Nishimoto, Yoshihiro,Wang, Fei,Yasuda, Makoto
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supporting information
p. 1706 - 1710
(2022/03/14)
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- Asymmetric reduction of aromatic heterocyclic ketones with bio-based catalyst Lactobacillus kefiri P2
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Abstract: Chiral heterocyclic secondary alcohols have received much attention due to their widespread use in pharmaceutical intermediates. In this study, Lactobacillus kefiri P2 biocatalysts isolated from traditional dairy products, were used to catalyze the asymmetric reduction of prochiral ketones to chiral secondary alcohols. Secondary chiral carbinols were obtained by asymmetric bioreduction of different prochiral substrates with results up to > 99% enantiomeric excess (ee). (R)-1-(benzofuran-2-yl)ethanol 5a, which can be used in the synthesis of pharmaceuticals such as bufuralols potent nonselective β-blockers antagonists, Amiodarone (cardiac anti-arrhythmic), and Benziodarone (coronary vasodilator), was produced in gram-scale, high yield and enantiomerically pure form using L. kefiri P2 biocatalysts. The gram-scale production was carried out, and 9.70?g of (R)-5a in enantiomerically pure form was obtained in 96% yield. Also, production of (R)-5a in terms of yield and gram scale through catalytic asymmetric reduction using the biocatalyst was the highest report so far. This is a cost-effective, clean and eco-friendly process for the preparation of chiral secondary alcohols compared to chemical processes. From an environmental and economic perspective, this biocatalytic method has great application potential, making it a green and sustainable way of synthesis. Graphical Abstract: [Figure not available: see fulltext.]
- Bayda?, Yasemin,Kalay, Erbay,?ahin, Engin
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p. 1147 - 1155
(2020/10/06)
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- Postsynthetic Modification of Half-Sandwich Ruthenium Complexes by Mechanochemical Synthesis
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A mild and environmentally friendly method to synthesize half-sandwich ruthenium complexes through the Wittig reaction between an aldehyde-tagged half-sandwich ruthenium complex and phosphorus ylide mechanochemically is reported herein. The mechanochemical synthesis of valuable half-sandwich ruthenium complexes resulted in a fast reaction, good yield with simple workup, and the avoidance of harsh reaction conditions and organic solvents. The synthesized half-sandwich ruthenium complexes exhibited high catalytic activity for transfer hydrogenation of ketones using 2-propanol as the hydrogen source and solvent. Density functional theory was carried out to propose a mechanism for the transfer hydrogenation process. The modeling suggests the importance of the labile p-cymene ligand in modulating the reactivity of the catalyst.
- Jia, Wei-Guo,Zhi, Xue-Ting,Li, Xiao-Dong,Zhou, Jun-Peng,Zhong, Rui,Yu, Haibo,Lee, Richmond
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p. 4313 - 4321
(2021/05/04)
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- Selective Carbon-Carbon Bond Amination with Redox-Active Aminating Reagents: A Direct Approach to Anilines?
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Amines are among the most fundamental motifs in chemical synthesis, and the introduction of amine building blocks via selective C—C bond cleavage allows the construction of nitrogen compounds from simple hydrocarbons through direct skeleton modification. Herein, we report a novel method for the preparation of anilines from alkylarenes via Schmidt-type rearrangement using redox-active amination reagents, which are easily prepared from hydroxylamine. Primary amines and secondary amines were prepared from corresponding alkylarenes or benzyl alcohols under mild conditions. Good compatibility and valuable applications of the transformation were also displayed.
- Qiu, Xu,Wang, Yachong,Su, Lingyu,Jin, Rui,Song, Song,Qin, Qixue,Li, Junhua,Zong, Baoning,Jiao, Ning
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supporting information
p. 3011 - 3016
(2021/09/13)
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- FUSED GLYCOSIDASE INHIBITORS
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Compounds of formula (I), wherein A, Z, E, R1, R2, m and n have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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Page/Page column 126
(2020/09/08)
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- Efficient Transfer Hydrogenation of Ketones using Methanol as Liquid Organic Hydrogen Carrier
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Herein, we demonstrate an efficient protocol for transfer hydrogenation of ketones using methanol as practical and useful liquid organic hydrogen carrier (LOHC) under Ir(III) catalysis. Various ketones, including electron-rich/electron-poor aromatic ketones, heteroaromatic and aliphatic ketones, have been efficiently reduced into their corresponding alcohols. Chemoselective reduction of ketones was established in the presence of various other reducible functional groups under mild conditions.
- Garg, Nidhi,Paira, Soumen,Sundararaju, Basker
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p. 3472 - 3476
(2020/05/29)
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- Reduction over Condensation of Carbonyl Compounds through a Transient Hemiaminal Intermediate Using Hydrazine
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Reduction of carbonyl moieties to the corresponding alcohol using simply hydrazine hydrate has been considerably unfeasible until now due to the well-known condensation reaction. However, herein, we report that using an excess of 20-fold equivalents, the reduction proceeds in excellent yields. 1H NMR study of the reaction and density functional theory (DFT) calculations indicate that the final fate of the hemiaminal intermediate is crucial to obtain the alcohol or the hydrazone.
- Vilches-Herrera, Marcelo,Gallardo-Fuentes, Sebastián,Aravena-Opitz, Mauricio,Yá?ez-Sánchez, Mauricio,Jiao, Haijun,Holz, Jens,B?rner, Armin,Lühr, Susan
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p. 9213 - 9218
(2020/08/14)
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- RETRACTED ARTICLE: The Manganese(I)-Catalyzed Asymmetric Transfer Hydrogenation of Ketones: Disclosing the Macrocylic Privilege
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The bis(carbonyl) manganese(I) complex [Mn(CO)2(1)]Br (2) with a chiral (NH)2P2 macrocyclic ligand (1) catalyzes the asymmetric transfer hydrogenation of polar double bonds with 2-propanol as the hydrogen source. Ketones (43 substrates) are reduced to alcohols in high yields (up to >99 %) and with excellent enantioselectivities (90–99 % ee). A stereochemical model based on attractive CH–π interactions is proposed.
- Passera, Alessandro,Mezzetti, Antonio
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supporting information
p. 187 - 191
(2019/12/11)
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- Asymmetric Deoxygenative Cyanation of Benzyl Alcohols Enabled by Synergistic Photoredox and Copper Catalysis?
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Summary of main observation and conclusion. An enantioselective deoxygenative cyanation of benzyl alcohols was accomplished for the first time through the synergistic photoredox and copper catalysis. This reaction features the use of organic photosensitizer and low-cost 3d metal catalyst, simple and safe operations, and extremely mild conditions. A variety of chiral benzyl nitriles were produced in generally good yields and high level of enantiocontrols from readily available feedstocks (22 examples, up to 93% yield and 92% ee).
- Chen, Hong-Wei,Lu, Fu-Dong,Cheng, Ying,Jia, Yue,Lu, Liang-Qiu,Xiao, Wen-Jing
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supporting information
p. 1671 - 1675
(2020/11/03)
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- Dihydropyrimidinones: Efficient one-pot green synthesis using Montmorillonite-KSF and evaluation of their cytotoxic activity
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A simple, efficient, cost-effective, recyclable and green approach has been developed for the synthesis of new dihydropyrimidinone analogs via the Biginelli reaction. The methodology involves a multicomponent reaction catalyzed by "HPA-Montmorillonite-KSF"as a reusable and heterogeneous catalyst. This method gives an efficient and much improved modification of the original Biginelli reaction, in terms of yield and short reaction times under solvent free conditions. All the derivatives were subjected to cytotoxicity screening against a panel of four different human cancer cell lines viz. colon (Colo-205), prostate (PC-3), leukemia (THP-1) and lung (A549) to check their effect on percentage growth. MTT [3-(4,5-dimethylthiazol-yl)-diphenyl tetrazoliumbromide] cytotoxicity assay was employed to check IC50 values. Of the synthesized analogs, 16a showed the best activity with IC50 of 7.1 ± 0.8, 13.1 ± 1.4, 13.8 ± 0.9 and 14.7 ± 1.1 μM against lung (A549), leukemia (THP-1), prostate (PC-3) and colon (Colo-205) cancer lines, respectively. The 16a analog was further checked for its effect on cancer cell properties through clonogenic (colony formation) and scratch motility (wound healing) assays and thereby was found that it reduced both the colony formation and migratory properties of the lung cancer cell line (A549). Further, molecular docking studies were performed with 16a to show its binding mode. This journal is
- Alharthi, Fahad A.,Alsalme, Ali,Dar, Bashir A.,Farooq, Saleem,Hamid, Abid,Hussain, Aashiq,Koul, S.
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p. 42221 - 42234
(2020/12/09)
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- A Practical and Stereoselective In Situ NHC-Cobalt Catalytic System for Hydrogenation of Ketones and Aldehydes
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Homogeneous catalytic hydrogenation of carbonyl groups is a synthetically useful and widely applied organic transformation. Sustainable chemistry goals require replacing conventional noble transition metal catalysts for hydrogenation by earth-abundant base metals. Herein, we report how a practical in situ catalytic system generated by easily available pincer NHC precursors, CoCl2, and a base enabled efficient and high-yielding hydrogenation of a broad range of ketones and aldehydes (over 50 examples and a maximum turnover number [TON] of 2,610). This is the first example of NHC-Co-catalyzed hydrogenation of C=O bonds using flexible pincer NHC ligands consisting of a N-H substructure. Diastereodivergent hydrogenation of substituted cyclohexanone derivatives was also realized by fine-tuning of the steric bulk of pincer NHC ligands. Additionally, a bis(NHCs)-Co complex was successfully isolated and fully characterized, and it exhibits excellent catalytic activity that equals that of the in-situ-formed catalytic system. Catalytic hydrogenation is a powerful tool for the reduction of organic compounds in both fine and bulk chemical industries. To improve sustainability, more ecofriendly, inexpensive, and earth-abundant base metals should be employed to replace the precious metals that currently dominate the development of hydrogenation catalysts. However, the majority of the base-metal catalysts that have been reported involve expensive, complex, and often air- and moisture-sensitive phosphine ligands, impeding their widespread application. From a mixture of the stable CoCl2, imidazole salts, and a base, our newly developed catalytic system that formed easily in situ enables efficient and stereoselective hydrogenation of C=O bonds. We anticipate that this easily accessible catalytic system will create opportunities for the design of practical base-metal hydrogenation catalysts. A practical in situ catalytic system generated by a mixture of easily available pincer NHC precursors, CoCl2, and a base enabled highly efficient hydrogenation of a broad range of ketones and aldehydes (over 50 examples and up to a turnover number [TON] of 2,610). Diastereodivergent hydrogenation of substituted cyclohexanone derivatives was also realized in high selectivities. Moreover, the preparation of a well-defined bis(NHCs)-Co complex via this pincer NHC ligand consisting of a N-H substructure was successful, and it exhibits equally excellent catalytic activity for the hydrogenation of C=O bonds.
- Zhong, Rui,Wei, Zeyuan,Zhang, Wei,Liu, Shun,Liu, Qiang
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supporting information
p. 1552 - 1566
(2019/06/14)
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- Oxidative β-Halogenation of Alcohols: A Concise and Diastereoselective Approach to Halohydrins
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β-Halohydrins bearing transformable halo- and hydroxyl groups, are easily converted into various valuable blocks in organic and pharmaceutical synthesis. A diastereoselective β-halogenation of benzylic alcohols was achieved under simple and low-cost conditions, which provided a direct synthesis of β-halohydrins. The simple reaction conditions, easily available reagents, high diastereoselectivities, and additional oxidant-free make this reaction very attractive and practical.
- Ai, Lingsheng,Wang, Weijin,Wei, Jialiang,Li, Qing,Song, Song,Jiao, Ning
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supporting information
p. 437 - 441
(2019/02/26)
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- ANNULATED GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein A, R, W1, W2, W3, W4, W5, W6, L, Q, Rx and u have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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Page/Page column 88; 89
(2019/03/12)
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- LINEAR GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein A, R, W, Q, L, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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Page/Page column 72-73
(2019/03/14)
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- Base-Mediated Meerwein-Ponndorf-Verley Reduction of Aromatic and Heterocyclic Ketones
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An experimental protocol to achieve the Meerwein-Ponndorf-Verley (MPV) reduction of ketones under mildly basic conditions is reported. The transformation is tolerant of a range of ketone substrates, including O- and S-containing heterocycles, is scalable, and shows potential to be used as a platform to access enantioenriched products. These studies provide a general method for achieving the reduction of ketones under mildly basic conditions and offer an alternative protocol to more well-known Al-based MPV reduction conditions.
- Boit, Timothy B.,Mehta, Milauni M.,Garg, Neil K.
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supporting information
p. 6447 - 6451
(2019/08/20)
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- PROCESS FOR THE SEPARATION OF ENANTIOMERS OF PIPERAZINE DERIVATIVES
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The invention relates to a process for preparing either enantiomer of a compound of formula (I), wherein X, Y and n have the meaning given in claim 1, with high enantiomeric excess (e.e.), by chiral resolution in the presence of a non-racemic, chiral acid.
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Page/Page column 30; 31
(2017/09/21)
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- ACID ADDITION SALTS OF PIPERAZINE DERIVATIVES
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The invention relates to acid addition salts of piperazine derivatives, as well as solid forms, such as polymorphic forms, thereof, which are useful as pharmaceutical ingredients and in particular as glycosidase inhibitors.
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Page/Page column 28
(2017/09/09)
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- PLANT GROWTH-PROMOTION AGENT AND METHOD FOR PROMOTING PLANT GROWTH
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The present invention concerns: a plant growth-promoting agent comprising a compound represented by Formula (I) or a salt thereof: wherein Ar1 represents a substituted or unsubstituted phenyl group, NZ represents a nitrogen-containing heterocyclic ring group or an acyclic nitrogen-containing group having a partial structure of the nitrogen-containing heterocyclic ring group, n is 0, 1, or 2, R1 and R2 each represent a hydrogen atom, a substituted or unsubstituted C1-3-alkyl group, a cyano group, or a carboxyl group, R1 and R2 may together form an oxo group, and when n is 2, R1 or R2 may be the same or different; and a method for promoting plant growth using the plant growth-promoting agent.
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Paragraph 0135; 0136
(2017/11/11)
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- GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein A, R, W, Q, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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Page/Page column 77
(2016/03/22)
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- Synthesis of piperonyl triazoles as anti-microbial agents
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Synthesis of a series of 1,4-substitued triazoles has been accomplished starting from piperonyl alcohols prepared by the addition reaction of piperonal with Grignard reagent. Key features of the synthesis include ZrCl4 catalyzed nucleophilic su
- Srinivas,Sunitha
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p. 102 - 109
(2017/01/18)
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- Synthesis of piperonyl triazoles as anti-microbial agents
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Synthesis of a series of 1,4-substitued triazoles has been accomplished starting from piperonyl alcohols prepared by the addition reaction of piperonal with Grignard reagent. Key features of the synthesis include ZrCl4 catalyzed nucleophilic su
- Srinivas,Sunitha
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p. 102 - 109
(2016/02/26)
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- Development of new highly potent imidazo[1,2-b[pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1
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Using a structure-based design approach, we have developed a new series of imidazo[1,2-b]pyridazines, targeting the calcium-dependent protein kinase-1 (CDPK1) from Toxoplasma gondii. Twenty derivatives were thus synthesized. Structure-activity relationships and docking studies confirmed the binding mode of these inhibitors within the ATP binding pocket of TgCDPK1. Two lead compounds (16a and 16f) were then identified, which were able to block TgCDPK1 enzymatic activity at low nanomolar concentrations, with a good selectivity profile against a panel of mammalian kinases. The potential of these inhibitors was confirmed in vitro on T. gondii growth, with EC50 values of 100 nM and 70 nM, respectively. These best candidates also displayed low toxicity to mammalian cells and were selected for further in vivo investigations on murine model of acute toxoplasmosis.
- Moine, Espérance,Dimier-Poisson, Isabelle,Enguehard-Gueiffier, Cécile,Logé, Cédric,Pénichon, Mélanie,Moiré, Nathalie,Delehouzé, Claire,Foll-Josselin, Beátrice,Ruchaud, Sandrine,Bach, Stéphane,Gueiffier, Alain,Debierre-Grockiego, Fran?oise,Denevault-Sabourin, Caroline
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- Direct trifluoromethylthiolation of alcohols under mild reaction conditions: Conversion of R-OH into R-SCF3
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A direct process for the trifluoromethylthiolation of allylic and benzylic alcohols under mild conditions has been developed. A wide range of free alcohols underwent nucleophilic substitution in the presence of stable CuSCF3 and BF3·Et2O to give the corresponding products in good to excellent yields.
- Nikolaienko, Pavlo,Pluta, Roman,Rueping, Magnus
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supporting information
p. 9867 - 9870
(2014/08/18)
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- GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein X1, X2, W, R1 to R5, L and m have the meaning according to the claims, are glucosidase inhibitors, and can be employed, inter alia, for the treatment of Alzheimer's disease.
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Page/Page column 107
(2014/10/15)
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- Palladium-catalyzed hydrogenation with use of ionic liquid bis(2-hydroxyethyl)ammonium formate [BHEA][HCO2] as a solvent and hydrogen source
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We designed ionic liquid bis(2-hydroxyethyl)ammonium formate [BHEA][HCO2] for use as a solvent and hydrogen donor for hydrogenation. Catalytic hydrogenation of aromatic ketones, nitro groups, and olefins with PdCl2 in [BHEA][HCO2] generated the corresponding reduction products. Selective reduction of aromatic ketones over aliphatic ketones was observed. Hydrogenolysis of benzyl ethers and benzyl amines also proceeded. All these reactions were successfully carried out in good to excellent yields under mild and nonflammable conditions. In addition, the ionic liquid and Pd source can be reused several times.
- Suzuki, Hideyuki,Yoshioka, Seiki,Igesaka, Ami,Nishioka, Hiromi,Takeuchi, Yasuo
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p. 6399 - 6403
(2013/07/25)
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- Nickel phthalocyanine assisted highly efficient and selective carbonyl reduction in polyethylene glycol-400
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Nickel phthalocyanine with polyethylene glycol- 400 is described as a reusable green catalytic system for highly chemo- and regioselective reduction of carbonyl compounds to corresponding alcohols at room temperature. The catalytic system showed wide substrate scope covering aromatic, hetero aromatic and aliphatic carbonyl compounds with high turnover number and frequency. In the present study, 1,3- and 1,4-benzenedicarbaldehydes have been regioselectively reduced to corresponding alcohols for the first time. The catalyst was reused up to seven times without any significance loss in activity. Springer Science+Business Media, LLC 2012.
- Verma, Praveen Kumar,Sharma, Upendra,Kumar, Neeraj,Bala, Manju,Kumar, Vishal,Singh, Bikram
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experimental part
p. 907 - 913
(2012/10/07)
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- Feeding the Heck reaction with alcohol: One-pot synthesis of stilbenes from aryl alcohols and bromides
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Aryl alcohols are employed as feedstock for the Heck reaction. Keggin-type heteropolyacids catalyse the selective dehydration of the alcohols to styrenes, which, in one-pot, undergo palladium-catalysed Heck arylation with aryl bromides, affording broadly functionalised stilbenes. The choice of solvent is critical for the cascade dehydration-Heck reaction, with electron-rich aryl alcohols preferring a basic medium while electron-deficient ones demanding solvents of lower basicity. Copyright
- Colbon, Paul,Barnard, Jonathan H.,Purdie, Mark,Mulholland, Keith,Kozhevnikov, Ivan,Xiao, Jianliang
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supporting information; body text
p. 1395 - 1400
(2012/07/03)
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- Non-flammable and reusable hydrogenation of aromatic ketones in ionic liquid
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A novel method of hydrogenation of aromatic ketones in the ionic liquid [BHEA][HCO2] was developed; this method is more enhanced in terms of flammability and reusability as compared to the conventional method (H 2 and Pd/C). The redu
- Suzuki, Hideyuki,Nishioka, Hiromi,Takeuchi, Yasuo
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experimental part
p. 3686 - 3688
(2012/09/21)
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- The palladium-catalyzed aerobic kinetic resolution of secondary alcohols: Reaction development, scope, and applications
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The first palladium-catalyzed enantioselective oxidation of secondary alcohols has been developed, utilizing the readily available diamine (-)-sparteine as a chiral ligand and molecular oxygen as the stoichiometric oxidant. Mechanistic insights regarding the role of the base and hydrogen-bond donors have resulted in several improvements to the original system. Namely, addition of cesium carbonate and tert-butyl alcohol greatly enhances reaction rates, promoting rapid resolutions. The use of chloroform as solvent allows the use of ambient air as the terminal oxidant at 23°C, resulting in enhanced catalyst selectivity. These improved reaction conditions have permitted the successful kinetic resolution of benzylic, allylic, and cyclopropyl secondary alcohols to high enantiomeric excess with good-toexcellent selectivity factors. This catalyst system has also been applied to the desymmetrization of meso-diols, providing high yields of enantioenriched hydroxyketones.
- Ebner, David C.,Bagdanoff, Jeffrey T.,Ferreira, Eric M.,McFadden, Ryan M.,Caspi, Daniel D.,Trend, Raissa M.,Stoltz, Brian M.
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supporting information; experimental part
p. 12978 - 12992
(2010/06/19)
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- Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy
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Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene (SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound 11a possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound 11a up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, compound 11a induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.
- Thurmond, John,Butchbach, Matthew E. R.,Palomo, Marty,Pease, Brian,Rao, Munagala,Bedell, Louis,Keyvan, Monica,Pai, Grace,Mishra, Rama,Haraldsson, Magnus,Andresson, Thorkell,Bragason, Gisli,Thosteinsdottir, Margret,Bjornsson, Jon Mar,Coovert, Daniel D.,Burghes, Arthur H. M.,Gurney, Mark E.,Singh, Jasbir
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p. 449 - 469
(2008/09/18)
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- Asymmetric synthesis of antimicrotubule biaryl hybrids of allocolchicine and steganacin
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The asymmetric synthesis of novel axially chiral hiaryl compounds 5 a-f containing a seven- or eight-memhered heterocyclic medium ring is described. These molecules can he considered to he structural hybrids of allocolchicine- and sleganacin-lype natural products. The synthesis featured an atropo-diastereoselective biaryl Suzuki coupling in which a benzylic stereocenter efficiently transferred its stereochemical information to the biaryl axis. The coupling conditions were optimized. and two biphenylphosphane ligands (DavePhos and S-Phos) were found to give Ihe highest yields and diastereoselectivities. A three-element stereochemical model was proposed to explain the observed diastereoselectivities. In a second key step, the medium ring of the target molecules was formed by a stercoselective SN1-type cyclodehydration that probably involved a configurationally stable carbocationic intermediate, as supported by calculations. Alternatively. S N2-type cyclizations were employed on the same Suzuki coupling products to give the target molecules in a stereodivergent or stereoconvergent manner. These cyclization methods furnished the target hybrid analogues 5 a-f with ee values above 94%. All analogues were evaluated as antimicrotubule agents and against a panel of cancer-cell lines using colchicine (1) and N-acetylcolchinol (3) as references. Promising activities were found for R,a R-configured compounds 5 a, b and 5 f; in particular, ethyl analogue 5 b showed a twofold antimicrotubule activity relative to colchicine.
- Joncour, Agnes,Decor, Anne,Liu, Jian-Miao,Tran Huu Dau, Marie-Elise,Baudoin, Olivier
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p. 5450 - 5465
(2008/03/12)
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- 2,4-DIAMINOQUINAZOLINES FOR SPINAL MUSCULAR ATROPHY
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2,4-Diaminoquinazolines of formulae I-IV and VI (I, II, III, IV and VI) are useful for treating spinal muscular atrophy (SMA).
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Page/Page column 49-50
(2010/02/15)
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- Trichosporon beigelli esterase (TBE): A versatile esterase for the resolution of economically important racemates
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A hydrolase producing strain Trichosporon beigelli esterase (TBE) isolated from local cottage cheese in its native form has displayed versatility and high efficacy in the kinetic resolution of a wide range of economically important substrates, which include racemic secondary alcohols, such as 1-(6-methoxy-2-naphthyl)ethanol (E ~ 316), 1-(3,4-methylenedioxyphenyl) ethanol and pentanol (E ~ 180 and 156 resp.), and alkyl esters of carboxylic acids such as ibuprofen (E ~ 340), 2-(benzylthio)propanoic acid (E ~ 1000). In other substrates such as in the primary alcohol 2-(6-methoxy-2- naphthyl)propan-1-ol and carboxylic acids such as 2-(5-bromo-6-methoxy-2- naphthyl)propanoic acid, 2-(2-naphthyloxy)propanoic acid, and substituted 2-thiopropanoic acids, it displayed moderate to low selectivity. Commercial lipases such as CCL, PPL, and PSL were also used in the resolution of the substrates for comparative studies.
- Koul, Surrinder,Koul, Jawahir Lal,Singh, Budh,Kapoor, Munish,Parshad, Rajinder,Manhas, Kuldeep S.,Taneja, Subhash C.,Qazi, Ghulam N.
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p. 2575 - 2591
(2007/10/03)
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- Method for preparing a benzylic-type ether
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The invention concerns a method for preparing a benzylic-type ether from an aromatic compound. The inventive method for preparing a benzylic-type ether from an aromatic compound is characterised in that it consists in: in a first step, acylating an aromatic compound by reacting said aromatic compound with an acylating agent, in the presence of an efficient amount of zeolite or a Friedel-Crafts catalyst leading to a ketonic compound; in a second step, reducing the carbonyl group into carbinol leading to a benzylic alcohol; in a third step, etherifying the hydroxyl group, by reacting the benzylic alcohol with another alcohol, in the presence of an efficient amount of zeolite.
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- Titanium fluoride complexes as catalysts for the enantioselective addition of Me3Al to aldehydes
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We report a Ti(IV) catalyst prepared in situ from TiF4 for the asymmetric addition of trimethylaluminum to aldehydes. The process we detail herein does not necessitate the use of excess trimethylaluminum or Ti(IV) reagent. Good enantioselectivities are achieved with a variety of aromatic and heteroaromatic aldehydes with the products isolated in high yield.
- Pagenkopf, Brian L.,Carreira, Erick M.
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p. 9593 - 9596
(2007/10/03)
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- A Convenient Procedure for the Reduction of Esters, Carboxylic Acids, Ketones and Aldehydes using Tetrabutylammonium Fluoride (or Triton B) and Polymethylhydrosiloxane
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A range of carboxylic esters and acids have been converted efficiently to the corresponding alcohols with polymethylhydrosiloxane in the presence of catalytic tetrabutylammonium fluoride. The reduction of ketones and aldehydes with PMHS and other alkoxysilanes in the presence of TBAF or benzyltrimethylammonium hydroxide is also described.
- Drew, Mark D.,Lawrence, Nicholas J.,Fontaine, David,Sehkri, Lakhdar,Bowles, Stephen A.,Watson, William
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p. 989 - 991
(2007/10/03)
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- Condensation of cyclic and acyclic imines with phthalide anions. Synthesis of protoberberines and substituted 3,4-dihydro-2-methyl-1(2H)-isoquinolones
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3,4-Dihydroisoquinolines react with anions derived from phthalides and 3-methylphthalides in tetrahydrofuran yielding 13-hydroxy-8-oxotetrahydroprotoberberines and 13-hydroxy-13-methyl-8-oxotetrahydroprotoberberines, respectively.Only one of two possible diastereomers is formed.The lactams may be reduced to the corresponding protoberberines with lithium aluminium hydride.The reaction of the acyclic imine, 3,4-dimethoxybenzylidenemethylamine, with anions derived from phthalide, 3-phenylphthalide, and 5,6-dimethoxyphthalide, has been investigated.In all cases separable mixtures of diastereomeric substituted 3,4-dihydro-1(2H)-isoquinolones were formed.
- Marsden, Richard,MacLean, David B.
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p. 1392 - 1399
(2007/10/02)
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- Studies on the chemical constituents of rutaceous plants. XLIX. Development of a versatile method for the synthesis of antitumor-active benzo[c]phenanthridine alkaloids. (1). Preparation of various 2,4-bisaryl-4-oxobutyronitriles and 2,4-bisaryl-4-oxobutyramides
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For the sake of establishment of a versatile synthetic method for benzo[c]phenanthridine alkaloids, improvement of the Robinson synthetic method was examined. Thirteen chalcones (7a-m) were prepared by condensation of two acetophenone derivatives (15 and 16) with eleven benzaldehyde derivatives (19a-k) as fundamental starting materials. Hydrocyanation of these chalcones (7a-1) except one (7m) gave the corresponding 2,4-bisaryl-4-oxobutyronitriles (8a-1). Eleven 2,4-bisaryl-4-oxobutyramides (9a-k) were also prepared.
- Ishii,Ishikawa,Deushi,et al.
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p. 3024 - 3038
(2007/10/02)
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