- Iron-Catalyzed Synthesis of C2 Aryl- and N-Heteroaryl-Substituted Tetrahydropyrans
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An iron-catalyzed cyclization of hydroxy allylic derivatives into tetrahydropyrans possessing an N-heteroaryl at C2 is disclosed. The reaction proceeds with good yield and in high diastereoselectivity in favor of the more stable isomer. The diastereoselectivity results from an iron-induced reopening of the tetrahydropyrans, allowing a thermodynamic equilibration. The method allows access to a variety of 2,6-disubstituted as well as 2,4,6-trisubstituted tetrahydropyrans that could be considered as attractive scaffolds for the pharmaceutical industry.
- Bosset, Cyril,Angibaud, Patrick,Stanfield, Ian,Meerpoel, Lieven,Berthelot, Didier,Guérinot, Amandine,Cossy, Janine
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- Rh(II)-Catalyzed Monocyclopropanation of Pyrroles and Its Application to the Synthesis Pharmaceutically Relevant Compounds
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Here we report Rh(II)-catalyzed monocyclopropanation reactions on pyrroles in the presence of aryldiazoacetates, providing the corresponding dearomatized products with high levels of enantioselectivity (up to >99% ee). Under the catalysis of Rh2/sub
- Fu, Jiantao,Wurzer, Nikolai,Lehner, Verena,Reiser, Oliver,Davies, Huw M. L.
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- Gold catalysis: Phenol synthesis in the presence of functional groups
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The effect of different substituants, such as bromo, chloromethyl, hydroxymethyl, formyl, acetyl, carboxy, and acylated hydroxymethyl and ammonium groups, on the furan ring of substrates in gold-catalyzed phenol synthesis has been investigated. The furan
- Hashmi, A. Stephen K.,Weyrauch, Jan P.,Kurpejovic, Elzen,Frost, Tanja M.,Miehlich, Burkhard,Frey, Wolfgang,Bats, Jan W.
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- Integration of oxidative arylation with sulfonyl migration: One-pot tandem synthesis of densely functionalized (NH)-pyrroles
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A one-pot synthesis of 2-aryl-3-alkyl/aryl-sulfonyl-(NH)-pyrroles from N-sulfonylpyrroles, developed for the first time, via palladium-catalyzed oxidative C-2 arylation followed by sulfonyl migration is described. The simple, easy access to the highly functionalized free-NH pyrroles secures opportunities for the preparation of compounds with promising biological activities in contemporary organic synthesis. The event of sulfonyl migration from pyrrole-N to C-3 is thermodynamically favored as revealed by density functional methods. The different plausible mechanisms for the migration of the sulfonyl group are also discussed.
- Laha, Joydev K.,Sharma, Shubhra,Bhimpuria, Rohan A.,Dayal, Neetu,Dubey, Gurudutt,Bharatam, Prasad V.
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- Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors
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The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.
- Zhang, Jing,Yang, Qingyi,Cross, Jason B.,Romero, Jan Antoinette C.,Poutsiaka, Katherine M.,Epie, Felix,Bevan, Douglas,Wang, Bin,Zhang, Yanzhi,Chavan, Ajit,Zhang, Xin,Moy, Terence,Daniel, Anu,Nguyen, Kien,Chamberlain, Brian,Carter, Nicole,Shotwell, Joseph,Silverman, Jared,Metcalf, Chester A.,Ryan, Dominic,Lippa, Blaise,Dolle, Roland E.
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- 2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors: Design, synthesis and structure-activity relationship study
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Glycogen phosphorylase (GP), which plays a crucial role in the conversion of glycogen to glucose-1-phosphate, is a target for therapeutic intervention in diabetes. In this study, we report the design and synthesis of 29 new derivatives of 2-oxo-1,2-dihydro pyridin-3-yl amides, as potential inhibitors of GP. The hit rate (45%) was high with 13 compounds inhibiting GPa (between 33% at 4.40 mM and an IC50 of 1.92 μM). Two lead compounds were identified as compounds exhibiting good GPa inhibition (IC50 = 2.1 and 1.92 μM). SAR analysis of these compounds revealed sensitivity of GPa to the length of the 2-oxo-1,2-dihydro pyridin-3-yl amide derivative and a preference for inclusion of a 3,4-dichlorobenzyl moiety.
- Loughlin, Wendy A.,Jenkins, Ian D.,Karis, N. David,Schweiker, Stephanie S.,Healy, Peter C.
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- Pd-catalyzed allylative dearomatisation using Grignard reagents
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Pd-catalyzed allylative dearomatisation of naphthyl halides is shown to be feasible by employing Grignard reagents. The high reactivity of the nucleophile allows for fast reactions and low catalyst loading, while a plethora of successfully substituted compounds illustrate the broad scope. Five membered heteroaromatic compounds are also demonstrated to be reactive under similar conditions.
- Boldrini, Cosimo,Harutyunyan, Syuzanna R.
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supporting information
p. 11807 - 11810
(2021/11/30)
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- Dipyrromethene-Triazolylidene Silver Complexes: Synthesis, Structure and Opportunities
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The synthesis and characterization of unusual silver triazolylidene-containing dipyrromethene complexes are described. The carbene TAD-N3C-H obtained from its parent Triazole-Appended Dipyrromethene (TAD-N4) is an excellent ligand fo
- Rago, Aurélie,Guérin, Charles,Framery, Eric,Jean-Gérard, Ludivine,Comby-Zerbino, Clothilde,Dugourd, Philippe,Andrioletti, Bruno
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supporting information
p. 4409 - 4414
(2020/10/02)
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- Serendipitous base catalysed condensation-heteroannulation of iminoesters: a regioselective route to the synthesis of 4,6-disubstituted 5-azaindoles
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A serendipitous discovery of a novel one-pot synthesis of 4,6-disubstituted 5-azaindoles is reported herein. In the presence of Hunig's base, various N-substituted pyrrole-2-carboxaldehydes have been efficiently transformed into their corresponding 4,6-disubstituted 5-azaindoles through an imine mediated cascade condensation-heteroannulation. The synthetic value of the methodology is established by preparing a novel chemical analogue of a cannabinoid receptor type 2 (CB2) agonist.
- Chelvam, Venkatesh,Dudhe, Premansh,Pathak, Biswarup,Venkatasubbaiah, Krishnan
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supporting information
p. 1582 - 1587
(2020/03/06)
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- Ru-Catalyzed Carbonylative Murai Reaction: Directed C3-Acylation of Biomass-Derived 2-Formyl Heteroaromatics
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The Murai reaction is a ruthenium-catalyzed transformation leading to alkylated arenes through the C?C bond formation between an alkene and an arene bearing a directing group. Discovered in the nineties, this useful C?H activation based coupling has been the object of intense study since its discovery. After having studied the Murai reaction on 2-formylfurans of biomass derivation, we describe here the carbonylative version applied to 2-formylfurans, 2-formylpyrrols and 2-formylthiophenes. This acylation reaction takes place regioselectively at C3 position of the heterocyclopentadienes thanks to the installation of removable imine directing groups. The transformation can be achieved by treating the two reaction partners with a catalytic amount of Ru3(CO)12, in toluene at 120–150 °C, after CO bubbling, at atmospheric pressure. DFT computations of the full catalytic cycle help in deciphering the mechanism of this transformation, and to rationalize the different behaviors depending on the nature of imine directing groups. (Figure presented.).
- Sala, Roberto,Roudesly, Fares,Veiros, Luis F.,Broggini, Gianluigi,Oble, Julie,Poli, Giovanni
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supporting information
p. 2486 - 2493
(2020/05/06)
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- Proton-exchanged montmorillonite-mediated reactions of hetero-benzyl acetates: Application to the synthesis of Zafirlukast
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Proton-exchanged montmorillonite (H-mont) with outstanding surface characteristics can provide abundant acidic sites in the mesopores, and serve as an efficient heterogeneous catalyst for the synthesis of heterocycle-containing diarylmethanes via Friedel-Crafts-like alkylation of (hetero)arenes by heterobenzyl acetates under mild reaction conditions without requiring any additives or an inert atmosphere. Using this strategy, the gram-scale synthesis of indole-containing diarylmethane 13 has been accomplished in good yield for the preparation of Zafirlukast. In addition, H-mont can be applied to the nucleophilic substitution reactions of heterobenzyl acetate 5p with a variety of alcohols and 1,3-dicarbonyl compounds.
- Yang, Lei,Chen, Xuan,Ni, Kaidong,Li, Yuansheng,Wu, Jianhong,Chen, Weilin,Ji, Yin,Feng, Lili,Li, Fei,Chen, Dongyin
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supporting information
(2020/06/28)
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- Arene Trifunctionalization with Highly Fused Ring Systems through a Domino Aryne Nucleophilic and Diels–Alder Cascade
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A convenient and efficient domino aryne process was developed under transition-metal-free conditions to generate a range of tetra- and pentacyclic ring systems. This transformation was realized via a 1,2-benzdiyne through a nucleophilic and Diels–Alder reaction cascade using styrene as the diene moiety. Three new chemical bonds, namely one C?N and two C?C bonds, and two benzofused rings could be constructed concomitantly, which was made possible by distinct chemoselective control at both the 1,2-aryne and 2,3-aryne stages. Moreover, in-depth studies were carried out on the domino aryne precursors and controlling the diastereoselectivity.
- He, Jia,Jia, Zizi,Tan, Hongcheng,Luo, Xiaohua,Qiu, Dachuan,Shi, Jiarong,Xu, Hai,Li, Yang
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supporting information
p. 18513 - 18518
(2019/11/19)
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- Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1
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Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.
- Trilles, Richard,Beglov, Dmitri,Chen, Qiujia,He, Hongzhen,Wireman, Randall,Reed, April,Chennamadhavuni, Spandan,Panek, James S.,Brown, Lauren E.,Vajda, Sandor,Porco, John A.,Kelley, Mark R.,Georgiadis, Millie M.
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p. 1971 - 1988
(2019/02/19)
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- Syntheses of Polycyclic Tetrahydrofurans by Cascade Reactions Consisting of Five-Membered Ring Selective Prins Cyclization and Friedel-Crafts Cyclization
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A novel cascade reaction consisting of a five-membered ring selective Prins cyclization and a subsequent Friedel-Crafts cyclization is reported. Treatment of homocinnamyl alcohols and aromatic aldehydes with BF3·OEt2 in CH2/sub
- Sakata, Yuki,Yasui, Eiko,Takatori, Kazuhiko,Suzuki, Yuji,Mizukami, Megumi,Nagumo, Shinji
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p. 9103 - 9118
(2018/07/21)
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- Intramolecular Didehydro-Diels-Alder Reaction for the Synthesis of Benzo- and Dihydrobenzo-Fused Heterocycles
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Using an intramolecular didehydro-Diels-Alder reaction, ene-yne substituted pyrroles, thiophenes, and furans afford functionalized indoles, benzothiophenes, and benzofurans and the corresponding dihydroaromatic products. Product selectivity for the aromatic or dihydroaromatic product is controlled by the reaction conditions, which vary depending upon the substrate.
- Bober, Ashley E.,Proto, Justin T.,Brummond, Kay M.
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supporting information
p. 1500 - 1503
(2017/04/13)
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- Aromatic-ring azacyclo derivatives and application thereof
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Aromatic-ring azacyclo derivatives and an application thereof are provided. The invention relates to compounds represented by the formula (V), and a preparation method and an application thereof in medicines. In particular, the invention relates to derivatives of the compounds represented by the general formula (V), and a preparation method and the application thereof as therapeutic agents in prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, type-II diabetes, hyperglycemia, obesity or insulin resistance syndromes and metabolic syndromes. The compounds disclosed by the invention also can reduce total cholesterol, LDL-cholesterol and triglycerides, increase the expression of hepatic LDL receptors and inhibit the expression of PCSK9.
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Paragraph 0555; 0556; 0557
(2016/10/09)
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- NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF BACTERIAL INFECTIOUS DISEASES
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Compounds are disclosed that have a formula represented by the following: wherein A, B, R1, R2 and R3 are as defined herein. Novel compounds of the invention may be prepared as a pharmaceutical composition, and may be useful in the treatment of infectious diseases, in particular bacterial infectious diseases. The compounds may be active against a specific enzyme in the bacterial DNA replicative process, DNA polymerase IIIE.
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Paragraph 0258-0259
(2016/10/31)
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- Palladium-catalyzed regioselective allylation of five-membered heteroarenes with allyltributylstannane
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Palladium-catalyzed allylation reactions of 2-(chloromethyl)thiophenes, 2-(chloromethyl)furans, and N-protected 2-(chloromethyl)-1H-pyrroles with allyltributylstannane were described in this study. This type of allylation reaction regioselectively occurred on the heteroarene rings to produce allylated dearomatization products or allylated heteroarenes with satisfactory yields.
- Zhang, Sheng,Yu, Xiaoqiang,Feng, Xiujuan,Yamamoto, Yoshinori,Bao, Ming
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supporting information
p. 3842 - 3845
(2015/03/30)
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- Short and efficient synthesis of fluorinated δ-lactams
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The diastereoselective synthesis of fluorinated δ-lactams has been achieved through an efficient five step process. The route can tolerate a range of functionalities, and provides a quick route for the generation of new fluorinated medicinal building blocks.
- Cogswell, Thomas J.,Donald, Craig S.,Long, De-Liang,Marquez, Rodolfo
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p. 717 - 728
(2015/02/19)
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- Silver Tetrafluoroborate-Catalyzed Oxa-Diels-Alder Reaction between Electrically Neutral Dienes and Aldehydes
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Chemoselective oxa-Diels-Alder reactions between electrically neutral 1,3-dienes and various aldehydes were achieved using the commercially available silver tetrafluoroborate (AgBF4) as catalyst. This catalytic process has high functional group tolerance. Heteroatoms at the β-position of the aryl aldehydes can greatly promote the reactivity of the substrates even with heterocyclic aldehydes that were previously believed to be unreactive for the oxa-Diels-Alder reaction. In addition, acroleins with β-heteroatom substitution are also good substrates. High chemoselectivity and regioselectivity were achieved at room temperature for the oxa-Diels-Alder reaction between acroleins and stoichiometric simple 1,3-dienes.
- Zou, Xiaodong,Yang, Lizheng,Liu, Xiangli,Sun, Hao,Lu, Hongjian
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supporting information
p. 3040 - 3046
(2015/11/03)
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- BRANIMYCIN DERIVATIVES AND THEIR USE FOR THE TREATMENT OF BACTERIAL INFECTIOUS DISEASES
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A compound is disclosed that has a formula represented by Formula (I). The novel compound of the invention may be prepared as a pharmaceutical composition, and may be useful in the treatment of infectious diseases, in particular bacterial infectious disea
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Paragraph 00136
(2015/03/16)
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- BRANIMYCIN DERIVATIVES AND THEIR USE FOR THE TREATMENT OF BACTERIAL INFECTIOUS DISEASES
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Compounds are disclosed that have a formula represented by Formula (I) wherein A, B, R1, R2 and R3 are as defined herein. Novel compounds of the invention may be prepared as a pharmaceutical composition, and may be useful in the treatment of infectious diseases, in particular bacterial infectious diseases. The compounds may be active against a specific enzyme in the bacterial DNA replicative process, DNA polymerase IIIE.
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Paragraph 00185
(2015/03/16)
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- Substituted 2,2′-bipyrroles and pyrrolylfurans via intermediate isoxazolylpyrroles
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We describe a new synthesis of the 3-chloro-(4′-methoxy)-2,2′- pyrrolylfuran segment (3) of (+)-roseophilin. The route exploits a isoxazoylpyrrole intermediate, wherein the isoxazole ring serves as a β-diketone equivalent and a directing group for palladium catalyzed chlorination of the attached pyrrole. Subsequent reduction of the N-O bond and acid promoted cyclization afford roseophilin segment 3b in five steps and 19% overall yield. This strategy was extended to the synthesis of 3-chloro-(4′-alkoxy)-2,2′-pyrrolylfurans (16a-c) and 4-alkoxy-2,2′-bipyrroles (20a-c), which are building blocks to synthesize bioactive prodiginine natural products and their congeners.
- Frederich, James H.,Matsui, Jennifer K.,Chang, Randy O.,Harran, Patrick G.
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supporting information
p. 2645 - 2647
(2013/06/26)
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- Synthesis of hydrodipyrrins tailored for reactivity at the 1- and 9-positions
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A collection of 33 hydrodipyrrins (9 targets, 21 intermediates, and 3 byproducts) has been prepared. The hydrodipyrrins (dihydrodipyrrins, tetrahydrodipyrrins, and hexahydrodipyrrins) contain a pyrrole ring and a geminal-dimethyl substituted 1-pyrroline (
- Kim, Han-Je,Dogutan, Dilek Kiper,Ptaszek, Marcin,Lindsey, Jonathan S.
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- Hydrazines and azides via the metal-catalyzed hydrohydrazination and hydroazidation of olefins
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The discovery, study, and implementation of the Co- and Mn-catalyzed hydrohydrazination and hydroazidation reactions of olefins are reported. These reactions are equivalent to direct hydroaminations of C-C double bonds with protected hydrazines or hydrazoic acid but are based on a different concept in which the H and the N atoms come from two different reagents, a silane and an oxidizing nitrogen source (azodicarboxylate or sulfonyl azide). The hydrohydrazination reaction using di-tert-butyl azodicarboxylate is characterized by its ease of use, large functional group tolerance, and broad scope, including mono-, di-, tri-, and tetrasubstituted olefins. Key to the development of the hydroazidation reaction was the use of sulfonyl azides as nitrogen sources and the activating effect of tert-butyl hydroperoxide. The reaction was found to be efficient for the functionalization of mono-, di-, and trisubstituted olefins, and only a few functional groups are not tolerated. The alkyl azides obtained are versatile intermediates and can be transformed to the free amines or triazoles without isolation of the azides. Preliminary mechanistic investigations suggest a rate-limiting hydrocobaltation of the alkene, followed by an amination reaction. Radical intermediates cannot be ruled out and may be involved.
- Waser, Jerome,Gaspar, Boris,Nambu, Hisanori,Carreira, Erick M.
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p. 11693 - 11712
(2007/10/03)
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- The reaction of N-magnesium derivatives of pyrroles with N- mesylchloromethylpyrroles: A synthesis of dipyrrylmethanes
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Attachment of an alkyl- or arylsulfonyl group at the nitrogen atom of a pyrrole reduces the aromaticity and electron availability of the system. This is confirmed by the structure of an N-tosylated chloromethylpyrrole determined by X-ray crystallography. In agreement, N-mesylated chloromethylpyrroles are handleable materials which react smoothly with N- magnesium derivatives of pyrroles to provide a novel route for synthesis of dipyrrylmethanes. Several examples of this synthesis are described, including the construction of molecules carrying deuterium at the interpyrrolic methylene group.
- Abell, Andrew D.,Nabbs, Brent K.,Battersby, Alan R.
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p. 8163 - 8169
(2007/10/03)
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- Rhodium-catalyzed hydroformylation of 2-vinyl- and 3-vinyl-1-tosylpyrroles as a convenient synthetic route to the corresponding 2-(1-tosylpyrrolyl)propanals and derivatives
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2-(1-Tosylpyrrolyl)propanals 2a-b were conveniently prepared (70% yield) via rhodium-catalyzed hydroformylation of the corresponding 2-vinyl- and 3-vinyl-1-tosylpyrroles 1a-b and successfully transformed into some new derivatives (50-90% yield).
- Settambolo, Roberta,Caiazzo, Aldo,Lazzaroni, Raffaello
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p. 4111 - 4120
(2007/10/03)
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- Synthesis of enantiomerically pure D- and L-(heteroaryl)alanines by asymmetric hydrogenation of (Z)-α-amino-α,β-didehydro esters
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Homogeneous asymmetric hydrogenation of a wide range of methyl and tert-butyl (Z)-2-(acylamino)-3-(heteroaryl)acrylates (see 1a-f and 2a-d, f, g, resp.) catalyzed by diphosphinerhodium catalysts was studied for the synthesis of enantiomerically pure 3-fur
- Masquelin,Broger,Muller,Schmid,Obrecht
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p. 1395 - 1411
(2007/10/02)
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- THE CHEMISTRY OF VICINAL TRICARBONYLS A TOTAL SYNTHESIS OF PRODIGIOSIN
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The addition of primary amines to alkenyl vicinal tricarbonyls leads to 5-substituted-3-hydroxypyrroles.This reaction has been employed in a synthesis of the 2-formyl-3-methoxy-α,α'-bipyrrole precursor of the prodigiosin family of natural products.
- Wasserman, Harry H.,Lombardo, Louis J.
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p. 1725 - 1728
(2007/10/02)
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- Photochemical Transformations, 65. The 3? -> 3?-Route to 1H-Azepines/Benzene Imines
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With several newly prepared substrates the influence of substituents upon the individual steps in the 3? -> 3?-route to 1H-azepines is more precisely defined: The C-unsubstituted 7-azanorbornadiene 2a, its 2,3-dichloro derivative 2b, the dimethyl 5,6-dichloro-2,3-dicarboxylate 2c, and the diesters 2d, e with dipolarophilic groups at C-1/N-7 are selectively isomerized by sensitized/direct photoexcitation into the azaquadricyclanes 29a-e, some of which are highly unstable.For the thermal conversion of the basic skeleton (N-Tos)29a the kinetic parameters have been determined (benzene): Ea = 28.0 +/- 0.2 kcal/mol, lg A = 15.7; ΔH* = 27.3 +/- 0.2 kcal/mol, ΔS* = 11.1 +/- 0.7 e.u.This barrier is lowered more efficiently by the chloro (29b, c) than by the methoxycarbonyl substituents (29f), with the former (latter) causing exclusive scission of the opposite (neighbouring) cyclopropane bonds.The intermediate azomethine ylides are captured with dipolarophilic reagents more or less efficiently depending on their substitution pattern.In the case of 29d(28d) the intramolecular addition of the unactivated yne component (37) at -30C is so fast, that azepine formation is almost totally suppressed (?2 + ?2 + Σ2>, 36?).The azepine/benzene imine equilibrium mixture 31c 32c (ca. 90:10) crystallizes as 31c (X-ray crystal structure analysis).
- Prinzbach, Horst,Bringmann, Horst,Fritz, Hans,Markert, Juergen,Knothe, Lothar,et al.
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p. 616 - 644
(2007/10/02)
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