- Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase
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Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.
- Abell, Lynn M.,Basso, Michael D.,Cantor, Glenn H.,Clark, Charles G.,Dilger, Andrew K.,Dongre, Ashok,Duclos, Franck,Duke, Gerald,Gao, Ji,Jusuf, Sutjano,Khan, Javed,Kick, Ellen K.,Kopcho, Lisa M.,Krishnakumar, Arathi,Locke, Gregory A.,Onorato, Joelle M.,Shaw, Scott A.,Spronk, Steven A.,Viet, Andrew,Vokits, Benjamin P.,Wexler, Ruth R.,Zhao, Lei
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Read Online
- A Modular Synthesis of Teraryl-Based α-Helix Mimetics, Part 4: Core Fragments with Two Halide Leaving Groups Featuring Side Chains of Proteinogenic Amino Acids
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Teraryl-based α-helix mimetics have proven to be useful compounds for the inhibition of protein-protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl-based α-helix mimetics using a benzene core unit featuring two halide leaving groups of differentiated reactivity in the Pd-catalyzed cross-coupling used for teraryl assembly. The use of para-bromo iodoarene core fragments resolved the issue of hydrolysis during cross-coupling that was observed when using triflate as a leaving group. We report a complete set of para-bromoiodoarene core fragments decorated with side chains of all proteinogenic amino acids relevant for PPI (Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Ser, Thr, Trp, Tyr and Val). In order to be compatible with general cross-coupling conditions, some of the nucleophilic side chains had to be provided in a protected form to serve as stable building blocks.
- Blesl, Julia,Breinbauer, Rolf,Schreiner, Till,Trobe, Melanie,Vareka, Martin
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supporting information
(2022/03/01)
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- Scalable Continuous Synthesis of Organozinc Reagents and Their Immediate Subsequent Coupling Reactions
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The continuous synthesis of organozinc reagents and their immediately following subsequent also continuous consumption in catalyzed and noncatalyzed coupling reactions were investigated. In the first step, a bed of Zn turnings at variable liquid throughputs and concentrations of organic halide solutions was used, and the formed Zn organometallics were analyzed for quality control. They were then directly pumped into a second step, namely, Reformatsky, Saytzeff, and Negishi coupling reactions. In the organozinc halides' formation, a novel process window was employed by using a large molar excess of Zn turnings and investigating mechanical as well as chemical Zn activation. Subsequent couplings of the freshly prepared Zn organometallics were done using examples of a Reformatsky, Saytzeff, and Negishi coupling reaction. For the Zn organometallics' formation, a laboratory-scale reactor setup previously built for Grignard reagent formation was evaluated including a Zn replenishing unit; the same reactor was also used in the metal-catalyzed subsequent step (Negishi coupling). The main objective of this work was to establish the scalable continuous formation of Zn organometallic reagents enabling fast and safe process optimization, analyze the reagents for their purity, and then immediately consume them in various follow-up steps, always only leaving a very small amount of reactive and sensitive organometallic reagent in the setup. It was found that full conversion of the employed halides could be achieved within a single passage through the reactor with organozinc yields of 82-92%, as well as being able to successfully perform subsequent non- and metal-catalyzed coupling steps with yields of up to 92%. A pilot-scale setup allowing a liquid throughput of up to 3-5 L/h has also been built and is ready to be tested with the synthesis as established here.
- Menges-Flanagan, Gabriele,Deitmann, Eva,G?ssl, Lars,Hofmann, Christian,L?b, Patrick
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p. 427 - 433
(2021/01/09)
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- Structure-Based Design of Highly Potent Toll-like Receptor 7/8 Dual Agonists for Cancer Immunotherapy
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Activation of the toll-like receptors 7 and 8 has emerged as a promising strategy for cancer immunotherapy. Herein, we report the design and synthesis of a series of pyrido[3,2-d]pyrimidine-based toll-like receptor 7/8 dual agonists that exhibited potent and near-equivalent agonistic activities toward TLR7 and TLR8. In vitro, compounds 24e and 25a significantly induced the secretion of IFN-α, IFN-γ, TNF-α, IL-1β, IL-12p40, and IP-10 in human peripheral blood mononuclear cell assays. In vivo, compounds 24e, 24m, and 25a significantly suppressed tumor growth in CT26 tumor-bearing mice by remodeling the tumor microenvironment. Additionally, compounds 24e, 24m, and 25a markedly improved the antitumor activity of PD-1/PD-L1 blockade. In particular, compound 24e combined with the anti-PD-L1 antibody led to complete tumor regression. These results demonstrated that TLR7/8 agonists (24e, 24m, and 25a) held great potential as single agents or in combination with PD-1/PD-L1 blockade for cancer immunotherapy.
- Wang, Zhisong,Gao, Yan,He, Lei,Sun, Shuhao,Xia, Tingting,Hu, Lu,Yao, Licheng,Wang, Liangliang,Li, Dan,Shi, Hui,Liao, Xuebin
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supporting information
p. 7507 - 7532
(2021/06/28)
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- C(sp3)?C(sp3) Bond Formation via Electrochemical Alkoxylation and Subsequent Lewis Acid Promoted Reactions
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A two-step transition metal-free methodology for the C(sp3)?C(sp3) functionalisation of saturated N-heterocyclic systems is disclosed. First, aminal derivatives are generated through the anodic oxidation of readily accessible carboxylic acids. Then, in the presence of BF3 ? OEt2, iminium ions are unmasked and rapidly alkylated by organozinc reagents under flow conditions. Secondary, tertiary and quaternary carbon centers have been successfully assembled using this methodology. Such an approach is especially relevant to drug discovery since it increases C(sp3)-functionalities rapidly within a molecular framework. As proof of concept, our methodology was applied to derivatization of peptides and an API. (Figure presented.).
- López, Enol,van Melis, Carlo,Martín, Raúl,Petti, Alessia,de la Hoz, Antonio,Díaz-Ortíz, ángel,Dobbs, Adrian P.,Lam, Kevin,Alcázar, Jesús
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supporting information
p. 4521 - 4525
(2021/08/06)
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- Role of Electron-Deficient Olefin Ligands in a Ni-Catalyzed Aziridine Cross-Coupling to Generate Quaternary Carbons
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We previously reported the development of an electron-deficient olefin (EDO) ligand, Fro-DO, that promotes the generation of quaternary carbon centers via Ni-catalyzed Csp3-Csp3 cross-coupling with aziridines. By contrast, electronically and structurally similar EDO ligands such as dimethyl fumarate and electron-deficient styrenes afford primarily β-hydride elimination side reactivity. Only a few catalyst systems have been identified that promote the formation of quaternary carbons via Ni-catalyzed Csp3-Csp3 cross-coupling. Although Fro-DO represents a promising ligand in this regard, the basis for its superior performance is not well understood. Here we describe a detailed mechanistic study of the aziridine cross-coupling reaction and the role of EDO ligands in facilitating Csp3-Csp3 bond formation. This analysis reveals that cross-coupling proceeds by a Ni0/II cycle with a NiII azametallacyclobutane catalyst resting state. Turnover-limiting C-C reductive elimination occurs from a spectroscopically observable NiII-dialkyl intermediate bound to the EDO. Computational analysis shows that Fro-DO accelerates turnover limiting reductive elimination via LUMO lowering. However, it is no more effective than dimethyl fumarate at reducing the barrier to Csp3-Csp3 reductive elimination. Instead, Fro-DO's unique reactivity arises from its ability to associate favorably to NiII intermediates. Natural bond order second-order perturbation theory analysis of the catalytically relevant NiII intermediate indicates that Fro-DO binds to NiII through an additional stabilizing donor-acceptor interaction between its sulfonyl group and NiII. Design of new ligands to evaluate this proposal supports this model and has led to the development of a new and tunable ligand framework.
- Estrada, Jesús G.,Williams, Wendy L.,Ting, Stephen I.,Doyle, Abigail G.
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supporting information
p. 8928 - 8937
(2020/05/13)
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- Stereoselective approach to access 3-tert-Butyl-Dimethylsiloxy-2,6-Substituted piperidines through nucleophilic addition of N,O-acetals with organozinc reagents
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An efficient approach to access chiral 3-tert-butyl-dimethylsiloxy 2,6-disubstituted 6-benzyl piperidines was developed through nucleophilic addition of N,O-acetals with organozinc reagents. A number of substituted benzyl zinc reagents could react with N,
- Chen, Zhao-Dan,Chen, Zhuo,Wang, Qiao-E,Si, Chang-Mei,Wei, Bang-Guo
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supporting information
(2020/06/03)
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- Formation of quaternary carbons through cobalt-catalyzed C(sp3)-C(sp3) Negishi cross-coupling
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Formation of all-carbon-substituted quaternary carbons is a key challenge in organic and medicinal chemistry. We report a cobalt-catalyzed C(sp3)-C(sp3) cross-coupling that allows for the introduction of benzyl, heteroarylmethylzinc and allyl groups to halo-carbonyl substrates. The cross-coupling reaction is selective for C(sp3)-over C(sp2)-halides, in contrast to most used catalytic metals, and allows access to novel scaffolds of pharmaceutical interest. NMR mechanistic studies suggest the presence of Co(0) complexes as catalytic species. This journal is
- Palao, Eduardo,López, Enol,Torres-Moya, Iván,De La Hoz, Antonio,Díaz-Ortiz, ángel,Alcázar, Jesús
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supporting information
p. 8210 - 8213
(2020/08/17)
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- Fukuyama Cross-Coupling Approach to Isoprekinamycin: Discovery of the Highly Active and Bench-Stable Palladium Precatalyst POxAP
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An efficient and user-friendly palladium(II) precatalyst, POxAP (post-oxidative-addition precatalyst), was identified for use in Fukuyama cross-coupling reactions. Suitable for storage under air, the POxAP precatalyst allowed reaction between thioesters and organozinc reagents with turnover numbers of ~90000. A series of 23 ketones were obtained with yields ranging from 53 to 99%. As proof of efficacy, an alternative approach was developed for the synthesis of a key precursor of the natural product isoprekinamycin.
- Tang, Shuang-Qi,Bricard, Jacques,Schmitt, Martine,Bihel, Frédéric
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supporting information
p. 844 - 848
(2019/01/30)
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- PYRUVATE KINASE ACTIVATORS FOR USE IN TREATING BLOOD DISORDERS
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Described herein are compounds that activate pyruvate kinase R, pharmaceutical compositions and methods of use thereof. These compounds are represented by Formula (I): Formula (I) wherein R', R2, L', and L2 are as defined herein.
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Page/Page column 124; 125
(2019/03/05)
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- Indium-Mediated Synthesis of Benzylic Hydroperoxides
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An indium(0)-metal-mediated efficient synthesis of benzylic hydroperoxides is described. The reaction proceeds efficiently with a broad range of benzyl bromides under aerobic conditions at room temperature to afford benzyl hydroperoxides in good to excellent yields. In addition, the tandem hydroperoxidation-Michael addition of (E)-1-(bromomethyl)-2-(2-nitrovinyl)benzene was also demonstrated.
- Hou, Yuxuan,Hu, Jinjin,Xu, Ruigang,Pan, Shulei,Zeng, Xiaofei,Zhong, Guofu
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supporting information
p. 4428 - 4432
(2019/06/17)
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- Novel preparation of N-arylmethyl-N-arylmethyleneamine N-oxides from benzylic bromides with zinc and isobutyl nitrite
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Treatment of benzylic bromides with Zn and LiCl, followed by the reaction with i-butyl nitrite gave N-arylmethyl-N-arylmethyleneamine N-oxides in moderate yields. The present reaction is a novel and simple method for the preparation of nitrones from benzylic bromides, although the yields are moderate.
- Yanai, Kei,Togo, Hideo
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p. 3523 - 3529
(2019/05/24)
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- Ultrasound assisted nitratobis(triphenyl phosphine) copper(I) catalyzed conjugate addition of alkyl or aryl bromides to α,β-unsaturated cyanoester
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The α,β-unsaturated cyanoester was obtained from p-methoxy benzaldehyde and ethyl cyano acetate by reported method. The conjugated addition products were synthesized from alkyl or aryl bromides and α,β-unsaturated cyanoester in the presence of 10 mol % Cu(I) catalyst in high yields within 17-21 min under ultrasound irradiation.
- Pise, Ashok S.,Burungale, Arvind S.,Devkate, Santosh S.,Gawade, Ramesh B.,Jadhav, Sunil D.
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p. 348 - 352
(2019/01/19)
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- Direct Reductive N-Functionalization of Aliphatic Nitro Compounds
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The first general protocol for the direct reductive N-functionalization of aliphatic nitro compounds is presented. The nitro group is partially reduced to a nitrenoid, with a mild and readily available combination of B2pin2 and zinc organyls. Thereby, the formation of an unstable nitroso intermediate is avoided, which has so far severely limited reductive transformations of aliphatic nitro compounds. The reaction is concluded by an electrophilic amination of zinc organyls.
- Rauser, Marian,Ascheberg, Christoph,Niggemann, Meike
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supporting information
p. 3970 - 3974
(2018/02/26)
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- O2-Mediated Oxidation of Aminoboranes through 1,2-N Migration
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In analogy to the classical reaction of C?B bonds with peroxides, the first oxidative functionalization of aminoboranes through a 1,2-N migration was realized. Readily available aliphatic nitro compounds are thereby transformed into N- and O-functionalized hydroxylamines in a single synthetic operation. Addition of hazardous peroxides is avoided. Instead, the insertion of O2, as the terminal oxidant, into Zn?C bonds provides the necessary peroxides. The required zinc organyls, in turn, are formed through a boron-to-zinc exchange, from an organoboronic ester byproduct of the nitro-to-aminoborane transformation.
- Rauser, Marian,Warzecha, Daniel P.,Niggemann, Meike
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supporting information
p. 5903 - 5907
(2018/05/14)
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- Visible-Light-Induced Nickel-Catalyzed Negishi Cross-Couplings by Exogenous-Photosensitizer-Free Photocatalysis
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The merging of photoredox and transition-metal catalysis has become one of the most attractive approaches for carbon–carbon bond formation. Such reactions require the use of two organo-transition-metal species, one of which acts as a photosensitizer and t
- Abdiaj, Irini,Fontana, Alberto,Gomez, M. Victoria,de la Hoz, Antonio,Alcázar, Jesús
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supporting information
p. 8473 - 8477
(2018/04/30)
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- Mechanochemical Activation of Zinc and Application to Negishi Cross-Coupling
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A form independent activation of zinc, concomitant generation of organozinc species and engagement in a Negishi cross-coupling reaction via mechanochemical methods is reported. The reported method exhibits a broad substrate scope for both C(sp3)–C(sp2) and C(sp2)–C(sp2) couplings and is tolerant to many important functional groups. The method may offer broad reaching opportunities for the in situ generation organometallic compounds from base metals and their concomitant engagement in synthetic reactions via mechanochemical methods.
- Cao, Qun,Howard, Joseph L.,Wheatley, Emilie,Browne, Duncan L.
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supporting information
p. 11339 - 11343
(2018/08/28)
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- Efficient analoging around ethionamide to explore thioamides bioactivation pathways triggered by boosters in Mycobacterium tuberculosis
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Ethionamide is a key antibiotic prodrug of the second-line chemotherapy regimen to treat tuberculosis. It targets the biosynthesis of mycolic acids thanks to a mycobacterial bioactivation carried out by the Baeyer-Villiger monooxygenase EthA, under the control of a transcriptional repressor called EthR. Recently, the drug-like molecule SMARt-420, which triggers a new transcriptional regulator called EthR2, allowed the derepression a cryptic alternative bioactivation pathway of ethionamide. In order to study the bioactivation of a collection of thioisonicotinamides through the two bioactivation pathways, we developed a new two-step chemical pathway that led to the efficient synthesis of eighteen ethionamide analogues. Measurements of the antimycobacterial activity of these derivatives, used alone and in combination with boosters BDM41906 or SMARt-420, suggest that the two different bioactivation pathways proceed via the same mechanism, which implies the formation of similar metabolites. In addition, an electrochemical study of the aliphatic thioisonicotinamide analogues was undertaken to see whether their oxidation potential correlates with their antitubercular activity measured in the presence or in the absence of the two boosters.
- Prieri, Marion,Frita, Rosangela,Probst, Nicolas,Sournia-Saquet, Alix,Bourotte, Marilyne,Déprez, Benoit,Baulard, Alain R.,Willand, Nicolas
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- Access to Functionalized Quaternary Stereocenters via the Copper-Catalyzed Conjugate Addition of Monoorganozinc Bromide Reagents Enabled by N, N-Dimethylacetamide
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Monoorganozinc reagents, readily obtained from alkyl bromides, display excellent reactivity with β,β-disubstituted enones and TMSCl in the presence of Cu(I) and Cu(II) salts to synthesize a variety of cyclic functionalized β-quaternary ketones in 38-99% yields and 9:1-20:1 diastereoselectivities. The conjugate addition features a pronounced improvement in DMA using monoorganozinc bromide reagents. A simple one-pot protocol that harnesses in situ generated monoorganozinc reagents delivers comparable product yields.
- Fulton, Tyler J.,Alley, Phebe L.,Rensch, Heather R.,Ackerman, Adriana M.,Berlin, Cameron B.,Krout, Michael R.
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p. 14723 - 14732
(2018/11/23)
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- Rhodium-Catalyzed Desymmetrization of meso -Glutaric Anhydrides to Access Enantioenriched anti, anti -Polypropionates
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An expedient desymmetrization of 3,5-dimethyl-4-alkoxyglutaric anhydrides to access anti, anti -polypropionates is described. The previously unknown anhydrides are rapidly assembled from readily available precursors. A Rh(I)· t -BuPHOX catalyst system was found to provide good yield and high selectivities. With these conditions, the trisubstituted anhydrides were desymmetrized with various alkyl zinc reagents to provide synthetically useful enantioenriched anti,anti -2,4-dimethyl-3-hydroxy-δ-ketoacids. An identical catalyst system also affords access to syn, syn -stereotriads as well as a partial kinetic resolution of a chiral anhydride.
- Cochran, Brian M.,Henderson, Daniel D.,Thullen, Scott M.,Rovis, Tomislav
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supporting information
p. 306 - 309
(2017/10/26)
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- Straightforward Synthesis of 2- and 2,8-Substituted Tetracenes
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A simple regiospecific route to otherwise problematic substituted tetracenes is described. The diverse cores (E)-1,2-Ar1CH2(HOCH2)C=C(CH2OH)I (Ar1=Ph, 4-MePh, 4-MeOPh, 4-FPh) and (E)-1,2-I(HOCH2)C=C(CH2OH)I, accessed from ultra-low cost HOCH2C≡CCH2OH at multi-gram scales, allow the synthesis of diol libraries (E)-1,2-Ar1CH2(HOCH2)C=C(CH2OH)CH2Ar2 (Ar2=Ph, 4-MePh, 4-iPrPh, 4-MeOPh, 4-FPh, 4-BrPh, 4-biphenyl, 4-styryl; 14 examples) by efficient Negishi coupling. Copper-catalysed aerobic oxidation cleanly provides dialdehydes (E)-1,2-Ar1CH2(CHO)C=C(CHO)CH2Ar2, which in many cases undergo titanium(IV) chloride-induced double Bradsher closure, providing a convenient method for the synthesis of regiochemically and analytically pure tetracenes (12 examples). The sequence is typically chromatography-free, scalable, efficient and technically simple to carry out.
- Woodward, Simon,Ackermann, Miriam,Ahirwar, Saurabh K.,Burroughs, Laurence,Garrett, Mary Robert,Ritchie, John,Shine, Jonathan,Tyril, Bj?rk,Simpson, Kevin,Woodward, Peter
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supporting information
p. 7819 - 7824
(2017/06/06)
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- Alkynylthioimidazolium Salts: Efficient Reagents for the Synthesis of Alkynyl Sulfides by Electrophilic Thioalkynylation
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The efficient synthesis of a series of alkynylthioimidazolium salts through reaction of organozinc compounds with dibromo(imidazolium)sulfuranes is reported. Addition of Grignard reagents to these new species provided a highly modular, clean, and scalable access to a broad variety of alkynyl sulfides in good-to-excellent yields. The utility of this protocol was showcased by the preparation of alkynyl sulfides, which are particularly difficult to obtain or simply unavailable through the existing methodologies. In addition, the synthetic method was extended to the preparation of alkynyl selenides.
- Pe?a, Javier,Talavera, Garazi,Waldecker, Bernd,Alcarazo, Manuel
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supporting information
p. 75 - 78
(2017/01/09)
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- A study of Negishi cross-coupling reactions with benzylzinc halides to prepare original 3-ethoxypyrazoles
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The Negishi palladium-catalyzed cross-coupling reaction between 3-ethoxy-4-iodo-1H-pyrazole and various benzylzinc halides was extensively studied. Using simplified, robust, and optimized reaction conditions, a series of electron-poor benzylzinc halides w
- Coutant, Eloi P.,Janin, Yves L.
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p. 511 - 516
(2015/02/19)
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- Original 2-(3-Alkoxy-1 H -pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)
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Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in our previous report, the structure-activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH.
- Lucas-Hourani, Marianne,Munier-Lehmann, Hélène,El Mazouni, Farah,Malmquist, Nicholas A.,Harpon, Jane,Coutant, Eloi P.,Guillou, Sandrine,Helynck, Olivier,Noel, Anne,Scherf, Artur,Phillips, Margaret A.,Tangy, Frédéric,Vidalain, Pierre-Olivier,Janin, Yves L.
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p. 5579 - 5598
(2015/08/03)
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- Efficient and General Aerobic Oxidative Cross-Coupling of THIQs with Organozinc Reagents Catalyzed by CuCl2: Proof of a Radical Intermediate
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A general new method for the highly concise synthesis of C-1-alkylated tetrahydroisoquinolines (THIQ) is reported. The CuCl2-catalyzed procedure is based on a coupling of nonfunctionalized THIQs with organozinc reagents under aerobic conditions. It proceeds in high yields and is broadly applicable to a wide range of substrates. It relies on a regioselective sp3 C-H bond activation allowing for an sp3-sp3 bond union under mild reaction conditions in a rapid and effective manner. Mechanistically it involves an iminium ion intermediate that is formed via an organic radical involving a single-electron-transfer process. For the first time for this type of reaction a radical intermediate has been proven by EPR spectroscopy.
- Wang, Tongtong,Schrempp, Michael,Berndh?user, Andreas,Schiemann, Olav,Menche, Dirk
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supporting information
p. 3982 - 3985
(2015/09/01)
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- Electron-deficient olefin ligands enable generation of quaternary carbons by Ni-catalyzed cross-coupling
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A Ni-catalyzed Negishi cross-coupling with 1,1-disubstituted styrenyl aziridines has been developed. This method delivers valuable β-substituted phenethylamines via a challenging reductive elimination that affords a quaternary carbon. A novel electron-deficient olefin ligand, Fro-DO, proved crucial for achieving high rates and chemoselectivity for C-C bond formation over β-H elimination. This ligand is easy to access, is stable, and presents a modular framework for reaction discovery and optimization. We expect that these attributes, combined with the fact that the ligands impart distinct electronic properties to a metal, will support the invention of new transformations not previously possible using established ligands.
- Huang, Chung-Yang,Doyle, Abigail G.
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supporting information
p. 5638 - 5641
(2015/05/20)
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- COMPOSITIONS USEFUL FOR TREATING DISORDERS RELATED TO KIT
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Compounds and compositions useful for treating disorders related to KIT and PDFGR are described herein.
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Paragraph 0159; 0168; 0169
(2015/04/28)
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- Reactions of organozinc reagents with potassium bromodifluoroacetate
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A practical method for the synthesis of gem-difluorinated compounds from organozinc reagents is described. Potassium bromodifluoroacetate serves as a source of CF2-fragment, which is inserted into carbonzinc bond of organozinc reagents. The intermediate difluorinated organozinc species can be protonated, brominated or coupled with allylic electrophiles.
- Levin, Vitalij V.,Zemtsov, Artem A.,Struchkova, Marina I.,Dilman, Alexander D.
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- 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B
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Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC 50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.
- Zhi, Ying,Gao, Li-Xin,Jin, Yi,Tang, Chun-Lan,Li, Jing-Ya,Li, Jia,Long, Ya-Qiu
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p. 3670 - 3683
(2014/07/07)
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- Highly regioselective three-component domino heck-negishi coupling reaction for the functionalization of purines at C6
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A highly regioselective three-component domino Heck-Negishi coupling reaction has been developed. Organozinc reagents are used to trap an alkylpalladium intermediate of olefins for a first example in the domino Heck reaction. This reaction is applicable t
- Wang, Dong-Chao,Niu, Hong-Ying,Xie, Ming-Sheng,Qu, Gui-Rong,Wang, Hui-Xuan,Guo, Hai-Ming
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supporting information
p. 262 - 265
(2014/01/23)
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- Reaction of organozinc halides with aryl isocyanates
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Reformatsky reagent, benzylzinc bromide or alkylzinc iodides react with aryl isocyanates directly to give corresponding N-substituted carbamates under mild reaction conditions. However, the reaction of allylzinc bromide or propargylzinc bromide with aryl isocyanates produces the corresponding N-substituted amides. The reactions provide alternative methods for the synthesis of N-substituted carbamates or amides.
- Yang, Haoran,Huang, Danfeng,Wang, Ke-Hu,Xu, Changming,Niu, Teng,Hu, Yulai
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supporting information
p. 2588 - 2593
(2013/03/28)
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- Radical migration-addition of N-tert-butanesulfinyl imines with organozinc reagents
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A novel migration-addition sequence was discovered for the reaction of enantioenriched N-tert-butanesulfinyl iminoacetate 1a with functionalized benzylzinc bromide reagents, producing tert-leucine derivatives in excellent diastereoselectivity (dr 98:2). The absolute configurations of two new chiral centers were unambiguously assigned by chemical transformations and X-ray crystallography. In addition, the regio- and diastereoselectivities of this novel reaction were both explained through the key N-sulfinamine intermediate M6 generated by the tert-butyl radical attack on the imine. Computational analysis of this reaction process, which was performed at the B3LYP/6-311++G(3df,2p)//B3LYP/6-31G-LANL2DZ level, also supported our proposed two-stage mechanism.
- Huang, Wei,Ye, Jian-Liang,Zheng, Wei,Dong, Han-Qing,Wei, Bang-Guo
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p. 11229 - 11237
(2013/12/04)
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- Lithium organozincate complexes LiRZnX2: Common species in organozinc chemistry
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We have used a combination of electrospray ionization (ESI) mass spectrometry, electrical conductivity measurements, and NMR spectroscopy to investigate the effect of LiCl on solutions of organylzinc halides RZnX (R = Bu, Bn, Ph; X = halogen) and dibutylzinc Bu2Zn in tetrahydrofuran. In the case of RZnX, the addition of LiX (X = Cl) leads to a steep rise of the ESI signal intensities of RZnX2- organozincate anions. At the same time, the electrical conductivities strongly increase and the NMR absorptions of the α-H atoms of BuZnX shift upfield. These results consistently point to the formation of lithium organozincates Li +RZnX2-. As the most common syntheses of RZnX reagents involve stoichiometric amounts of LiX salts, Li+RZnX 2- complexes are supposedly widespread and may hold the key to understanding the marked effects of LiCl on the reactivity of organozinc halides. In contrast, we find Bu2Zn to have a much lower tendency to add LiCl and form ate complexes. This result is in line with the weak effect of LiCl on the reactivity of diorganozinc compounds reported in the literature.
- Fleckenstein, Julia E.,Koszinowski, Konrad
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p. 5018 - 5026
(2011/11/07)
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- PYRIMIDINE DERIVATIVES
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Novel pyrimidine derivatives of the formula STR1 represents: either a group: STR2 or a group: STR3 having angiotensin II inhibiting activity.
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