- Design, Synthesis, and Conformation-Activity Study of Unnatural Bridged Bicyclic Depsipeptides as Highly Potent Hypoxia Inducible Factor-1 Inhibitors and Antitumor Agents
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By carrying out structural modifications based on the bicyclic peptide structure of echinomycin, we successfully synthesized various powerful antitumor derivatives. The ring conformation in the obtained compounds was restricted by cross-linking with an unnatural bond. The prepared derivatives were demonstrated to strongly suppress the hypoxia inducible factor (HIF)-1 transcriptional activation and hypoxia induction of HIF-1 protein expression. Particularly, alkene-bridged derivative 12 exhibited remarkably potent cytotoxicity (IC50 = 0.22 nM on the MCF-7 cell line) and HIF-1 inhibition (IC50 = 0.09 nM), which considerably exceeded those of echinomycin. Conformational analyses and molecular modeling studies revealed that the biological activities were enhanced following restriction of the conformation by cross-linking through a metabolically stable and rigid bridge bond. In addition, we proposed a new globular conformation stabilized by intramolecular πstacking that can contribute to the biological effects of bicyclic depsipeptides. The developments presented in the current study serve as a useful guide to expand the chemical space of peptides in drug discovery.
- Koike, Kota,Nagano, Masanobu,Ebihara, Masahiro,Hirayama, Tasuku,Tsuji, Mieko,Suga, Hiroaki,Nagasawa, Hideko
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p. 4022 - 4046
(2020/06/08)
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- Enantioselective desymmetrization via carbonyl-directed catalytic asymmetric hydroboration and Suzuki-Miyaura cross-coupling
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The rhodium-catalyzed enantioselective desymmetrization of symmetric γ,δ-unsaturated amides via carbonyl-directed catalytic asymmetric hydroboration (directed CAHB) affords chiral secondary organoboronates with up to 98% ee. The chiral γ-borylated products undergo palladium-catalyzed Suzuki-Miyaura cross-coupling via the trifluoroborate salt with stereoretention.
- Hoang, Gia L.,Yang, Zhao-Di,Smith, Sean M.,Miska, Judy L.,Prez, Damaris E.,Zeng, Xiao Cheng,Takacs, James M.,Pal, Rhitankar,Pelter, Libbie S. W.
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supporting information
p. 940 - 943
(2015/03/30)
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- Rate and product studies on the solvolyses of allyl chloroformate
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The solvolysis rate constants of allyl chloroformate (CH 2=CHCH2OCOCl, 3) in 30 different solvents are well correlated with the extended Grunwald-Winstein equation, using the NT solvent nucleophilicity scale and YCl solvent ionizing scale, with the sensitivity values of 0.93 ± 0.05 and 0.41 ± 0.02 for l and m, respectively. These l and m values can be considered to support a S N2 reaction pathway. The activation enthalpies (ΔH≠) were 12.5 to 13.4 kcal·mol-1 and the activation entropies (ΔS≠) were -34.4 to -37.3 cal·mol-1·K -1, which is also consistent with the proposed bimolecular reaction mechanism. The solvent kinetic isotope effect (SKIE, kMeOH/k MeOD) of 2.16 was also in accord with the SN2 mechanism. The values of product selectivity (S) for the solvolyses of 3 in alcohol/water mixtures was 1.3 to 3.9, which is also consistent with the proposed bimolecular reaction mechanism.
- Koh, Han Joong,Kang, Suk Jin
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p. 4117 - 4121
(2013/08/23)
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- Pd-catalyzed reaction of allyl carbonate with polyols: The role of CO 2 in transesterification versus etherification of glycerol
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An intermolecular Pd/PPh3-catalyzed transesterification of diallyl carbonate with glycerol to generate glycerol carbonate has been developed. Analysis of the reaction kinetics in THF indicates a first-order dependence on Pd and diallyl carbonate, that the Pd bears two phosphines during the turnover limiting event, and that increasing the glycerol concentration inhibits reaction, possibly via change in the polarity of the medium. 13C isotopic labeling studies demonstrate that the Pd-catalyzed transesterification requires at least one allyl carbonate moiety and that there is rapid equilibrium of the allyl carbonate with CO2 in solution, even when present only at low concentrations. A mechanism that is consistent with these results involves oxidative addition of the allyl carbonate to Pd followed by reversible decarboxylation, with the intermediate I·1- and I·3-allyl Pd alkoxides mediating direct and indirect transesterification reactions with the glycerol. Using this model, successful simulations of the kinetics of reactions conducted under atmospheres of N2 or CO2 could be achieved, including switching in selectivity between etherification and transesterification in the early stages of reaction. Reactions with the higher polyols threitol and erythritol are also efficient, generating the terminal (1,2) monocarbonates with high selectivity. It's a gas: A Pd-catalyzed transesterification of diallyl carbonate with polyols has been developed. The CO2 concentration is shown to control the relative rates of etherification and transesterification. Kinetic and isotopic labeling studies suggest that intermediate I·1-allyl Pd alkoxides mediate indirect intermolecular transesterification. The higher polyols erythritol and threitol selectively generate monocarbonates. Copyright
- Gordillo, Alvaro,Lloyd-Jones, Guy C.
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supporting information; experimental part
p. 2660 - 2665
(2012/04/11)
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- METHOD OF PREPARING DIALKYLCARBONATES
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The present invention relates to a process of preparing dialkylcarbonates, and particularly to an improved process of preparing dialkylcarbonates, which comprises performing a reaction between an alcohol compound and a chloroformate derivative in the presence of an imidazole compound, thereby enabling to prepare dialkylcarbonates with high yield in a mild condition without using toxic raw materials and to easily separate impurities.
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Page/Page column 8; 9
(2008/06/13)
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- Palladium-catalysed coupling between allyl carbonates and triethyl methanetricarboxylate (TEMT)
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Triethyl methanetricarboxylate (TEMT) is allylated by allylic carbonates in the presence of catalytic amounts of Pd(0) complexes; the reaction, conducted in very mild conditions, is fast and gives high yields of the title products.
- Cravotto, Giancarlo,Giovenzana, Giovanni B.,Sisti, Massimo,Palmisano, Giovanni
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p. 1639 - 1646
(2007/10/03)
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- Pd(0)-based synthetic approaches to 1,1-disubstituted-3,4-dimethylenecyclopentanes as intermediates in the preparation of a,a-disubstituted amino acid derivatives possessing indane and diazaindane skeletons
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A comparison is established between ethyl nitroacetate and ethyl N(diphenylmelhylene)glycinate as anionic glycine equivalents for the preparation of bicyclic or tricyclic a.adisubstituted amino acids. Palladiummediated approaches to 1.1disubstituted-3,4-di methylene cyclopentanes are presented (intramolecular reductive coupling of 2.6-dibromol.6dienes and cycloisomerization of 1.6enynes). Springer-Verlag Iberica 1997.
- Loepez, Anna,Moreno-Manas, Marcial,Pleixats, Roser,Roglans, Anna
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p. 355 - 362
(2007/10/03)
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- A novel synthesis of dialkyl carbonates from carbon dioxide, alcohols, and tert-amines mediated by acetylene
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A novel acetylene-mediated reaction of carbon dioxide with alcohols and tert-amines leads to effective formations of dialkyl carbonates and alkyl N,N-dialkylcarbamates without catalyst.
- Sasaki, Yoshiyuki
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p. 825 - 826
(2007/10/03)
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- C-Allylation of L-Ascorbic acid under Palladium(0) Catalysis
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L-Ascorbic acid (1) is efficiently allylated at C-2 with primary and secondary allylic substrates by using palladium(0) catalysis.Hydrogenation of the resulting allylated compounds 6 affords L-ascorbic acid derivatives with saturated chains at C-2.
- Moreno-Manas, Marcial,Pleixats, Roser,Villarroya, Merce
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p. 4925 - 4928
(2007/10/02)
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- On the Regio- and Stereoselectivity of Bu4N-Catalyzed Allylic Alkylation
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Bu4N has been found to catalyze the alkylation of allylic carbonate with malonate anion.The reaction proceeds with good regioselectivity, the nucleophile attacking predominantly at the carbon where the leaving group was attached.Retention of configuration of the double bond during the course of reaction was observed.Alkylation of methyl (Z)-5-carbomethoxy-1-cyclohexen-3-yl carbonate with sodium salt of dimethyl malonate yielded dimethyl ((Z)-5-carbomethoxy-1-cyclohexen-3-yl)malonate in a highly stereoselective fashion, and a net retention of configuration at the center undergoing substitution is thus established.On the basis of regio- and stereochemical results, a reaction pathway involving an ?-allyliron complex has been suggested.
- Xu, Yuanyao,Zhou, Bo
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p. 974 - 977
(2007/10/02)
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- Palladium-Catalyzed Decarboxylation-Carbonylation of Allylic Carbonates To Form β,γ-Unsaturated Esters
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Allyl alkyl carbonates undergo a smooth decarboxylation-carbonylation reaction to afford β,γ-unsaturated esters at 50 deg C under atmospheric or low pressure of carbon monoxide and neutral conditions in the presence of palladium-phosphine complexes as catalysts.The reaction offers a very good method for the preparation of β,γ-unsaturated esters from allylic alcohols.
- Tsuji, Jiro,Sato, Koji,Okumoto, Hiroshi
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p. 1341 - 1344
(2007/10/02)
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