- Synthesis of Succinimides via Intramolecular Alder-Ene Reaction of 1,6-Enynes
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A novel and convenient method has been developed for the facile synthesis of functionalized succinimide derivatives via intramolecular Alder-ene reaction of 1,6-enynes. This reaction features mild and metal-free reaction conditions, which offers a green and efficient entry to synthetically important succinimide scaffolds. Preliminary mechanistic studies suggest that a diradical intermediate might be involved in this transformation.
- Chen, Xia,Lu, Yuling,Guan, Zhenhua,Gu, Lianghu,Chen, Chunmei,Zhu, Hucheng,Luo, Zengwei,Zhang, Yonghui
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- New indenyl titanium catalysts for syndiospecific styrene polymerizations
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A series of multi-methyl-substituted indenes as well as allylindene, n-propylindene, n-but-1-enylindene, and n-butylindene have been prepared in good yields. The substituted indenes were converted into trimethylsilyl derivatives via reactions of intermediate organolithium complexes with chlorotrimethylsilane. The corresponding titanium complexes were synthesized in excellent yields from reactions of the trimethylsilyl derivatives with TiCl4. The titanium complexes were evaluated as styrene polymerization catalysts in toluene solution when activated by methylaluminoxane. In general, catalytic activities decreased with each additional methyl substituent. Syndiospecificities were very high (90-95%).
- Ready, Thomas E.,Chien, James C.W.,Rausch, Marvin D.
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- Safe, selective, and high-yielding synthesis of acryloyl chloride in a continuous-flow system
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Acid chlorides are an important class of compounds and their high reactivity and instability has prompted us to develop a straightforward procedure for their synthesis with ondemand and on-site synthesis possibilities. The focus of this report is acryloyl chloride, mainly important for the acrylate and polymer industry. A continuous-flow methodology was developed for the fast and selective synthesis of the otherwise highly unstable acryloyl chloride. Three routes were investigated in a microreactor setup and all three can potentially be used for its production. The methodology was further expanded to the synthesis of other unstable acid chlorides by both the thionyl chloride and the oxalyl chloride mediated processes. The most sustainable method was the oxalyl chloride mediated procedure under solvent-free conditions, in which nearequimolar amounts of carboxylic acid and oxalyl chloride were used in the presence of catalytic amounts of DMF at room temperature. Within 1 to 3 min, nearly full conversions into the acid chlorides were achieved.
- Movsisyan, Marine,Heugebaert, Thomas S. A.,Dams, Rudy,Stevens, Christian V.
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- Stereodivergent, Chemoenzymatic Synthesis of Azaphilone Natural Products
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Selective access to a targeted isomer is often critical in the synthesis of biologically active molecules. Whereas small-molecule reagents and catalysts often act with anticipated site- and stereoselectivity, this predictability does not extend to enzymes. Further, the lack of access to catalysts that provide complementary selectivity creates a challenge in the application of biocatalysis in synthesis. Here, we report an approach for accessing biocatalysts with complementary selectivity that is orthogonal to protein engineering. Through the use of a sequence similarity network (SSN), a number of sequences were selected, and the corresponding biocatalysts were evaluated for reactivity and selectivity. With a number of biocatalysts identified that operate with complementary site- and stereoselectivity, these catalysts were employed in the stereodivergent, chemoenzymatic synthesis of azaphilone natural products. Specifically, the first syntheses of trichoflectin, deflectin-1a, and lunatoic acid A were achieved. In addition, chemoenzymatic syntheses of these azaphilones supplied enantioenriched material for reassignment of the absolute configuration of trichoflectin and deflectin-1a based on optical rotation, CD spectra, and X-ray crystallography.
- Pyser, Joshua B.,Baker Dockrey, Summer A.,Benítez, Attabey Rodríguez,Joyce, Leo A.,Wiscons, Ren A.,Smith, Janet L.,Narayan, Alison R. H.
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- Rhodium(III)-Catalyzed Aerobic Oxidative C-H Olefination of Unsaturated Acrylamides with Unactivated Olefins
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A rhodium(III)-catalyzed aerobic oxidative cross-coupling of acrylamides with unactivated alkenes via vinylic C-H activation has been developed. The present cross-coupling reaction was examined with a variety of differently functionalized acrylamides and unactivated olefins. In these reactions, highly valuable amide-functionalized butadienes were prepared in good to excellent yields. This protocol was also compatible with Weinreb amides. A possible reaction mechanism involving the chelation-assisted vinylic C-H activation via a carboxylate-assisted deprotonation pathway is proposed.
- Logeswaran, Ravichandran,Jeganmohan, Masilamani
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- Synthesis of coumaperine derivatives: Their NF-κB inhibitory effect, inhibition of cell migration and their cytotoxic activity
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Coumaperine (an amide alkaloid, present in white piper) and its derivatives were synthesized and investigated for their cytotoxicity against L428 and A549 cells and their NF-κB inhibitory activity. It was found that the coumaperine derivatives CP-9 and CP-38 suppress NF-κB subunits p50 and p65 in nuclear fractions by western blot and by NF-κB luciferase reporter gene assay in a dose dependent manner. Confirmation of these results was obtained by confocal microscopy. CP-9, CP-32 and CP-38 also exhibited dose dependent cell cytotoxicity in a L428?cells expressing constitutively active NF-κB and in A549?cells, with an IC50 value of 43.25?μg/ml, 0.39?μg/ml and 16.85?μg/ml respectively against L428?cells and 57.15?μg/ml, 69.1?μg/ml and 63.2?μg/ml respectively against A549?cells. In addition, the coumaperine derivatives show remarkable inhibitory activity on the cancer cell migration assay against A549 lung adenocarcinoma cells at the concentrations of 5?μg/ml, 10?μg/ml, and 5?μg/ml of CP-9, CP-32 and CP-38 respectively. Aromatic substituents and number of olefinic double bond in coumaperine derivatives found to influence the inhibitory activity. In luciferase reporter gene assay, di-olefin conjugated coumaperine derivatives, CP-38, CP-32 and PIP exhibited higher inhibitory activity than their corresponding tri-olefin conjugated coumaperine derivatives, CP-102, CP-146 and PIP-155 respectively. CP-32 with a stronger electron donating group (-N(CH3)2) showed better inhibitory activity in luciferase reporter gene assay and in cell proliferation of L428?cells. Simple coumaperine derivative (CP-9, with no substituent) effectively inhibited A549?cells proliferation and migration than the other coumaperine derivatives. CP-9 and CP-38 diminish significantly the NF-κB subunits (p50 and p65) of L428?cells in nuclear fractions at the dosage of 10?μg/ml and 30?μg/ml respectively. Which clearly shows that CP-9 and CP-38 inactivate the NF-κB pathway in?vitro.
- Nandakumar, Natarajan,Muthuraman, Subramani,Gopinath, Pushparathinam,Nithya, Pattusamy,Gopas, Jacob,Kumar, Rajendran Saravana
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- SYNTHESE REGIOSPECIFIQUE D'AMIDO-1 VINYL-2 CYCLOPROPANES A PARTIR DE LITHIENS ALLYLIQUES MONOHALOGENES ET D'AMIDES TERTIAIRES α-ETHYLENIQUIES
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Chloroallyllitium and gem-chloro(methyl)allyllithium readly react, via conjugated addition and cyclisation, with α-ethylenic aliphatic tertiary amides to produce, in a "one-pot" reaction, alkyl-substituted 1-amido-2-vinylcyclopropanes.
- Ongoka, Pascal,Mauze, Bernard,Miginiac, Leone
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- Structure activity studies with xenobiotic substrates using carboxylesterases isolated from Arabidopsis thaliana
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Carboxylesterases (CXEs) catalyse the hydrolysis of xenobiotics and natural products radically altering their biological activities. Whereas the substrate selectivity of animal CXEs, such as porcine liver esterase (PLE) have been well studied, the respective enzymes in plants have yet to be defined and their activities determined. Using Arabidopsis thaliana (At) as a source, five representative members of the α/β hydrolase AtCXE family of proteins have been cloned, expressed and the purified recombinant proteins assayed for esterase activity with xenobiotic substrates. Two members, AtCXE5 and AtCXE18 were found to be active carboxylesterases, though AtCXE5 proved to be highly unstable as a soluble protein. AtCXE18 and the previously characterised S-formylglutathione hydrolase from Arabidopsis (AtSFGH) were assayed against a series of esters based on methylumbelliferone in which the acyl moiety was varied with respect to size and conformation. The same series was used to assay crude esterase preparation from Arabidopsis plants and the results compared with those obtained with the commonly used PLE. With straight chain esters, AtCXE18 behaved like PLE, but the Arabidopsis hydrolases proved less tolerant of branched chain acyl components than the mammalian enzyme. While none of the enzyme preparations accurately reflected all the activities determined with crude Arabidopsis protein extracts, the plant enzymes proved more useful than PLE in predicting the hydrolysis of the more sterically constrained esters.
- Cummins, Ian,Landrum, Marie,Steel, Patrick G.,Edwards, Robert
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- Selective α-arylation of α,β-unsaturated imides mediated by a visible light photoredox catalyst
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Visible light-mediated α-arylation of α,β-unsaturated imides is achieved via aminium radicals generated from diarylalkylamines using a photoredox catalyst. On the basis of emission quenching experiments, a plausible pathway of the reaction is discussed.
- Ando, Yuki,Kamatsuka, Takuto,Shinokubo, Hiroshi,Miyake, Yoshihiro
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- Synthesis of thiolactone building blocks as potential precursors for sustainable functional materials
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A library of multifunctional monomers from homocysteine thiolactone and thioparaconic acid were synthesized using straightforward chemistry routes. A generic protocol was developed, leading to multi-gram amounts of the targeted compounds and enabling up-scaling experiments for promising compounds in the area of functional coatings. Aspects considered during selection of targets and synthesis pathways included functional diversity, expected physical properties, sustainability and commercial availability of reagents, as well as feasibility to achieve an industrially relevant process. Trends were observed in yield, physical properties and chemical behavior.
- Frank, Daniel,Espeel, Pieter,Claessens, Sven,Mes, Edwin,Du Prez, Filip E.
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- Effect of Transition Metals on Chemodivergent Cross-Coupling of Acrylamides with Vinyl Acetate via C-H Activation
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A novel chemodivergent cross-coupling of acrylamides and vinyl acetates has been realized via metal-catalyzed vinylic C-H activation. The selective olefinic C-H vinylation and alkenylation reaction was examined with a variety of differently functionalized acrylamides. The reaction efficiently generates a range of highly synthetically valuable butadienes with good functional group tolerance in good to moderate yields. A possible catalytic reaction mechanism involving the chelation-assisted olefinic C-H activation via an acetate-assisted deprotonation pathway is proposed.
- Logeswaran, Ravichandran,Jeganmohan, Masilamani
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supporting information
p. 5679 - 5683
(2021/08/03)
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- Quorum sensing and nf-κb inhibition of synthetic coumaperine derivatives from piper nigrum
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Bacterial communication, termed Quorum Sensing (QS), is a promising target for virulence attenuation and the treatment of bacterial infections. Infections cause inflammation, a process regulated by a number of cellular factors, including the transcription Nuclear Factor kappa B (NF-κB); this factor is found to be upregulated in many inflammatory diseases, including those induced by bacterial infection. In this study, we tested 32 synthetic derivatives of coumaperine (CP), a known natural compound found in pepper (Piper nigrum), for Quorum Sensing Inhibition (QSI) and NF-κB inhibitory activities. Of the compounds tested, seven were found to have high QSI activity, three inhibited bacterial growth and five inhibited NF-κB. In addition, some of the CP compounds were active in more than one test. For example, compounds CP-286, CP-215 and CP-158 were not cytotoxic, inhibited NF-κB activation and QS but did not show antibacterial activity. CP-154 inhibited QS, decreased NF-κB activation and inhibited bacterial growth. Our results indicate that these synthetic molecules may provide a basis for further development of novel therapeutic agents against bacterial infections.
- Baruch, Yifat,Gopas, Jacob,Kadosh, Yael,Kumar, Rajendran Saravana,Kushmaro, Ariel,Muthuraman, Subramani,Yaniv, Karin
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supporting information
(2021/05/28)
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- Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities
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Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a - 2d , 3a - 3g , and 4a - 4t , were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f , with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50= 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50= 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.
- Feng, Jia-Hao,He, Qi-Wei,Hou, Ji-Qin,Hu, Xiao-Long,Long, Huan,Wang, Bao-Lin,Wang, Hao,Wang, Quan,Wang, Rong,Ye, Wen-Cai,Zhang, Li-Xin,Zhang, Xiao-Qi
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p. 1954 - 1966
(2021/07/20)
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- Bromo Radical-Mediated Photoredox Aldehyde Decarbonylation towards Transition-Metal-Free Hydroalkylation of Acrylamides at Room Temperature
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Herein, we report a visible-light-mediated hydroalkylation reaction of alkenes using easily available aldehydes as alkyl sources via bromo radical-promoted photoredox decarbonylation. This protocol provides an alternative entry to C(sp3)?C(sp3) bond formation and features considerable advantages including mild and clean reaction conditions, obviation for transition-metal catalyst, and good functional group compatibility.
- Deng, Guo-Jun,Huang, Huawen,Sun, Zhaozhao,Wang, Qiaolin
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supporting information
(2021/12/03)
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- Synthesis of Forms of a Chiral Ruthenium Complex Containing a Ru-Colefin(sp2) Bond and Their Application to Catalytic Asymmetric Cyclopropanation Reactions
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Organometallic complexes [Ru-Colefin(sp2)-Ru(II)-Pheox 2a-2d] containing a Ru-Colefin(sp2) bond have been prepared from unsaturated chiral oxazoline derivatives and evaluated for asymmetric cyclopropanation reactions. The corresponding optically active cyclopropanes were obtained with high yields and high stereoselectivities (≥99/2) bond. In particular, Ru(II)-Prox catalyst 2c, in which there was no geminal substituent on the metal, was shown to have the highest enantioselectivities.
- Fujisawa, Ikuhide,Inoue, Hayato,Iwasa, Seiji,Phan Thi Thanh, Nga
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supporting information
(2020/02/15)
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- Nickel-Catalyzed Alkyl-Alkyl Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for the Synthesis of Alkylcyclopropanes
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Cross-electrophile coupling reactions of two Csp3-X bonds remain challenging. Herein we report an intramolecular nickel-catalyzed cross-electrophile coupling reaction of 1,3-diol derivatives. Notably, this transformation is utilized to synthesize a range of mono- and 1,2-disubstituted alkylcyclopropanes, including those derived from terpenes, steroids, and aldol products. Additionally, enantioenriched cyclopropanes are synthesized from the products of proline-catalyzed and Evans aldol reactions. A procedure for direct transformation of 1,3-diols to cyclopropanes is also described. Calculations and experimental data are consistent with a nickel-catalyzed mechanism that begins with stereoablative oxidative addition at the secondary center.
- Chen, Pan-Pan,Hong, Xin,Jarvo, Elizabeth R.,McGinnis, Tristan M.,Sanford, Amberly B.,Thane, Taylor A.
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supporting information
(2020/03/23)
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- Isoalantolactone derivative, pharmaceutical composition and application thereof
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The invention relates to an isoalantolactone derivative, a pharmaceutical composition and application thereof, especially use of the isoalantolactone derivative shown as formula (I) or a salt pharmaceutical compound thereof in preparation of adjuvant drugs treating cancer, a pharmaceutical composition containing a therapeutically effective amount of isoalantolactone derivative (I) or its salt anda pharmaceutically acceptable carrier or a composition with other anticancer drugs.
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Paragraph 0014
(2019/02/02)
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- Design, synthesis and identification of novel coumaperine derivatives for inhibition of human 5-LOX: Antioxidant, pseudoperoxidase and docking studies
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5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 μM. Their IC50 values are 2.1 ± 0.2 μM and 2.3 ± 0.2 μM respectively, and are comparable to zileuton, IC50 = 1.4 ± 0.2 μM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 μM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 μM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug.
- Muthuraman, Subramani,Sinha, Shweta,Vasavi,Waidha, Kamran Manzoor,Basu, Biswarup,Munussami, Punnagai,Balamurali,Doble, Mukesh,Saravana Kumar, Rajendran
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supporting information
p. 604 - 619
(2019/01/14)
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- Formamide catalyzed activation of carboxylic acids-versatile and cost-efficient amidation and esterification
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A novel, broadly applicable method for amide C-N and ester C-O bond formation is presented based on formylpyrrolidine (FPyr) as a Lewis base catalyst. Herein, trichlorotriazine (TCT), which is the most cost-efficient reagent for OH-group activation, was employed in amounts of ≤40 mol% with respect to the starting material (100 mol%). The new approach is distinguished by excellent cost-efficiency, waste-balance (E-factor down to 3) and scalability (up to >80 g). Moreover, high levels of functional group compatibility, which includes acid-labile acetals and silyl ethers, are demonstrated and even peptide C-N bonds can be formed. In comparison to reported amidation procedures using TCT, yields are considerably improved (for instance from 26 to 91%) and esterification is facilitated for the first time in synthetically useful yields. These significant enhancements are rationalized by activation by means of acid chlorides instead of less electrophilic acid anhydride intermediates.
- Huy, Peter H.,Mbouhom, Christelle
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p. 7399 - 7406
(2019/08/20)
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- PROCESS FOR THE PREPARATION OF PIPERINE
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The present application relates to a process for the preparation of piperine of high purity having low concentrations of isomeric impurities.
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Page/Page column 9; 14; 17
(2019/05/02)
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- Visible light photocatalytic asymmetric synthesis of pyrrolo[1,2-: A] indoles via intermolecular [3+2] cycloaddition
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The intermolecular diastereoselective and enantioselective synthesis of pyrrolo[1,2-a]indoles is developed through a [3+2] cycloaddition between silyl-indole derivatives and α,β-unsaturated N-acyl oxazolidinones by merging photocatalysis and Lewis acid catalysis.
- Casado-Sánchez, Antonio,Domingo-Legarda, Pablo,Cabrera, Silvia,Alemán, José
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supporting information
p. 11303 - 11306
(2019/09/30)
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- SPIRO-LACTAM NMDA MODULATORS AND METHODS OF USING SAME
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 68
(2018/03/28)
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- Formal Lossen Rearrangement/[3+2] Annulation Cascade Catalyzed by a Modified Cyclopentadienyl RhIII Complex
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It has been established that a cyclopentadienyl RhIII complex with two phenyl groups and a pendant amide moiety catalyzes the formal Lossen rearrangement/[3+2] annulation cascade of N-pivaloyl benzamides and acrylamides with alkynes leading to substituted indoles and pyrroles. Mechanistic studies revealed that this cascade reaction proceeds via not the Lossen rearrangement to form anilides or enamides but C?H bond cleavage, alkyne insertion, and the formal Lossen rearrangement.
- Yamada, Takayuki,Shibata, Yu,Kawauchi, Susumu,Yoshizaki, Soichi,Tanaka, Ken
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supporting information
p. 5723 - 5727
(2018/04/11)
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- Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline as potential EGFR inhibitors
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Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.09 ± 0.04 μM, 1.34 ± 0.13 μM and 1.23 ± 0.09 μM, respectively. Eight selected compounds were further selected to evaluated for the inhibitory activity against EGFR kinase. Three of them showed equal activity against EGFR kinase to positive control afatinib. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that the compound 13a could induce apoptosis of human lung cancer A549 cells.
- OuYang, Yiqiang,Zou, Wensheng,Peng, Liang,Yang, Zunhua,Tang, Qidong,Chen, Mengzi,Jia, Shuang,Zhang, Hong,Lan, Zhou,Zheng, Pengwu,Zhu, Wufu
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- Preliminary investigations into the synthesis and antimicrobial activities of boron-containing capsaicinoids
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This preliminary study reports on the synthesis of two new boron-capsaicin derivatives containing either a short or long chain aliphatic tail group using an iridium catalyzed hydroboration reaction with pinacolborane. The boronate ester groups reside on the terminal position of the tail group and are necessary for the bioactivity of these compounds. Indeed, both compounds showed considerable activity against two Gram-positive bacteria, including Vancomycin-resistant Enterococcus. Vancomycin is considered the last resort medication for the treatment of septicemia, and new antibacterial agents that can treat sepsis are of paramount importance. The more lipophilic boron compound with the longer aliphatic chain also showed antifungal activity against Saccharomyces cerevisiae.
- Ramsaywack, Sharwatie,Bos, Allyson,Vogels, Christopher M.,Gray, Christopher A.,Westcott, Stephen A.
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supporting information
p. 1065 - 1070
(2018/11/24)
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- Solvent-free regioselective synthesis of novel isoxazoline and pyrazoline N-substituted saccharin derivatives under microwave irradiation
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Novel isoxazoline and pyrazoline derivatives of N-substituted saccharin were synthesized in good yields by 1,3-dipolar cycloaddition of N-crotonoyl- or N-cinnamoylsaccharin as dipolarophile to arylnitrile oxides or nitrile imines using p-HAP300 as catalyst under solvent-free microwave conditions. In this process, the yields were significantly improved compared to classical conditions without alteration of the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed.
- Saber, Aziza,Driowya, Mohsine,Alaoui, Soukaina,Marzag, Hamid,Demange, Luc,álvarez, Eleuterio,Benhida, Rachid,Bougrin, Khalid
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- Regiocontrolled Coupling of Aromatic and Vinylic Amides with α-Allenols to Form γ-Lactams via Rhodium(III)-Catalyzed C-H Activation
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A mild, regiocontrolled coupling of aromatic and vinylic amides with α-allenols to form γ-lactams via rhodium(III)-catalyzed C-H activation has been demonstrated. This [4 + 1] annulation reaction provides an efficient method for the synthesis of isoindolinones and 1,5-dihydro-pyrrol-2-ones bearing a tetrasubstituted carbon atom α to the nitrogen atom with good functional group tolerance. The hydroxyl group in the allene substrate is essential in controlling the chemo- and regioselectivity of the reaction probably by coordination interaction with the rhodium catalyst.
- Zhou, Zhi,Liu, Guixia,Lu, Xiyan
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supporting information
p. 5668 - 5671
(2016/11/17)
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- Nonpeptidic Selective Inhibitors of the Chymotrypsin-Like (β5 i) Subunit of the Immunoproteasome
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Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide-based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin-like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell-based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i-selective probes for possible application in noncancer diseases related to the immunoproteasome.
- Sosi?, Izidor,Gobec, Martina,Brus, Boris,Knez, Damijan,?ivec, Matej,Konc, Janez,Le?nik, Samo,Ogrizek, Mitja,Obreza, Ale?,?igon, Du?an,Jane?i?, Du?anka,Mlinari?-Ra??an, Irena,Gobec, Stanislav
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supporting information
p. 5745 - 5748
(2016/05/09)
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- Trans N-ethyl-N-(2 the [...] -alkyl-phenyl) - 2-butenamide synthetic method
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The invention relates to a synthesis method for trans N-ethyl-N-(2'-alkyl phenyl)-2-butenamide. The method comprises the steps of: 1) adding trans 2- butenoic acid into a reaction bottle, conducting dilution with an alkane solvent, performing cooling to 0-10DEG C, adding thionyl chloride dropwise, and then carrying out reaction at 10-50DEG C for 3-4h for standby use; 2) adding N-ethyl-2-alkyl aniline into the reaction bottle, conducting dilution with an alkane solvent, adding an alkaline aqueous solution, subjecting the mixed solution to stirring reaction at room temperature, adding the mixed solution obtained in step 1) slowly in a dropwise manner, and then carrying out reaction at 60-90DEG C for 5-6h at the end of dropwise adding; and 3) at the end of the reaction, separating out the organic phase, and washing the organic phase to neutral by water, conducting room temperature distillation to remove the solvent, and then performing pressure reduced distillation to separate the product. The method is simple, has high product yield, and can produce the high purity trans-structure product.
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Paragraph 0024; 0025
(2016/10/07)
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- PSORALEN DERIVATIVES AS NON-PEPTIDIC INHIBITORS OF CHYMOTRYPSIN-LIKE ACTIVITY OF THE IMMUNOPROTEASOME
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This invention relates to new inhibitors of chymothrypsin-like activity of the immunoproteasome (inhibitors of β5? or LMP7 subunit) with the general formula (I), where substituents are described in patent description. Compounds can be in the form of pure enantiomers or as racemic mixtures, or in the form of pharmaceutically acceptable salts. The present invention relates to the use of these inhibitors for the treatment of diseases where immunoproteasome activity is increased.
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Paragraph 0202; 0203; 0204; 0205
(2016/10/11)
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- Visible light induced radical cyclization of o-iodophenylacrylamides: A concise synthesis of indolin-2-one
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A [Ir(ppy)2(dtb-bpy)]PF6-catalyzed intramolecular radical cyclization of o-iodophenylacrylamides affording indolin-2-ones in moderate to excellent yields via 5-exo-trig radical cyclization under visible light is presented. This method provides new access to the synthesis of indolin-2-ones under mild reaction conditions. This journal is
- Dong, Wuheng,Liu, Yan,Hu, Bei,Ren, Kai,Li, Yuyuan,Xie, Xiaomin,Jiang, Yuexiu,Zhang, Zhaoguo
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supporting information
p. 4587 - 4590
(2015/05/27)
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- PROTEIN TYROSINE KINASE MODULATORS AND METHODS OF USE
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Heterocyclic pyrimidine compounds that modulate mutant-selective epidermal growth factor receptor (EGFR) and ALK kinase activity are disclosed. More specifically, the invention provides pyrimidines which inhibit, regulate and/or modulate kinase receptor, particularly in selectively modulation of various EGFR mutant activity and ALK kinase activity have been disclosed. Pharmaceutical compositions comprising the pyrimidine derivative,and methods of treatment for diseases associated with protein kinase enzymatic activity, particularly EGFR or ALK kinase activity including non-small cell lung cancer comprising administration of the pyrimidine derivative are disclosed.
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Page/Page column 52; 53
(2015/02/02)
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- An LC-MS/MS method to quantify acylcarnitine species including isomeric and odd-numbered forms in plasma and tissues
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Acylcarnitines are intermediates of fatty acid and amino acid oxidation found in tissues and body fluids. They are important diagnostic markers for inherited diseases of peroxisomal and mitochondrial oxidation processes and were recently described as biomarkers of complex diseases like the metabolic syndrome. Quantification of acylcarnitine species can become challenging because various species occur as isomers and/or have very low concentrations. Here we describe a new LC-MS/MS method for quantification of 56 acylcarnitine species with acyl-chain lengths from C2 to C18. Our method includes amino acid-derived positional isomers, like methacrylyl-carnitine (2-M-C3:1-CN) and crotonyl-carnitine (C4:1-CN), and odd-numbered carbon species, like pentadecanoyl-carnitine (C15:0-CN) and heptadecanoyl-carnitine (C17:0-CN), occurring at very low concentrations in plasma and tissues. Method validation in plasma and liver samples showed high sensitivity and excellent accuracy and precision. In an application to samples from streptozotocin-treated diabetic mice, we identified significantly increased concentrations of acylcarnitines derived from branched-chain amino acid degradation and of odd-numbered straight-chain species, recently proposed as potential biomarkers for the metabolic syndrome. In conclusion, the LC-MS/MS method presented here allows robust quantification of isomeric acylcarnitine species and extends the palette of acylcarnitines with diagnostic potential derived from fatty acid and amino acid metabolism.
- Giesbertz, Pieter,Ecker, Josef,Haag, Alexander,Spanier, Britta,Daniel, Hannelore
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p. 2029 - 2039
(2015/11/17)
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- CONDENSED HETEROCYCLIC COMPOUND
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The present invention provides a fused heterocyclic compound having an RORγt inhibitory action. The present invention relates to a compound represented by the formula (I'): wherein each symbol is as defined in the specification, provided that 2-(2-((4-cyanophenyl)amino)-2-oxoethoxy)-N-(9-ethyl-9H-carbazol-3-yl)acetamide and N-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3-methylpentanediamide are excluded, or a salt thereof.
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Paragraph 0503; 0504
(2014/08/06)
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- Organocatalytic access to enantioenriched dihydropyran phosphonates via an inverse-electron-demand hetero-Diels-Alder reaction
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The enantioselective inverse-electron-demand hetero-Diels-Alder reaction of the remote olefin functionality in dienamines has been developed by the simultaneous activation of α,β-unsaturated aldehydes and acyl phosphonates. The dual activation is based on an organocatalyst that activates both the α,β-unsaturated aldehyde, through dienamine formation, and the acyl phosphonate by hydrogen-bonding. The enantioselective reaction results in the formation of dihydropyran frameworks with three contiguous stereogenic centers. Different substitution patterns are possible for both the heterodiene and the dienophile, and the target products are obtained in good yields and up to 92% ee. The potential of the reaction is demonstrated by transformation of the products into valuable and complex synthons.
- Weise, Christian F.,Lauridsen, Vibeke H.,Rambo, Raoní S.,Iversen, Eva H.,Olsen, Marie-Luise,J?rgensen, Karl Anker
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p. 3537 - 3546
(2014/05/06)
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- Ligand-promoted alkylation of C(sp3)-H and C(sp2)-H bonds
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9-Methylacridine was identified as a generally effective ligand to promote a Pd(II)-catalyzed C(sp3) - H and C(sp2) - H alkylation of simple amides with various alkyl iodides. This alkylation reaction was applied to the preparation of unnatural amino acids and geometrically controlled tri- and tetrasubstituted acrylic acids.
- Zhu, Ru-Yi,He, Jian,Wang, Xiao-Chen,Yu, Jin-Quan
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supporting information
p. 13194 - 13197
(2015/03/30)
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- Total regio- and diastereocontrol in the aldol reactions of dienolborinates
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It is reported that appropriate dienolborinates can provide access to both diastereomers of 2-(hydroxymethyl)but-3-enoates through exclusive α-regiocontrol in a non-vinylogous pathway. Contrary to previous reports in which dialkylchloroboranes failed to enolize propanoates, acidity-enhanced but-3-enoates readily undergo enolization, offering unprecedented control over the formation of these valuable synthons. The first example of an aldol reaction in the presence of a phosphine-borane adduct is also reported.
- Ramachandran, P. Veeraraghavan,Nicponski, Daniel,Kim, Bomi
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supporting information
p. 1398 - 1401
(2013/05/09)
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- Synthesis, antimycobacterial, antiviral, antimicrobial activity and QSAR studies of N2-acyl isonicotinic acid hydrazide derivatives
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A series of N2-acyl isonicotinic acid hydrazides (1-17) was synthesized and tested for its in vitro antimycobacterial activity against Mycobacterium tuberculosis and the results indicated that the compound, isonicotinic acid N′- tetradecanoyl-hydrazide (12) was more active than the reference compound isoniazid. The results of antimicrobial activity of the synthesized compounds against S. aureus, B. subtilis, E. coli, C. albicans and A. niger indicated that compounds with dichloro, hydroxyl, tri-iodo and N 2 -tetradecanoyl substituent were the most active ones. The antiviral activity studies depicted that none of the tested compounds were active against DNA or RNA viruses. The multi-target QSAR model was found to be effective in describing the antimicrobial activity of N2-acyl isonicotinic acid hydrazides.
- Judge, Vikramjeet,Narasimhan, Balasubramanian,Ahuja, Munish,Sriram, Dharmarajan,Yogeeswari, Perumal,De Clercq, Erik,Pannecouque, Christophe,Balzarini, Jan
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- Convenient synthesis of various substituted homotaurines from alk-2-enamides
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Various substituted homotaurines (=3-aminopropane-1-sulfonic acids) 6 were readily synthesized in satisfactory to good yields via the Michael addition of thioacetic acid to alk-2-enamides 3 (→4), followed by LiAlH4 reduction (→5) and performic acid oxidation (Scheme 1). The configuration of 'anti'-disubstituted homotaurine 'anti'-6h was deduced from the 3-(acetylthio)alkanamide (=S-(3-amino-1,2-dimethyl-3-oxopropyl) ethanethioate)'anti'-4h formed in the Michael addition, which was identified via the Karplus equation analysis, and confirmed by X-ray diffraction analysis. The current route is an efficient method to synthesize diverse substituted homotaurines, including 1-, 2-, and N-monosubstituted, as well as 1,2-, 1,N-, 2,N-, and N,N-disubstituted homotaurines (Table). Copyright
- Nai, Youfeng,Xu, Jiaxi
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p. 1355 - 1365
(2013/08/23)
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- Rh(III)-catalyzed halogenation of vinylic C-H bonds: Rapid and general access to Z-halo acrylamides
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Herein, the regio- and stereoselective iodination, along with some examples for the bromination, of readily available acrylamides to access a variety of differently substituted Z-haloacrylic acid derivatives is reported. The reaction proceeds under mild conditions via a Rh(III)-catalyzed C-H-activation/ halogenation mechanism and represents a rare example of a direct halogenation of electron-poor acrylic acid derivatives.
- Kuhl, Nadine,Schroeder, Nils,Glorius, Frank
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supporting information
p. 3860 - 3863
(2013/09/02)
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- A protocol for accessing the β-azidation of α,β-unsaturated carboxylic acids
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This contribution reports the preparation and use of a new immobilized catalyst, PS-DABCOF (9), which has been specifically designed to access for the first time the efficient β-azidation of α,β-unsaturated carboxylic acids.
- Angelini, Tommaso,Bonollo, Simona,Lanari, Daniela,Pizzo, Ferdinando,Vaccaro, Luigi
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supporting information
p. 4610 - 4613
(2012/10/30)
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- One-Step Synthesis Method of 2,9-Dimethyl-4,7-Diphenyl-1,10- Phenanthroline
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This invention, which belongs to the field of organic synthesis, involves “One-step synthetic method of 2,9-dimethyl-1,7-diphenyl-1,10-phenanthroline”. This method uses O-phenylenediamine and formula III to react under the condition of mixed-shrinking agent, the synthesis can be completed in one step, the stated mixed-shrinking agent is mixture of hydrochloric acid and organic acid. The organic acid serves as phase transfer catalyst and shrinking agent, meanwhile, as buffer reagent, organic acid reduces polymerization of III, and side products as well. The products gained are of high purity and the reaction is mild and easy to control. Since there is no polluting material added and generated, the waste is safe to discharge. In the after treatment of reaction, ketone solvent is used to reduce separation step and product lost, thus improving yield.
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Page/Page column 3
(2012/07/13)
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- Undirected arene and chelate-assisted olefin C-H bond activation: [Rh IIICp*]-catalyzed dehydrogenative alkene-arene coupling as a new pathway for the selective synthesis of highly substituted Z olefins
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Undirected/Directed Cross-Coupling: A new dehydrogenative Rh III-catalyzed cross-coupling reaction between bromoarenes bearing no directing group and vinylic substrates substituted by a chelating group is reported. An original reaction mechanism enables the use of internal alkenes in a Z-selective coupling. The application of 1,3-disubstituted or 1,2-homodisubstituted arenes leads to the formation of highly functionalized, complex, and valuable olefins as one single isomer. Copyright
- Wencel-Delord, Joanna,Nimphius, Corinna,Patureau, Frederic W.,Glorius, Frank
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supporting information; experimental part
p. 1208 - 1212
(2012/07/28)
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- Chiral monooxazolines as modular copper(I)-heterocomplex building blocks: Investigations on the catalytic asymmetric cyclopropanation of alkenes
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Novel chiral monodentate oxazoline ligands have been synthesized in good yields. The catalytic activity of these monodentate oxazoline/Cu catalysts was evaluated in the catalytic asymmetric cyclopropanation of styrene and α-methylstyrene, giving moderate to good enantioselectivities (up to 74% ee for the trans-cyclopropane product) and full conversions (up to 100%). In an attempt to enhance the enantioselectivities of the cyclopropanations, heterocombinations of these ligands were used. Unfortunately, with the data set that was used in this study, no improvements were observed. However, to gain an insight into the nature of the active catalyst present under these circumstances, NMR, mass spectrometric and computational studies were carried out and indicated the presence of bidentate heterocomplexes in the equilibrium mixture. Analysis of the stereoselectivities (ees and des) did not prove very useful in pin-pointing the identity of the active chiral catalyst and only afforded a very weak conclusion. In order to ascertain the importance of the π-π interactions, the monodentate oxazoline ligands 3a and 3b were synthesized and screened in these reactions, and the resulting stereoselectivities were compared to the results obtained using ligands 1a and 1b. There seemed to be very weak π-π interactions at work.
- Carreiro, Elisabete P.,Ramalho, J.P. Prates,Burke, Anthony J.
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experimental part
p. 4640 - 4648
(2011/07/08)
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- Synthesis of β,γ-unsaturated primary amides from α,β-unsaturated acids and investigation of the mechanism
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α,β-Unsaturated acids, through their acid chlorides, react with tritylamine in the presence of triethylamine under mild conditions, to afford in high yield and high regioselectivity the corresponding β,γ- unsaturated tritylamides. Detritylation with TFA generates quantitatively β,γ-unsaturated primary amides. An investigation of this deconjugative isomerization was performed.
- Theodorou, Vassiliki,Gogou, Marina,Philippidou, Maria,Ragoussis, Valentine,Paraskevopoulos, Georgios,Skobridis, Konstantinos
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experimental part
p. 5630 - 5634
(2011/08/22)
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- 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: Synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation
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A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]- benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2χv) in describing the antimicrobial activity of synthesized compounds (1-20).
- Yadav, Snehlata,Kumar, Pradeep,De Clercq, Erik,Balzarini, Jan,Pannecouque, Christophe,Dewan, Sharwan Kumar,Narasimhan, Balasubramanian
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scheme or table
p. 5985 - 5997
(2011/01/13)
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- Inhibition of mycobacterial growth by plumbagin derivatives
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Electron transport and respiratory pathways are active in both latent and rapidly growing mycobacteria and remain conserved in all mycobacterial species. In mycobacteria, menaquinone is the sole electron carrier responsible for electron transport. Menaquinone biosynthesis pathway is found to be essential for the growth of mycobacteria. Structural analogs of the substrate or product of this pathway are found to be inhibitory for the growth of Mycobacterium smegmatis and M. tuberculosis. Several plumbagin [5-hydroxy-2-methyl-1, 4-naphthaquinone] derivatives have been analyzed for their inhibitory effects of which butyrate plumbagin was found to be most effective on M. smegmatis mc 2155, whereas crotonate plumbagin showed greater activity on M. tuberculosis H37Rv. Effect on electron transport and respiration was demonstrated by butyrate plumbagin inhibiting oxygen consumption in M. smegmatis. Structural modifications of these molecules can further be improved upon to generate new molecules against mycobacteria.
- Mathew, Ritta,Kruthiventi, Anil K.,Prasad, Jalli V.,Kumar, Sadula P.,Srinu, Garlapati,Chatterji, Dipankar
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experimental part
p. 34 - 42
(2011/04/15)
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- Total synthesis of racemic laurenditerpenol, an HIF-1 inhibitor
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(Figure Presented) The convergent total synthesis of the HIF-1 inhibitor laurenditerpenol 1 and its diastereomer 1′ is reported. The key step involves the Julia-Kocienski olefination-reduction process between the sulfone 55 and the aldehyde 54. The unusual trimethylated oxanorbornane sulfone 55 was successfully synthesized from the known exo Diels-Alder adduct 24 of 2,5-dimethylfuran 7 and maleic anhydride 23 in 8 steps. The aldehyde 54 was prepared by ring-opening and elaboration of lactone 41. In addition, four analogues of 1 were also successfully synthesized for biological testing.
- Jung, Michael E.,Im, G.-Yoon Jamie
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supporting information; experimental part
p. 8739 - 8753
(2010/03/04)
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- Enantioselective 1,3-dipolar cycloadditions of diazoacetates with electron-deficient olefins
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Equation presented A general strategy for highly enantioselective 1,3-dipolar cycloaddition of diazoesters to β-substituted, α-substituted, and α,β-disubstituted α,β-unsaturated pyrazolidinone imides is described. Cycloadditions utilizing less reactive α,β-disubstituted dipolarophiles require elevated reaction temperatures, but still provide the corresponding pyrazolines with excellent enantioselectivities. Finally, an efficient synthesis of (-)-manzacidin A employing this cycloaddition methodology as a key step is illustrated.
- Sibi, Mukund P.,Stanley, Levi M.,Soeta, Takahiro
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p. 1553 - 1556
(2008/02/04)
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- Tandem [2+2] cycloaddition and Cope rearrangement in reactions of cross-conjugated azatrienes with conjugated ketenes: a facile single step synthesis of novel azocinone derivatives
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A facile single step synthesis of novel azocinone derivatives involving tandem [2+2] cycloaddition and Cope rearrangement in the reactions of cross-conjugated azatrienes with vinyl/isopropenyl ketenes supported by theoretical calculations is reported.
- Singh, Parvesh,Bhargava, Gaurav,Mahajan, Mohinder P.
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p. 11267 - 11273
(2007/10/03)
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- An entry to a chiral dihydropyrazole scaffold: Enantioselective [3 + 2] cycloaddition of nitrile imines
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We have developed a versatile strategy to access dihydropyrazoles in highly enantioenriched form. Dipolar cycloaddition of electron-deficient acceptors and in situ-generated nitrile imines proceeds with high regio- and enantioselectivity using 10 mol % chiral Lewis acid catalyst. A variety of dihydropyrazoles that incorporate functionality for further manipulation have been prepared. Copyright
- Sibi, Mukund P.,Stanley, Levi M.,Jasperse, Craig P.
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p. 8276 - 8277
(2007/10/03)
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