- Fluorous mixture synthesis of fluorous-Fmoc reagents using a one-pot double tagging strategy
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The concise synthesis of fluorous Fmoc (f-Fmoc) reagents bearing C 3F7 or C4F9 or C6F 13 chains were achieved by fluorous mixture synthesis. The fluorous tagging process was effectively conducted using Heck type reaction of the bis-diazonium salt and the corresponding fluorous olefine, each bearing a different fluorous tag, by a one-pot double tagging strategy. At the final stage, each f-Fmoc reagent was separated from the mixture of three f-Fmoc reagents by fluorous solid phase extraction.
- Sugiyama, Yuya,Ishihara, Kazuki,Masuda, Yuka,Kobayashi, Yuki,Hamamoto, Hiromi,Matsugi, Masato
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- Development of efficient processes for multi-gram scale and divergent preparation of fluorous-Fmoc reagents
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An optimized, multi-gram scale synthesis of fluorous-Fmoc reagents is described. Fmoc reagents bearing C3F7, C4F9, and C6F13 chains were prepared on multi-gram scale (ca. 1.0-7.0 g) in eight steps with overall yields of 73%, 60%, and 90%, respectively. The order of addition of the fluorous alkenes in a one-pot double tagging Heck reaction was also investigated in order to conduct an encoded mixture synthesis of f-Fmoc reagents. The target f-Fmoc reagents bearing C3F7, C4F9, and C6F13 chains could be effectively separated based on the fluorine content of the molecules.
- Sugiyama, Yuya,Endo, Natsuki,Ishihara, Kazuki,Kobayashi, Yuki,Hamamoto, Hiromi,Shioiri, Takayuki,Matsugi, Masato
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- Structure-activity relationship (SAR) studies on the mutagenic properties of 2,7-diaminofluorene and 2,7-diaminocarbazole derivatives
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We discovered that 2,7-diaminofluorene or 2,7-diaminocarbazole moiety can be employed as a core structure of highly effective NS5A inhibitors that are connected through amide bonds to proline-valine-carbamate motifs. Amide bonds can be easily cleaved via various metabolic pathways upon administration into the body, and metabolites containing 2,7-diaminofluorene and 2,7-diaminocarbazole core structures have been known to be strong mutagens. To avoid the mutagenesis issue of these core structures, we examined various functional groups at the C9 or N9 position of 2,7-diaminofluorene or 2,7-diaminocarbazole, respectively, through the Ames test in TA98 and TA100 mutants of Salmonella typhimurium LT-2. We discovered that, through proper alkyl substitution at the C9 or N9 position, 2,7-diaminofluorene and 2,7-diaminocarbazole moieties can be successfully employed in drug discovery without necessarily causing mutagenicity problems.
- Kim, Byeong Wook,Lee, Hwa,Keum, Gyochang,Kim, B. Moon
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supporting information
(2020/11/27)
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- An expeditious and highly efficient synthesis of substituted pyrroles using a low melting deep eutectic mixture
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An expeditious green method for the synthesis of diverse valued substituted pyrroles through a Paal-Knorr condensation reaction, using a variety of amines and 2,5-hexanedione/2,5-dimethoxytetrahydrofuran in the presence of a low melting mixture ofN,N’-dimethylurea andL-(+)-tartaric acid (which acts as a dual catalyst/solvent system), has fruitfully been revealed. Herein, we have disclosed the applicability of this simple yet effective strategy for the generation of mono- and dipyrroles in good to excellent yields. Moreover,C3-symmetric tripyrrolo-truxene derivatives have also been assembled by means of cyclotrimerization, Paal-Knorr and Clauson-Kaas reactions as crucial steps. Interestingly, the melting mixture was recovered and reused with only a gradual decrease in the catalytic activity (over four cycles) without any significant drop in the yield of the product. This particular methodology is simple, rapid, environmental friendly, and high yielding for the generation of a variety of pyrroles. To the best of our knowledge, the present work reveals the fastest greener method reported up to this date for the construction of substituted pyrroles by utilizing the Paal-Knorr synthetic protocol, achieving impressive yields under operationally simple reaction conditions without involving any precarious/dangerous catalysts or unsafe volatile organic solvents.
- Alvi, Shakeel,Ali, Rashid
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p. 9732 - 9745
(2021/12/01)
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- Design and synthesis of novel symmetric fluorene-2,7-diamine derivatives as potent hepatitis C virus inhibitors
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Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors; the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC50) = 36 pM and a selectivity index of >2.78 × 106). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC50 = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group.
- Mousa, Mai H. A.,Ahmed, Nermin S.,Schwedtmann, Kai,Frakolaki, Efseveia,Vassilaki, Niki,Zoidis, Grigoris,Weigand, Jan J.,Abadi, Ashraf H.
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- Stereoselective Postassembly CH Oxidation of Self-Assembled Metal-Ligand Cage Complexes
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Self-assembled Fe-iminopyridine cage complexes containing doubly benzylic methylene units such as fluorene and xanthene can be selectively oxidized at the ligand backbone with tBuOOH, with no competitive oxidation observed at the metal centers. The self-assembled cage structure controls the reaction outcome, yielding oxidation products that are favored by the assembly, not by the reactants or functional groups. Whereas uncomplexed xanthene and fluorene control ligands are solely oxidized to the ketone equivalents with tBuOOH, the unfavorability of the self-assembled ketone cages forces the reaction to form the tbutyl peroxide and alcohol-containing oxidation products, respectively. In addition, the oxidation is diastereoselective, with only single isomers of the cage assemblies formed, despite the presence of as many as 10 stereocenters in the final product. The self-assembled structures exploit self-complementary hydrogen bonding and geometrical constraints to direct the postassembly reactions to outcomes not observed in free solution. This selectivity is reminiscent of the fine control of post-translational modification seen in biomacromolecules.
- Holloway, Lauren R.,Bogie, Paul M.,Lyon, Yana,Julian, Ryan R.,Hooley, Richard J.
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supporting information
p. 11435 - 11442
(2017/09/25)
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- Tetraguanidino-functionalized phenazine and fluorene dyes: Synthesis, optical properties and metal coordination
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In this work the first phenazine derivatives with guanidino substituents were prepared and their structural and electronic properties studied in detail. The guanidino groups decrease the HOMO-LUMO gap, massively increase the quantum yield for fluorescence and offer sites for metal coordination. The yellow-orange colored 2,3,7,8-tetraguanidino-substituted phenazine shows intense fluorescence. The wavelength of the fluorescence signal is strongly solvent dependent, covering a region from 515 nm in Et2O solution (with a record quantum yield of 0.39 in Et2O) to 640 nm in water. 2,3-Bisguanidino-substituted phenazine is less fluorescent (maximum quantum yield of 0.17 in THF), but exhibits extremely large Stokes shifts. In contrast, guanidino-functionalized fluorenes emit only very weakly. Subsequently, the influence of coordination on the electronic properties and especially the fluorescence of the phenazine system was analysed. Coordination first takes place at the guanidino groups, and leads to a blue shift of the luminescence signal as well as a massive decrease of the luminescence lifetime. Luminescence is almost quenched completely upon CuI coordination. On the other hand, in the case of ZnII coordination the fluorescence signal remains strong (quantum yield of 0.36 in CH3CN). In the case of strong zinc Lewis acids, an excess of metal compound leads to additional coordination at the phenazine N atoms. This is accompanied by significant red-shifts of the lowest-energy transition in the absorption and fluorescence spectra. Pentanuclear complexes with two phenazine units were isolated and structurally characterized, and further aggregation leads to chain polymers. This journal is
- Bindewald, Elvira,Lorenz, Roxana,Hübner, Olaf,Brox, Dominik,Herten, Dirk-Peter,Kaifer, Elisabeth,Himmel, Hans-J?rg
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p. 3467 - 3485
(2015/03/05)
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- Variation of the backbone conjugation in NLO model compounds: Torsion-angle-restricted, biphenyl-based push-pull-systems
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Terminal piperidinyl- and nitro-functionalized biphenyls, bridged between the 2 and. 2′ positions by a variable number of methylene groups, are synthesized and fully characterized. These push-pull systems with defined and restricted torsion angles between their phenyl rings are ideal model compounds to investigate the influence of the chromophore's conjugation in nonlinear optic (NLO) responses, A general synthetic route that can be implemented to access these model compounds is reported, starting from dibromo or ditriflate biphenyls. Hartwig-Buchwald cross-coupling, a selective azacycloalkylation of diaminobiphenyls and a mild oxidation of primary amines to nitro groups in the presence of a tertiary amine summarizes the synthetic pathway towards the desired model compounds. NLO properties of the series of torsionally constrained push-pull biphenyls are collected by electric-field-induced second-harmonic generation (EFISH) experiments. The results agree qualitatively with semi-empirical simulations based on the AM1 Hamiltonian. A. linear dependence of the quadratic response on the cos2(o) of the inter-aryl dihedral angle is observed, which points to oscillator strength loss as the dominant effect of increasing backbone twist
- Rotzler, Juergen,Vonlanthen, David,Barsella, Alberto,Boeglin, Alex,Fort, Alain,Mayor, Marcel
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experimental part
p. 1096 - 1110
(2010/04/27)
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- Functionalized Photoreactive Compounds
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The present invention concerns functionalized photoreactive compounds of formula (I), that are particularly useful in materials for the alignment of liquid crystals. Due to the adjunction of an electron withdrawing group to specific molecular systems bearing an unsaturation directly attached to two unsaturated ring systems, exceptionally high photosensitivities, excellent alignment properties as well as good mechanical robustness could be achieved in materials comprising said functionalized photoreactive compounds of the invention.
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- Synthesis, DNA affinity, and antiprotozoal activity of fused ring dicationic compounds and their prodrugs
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Dicationic guanidine, N-alkylguanidine, and reversed amidine derivatives of fused ring systems (9a-d, 12a-c, 13a, and 13b) have been synthesized from their corresponding bis-amines. DNA binding studies suggest that the diguanidines and the N-alkyl diguanidines fluorenes bind in the minor groove in a manner similar to that of the previously reported dicationic carbazole derivatives. The diguanidines and the N-alkyl diguanidines showed promising in vitro activity against both Trypanosoma brucei rhodesiense and Plasmodium falciparum. Promising in vivo biological results were obtained for the dicationic N-isopropylguanidino-9H-fluorene (12c), giving 4/4 cures of the treated animals in the STIB900 animal model for African trypanosomiasis. The N-methyl analogue (12a) showed high activity as well. In addition, with the goal of enhancing the oral bioavailability, two novel classes of potential guanidine prodrugs were prepared. The N-alkoxyguanidine derivatives (12d) and (12e) were not effective as prodrugs. In contrast, a number of the carbamates (11a,c-e) showed promising activity. The value of the carbamate prodrugs was clearly demonstrated by the results for (11c), which gave 4/4 cures on oral administration in the STIB900 mouse model.
- Arafa, Reem K.,Brun, Reto,Wenzler, Tanja,Tanious, Farial A.,Wilson, W. David,Stephens, Chad E.,Boykin, David W.
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p. 5480 - 5488
(2007/10/03)
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- Reduction of nitroaromatics by non-metal hydrazinolysis
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High temperature (160°C) can substitute for a metal catalyst in achieving the complete reduction of nitroaromatic compounds to corresponding amines by hydrazine.
- Abdel-Baky,Zhuang,Giese
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p. 161 - 165
(2007/10/02)
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