- Ruthenium-catalyzed intramolecular arene C(sp2)-H amidation for synthesis of 3,4-dihydroquinolin-2(1 H)-ones
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We report the [Ru(p-cymene)(l-proline)Cl] ([Ru1])-catalyzed cyclization of 1,4,2-dioxazol-5-ones to form dihydroquinoline-2-ones in excellent yields with excellent regioselectivity via a formal intramolecular arene C(sp2)-H amidation. The reactions of the 2- and 4-substituted aryl dioxazolones proceeds initially through spirolactamization via electrophilic amidation at the arene site, which is para or ortho to the substituent. A Hammett correlation study showed that the spirolactamization is likely to occur by electrophilic nitrenoid attack at the arene, which is characterized by a negative ρ value of -0.73.
- Au, Chi-Ming,Ling, Cho-Hon,Sun, Wenlong,Yu, Wing-Yiu
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p. 3310 - 3314
(2021/05/29)
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- Towards practical earth abundant reduction catalysis: Design of improved catalysts for manganese catalysed hydrogenation
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Manganese catalysts derived from tridentate P,N,N ligands can be activated easily using weak bases for both ketone and ester hydrogenations. Kinetic studies indicate the ketone hydrogenations are 0th order in acetophenone, positive order in hydrogen and 1st order in the catalyst. This implies that the rate determining step of the reaction was the activation of hydrogen. New ligand systems with varying donor strength were studied and it was possible to make the hydrogen activation significantly more efficient; a catalyst displaying around a 3-fold increase in initial turn-over frequencies for the hydrogenation of acetophenone relative to the parent system was discovered as a result of these kinetic investigations. Ester hydrogenations and ketone transfer hydrogenation (isopropanol as reductant) are first order for both the substrate and catalysts. Kinetic studies also gained insight into catalyst stability and identified a working range in which the catalyst is stable throughout the catalytic reaction (and a larger working range where high yields can still be achieved). The new more active catalyst, combining an electron-rich phosphine with an electron-rich pyridine is capable of hydrogenating acetophenone using as little as 0.01 mol% catalyst at 65 °C. In all, protocols for reduction of 21 ketones and 15 esters are described.
- Widegren, Magnus B.,Clarke, Matthew L.
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p. 6047 - 6058
(2019/11/14)
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- Catalytic activation of unstrained C(aryl)–C(aryl) bonds in 2,2′-biphenols
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Transition metal catalysis has emerged as an important means for C–C activation that allows mild and selective transformations. However, the current scope of C–C bonds that can be activated is primarily restricted to either highly strained systems or more polarized C–C bonds. In contrast, the catalytic activation of non-polar and unstrained C–C moieties remains an unmet challenge. Here we report a general approach for the catalytic activation of the unstrained C(aryl)–C(aryl) bonds in 2,2′-biphenols. The key is to utilize the phenol moiety as a handle to install phosphinites as a recyclable directing group. Using hydrogen gas as the reductant, monophenols are obtained with a low catalyst loading and high functional group tolerance. This approach is also applied to the synthesis of 2,3,4-trisubstituted phenols. A further mechanistic study suggests that the C–C activation step is mediated by a rhodium(i) monohydride species. Finally, a preliminary study on breaking the inert biphenolic moieties in lignin models is illustrated.
- Zhu, Jun,Wang, Jianchun,Dong, Guangbin
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- Transfer Hydrogenation of Alkenes Using Ethanol Catalyzed by a NCP Pincer Iridium Complex: Scope and Mechanism
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The first general catalytic approach to effecting transfer hydrogenation (TH) of unactivated alkenes using ethanol as the hydrogen source is described. A new NCP-type pincer iridium complex (BQ-NCOP)IrHCl containing a rigid benzoquinoline backbone has been developed for efficient, mild TH of unactivated C-C multiple bonds with ethanol, forming ethyl acetate as the sole byproduct. A wide variety of alkenes, including multisubstituted alkyl alkenes, aryl alkenes, and heteroatom-substituted alkenes, as well as O- or N-containing heteroarenes and internal alkynes, are suitable substrates. Importantly, the (BQ-NCOP)Ir/EtOH system exhibits high chemoselectivity for alkene hydrogenation in the presence of reactive functional groups, such as ketones and carboxylic acids. Furthermore, the reaction with C2D5OD provides a convenient route to deuterium-labeled compounds. Detailed kinetic and mechanistic studies have revealed that monosubstituted alkenes (e.g., 1-octene, styrene) and multisubstituted alkenes (e.g., cyclooctene (COE)) exhibit fundamental mechanistic difference. The OH group of ethanol displays a normal kinetic isotope effect (KIE) in the reaction of styrene, but a substantial inverse KIE in the case of COE. The catalysis of styrene or 1-octene with relatively strong binding affinity to the Ir(I) center has (BQ-NCOP)IrI(alkene) adduct as an off-cycle catalyst resting state, and the rate law shows a positive order in EtOH, inverse first-order in styrene, and first-order in the catalyst. In contrast, the catalysis of COE has an off-cycle catalyst resting state of (BQ-NCOP)IrIII(H)[O(Et)···HO(Et)···HOEt] that features a six-membered iridacycle consisting of two hydrogen-bonds between one EtO ligand and two EtOH molecules, one of which is coordinated to the Ir(III) center. The rate law shows a negative order in EtOH, zeroth-order in COE, and first-order in the catalyst. The observed inverse KIE corresponds to an inverse equilibrium isotope effect for the pre-equilibrium formation of (BQ-NCOP)IrIII(H)(OEt) from the catalyst resting state via ethanol dissociation. Regardless of the substrate, ethanol dehydrogenation is the slow segment of the catalytic cycle, while alkene hydrogenation occurs readily following the rate-determining step, that is, β-hydride elimination of (BQ-NCOP)Ir(H)(OEt) to form (BQ-NCOP)Ir(H)2 and acetaldehyde. The latter is effectively converted to innocent ethyl acetate under the catalytic conditions, thus avoiding the catalyst poisoning via iridium-mediated decarbonylation of acetaldehyde.
- Wang, Yulei,Huang, Zhidao,Leng, Xuebing,Zhu, Huping,Liu, Guixia,Huang, Zheng
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supporting information
p. 4417 - 4429
(2018/04/05)
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- Synthesis of the furo[2,3-b]chromene ring system of hyperaspindols a and B
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The synthesis of the unique furo[2,3-b]chromene ring system found in hyperaspidinols A and B, acylphloroglucinols from Hypericum chinense has been achieved in twelve steps. By comparison of the NMR spectra of the synthesized compounds with those of the natural products, a relative stereochemistry is suggested, especially that of the ketal carbon.
- Paterson, Danielle L.,Barker, David
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p. 265 - 270
(2015/04/14)
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- β-D-2′-C-methyl-2,6-diaminopurine ribonucleoside phosphoramidates are potent and selective inhibitors of hepatitis C virus (HCV) and are bioconverted intracellularly to bioactive 2,6-diaminopurine and guanosine 5′-triphosphate forms
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The conversion of selected β-d-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2′-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2′-C-Me-DAPN-TP and 2′-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2′-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 μM. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.
- Zhou, Longhu,Zhang, Hong-Wang,Tao, Sijia,Bassit, Leda,Whitaker, Tony,Mcbrayer, Tamara R.,Ehteshami, Maryam,Amiralaei, Sheida,Pradere, Ugo,Cho, Jong Hyun,Amblard, Franck,Bobeck, Drew,Detorio, Mervi,Coats, Steven J.,Schinazi, Raymond F.
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p. 3445 - 3458
(2015/05/05)
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- Ortho-dearomatization of phenols creating all-carbon spiro-bicycles
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A range of alkene-linked phenols are generally and reliably dearomatized specifically at their ortho-positions to create all-carbon quaternary stereogenic centers at the corresponding spiro-ring junctions, thus establishing a viable solution to the long-standing synthetic challenge.
- Zheng, Chao,Wang, Lu,Li, Jingjie,Wang, Leifeng,Wang, David Zhigang
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p. 4046 - 4049
(2013/09/12)
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- PURINE MONOPHOSPHATE PRODRUGS FOR TREATMENT OF VIRAL INFECTIONS
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The present invention is directed to compounds, compositions and methods for treating or preventing viral infections using nucleoside analog monophosphate prodrugs. More specifically, HCV, Norovirus, Saporovirus, Dengue virus, Chikungunya virus and Yellow fever in human patients or other animal hosts. The compounds are certain 2,6-diamino 2-C-methyl purine nucleoside monophosphate prodrugs and modified prodrug analogs, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof. In particular, the compounds show potent antiviral activity against HCV, Norovirus, Saporovirus, Dengue virus, Chikungunya virus and Yellow fever. This invention teaches how to modify the metabolic pathway of 2,6-diamino 2'-C-methyl purine and deliver nucleotide triphosphate(s) to polymerases at heretofore unobtainable therapeutically-relevant concentrations.
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Page/Page column 54-55
(2012/12/13)
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- Enantioselective synthesis of functionalized 1-benzoxepines by phenoxide ion mediated 7-endo-tet carbocyclization of cyclic sulfates
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A new asymmetric synthesis of 2,3-disubstituted 1-benzoxepines is described. Key steps include Sharpless asymmetric dihydroxylation of trans-α,β-unsaturated esters and phenoxide ion mediated intramolecular 7-endo-tet carbocyclization of syn-2,3-dihydroxy ester derived cyclic sulfates. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.
- Das, Sajal Kumar,Dinda, Subal Kumar,Panda, Gautam
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scheme or table
p. 204 - 207
(2009/06/21)
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- Co-catalyzed mild and chemoselective reduction of phenyl esters with NaBH4: a practical synthesis of (R)-tolterodine
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CoCl2 catalyzes effectively the chemoselective reduction of phenyl carboxylic esters to the corresponding saturated alcohols in high yields using NaBH4 at ambient conditions. By employing this methodology, the synthesis of (R)-tolterodine, a muscarinic receptor antagonist, has been achieved in high yield and optical purity.
- Jagdale, Arun R.,Sudalai, Arumugam
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p. 3790 - 3793
(2008/09/21)
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- POLYCYCLIC ACID COMPOUNDS USEFUL AS CRTH2 ANTAGONISTS AND ANTIALLERGIC AGENTS
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The present invention relates to a novel compound or a salt thereof, which is useful as a CRTH2 antagonist, especially as a medicament for disorder that participates eosinophil, for example, allergic disorder such as asthma, allergic rhinitis, allergic dermatitis, conjunctival inflammation, hives, eosinophilic bronchitis, food allergy, inflammation of the nasal sinuses, multiple sclerosis, angiitis, or chronic obstructive pulmonary disease (COPD) and the like.
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Page/Page column 110
(2008/12/06)
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- Second Generation of cycloSal-Pronucleotides with Esterase-Cleavable Sites: The "Lock-In"-Concept
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A conceptual extension of the cycloSal-pronucleotide approach is presented. The characteristic feature of the new cycloSal-derivatives of the anti-HIV active nucleoside analogue d4T 1 is the incorporation of an enzymatically cleavable carboxylic ester moiety with the intention to trap the triesters inside cells ("lock-in"-concept). CycloSal-triesters bearing different ester groups in the 3-or 5-position of the cycloSal-moiety are described. Surprisingly, only acetyl-and levulinyl esters are cleaved readily in CEM cell extracts while alkyl esters were found to be stable. Nevertheless, in in-vitro anti-HIV assays most of the compounds achieve the thymidine-kinase bypass, thus proving that they act at least as nucleotide delivery systems.
- Meier, Chris,Ruppel, Manuel F. H.,Vukadinovic, Dalibor,Balzarini, Jan
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- Leukotriene antagonists for use in the treatment or prevention of alzheimer's disease
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This invention provides methods for the treatment or prevention of Alzheimer's disease which comprises administering to a mammal in need thereof an effective amount of a compound having activity as a leukotriene antagonist.
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- Homologation d'hydroxymethyl anthraquinones
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2-Hydroxymethyl anthraquinones (Aq-CH2OH) bearing at least one phenolic group in the ortho position (C-1) afford in presence of triethyl orthoacetate and of a catalytic amount of p-toluenesulfonic acid, homologous esters of type Aq-CH2-CH2COOEt. 2-Hydroxy benzyl alcohol behaves similarly while 4-hydroxy benzyl alcohol gives only the corresponding benzyl ether.In situ, formation of both a protonated quinone methide from Aq-CH2OH and of diethoxy-1,1 ethene from triethyl orthoacetate followed by concerted or step-wise condensation accounts for the formation of the observed esters Aq-CH2-CH2COOEt.
- Gesson, Jean-Pierre,Renoux, Brigitte
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p. 901 - 904
(2007/10/02)
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- Effet de groupe partant dans l'hydrolyse d'orthoesters cycliques: changement de conformere reactif dans l'hydrolyse des diethoxy-2,2 tetrahydropyrannes
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The rates of hydrolysis of 6-substituted 2,2-diethoxy-3,4-dihydrobenzo-1-pyrans (X=MeO, Me, H, Cl) were determined at two temperatures in water/dioxan 2:1 by volume.The observed change of sign of the Hammett ρ constants (ρH3O+=-0.8; ρAH=0.7) is characteristic of a phenolate leaving group, i.e. of the rate-determining cleavage of the endocyclic C-O bond in the systems here studied; these results cleary indicate a change in the nature of the reactive conformer in hydrolysis of 2,2-diethoxy tetrahydropyrans.
- Lamaty, Gerard,Lorente, Philippe,Moreau, Claude
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p. 2651 - 2656
(2007/10/02)
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- Synthesis of 7,8,9,10,11,12,20,21,22,23,24,25-Dodecahydrodibenzotetraoxacyclodocosin, a Crown Ether
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A number of symmetrical diesters and an unsymmetrical type have been synthesised from pyrocatechol.Under conditions in which intramolecular acyloin formation was anticipated the product from one symmetrical compound, ethyl 4-(o-ethoxycarbonylpropoxyphenoxy)butyrate, was a cyclic bis-β-keto-ester resulting in reasonable yield from intermolecular Dieckmann cyclisation.Hydrolysis to the 9,22 diketone, and its reduction to 7,8,9,10,11,12,20,21,22,23,24,25-dodecahydrodibenzotetraoxacyclodocosin 'dibenzo-22-crown-4', proceeded smoothly.An unsymmetrical intermediate, methyl 4-(o-ethoxycarbonylmethoxypropylphenoxy)butyrate, was prepared for similar cyclisation and in preliminary experiments appeared to give acyloin and β-keto-ester products.The method represents a different approach to crown ether systems of certain types.
- Tyman, John H. P.,Grundy, Jesse,Brown, George R.
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p. 336 - 343
(2007/10/02)
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