- Kinetic resolution ofN-aryl β-amino alcoholsviaasymmetric aminations of anilines
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An efficient kinetic resolution ofN-aryl β-amino alcohols has been developedviaasymmetricpara-aminations of anilines with azodicarboxylates enabled by chiral phosphoric acid catalysis. Broad substrate scope and high kinetic resolution performances were afforded with this method. Control experiments supported the critical roles of the NH and OH group in these reactions.
- Guo, Zheng,Xie, Jinglei,Hu, Tao,Chen, Yunrong,Tao, Houchao,Yang, Xiaoyu
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supporting information
p. 9394 - 9397
(2021/09/22)
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- Reprogramming Epoxide Hydrolase to Improve Enantioconvergence in Hydrolysis of Styrene Oxide Scaffolds
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Enantioconvergent hydrolysis by epoxide hydrolase is a promising method for the synthesis of important vicinal diols. However, the poor regioselectivity of the naturally occurring enzymes results in low enantioconvergence in the enzymatic hydrolysis of styrene oxides. Herein, modulated residue No. 263 was redesigned based on structural information and a smart variant library was constructed by site-directed modification using an “optimized amino acid alphabet” to improve the regioselectivity of epoxide hydrolase from Vigna radiata (VrEH2). The regioselectivity coefficient (r) of variant M263Q for the R-isomer of meta-substituted styrene oxides was improved 40–63-fold, and variant M263V also exhibited higher regioselectivity towards the R-isomer of para-substituted styrene oxides compared with the wild type, which resulted in improved enantioconvergence in hydrolysis of styrene oxide scaffolds. Structural insight showed the crucial role of residue No. 263 in modulating the substrate binding conformation by altering the binding surroundings. Furthermore, increased differences in the attacking distance between nucleophilic residue Asp101 and the two carbon atoms of the epoxide ring provided evidence for improved regioselectivity. Several high-value vicinal diols were readily synthesized (>88% yield, 90%–98% ee) by enantioconvergent hydrolysis using the reprogrammed variants. These findings provide a successful strategy for enhancing the enantioconvergence of native epoxide hydrolases through key single-site mutation and more powerful enzyme tools for the enantioconvergent hydrolysis of styrene oxide scaffolds into single (R)-enantiomers of chiral vicinal diols. (Figure presented.).
- Li, Fu-Long,Qiu, Yan-Yan,Zheng, Yu-Cong,Chen, Fei-Fei,Kong, Xu–Dong,Xu, Jian-He,Yu, Hui-Lei
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supporting information
p. 4699 - 4706
(2020/09/21)
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- Epoxidation of Alkenes with Molecular Oxygen as the Oxidant in the Presence of Nano-Al 2O 3
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The nano-Al 2O 3-promoted epoxidation of alkenes with molecular oxygen as the oxidant has been developed, providing an efficient route to a variety of epoxides in moderate to excellent yields. The environmentally friendly and efficient nano-Al 2O 3catalyst could be easily recovered and reused five times without significant loss of activity.
- Zhou, Xuan,Wang, Qiong,Xiong, Wenfang,Wang, Lu,Ye, Rongkai,Xiang, Ge,Qi, Chaorong,Hu, Jianqiang
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supporting information
p. 1789 - 1794
(2020/09/18)
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- Regio- and chemoselective rearrangement of terminal epoxides into methyl alkyl and aryl ketones
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The development of the highly active pincer-type rhodium catalyst 2 for the nucleophilic Meinwald rearrangement of functionalised terminal epoxides into methyl ketones under mild conditions is presented. An excellent regio- and chemoselectivity is obtained for the first time for aryl oxiranes.
- Tian, Yingying,Jürgens, Eva,Kunz, Doris
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supporting information
p. 11340 - 11343
(2018/10/31)
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- Integration of Enhanced Sampling Methods with Saturation Transfer Difference Experiments to Identify Protein Druggable Pockets
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Saturation transfer difference (STD) is an NMR technique conventionally applied in drug discovery to identify ligand moieties relevant for binding to protein cavities. This is important to direct medicinal chemistry efforts in small-molecule optimization processes. However, STD does not provide any structural details about the ligand-target complex under investigation. Herein, we report the application of a new integrated approach, which combines enhanced sampling methods with STD experiments, for the characterization of ligand-target complexes that are instrumental for drug design purposes. As an example, we have studied the interaction between StOASS-A, a potential antibacterial target, and an inhibitor previously reported. This approach allowed us to consider the ligand-target complex from a dynamic point of view, revealing the presence of an accessory subpocket which can be exploited to design novel StOASS-A inhibitors. As a proof of concept, a small library of derivatives was designed and evaluated in vitro, displaying the expected activity.
- Magalh?es, Joana,Annunziato, Giannamaria,Franko, Nina,Pieroni, Marco,Campanini, Barbara,Bruno, Agostino,Costantino, Gabriele
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p. 710 - 723
(2018/03/30)
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- Green Organocatalytic Dihydroxylation of Alkenes
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An inexpensive, green, metal-free one-pot procedure for the dihydroxylation of alkenes is described. H2O2 and 2,2,2-trifluoroacetophenone were employed as the oxidant and organocatalyst, respectively, in this highly sustainable protocol in which a variety of homoallylic alcohols, aminoalkenes, and simple alkenes were converted into the corresponding polyalcohols in good to excellent yields. This process takes advantage of an epoxidation reaction followed by an acidic treatment in which water participates in the ring opening of the in situ prepared epoxide to lead to the desired product.
- Theodorou, Alexis,Triandafillidi, Ierasia,Kokotos, Christoforos G.
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p. 1502 - 1509
(2017/04/01)
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- Diastereoselective C?H Bond Amination for Disubstituted Pyrrolidines
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We report herein the improved diastereoselective synthesis of 2,5-disubstituted pyrrolidines from aliphatic azides. Experimental and theoretical studies of the C?H amination reaction mediated by the iron dipyrrinato complex (AdL)FeCl(OEt2) provided a model for diastereoinduction and allowed for systematic variation of the catalyst to enhance selectivity. Among the iron alkoxide and aryloxide catalysts evaluated, the iron phenoxide complex exhibited superior performance towards the generation of syn 2,5-disubstituted pyrrolidines with high diastereoselectivity.
- Iovan, Diana A.,Wilding, Matthew J. T.,Baek, Yunjung,Hennessy, Elisabeth T.,Betley, Theodore A.
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supporting information
p. 15599 - 15602
(2017/11/16)
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- Indium(III) Chloride Promoted Highly Efficient Tandem Rearrangement-α-Addition Strategy towards the Synthesis of α-Hydroxyamides
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A new tandem process is reported that provides access to α-hydroxyamides from epoxides for the first time. Herein, we explore InCl3-mediated tandem rearrangement of epoxides to aldehydes and α-addition of TosMIC to in situ derived aldehydes. An unprecedented C-C bond-forming reaction is disclosed that features mild conditions, high yields, and shorter reaction times.
- Lingaswamy, Kadari,Mohan, Dumpala,Krishna, Palakodety Radha,Prapurna, Y. Lakshmi
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supporting information
p. 1693 - 1698
(2016/07/06)
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- 2,2,2-Trifluoroacetophenone: An organocatalyst for an environmentally friendly epoxidation of alkenes
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A cheap, mild, fast, and environmentally friendly oxidation of olefins to the corresponding epoxides is reported using polyfluoroalkyl ketones as efficient organocatalysts. Namely, 2,2,2-trifluoroacetophenone was identified as an improved organocatalyst for the epoxidation of alkenes. Various olefins, mono-, di-, and trisubstituted, are epoxidized chemoselectively in high to quantitative yields utilizing 2-5 mol % catalyst loading and H2O 2 as the green oxidant.
- Limnios, Dimitris,Kokotos, Christoforos G.
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p. 4270 - 4276
(2014/06/09)
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- Chemoenzymatic epoxidation of alkenes based on peracid formation by a Rhizomucor miehei lipase-catalyzed perhydrolysis reaction
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A chemoenzymatic and selective method for the epoxidation of a series of cyclic and linear alkenes is described. Epoxides have been obtained in moderate to excellent conversions under mild reaction conditions through a two-step sequence, carried out in one-pot. This chemoenzymatic approach is based on a Rhizomucor miehei lipase-catalyzed perhydrolysis reaction to form the corresponding peracid, and subsequent epoxidation of the corresponding alkenes. Reaction parameters with influence in the biotransformation have been optimized specially focusing in the efficient enzymatic peracid formation by means of the correct choice of solvent, oxidant, and peracid precursor. This chemoenzymatic approach has been efficiently applied for the first time, in the regioselective chemical oxidation of (S)-carvone and limonene, both showing an opposite behavior for the oxidation of the internal and external C-C double bond, respectively.
- Méndez-Sánchez, Daniel,Ríos-Lombardía, Nicolás,Gotor, Vicente,Gotor-Fernández, Vicente
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p. 1144 - 1148
(2014/02/14)
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- Rhodium-catalyzed transannulation of N-sulfonyl-1,2,3-triazoles and epoxides: Regioselective synthesis of substituted 3,4-dihydro-2 H-1,4-oxazines
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Rhodium-catalyzed transannulation of 1,2,3-triazoles and ring-opening reactions of epoxides is described. A number of 3,4-dihydro-2H-1,4-oxazines are obtained in moderate yields probably involving generation of α-imino rhodium(II) carbene species.
- Ma, Xueji,Pan, Shanfei,Wang, Hangxiang,Chen, Wanzhi
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supporting information
p. 4554 - 4557
(2015/02/19)
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- The Ru-catalyzed enantioselective preparation of chiral halohydrins and their application in the synthesis of (R)-clorprenaline and (S)-sotalol
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The asymmetric transfer hydrogenation of a series of halo-substituted aryl methyl ketones, including those substituted in both α-methyl and aryl rings, was studied for the preparation of chiral halohydrins. Up to 99.7% ee was obtained with 2-chloro-1-(2-chlorophenyl)ethanone as the substrate and Ru-CsDPEN as the catalyst in an HCOONa/H2O system. (R)-Clorprenaline, a drug used in the treatment of respiratory disorders, such as bronchitis and asthma, and (S)-sotalol, a class-III antiarrhythmic compound, were prepared with these chiral halohydrins.
- Lu, Chuanjun,Luo, Zonghua,Huang, Ling,Li, Xingshu
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experimental part
p. 722 - 727
(2011/08/06)
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- Modified ibogaine fragments: Synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5- b]benzothiophenes
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Five phenyl-substituted derivatives and analogues of 1,2,3,4,5,6- hexahydroazepino[4,5-b]indole, 5, a major fragment of ibogaine (1), were synthesized and tested for binding to monoamine transporters, the NMDA receptor-coupled cation channel, and dopamine and opioid receptors. All five derivatives, 9 and 17a-d, displayed 8-10-fold higher affinity at the DA transporter than ibogaine and noribogaine (4). At the serotonin transporter, two compounds (9 and 17a) exhibited higher potency than ibogaine, while the rest had weaker binding affinities than the lead compound. In keeping with their structural similarity to ibogaine, all five compounds displayed weak to poor affinity for dopamine D1 and D2 receptors. However, two compounds, 17a,c, demonstrated moderate binding affinities at dopamine D3 receptors. All five compounds displayed weak to poor affinities for μ and κ opioid receptors and for the NMDA receptor-coupled cation channel. Despite the qualitative differences, derivatives and analogues of 5 may serve as useful substitutes for ibogaine.
- Efange, Simon M. N.,Mash, Deborah C.,Khare, Anil B.,Ouyang, Quinjie
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p. 4486 - 4491
(2007/10/03)
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- Bioactive tricyclic ibogaine analogs
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Ibogaine analogs are provided, which are phenyl-substituted-hexahydroazepino[4,5-b]indoles useful to treat cocaine addiction and the use of other addictive substances.
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- N-hydroxyalkyl derivatives of 3β-phenyltropane and 1-methylspiro[1H- indoline-3,4'-piperidine]: Vesamicol analogues with affinity for monoamine transporters
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As part of our ongoing structure-activity studies of the vesicular acetylcholine transporter ligand 2-(4-phenylpiperidino)cyclohexanol [vesamicol, 1), 22 N-hydroxy(phenyl)alkyl derivatives of 3β-phenyltropane, 6, and 1-methylspiro[1H-indoline-3,4'-piperidine], 7, were synthesized and tested for binding in vitro. Although a few compounds displayed moderately high affinity for the vesicular acetylcholine transporter, no compound was more potent than the prototypical vesicular acetylcholine transporter ligand vesamicol. However, a few derivatives of 6 displayed higher affinity for the dopamine transporter than cocaine. We conclude that modification of the piperidyl fragment of 1 will not lead to more potent vesicular acetylcholine transporter ligands.
- Efange, Simon M. N.,Kamath, Ashok P.,Khare, Anil B.,Kung, Mei-Ping,Mach, Robert H.,Parsons, Stanley M.
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p. 3905 - 3914
(2007/10/03)
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