- Enantio- and Diastereoselective, Complete Hydrogenation of Benzofurans by Cascade Catalysis
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We report an enantio- and diastereoselective, complete hydrogenation of multiply substituted benzofurans in a one-pot cascade catalysis. The developed protocol facilitates the controlled installation of up to six new defined stereocenters and produces architecturally complex octahydrobenzofurans, prevalent in many bioactive molecules. A unique match of a chiral homogeneous ruthenium-N-heterocyclic carbene complex and an in situ activated rhodium catalyst from a complex precursor act in sequence to enable the presented process.
- Gallagher, Timothy,Glorius, Frank,Hu, Tianjiao,Moock, Daniel,Wagener, Tobias
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supporting information
p. 13677 - 13681
(2021/05/10)
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- Biocatalytic Strategy for Highly Diastereo- and Enantioselective Synthesis of 2,3-Dihydrobenzofuran-Based Tricyclic Scaffolds
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2,3-Dihydrobenzofurans are key pharmacophores in many natural and synthetic bioactive molecules. A biocatalytic strategy is reported here for the highly diastereo- and enantioselective construction of stereochemically rich 2,3-dihydrobenzofurans in high enantiopurity (>99.9% de and ee), high yields, and on a preparative scale via benzofuran cyclopropanation with engineered myoglobins. Computational and structure-reactivity studies provide insights into the mechanism of this reaction, enabling the elaboration of a stereochemical model that can rationalize the high stereoselectivity of the biocatalyst. This information was leveraged to implement a highly stereoselective route to a drug molecule and a tricyclic scaffold featuring five stereogenic centers via a single-enzyme transformation. This work expands the biocatalytic toolbox for asymmetric C–C bond transformations and should prove useful for further development of metalloprotein catalysts for abiotic carbene transfer reactions.
- Vargas, David A.,Khade, Rahul L.,Zhang, Yong,Fasan, Rudi
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supporting information
p. 10148 - 10152
(2019/07/04)
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- Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
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Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
- Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
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supporting information
p. 8267 - 8276
(2017/06/27)
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- Palladium-Catalyzed Dearomatizing Difunctionalization of Indoles and Benzofurans
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A palladium-catalyzed dearomatizing difunctionalization of N-Boc-indoles and benzofurans to give tricyclic indolines and 2,3-dihydrobenzofurans with a fully substituted carbon center is described. Product formation occurs under mild conditions at room temperature with commercially available aryl boronic acids and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as a mild oxidant in good yields. 2-Carboxyalkyl-substituted indoles and benzofurans react under Pd-catalysis with aryl boronic acids and TEMPO through dearomatizing arylation/cyclization to the corresponding indolines and dihydrobenzofurans containing a lactone moiety bearing a fully substituted carbon center.
- Ramella, Vincenzo,He, Zhiheng,Daniliuc, Constantin G.,Studer, Armido
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supporting information
p. 2268 - 2273
(2016/05/19)
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- Visible light-induced monofluoromethylenation of heteroarenes with ethyl bromofluoroacetate
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Visible light-induced monofluoromethylenation of benzofurans and benzothiophenes with ethyl bromofluoroacetate was developed. This method provided a convenient access to novel α-fluoro-α-heteroarylesters under mild reaction conditions.
- Yu, Wei,Xu, Xiu-Hua,Qing, Feng-Ling
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supporting information
p. 6564 - 6567
(2016/08/09)
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- Zeolite-catalyzed synthesis of 2,3-unsubstituted benzo[b]furans via the intramolecular cyclization of 2-aryloxyacetaldehyde acetals
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An efficient and environmentally benign heterogeneous catalytic process for the synthesis of 2,3-unsubstituted benzo[b]furans has been established via the intramolecular cyclization of 2-aryloxyacetaldehyde acetals. By utilizing tin-exchanged H-β zeolite (Sn-β) as catalyst, a wide range of functionalized 2,3-unsubstituted benzo[b]furans could be prepared in good to excellent yields. The Sn-β zeolite catalyst also exhibited excellent shape selectivity on the cyclization of meta-substituted 2-aryloxyacetaldehyde acetals, and 6-substituted isomers were preferably formed up to 97% regio-selectivity. Moreover, Sn-β zeolite could be easily recovered and reused without any noticeable activity loss.
- Sun, Nan,Huang, Peng,Wang, Yifan,Mo, Weimin,Hu, Baoxiang,Shen, Zhenlu,Hu, Xinquan
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supporting information
p. 4835 - 4841
(2015/07/27)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 17
(2012/09/11)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 65
(2012/09/21)
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- PREPARATION OF BENZOFURANS AND USE THEREOF AS SYNTHETIC INTERMEDIATES
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The present invention provides several synthetic methods for preparing N-(2-butylbenzofuran-5-yl)-N-(methylsulfonyl)methanesulfonamide, a compound of formula (3), an intermediate in the preparation of Dronedarone. The present invention further provides a process for preparing Dronedarone, comprising the steps of converting 2-butyl-5-bis(methanesulfon)-amidobenzofuran of formula (3) to Dronedarone, wherein the 2-butyl-5-bis(methanesulfon)-amidobenzofuran of formula (3) is prepared by the processes of the present invention.
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Page/Page column 38
(2011/09/15)
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- Studies toward the discovery of the next generation of antidepressants. 3. Dual 5-HT1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines
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N-Aryloxylethylindolealkylamines (5) having dual 5-HT transporter and 5-HT1A affinity are described. These compounds represent truncated analogues of our previously reported piperidinyl derivatives (3). Compounds in this investigation were found to have more similar affinities and functional activities for the 5-HT1A receptor and 5-HT transporter. Though 5-HT1A antagonism is not consistently observed throughout series 5, several molecular features were found to be essential to obtain high and balanced activities. The proper placement of a heteroatom in the aryl ring and the length of the linkage used to tether the indole moiety had significant influence on 5-HT1A and 5-HT transporter affinities. Introduction of a halogen into the aryl ring usually lowered intrinsic activity and in some cases led to full 5-HT1A antagonists. Compounds 33 and 34 were observed to be full 5-HT1A antagonists with Ki values of approximately 30 nM for the 5-HT1A receptor and Ki values of 5 and 0.5 nM for the 5-HT transporter, respectively. Unfortunately, similar to our previous series (3), compounds in this report also had high affinity for the α1 receptor.
- Mewshaw, Richard E.,Zhou, Dahui,Zhou, Ping,Shi, Xiaojie,Hornby, Geoffrey,Spangler, Taylor,Scerni, Rosemary,Smith, Deborah,Schechter, Lee E.,Andree, Terrance H.
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p. 3823 - 3842
(2007/10/03)
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- ARYLPIPERAZINYL-CYCLOHEXYL INDOLE DERIVATIVES FOR THE TREATMENT OF DEPRESSION
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Compounds are provided which are useful for the treatment of serotonin-affected neurological disorders which comprise (I) wherein: Ra, R1, R2 and R3 are each, independently, hydrogen, or a substituent selected from halogen, CF3, alkyl, alkoxy, MeSO2, amino or aminocarbonyl (each optionally substituted by one or two groups selected from alkyl and benzyl) carboxy, or alkoxycarbonyl; or two adjacent of Ra and R1-4 together can form a 5-7 membered carbocyclic or heterocyclic ring which is optionally substituted by a substituent defined above; R4 is hydrogen, halogen, or alkyl; R5 is hydrogen, alkyl, arylalkyl, or aryl; R6 is hydrogen, halogen, CF3, CN, carbamide, alkoxy or benzyloxy; X1, X2 and X3 are each carbon or one of X1, X2 or X3 may be nitrogen; Y is CH or nitrogen; and Z is carbon or nitrogen; or pharmaceutically acceptable salts thereof.
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- NOVEL 1H-INDAZOLE COMPOUND
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The present invention provides a novel 1H-indazole compound having an excellent JNK inhibitory action. More specifically, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. Wherein R1 is a C6-C14 aromatic cyclic hydrocarbon group etc.; R2, R4 and R5 each independently represent a hydrogen atom, a halogen atom, a cyano group etc.; L is a single bond, or a C1-C6 alkylene group etc.; X is a single bond, or a group represented by -CO-NH- or -NH-CO-, etc.; and Y is a C3-C8 cycloalkyl group, a C6-C14 aromatic cyclic hydrocarbon group or a 5- to 14-membered aromatic heterocyclic group etc.
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- Design and Synthesis of a Fluoroindolocarbazole Series as Selective Topoisomerase I Active Agents. Discovery of Water-Soluble 3,9-Difluoro-12,13-dihydro-13-[6-amino-β-D-glucopyranosyll]-5H,13H-benzo[b] -thienyl[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (BMS-251873) with Curative Antitumor Activity against Prostate Carcinoma Xenograft Tumor Model
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A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
- Balasubramanian, Balu N.,St. Laurent, Denis R.,Saulnier, Mark G.,Long, Byron H.,Bachand, Carol,Beaulieu, Francis,Clarke, Wendy,Deshpande, Milind,Eummer, Jeffrey,Fairchild, Craig R.,Frennesson, David B.,Kramer, Robert,Lee, Frank Y.,Mahler, Mikael,Martel, Alain,Naidu, B. Narasimhulu,Rose, William C.,Russell, John,Ruediger, Edward,Solomon, Carola,Stoffan, Karen M.,Wong, Henry,Zimmermann, Kurt,Vyas, Dolatrai M.
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p. 1609 - 1612
(2007/10/03)
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- Bronchodilator and Antiulcer Phenoxypyrimidinones
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Series of 5-phenoxy-2(1H)-pyrimidinones, 5-phenoxy-4(3H)-pyrimidinones, and related compounds were prepared in a follow-up of a lead prepared as a potential cyclic nucleotide regulating agent.Compounds were evaluated for bronchodilator activity in histamine-challenged guinea pigs and for antiulcer activity in a cold-restraint, stressed rat ulcer model.Bronchodilator activity comparable to, or greater than, that of theophylline was found in both the 2(1H)- and 4(3H)-pyrimidinone series and was most prominent in analogues containing either an electron-withdrawing or -donating substituent in the para position of the phenoxy ring.Significant antiulcer activity was observed only in the 2(1H)-pyrimidinone series among three closely related analogues.One of these, 5-(m-methylphenoxy)-2(1H)-pyrimidinone (3), exhibited more potent antiulcer effects than the clinically useful antiulcer agent carbenoxolone, without demonstrating bronchodilator activity.
- Lipinski, C. A.,Stam, J. G.,Pereira, J. N.,Ackerman, N. R.,Hess, H.-J.
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p. 1026 - 1031
(2007/10/02)
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- 9-Thia- and oxothia- and 9-dioxothia-11,12-seco-prostaglandins and processes
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This invention relates to 9-thia-, 9-oxothia, and 9-dioxothia-11,12-seco-prostaglandins and processes for their manufacture. These compounds have prostaglandin-like biological activity and are particularly useful for the treatment of skin diseases such as psoriasis, for the prevention of Thrombus formation, in stimulating the production of growth hormone in intact animals, and as regulators of the immune response.
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- Substituted phenoxy-tridecanoic acids
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This invention relates to aryloxy-, and alkoxy-, arylthio-, and alkylthio-11,12-seco-prostaglandins and to processes for their manufacture. These compounds have prostaglandin-like activity and are particularly useful in fertility control such as for estru
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- Certain thiazolidine compounds
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This invention relates to novel 8-aza-9-oxo-11-thia-, -11-oxothia-, and -11-dioxothia-prostanoic acid compounds, salts, and derivatives thereof and also to processes for the preparation of such compounds. These compounds have prostaglandin-like biological activity and are particularly useful as renal vasodilators, for the treatment of certain autoimmune diseases, and in preventing thrombus formation.
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- Novel analogs of prostaglandins with 4-oxo-thiazolidinyl nucleus and method of preparation thereof
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This invention relates to novel 9-thia-, 9-oxothia-, and 9-dioxothia-11-oxo-12-azaprostanoic acid compounds, salts, and derivatives thereof and also to processes for the preparation of such compounds. These compounds have prostaglandin-like biological activity and are particularly useful as renal vasodilators, as platelet aggregation inhibitors, and for the treatment of certain autoimmune diseases.
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- 16-Ethers of 8-aza-9-dioxothia-11,12-seco-prostaglandins
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The invention is concerned with novel 16-aryloxy-, 16-alkoxy-, 16-arylthio- and 16-alkylthio-8-aza-9-dioxothia-11,12-seco-prostaglandins and processes for their preparation. These novel compounds are useful as pharmaceuticals since they can be used in ani
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