- Design and pharmacology of quinuclidine derivatives as M2-selective muscarinic receptor ligands
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In our search for M2-selective muscarinic receptor antagonists, we synthesized 1,3-disubstituted indenes. The effects of different basic moieties with regard to binding and selectivity towards the five distinct muscarinic receptor subtypes were investigated. The results show that the quinuclidine series afforded the most promising compounds in terms of both receptor affinity and M2-subtype selectivity.
- Boehme, Thomas M.,Keim, Christine,Dannhardt, Gerd,Mutschler, Ernst,Lambrecht, Guenter
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- Synthesis of 1-fluoroindan-1-carboxylic acid (FICA) and its properties as a chiral derivatizing agent
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1-Fluoroindan-1-carboxylic acid (FICA) (1) was designed and synthesized as its methyl ester (FICA Me ester) (4) in order to develop an efficient chiral derivatizing agent (CDA) which excels α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) in capability. FICA Me ester (4) was prepared by fluorination of methyl 1-hydroxyindan-1-carboxylate (3) with (diethylamino)sulfur trifluoride (DAST) and derived to the esters of racemic secondary alcohols by ester exchange reaction. The resulting ΔδF value was large in the case of 2-butyl ester of FICA (5a), whereas not detectable in the case of the corresponding MTPA ester (6a). The magnitude of the ΔδH values was similar to that of MTPA esters. The diastereomers of (R)-(-)-8-phenylmenthyl ester of FICA (5i) was separated and their 1H NMR analyses revealed that the concept of the modified Mosher's method was successfully applied to 5i.
- Takahashi, Tamiko,Kameda, Hiroaki,Kamei, Tomoyo,Ishizaki, Miyuki
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- Photoenzymatic Reductions Enabled by Direct Excitation of Flavin-Dependent "Ene"-Reductases
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Non-natural photoenzymatic reactions reported to date have depended on the excitation of electron donor-acceptor complexes formed between substrates and cofactors within protein active sites to facilitate electron transfer. While this mechanism has unlocked new reactivity, it limits the types of substrates that can be involved in this area of catalysis. Here we demonstrate that direct excitation of flavin hydroquinone within "ene"-reductase active sites enables new substrates to participate in photoenzymatic reactions. We found that by using photoexcitation these enzymes gain the ability to reduce acrylamides through a single electron transfer mechanism.
- Sandoval, Braddock A.,Clayman, Phillip D.,Oblinsky, Daniel G.,Oh, Seokjoon,Nakano, Yuji,Bird, Matthew,Scholes, Gregory D.,Hyster, Todd K.
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supporting information
p. 1735 - 1739
(2021/01/25)
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- Erratum: Photoenzymatic Reductions Enabled by Direct Excitation of Flavin-Dependent 'Ene'-Reductases (J. Am. Chem. Soc. (2021) 143:4 (1735-1739) DOI: 10.1021/jacs.0c11494)
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Support by the Department of Energy was inadvertently left out of the Acknowledgments and a coauthor's name was misspelled in the Supporting Information. The scientific part of the manuscript remains unchanged. The complete correct Acknowledgment paragraph is as follows.
- Sandoval, Braddock A.,Clayman, Phillip D.,Oblinsky, Daniel G.,Oh, Seokjoon,Nakano, Yuji,Bird, Matthew,Scholes, Gregory D.,Hyster, Todd K.
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supporting information
p. 3662 - 3662
(2021/04/09)
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- From Carbodiimides to Carbon Dioxide: Quantification of the Electrophilic Reactivities of Heteroallenes
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Kinetics of the reactions of isocyanates, isothiocyanates, carbodiimides, carbon disulfide, and carbon dioxide with carbanions or enamines (reference nucleophiles) have been measured photometrically in acetonitrile or DMSO solution at 20 °C. The resulting second-order rate constants and the previously published reactivity parameters N and sN of the reference nucleophiles were substituted into the correlation log k2(20 °C) = sN(N + E) to determine the electrophilicity parameters of the heteroallenes: TsNCO (E = -7.69) ? PhNCO (E = -15.38) > CS2 (E = -17.70) ≈ PhNCS (E = -18.15) > PhNCNPh (E = -20.14) ? CyNCNCy (E ≈ -30). An approximate value could be derived for CO2 (-16 E - 11). Quantum chemical calculations were performed at the IEFPCM(DMSO)/B3LYP-D3/6-311+G(d,p) level of theory and compared with experimental Gibbs activation energies. The distortion-interaction model was used to rationalize the different reactivities of O- and S-substituted heteroallenes. Eventually it is demonstrated that the electrophilicity parameters determined in this work can be used as ordering principle for literature-known reactions of heteroallenes.
- Li, Zhen,Mayer, Robert J.,Ofial, Armin R.,Mayr, Herbert
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supporting information
p. 8383 - 8402
(2020/05/22)
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- Gold(I)/Xiang-Phos-Catalyzed Asymmetric Intramolecular Cyclopropanation of Indenes and Trisubstituted Alkenes
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The first intramolecular enantioselective cyclopropanation of indenes and trisubstituted alkenes was accomplished by using new chiral phosphine X5 derived gold(I) complexes. This reaction is a straightforward, efficient method for constructing [5-3-6] fused-ring compounds with two vicinal all-carbon quaternary stereogenic centers, a core structure shared by numerous pharmacological products, and bioactive compounds. The salient features of this transformation include high enantioselectivity (up to >98% ee), excellent yield (>97%), and nice functional group tolerance.
- Zhang, Pei-Chao,Wang, Yidong,Zhang, Zhan-Ming,Zhang, Junliang
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supporting information
p. 7049 - 7052
(2018/11/24)
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- Dynamic enzymatic kinetic resolution of methyl 2,3-dihydro-1h-indene-1- carboxylate
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A new reaction setup for kinetic enzymatic resolution was established and is demonstrated for the case of the hydrolase-catalysed conversion of methyl 2,3-dihydro-1H-indene1-carboxylate (1) in conjunction with a base-catalysed racemisation. The system allows controlled racemisation, resulting in efficient dynamic kinetic resolution (DKR) of the title compound. Short reaction times and high enantio-selectivities were obtained with CAL-B and TBD (1,5,7-triazabicyclo[4,4.0]dec-5-ene). Compound (R)-1 (ee 95%) served as a starting material in a domino reaction that led to the biaryl indanyl ketone (R)-8, a lead compound for novel inhibitors of peptidyl-prolyl-cis/irans- isomerases, in 94 % ee. Wiley-VCH Verlag GmbH & Co. KGaA,.
- Pietruszka, Joerg,Simon, Robert Christian,Kruska, Fabian,Braun, Manfred
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experimental part
p. 6217 - 6224
(2010/03/26)
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- Flash photolysis of α-diazonaphthoquinones in aqueous solution: Determination of rates and equilibria for keto-enol tautomerization of 1-indene-3-carboxylic acid
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Flash photolysis of either 1-diazo-2(1H)naphthalenone (1a) or 2-diazo-1(2H)naphthalenone (1b) generates benzofulven-8-one (2). Hydrolysis of ketene 2 forms benzofulvene-8,8-diol (3), the enol tautomer of indene-3-carboxylic acid (4). pH rate profiles for the reactions 2 → 3 and 3 → 4 were determined in aqueous solution. Ketonization of 3 is catalyzed by acid and by base. Catalysis by protons saturates in strongly acidic solutions, thereby defining the first ionization constant of the enol, pKaE = 1.90 ± 0.05, catalysis by hydroxyl ions saturates in dilute base, defining the second ionization constant, pK′aE = 8.3 ± 0.2. The first (OH) and second (CH) ionization constants of 4 were determined by spectrophotometric titration, pKaK = 4.50 ± 0.03 and pK′aK = 15.2 ± 0.2. Two independent estimates of the enolization constants of 4 and 4-, the first based on thermodynamic cycles, the second on the ratio of enolization and ketonization rates, were combined to give pKE = 9.3 ± 0.3, pK′E = 6.6 ± 0.3. Ketene 2 is formed by irradiation of 1-bromo-2-naphthol at 12 K in an argon matrix, but neither it nor its isomer 2-bromo-1-naphthol were suitable for the generation and observation of 2 and 3 by flash photolysis in aqueous solution.
- Almstead, Ji-In Kim,Urwyler, Bernhard,Wirz, Jakob
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p. 954 - 960
(2007/10/02)
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- Kinetics and mechanism of the isomerization of 1H-indene-1-carboxylic acid to 1H-indene-3-carboxylic acid in aqueous solution and determination of their keto-enol equilibrium constants and acid dissociation constants of the keto and enol forms. Implication on the photolysis of diazonaphthoquinones
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Rates of isomerization of 1H-indene-1-carboxylic acid to 1H-indene-3-carboxylic acid were measured in dilute aqueous solutions of HClO4, NaOH, and CH3CO2H and H2PO4-, (CH3)3CPO3H-, and HCO3- buffers. This gave a rate profile which, together with the occurrence of general base catalysis and sizable primary kinetic isotope effects, indicates that the isomerization takes place through an enolization-reketonization reaction sequence. The equilibrium constant of the isomerization reaction is K = [indene-3-carboxylic acid]/[indene-1-carboxylic acid] = 200 in aqueous acid solution and K = 100 in base. The ratio of products formed by ketonization of the indenecarboxylic acid enol intermediate generated in the photolysis of 2-diazo-1 (2H)-naphthalenone is R = [indene-3-carboxylic acid]/[indene-1-carboxylic acid] = 0.47 in aqueous acid solution and R = 20 in base. The failure of previous investigations of the photolysis reaction to detect any indene-1-carboxylic acid as the product is attributed to the facile isomerization of this substance to indene-3-carboxylic acid and the preponderance of the latter at equilibrium. The enol intermediate of this isomerization reaction was also generated by flash photolysis of 2-diazo-1 (2H)-naphthalene and rates of its ketonization were measured in dilute aqueous HClO4 solutions. Analysis of the data gave the enol acidity constant pKaE = 2.09. The results, in combination with those for the isomerization reaction, also provided carbon acid acidity constants (KaK) and keto-enol equilibrium constants (KE) for the two acids: pKaK = 9.35 and pKE = 7.26 for indene-1-carboxylic acid and pKaK = 11.69 and pKE = 9.60 for indene-3-carboxylic acid.
- Andraos,Kresge,Popik
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p. 961 - 967
(2007/10/02)
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- Non-competitive NMDA receptor antagonists and methods for their use
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The present invention relates to novel NMDA receptor antagonists and methods for their use. The present invention also provided pharmaceutical compositions comprising such NMDA receptor antagonists.
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- TRANSFORMATIONS OF o-NAPHTHOQUINONE DIAZIDES IN ALIPHATIC ALCOHOLS
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During photodecomposition and thermal decomposition in hydroxyl-containing media (alcohols, water) o-naphthoquinone diazides in electronically excited and vibrationally excited states eliminate nitrogen, forming the corresponding ketocarbenes.The singlet ketocarbenes undergo intramolecular transformation (with ring contraction and the formation of 3-indenecarboxylic acid or its esters) and intermolecular transformation, forming 1,2-hydroxyalkoxynaphthalenes in reaction with alcohols.The triplet ketocarbenes undergo intermolecular transformations, forming 1- or 2-hydroxynaphthalenes.The composition and ratio of the final products from the decomposition of o-naphthoquinone diazides in alcohols depend significantly on the nature of the alcohol, the presence of oxygen, the presence of radical acceptors, and the spectral composition of the exciting light.
- Ponomareva, R. P.,Komagorov, A. M.,Andronova, N. A.
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p. 140 - 149
(2007/10/02)
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- Cycloaddition Reactions of Indenes. Adducts of 1H-Indene-3-carboxylic Acid with Ethylenic Dienophiles
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1H-Indene-3-carboxylic acid (1b) and its methyl ester (1c) react when heated via intermediate 2H-indenes (isoindenes) with the more reactive ethylenic dienophiles, giving the corresponding 1:1 Diels-Alder adducts as 1,2,3,4-tetrahydro-1,4-methanonaphthalene-1-carboxylic acid 2,3-derivatives 3.Thus, 1:1 adducts were obtained with 1b in refluxing xylene with maleic anhydride (3b, 71percent) and N-phenylmaleimide (3g, 46percent) and in refluxing 1,2-dichlorobenzene (but not in xylene) with dimethyl fumarate (5c, 19percent).The less reactive 1c gave a 1:1 adduct (3c, 43percent) in refluxing xylene with maleic anhydride but not with N-phenylmaleimide.That the reaction is quite sensitive to steric hindrance is shown by the facts that 1b failed to give 1:1 adducts in refluxing xylene with citraconic (methylmaleic) anhydride, dichloromaleic anhydride, β-nitrostyrene, tetracyanoethylene, and diethyldiazenedicarboxylate, neat at 130 deg C with phenylmaleic anhydride, or in refluxing 1,2-dichlorobenzene with cinnamic acid.The transformations which were carried out include hydrolysis of adduct 3b to the 2-endo,3-endo triacid 4b (64percent), Fischer esterification to the trimethylester 4d (69percent from 3b, 66percent from 4b), thermal dehydration of 4b back to 3b, and methanolysis of 3b to a monomethyl 3-ester (4e, 83percent) which underwent simple hydrolysis in 5percent NaOH to 4b (22percent) but epimerized during hydrolysis in methanolic 5percent KOH to the 2-endo,3-exo triacid 5a (83percent, similarly from 4d, 60percent), which at 300 deg C were reepimerized and dehydrated to 3b (22percent).Hydrolysis of the 2,3-diester adduct 5c with both 5percent NaOH (68percent) and methanolic 5percent KOH (60percent) also gave 5a, showing that 5c has the same stereochemistry as 5a.With diazomethane, 5a gave its trimethyl ester (5b, 59percent).Hydrolysis of adduct 3c with 5percent NaOH gave 4b (68percent), while neutral hydrolysis gave the 1-methyl ester 4c(78percent as a hydrate), which at 150-160 deg C was reconverted to 3c (99percent).Epimerization also occurred during the acidic hydrolysis of adduct 3g, giving 5a (11percent).With diazomethane, 3g gave the 1-methyl ester 3h (72percent), which was not obtained directly by reaction of 1c with N-phenylmaleimide.
- Noland, Wayland E.,Landucci, Lawrence L.,Kameswaran, Venkataraman
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p. 3456 - 3461
(2007/10/02)
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- Carboxylation of compounds
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Method of carboxylating a compound of the group of R-C CH, RCH2 CN, indene, cyclopentadiene or fluorene, where R is hydrocarbyl, comprising contacting said compound with carbon dioxide under substantially anhydrous conditions in the presence of a base of the formula: SPC1 Where X is sodium or potassium, R1 is hydrogen or alkyl and subsequently acidifying the resultant reaction product to form the carboxylated product.
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