- Hydrogenated Poly(Dewar benzene): A Compact Cyclic Olefin Polymer with Enhanced Thermomechanical Properties
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Dihydro Dewar benzene(bicyclo[2.2.0]hex-2-ene) was synthesized and polymerized using the Grubbs third generation catalyst. The corresponding ring-opening metathesis polymerization proceeded in a controlled manner, as determined by a linear relationship between the molecular weight of the polymer produced and the monomer-To-catalyst feed ratio as well as an ability to extend polymer chains through exposure to an additional monomer. Subsequent treatment with tosylhydrazide afforded the corresponding hydrogenated derivative. The hydrogenated polymer was found to exhibit high melting and decomposition temperatures as well as a relatively high Young's modulus when compared to other polyolefins [e.g., hydrogenated poly(norbornene) and poly(ethylene)]. The enhanced thermal and mechanical properties were found to originate from a relatively low phase transition entropy combined with high polymer crystallinity, features that were attributed to restricted bond rotation within the repeating units of the hydrogenated polymer.
- Bielawski, Christopher W.,Lee, Stanfield Y.,Seo, Jinwon
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Read Online
- Development and Execution of a Production-Scale Continuous [2 + 2] Photocycloaddition
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This article details the approach to large-scale production of cyclobutane 2 by the continuous-flow [2 + 2] photocycloaddition of maleic anhydride and ethylene, including (1) focused reaction optimization and development of a robust isolation protocol, (2) the approach to equipment design and process safety, and (3) the results of commissioning tests and production runs delivering the target compound at throughputs exceeding 5 kg/day.
- Beaver, Matthew G.,Zhang, En-Xuan,Liu, Zhi-Qing,Zheng, Song-Yuan,Wang, Bin,Lu, Jiang-Ping,Tao, Jian,Gonzalez, Miguel,Jones, Sian,Tedrow, Jason S.
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p. 2139 - 2146
(2020/06/05)
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- Phosphodiesterase inhibitor and applications thereof
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The invention belongs to the technical field of medicines, particularly relates to phosphodiesterase inhibitor compounds shown as formula (I), or pharmaceutically acceptable salts and stereoisomers thereof, and further relates to pharmaceutical preparations and pharmaceutical compositions of the compounds and application of the pharmaceutical preparations and the pharmaceutical compositions. In the formula (I), R1 and R2 are defined in the specification. The compounds provided by the invention can be used for preparing medicines for treating or preventing related diseases mediated by PDE9 kinase.
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Paragraph 0053-0057
(2020/01/12)
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- Finding the Perfect Match: A Combined Computational and Experimental Study toward Efficient and Scalable Photosensitized [2 + 2] Cycloadditions in Flow
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With ever-evolving light-emitting diode (LED) technology, classical photochemical transformations are becoming accessible with more efficient and industrially viable light sources. In combination with a triplet sensitizer, we report the detailed exploration of [2 + 2] cycloadditions, in flow, of various maleic anhydride derivatives with gaseous ethylene. By the use of a flow reactor capable of gas handling and LED wavelength/power screening, an in-depth optimization of these reactions was carried out. In particular, we highlight the importance of matching the substrate and sensitizer triplet energies alongside the light source emission wavelength and power. Initial triplet-sensitized reactions of maleic anhydride were hampered by benzophenone's poor absorbance at 375 nm. However, density functional theory (DFT) calculations predicted that derivatives such as citraconic anhydride have low enough triplet energies to undergo triplet transfer from thioxanthone, whose absorbance matches the LED emission at 375 nm. This observation held true experimentally, allowing optimization and further exemplification in a larger-scale reactor, whereby >100 g of material was processed in 10 h. These straightforward DFT calculations were also applied to a number of other substrates and showed a good correlation with experimental data, implying that their use can be a powerful strategy in targeted reaction optimization for future substrates.
- Williams, Jason D.,Nakano, Momoe,Gérardy, Romaric,Rincón, Juan A.,De Frutos, óscar,Mateos, Carlos,Monbaliu, Jean-Christophe M.,Kappe, C. Oliver
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supporting information
p. 78 - 87
(2019/01/24)
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- Finding the Perfect Match: A Combined Computational and Experimental Study toward Efficient and Scalable Photosensitized [2 + 2] Cycloadditions in Flow
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With ever-evolving light-emitting diode (LED) technology, classical photochemical transformations are becoming accessible with more efficient and industrially viable light sources. In combination with a triplet sensitizer, we report the detailed exploration of [2 + 2] cycloadditions, in flow, of various maleic anhydride derivatives with gaseous ethylene. By the use of a flow reactor capable of gas handling and LED wavelength/power screening, an in-depth optimization of these reactions was carried out. In particular, we highlight the importance of matching the substrate and sensitizer triplet energies alongside the light source emission wavelength and power. Initial triplet-sensitized reactions of maleic anhydride were hampered by benzophenone's poor absorbance at 375 nm. However, density functional theory (DFT) calculations predicted that derivatives such as citraconic anhydride have low enough triplet energies to undergo triplet transfer from thioxanthone, whose absorbance matches the LED emission at 375 nm. This observation held true experimentally, allowing optimization and further exemplification in a larger-scale reactor, whereby >100 g of material was processed in 10 h. These straightforward DFT calculations were also applied to a number of other substrates and showed a good correlation with experimental data, implying that their use can be a powerful strategy in targeted reaction optimization for future substrates.
- Williams, Jason D.,Nakano, Momoe,Gérardy, Romaric,Rincón, Juan A.,De Frutos, óscar,Mateos, Carlos,Monbaliu, Jean-Christophe M.,Kappe, C. Oliver
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supporting information
(2019/01/21)
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- LADDERANE LIPID COMPOUNDS AND LIPOSOMES AND METHODS OF PREPARING AND USING THE SAME
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Methods for preparing a variety of ladderane precursors, ladderane compounds and ladderane lipids are provided. Also provided are methods of preparing a liposome from the ladderane lipids disclosed herein, and compositions thereof. Aspects of the invention include encapsulated one or more cargo moieties in the liposome or compositions thereof and use of the subject liposome compositions as vehicles in drug delivery, imaging, diagnostics and other medical applications. Aspects of the methods disclosed herein include administering a liposomal composition comprising a pharmaceutical agent to a subject under conditions sufficient to deliver the composition to a site of interest in the subject, and release the pharmaceutical agent from the liposomal composition.
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Page/Page column 51; 52
(2018/03/25)
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- Chemical Synthesis and Self-Assembly of a Ladderane Phospholipid
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Ladderane lipids produced by anammox bacteria constitute some of the most structurally fascinating yet poorly studied molecules among biological membrane lipids. Slow growth of the producing organism and the inherent difficulty of purifying complex lipid mixtures have prohibited isolation of useful amounts of natural ladderane lipids. We have devised a highly selective total synthesis of ladderane lipid tails and a full phosphatidylcholine to enable biophysical studies on chemically homogeneous samples of these molecules. Additionally, we report the first proof of absolute configuration of a natural ladderane.
- Mercer, Jaron A. M.,Cohen, Carolyn M.,Shuken, Steven R.,Wagner, Anna M.,Smith, Myles W.,Moss, Frank R.,Smith, Matthew D.,Vahala, Riku,Gonzalez-Martinez, Alejandro,Boxer, Steven G.,Burns, Noah Z.
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supporting information
p. 15845 - 15848
(2016/12/23)
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- NOVEL HEPATITIS C VIRUS INHIBITORS
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The invention provides compounds of formula (I): wherein Rings A and A' are independently 5-membered optionally substituted aromatic heterocycles; Q is C(=O)NR1R1' or formula U is C(R4)2, O, S, S(=O)2, C(R4)2C(R4)2, CH2O, OCH2, CH2S, SCH2, CH2S(=O)2, S(=O)CH2 or C=C(Ru )2; X is CH2, CHR12, CR12R12, O, S, S(=O)2 or NRx; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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Page/Page column 80
(2013/07/05)
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- Structure-mechanochemical activity relationships for cyclobutane mechanophores
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Ultrasound activation of mechanophores embedded in polymer backbones has been extensively studied of late as a method for realizing chemical reactions using force. To date, however, there have been few attempts at systematically investigating the effects of mechanophore structure upon rates of activation by an acoustic field. Herein, we develop a method for comparing the relative reactivities of various cyclobutane mechanophores. Through the synthesis and ultrasonic irradiation of a molecular weight series of poly(methyl acrylate) polymers in which each macromolecule has a single chain-centered mechanophore, we find measurable and statistically significant shifts in molecular weight thresholds for mechanochemical activation that depend on the structure of the mechanophore. We also show that calculations based on the constrained geometries simulate external force method reliably predict the trends in mechanophore reactivity. These straightforward calculations and the experimental methods described herein may be useful in guiding the design and the development of new mechanophores for targeted applications.
- Kryger, Matthew J.,Munaretto, Alexander M.,Moore, Jeffrey S.
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supporting information; experimental part
p. 18992 - 18998
(2012/02/05)
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- Synthesis of the constrained glutamate analogues (2S,1′R,2′R)- and (2S,1′S,2′S)-2-(2′-carboxycyclobutyl)glycines L-CBG-II and L-CBG-I by enzymatic transamination
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Optically pure trans-cyclobutane analogues of glutamic acid are prepared by highly selective enzymatic transamination of a single racemic trans-cyclobutane α-ketoglutaric acid derivative 5, which is synthesized in five steps from maleic anhydride. (2S,1′R,2′R)- and (2S,1′S,2′S)-2- (2′-carboxycyclobutyl)glycines L-CBG-II and L-CBG-I are obtained using aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT), respectively.
- Gu, Xin,Xian, Mo,Roy-Faure, Sophie,Bolte, Jean,Aitken, David J.,Gefflaut, Thierry
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p. 193 - 196
(2007/10/03)
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- Stereoselective chemoenzymatic synthesis of the four stereoisomers of L-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3
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The four stereoisomers of L-2-(2-carboxycyclobutyl)glycine, L-CBG-I, L-CBG-II, L-CBG-III, and L-CBG-IV, were synthesized in good yield and high enantiomeric excess, from the corresponding cis and trans-2- oxalylcyclobutanecarboxylic acids 5 and 6 using the enzymes aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT) from Escherichia coli. The four stereoisomeric compounds were evaluated as potential ligands for the human excitatory amino acid transporters, subtypes 1, 2, and 3 (EAAT1, EAAT2, and EAAT3) in the FLIPR membrane potential assay. While the one trans-stereoisomer, L-CBG-I, displayed weak substrate activity at all three transporters, EAAT1-3, we found a particular pharmacological profile for the other trans-stereoisomer, L-CBG-II, which displayed EAAT1 substrate activity and inhibitory activity at EAAT2 and EAAT3. Whereas L-CBG-III was found to be a weak inhibitor at all three EAAT subtypes, the other cis-stereoisomer L-CBG-IV was a moderately potent inhibitor with 20-30-fold preference for EAAT2/3 over EAAT1.
- Faure, Sophie,Jensen, Anders A.,Maurat, Vincent,Gu, Xin,Sagot, Emmanuelle,Aitken, David J.,Bolte, Jean,Gefflaut, Thierry,Bunch, Lennart
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p. 6532 - 6538
(2007/10/03)
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- Process for producing optically active hemiesters
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There is disclosed a process for producing an optically active hemiester of formula (1): 1wherein R1, R2 and R5 represent the same meanings as described below, which comprises reacting a cyclic acid anhydride of formula (2): 2wherein R1 and R2 are different and independently represent a hydrogen atom, a halogen atom, an alkyl group optionally substituted with an alkoxy group or a halogen atom, and the like, with a hydroxy compound of formula (3): R3OH ??(3) wherein R3 represents an alkyl group optionally substituted with an alkoxy group, a phenoxy group, a dialkylamino group or a halogen atom and the like, in the presence of an asymmetric catalyst.
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- Practical and Highly Enantioselective Ring Opening of Cyclic Meso-Anhydrides Mediated by Cinchona Alkaloids
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The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of methanol leading to optically active hemiesters is described. Very structurally diverse anhydrides are converted into their corresponding methyl monoesters, and either enantiomer can be obtained with up to 99% ee by using quinine or quinidine as directing additive. After the reaction, the alkaloids can be recovered almost quantitatively and reused without loss of enantioselectivity. Additionally, a catalytic protocol which permits the substoichiometric use of quinidine in the presence of easily accessible pentamethylpiperidine (pempidine) is presented.
- Bolm, Carsten,Schiffers, Ingo,Dinter, Christian L.,Gerlach, Arne
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p. 6984 - 6991
(2007/10/03)
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- Synthesis of Small-Medium Ring Thioanhydrides
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Reaction of five-membered ring anhydrides with sodium sulfide has previously been employed for synthesis of the corresponding thioanhydrides in low yields.Re-examination of the stoichiometry reveals reaction of cyclic anhydride with sodium sulfide (2:1 respectively), affords the thioanhydride accompanied by the corresponding dicarboxylate in a 1:1 molar ratio.The mechanistic pathway for this reaction has also been elucidated.Optimization of reaction conditions has resulted in the synthesis of a variety of four to seven-membered ring thioanhydride in yields approaching theoretical.
- Kates, Michael J.,Schauble, J. Herman
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p. 971 - 978
(2007/10/02)
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- Stereochemistry and Mechanism of the Reverse Ene Reaction of cis-2-Alkyl-1-alkenylcyclobutanes. Stereoelectronic Control in a System Showing Marginal Energetic Benefit of Concert
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In the temperature range 243.8-267.5 °C, the racemic cyclobutanes (1RS,2RS,1′SR)-1-(1-methoxyethyl)-2- vinylcyclobutane (16b) and (1SR,2SR,1′SR)-1-(1-methoxyethyl)-2-vinylcyclobutane (17b) each undergo a sigmatropic hydrogen shift (reverse ene reaction) amounting to about 18% of the total pyrolysis product, in addition to four other unimolecular processes. The other four reactions are [2 + 2]-cycloreversion, epimerization, double epimerization, and sigmatropic carbon 1,3-rearrangement. Overall disappearance of reactant occurs with first-order kinetics. The activation parameters determined for 16b are Ea = 47.8 ± 2.1 kcal/mol and log A = 14.8 ± 0.9, and for 17b they are Ea = 48.6 ± 2.2 kcal/mol and log A = 15.2 ± 0.9 (A, s-1). In the reverse ene reactions, vinyl derivatives 16b and 17b yield (2E,6Z)-2-methoxyocta-2,6-diene ((E,Z)-18) and (2Z,6Z)-2-methoxyocta-2,6-diene ((Z,Z)-18), respectively, with stereospecificities of 95 and 91%. These are minimum values because of the competing interconversion of the reactant cyclobutanes 16b and 17b. Correction for this gives a stereospecificity of about 220:1 for the 6Z reverse ene product formed directly from 16b and about 35:1 for that from 17b. This demonstrates high stereospecificity at the double bond of the product derived from the migration origin. Secondary 1,3-deuterium kinetic isotope effects (ΔΔG*), measured at 517 K) for [2 + 2]-cycloreversion, epimerization, and sigmatropic carbon 1,3-rearrangement of 10-20 (±120) and 80-180 (±240) cal/mol were measured for 16b and 17b. Primary isotope effects for reverse ene hydrogen shift were 980 ± 125 and 1760 ± 290 cal/mol, respectively. The stereochemistry at the terminus of migration can be determined in the corresponding cyclobutanes bearing a propenyl instead of a vinyl group. The enantiomerically enriched isotopically labeled cyclobutane (1R,2R,1′S)-(-)-1-(1-methoxyethyl)-2-(2-deuterio-1(E)-propenyl)cyclobutane ((-)-37) having 93.2% ee was prepared in nine steps from (S)-(-)-3-butyn-2-ol. The reverse ene reaction accounts for roughly 5% of the total product in the pyrolysis of the propenyl derivative (-)-37-d at 239.3 °C. The principal reverse ene product is (2E,6Z)-8(S)- deuterio-2-methoxynona-2,6-diene (45), formed with roughly 13:1 stereospecificity compared to the next most prevalent double bond isomer. The product 8(S)-45 was chemically degraded to (S)-2-deuteriopropanoic acid, which was subsequently converted to the corresponding propanoate ester 49/50 with (R)-(+)-methyl mandelate. Analysis of the diastereomeric excess of this ester by 1H and 2H NMR indicates that 8(S)-45 is formed from (1R,2R,1′5)-(-)-37-d with 68.9 ± 4.9% (1H NMR) or 80.5 ± 3.3% (2H NMR) transfer of stereogenicity. Taking into account potential stereochemical contaminants, the actual stereogenicity transfer may be as high as 100% but not lower than 64%. This suffices to show that a suprafacial hydrogen transfer dominates the retro ene reaction in the propenyl case and probably also in the vinyl cases. The results from 16b, 17b, and 37 are interpreted in terms of a dominant concerted mechanism for the reverse ene reactions of these compounds. They are consistent with a transition-state structure in which the alkenyl moiety is endo with respect to the ring and the breaking C-H bond orbital is aligned with the breaking C-C ring bond. This is the sole geometry consistent with predictions based on the conservation of orbital symmetry and orbital overlap control.
- Getty, Stephen J.,Berson, Jerome A.
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p. 4607 - 4621
(2007/10/02)
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- Elimination and Addition Reactions. Part 43. Eliminative Fission of Cyclobutanes and the Relationship between Strain and Reactivity in Cyclobutanes and Cyclopropanes
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Eliminative fission of cyclobutanes has been compared with that of analogous cyclopropanes; reactivity differences of 103.7-104.8 have been determined.In both sets of compounds, mechanisms have been shown to involve rate-determining ring fission.The possibilities that the large reactivity differences between the comparably strained systems are due either to peculiarity in the cyclobutane structures or to their abnormally slow deprotonation are rejected.Analysis of strain in the two systems suggests that as ring fission occurs, dispersal of the excess of enthalpy of the cyclobutanes is a less sensitive function of extension of a bond in the ring than for the cyclopropanes.The behaviour of these systems is compared with cleavage of cyclopropanes and cyclobutanes in other reactions; the results are remarkably similar.Calculations using the MINDO3 programme have been carried out for eliminative fissions of cyclopropylmethyl and cyclobutylmethyl carbanions.These reproduce remarkably closely the difference between the heats of formation of the species at the energy maxima for fission of each ring size; the maximum for fission of the cyclobutane is considerably displaced along the reaction co-ordinate towards product.
- Earl, Harold A.,Stirling, Charles J. M.
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p. 1273 - 1280
(2007/10/02)
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- The Synthesis and Cycloaddition Reactions of 3-Azabicyclohex-2-ene 3-oxide and 3-Azabicyclohept-2-ene 3-oxide. Highly Strained Bicyclic Nitrones
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The synthesis of two strained bicyclic nitrones is described.Subsequent cycloadditions demonstrated a high degree of regiochemical and stereochemical control.
- Tufariello, Joseph J.,Milowsky, Arnold S.,Al-Nuri, Mohammed,Goldstein, Steven
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p. 267 - 270
(2007/10/02)
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- 2-Acyl-4-oxo-pyrazino-isoquinoline derivatives and process for the preparation thereof
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2-Acyl-4-oxo-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives of the formula STR1 wherein COR is the acyl radical of an up to 26 carbon atom acid and their physiologically acceptable acid addition and quaternary ammonium salts, are anthelmintics and can be produced by reacting 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline with an acid or a reactive functional derivative thereof.
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