- Synthesis, vibrational spectroscopy and X-ray structural characterization of novel NIR emitter squaramides
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Two new 2-naphthyl squaramides, 3-methoxy ?4-(2-naphtalenylamino)-3-cyclobutene-1,2-dione (SQ-NPh1) and bis-3,4-(2-naphtalenylamino)-3-cyclobutene-1,2-dione (SQ-NPh2) were synthesized via condensation reaction between the dimethylsquarate and 2-naphthylam
- ávila-Costa, Marina,Donnici, Claudio L.,dos Santos, Jordana Dias,Diniz, Renata,Barros-Barbosa, Alexandre,Cuin, Alexandre,de Oliveira, Luiz Fernando Cappa
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Read Online
- Synthesis of 5-O-methylembelin
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A general synthetic route to 3-alkyl-2-hydroxy-5-methoxy-1,4-benzoquinones and the total synthesis of 5-O-methylembelin is reported based upon ring expansion of substituted cyclobutenes.
- Miles, D.Howard,Payne, Matthew
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Read Online
- Bifunctional Iminophosphorane-Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α,β-Unsaturated Amides
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The first metal-free catalytic intermolecular enantioselective Michael addition to unactivated α,β-unsaturated amides is described. Consistently high enantiomeric excesses and yields were obtained over a wide range of alkyl thiol pronucleophiles and elect
- Dixon, Darren J.,Formica, Michele,Hamlin, Trevor A.,Rozsar, Daniel,Yamazaki, Ken
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supporting information
p. 1006 - 1015
(2022/02/03)
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- The kinetic resolution of oxazinones by alcoholysis: access to orthogonally protected β-amino acids
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The catalytic, alcoholytic kinetic resolution of oxazinones is reported. A novel, stereochemically dense cinchona alkaloid-based catalyst can facilitate the highly enantiodiscriminatory (Sup to 101) ring-opening of oxazinones equipped with electrophilic aryl units to generate orthogonally protected β-amino acids for the first time.
- Cronin, Sarah A.,Connon, Stephen J.
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supporting information
p. 7348 - 7352
(2021/09/07)
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- Regorafenib analogues and their ferrocenic counterparts: Synthesis and biological evaluation
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Approved by the FDA in 2012, regorafenib is one of the last chance treatments for colorectal cancer. While various analogues have already been prepared, ferrocenic derivatives have never been evaluated. In this study, we prepared various ferrocene-containing derivatives of regorafenib and recorded their biological activity in kinase and cellular assays. This led to the identification of a squaramide derivative which shows a good cellular activity and three ferrocene analogues with promising activity in both kinase and cellular assays. This journal is
- Wilde, Myron,Arzur, Danielle,Baratte, Blandine,Lefebvre, Dorian,Robert, Thomas,Roisnel, Thierry,Le Jossic-Corcos, Catherine,Bach, Stéphane,Corcos, Laurent,Erb, William
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supporting information
p. 19723 - 19733
(2020/12/04)
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- NOVEL OXADIAZOLE COMPOUNDS FOR CONTROLLING OR PREVENTING PHYTOPATHOGENIC FUNGI
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The present invention discloses a compound of formula (I), wherein, R1, L1,A, k, L2, W, L4, R5, R8 and R9 are as defined in the detailed description. The present invention furthe
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Page/Page column 67
(2020/10/21)
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- Discovery of N-Cyano-sulfoximineurea Derivatives as Potent and Orally Bioavailable NLRP3 Inflammasome Inhibitors
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NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC50 = 7 nM) and analogues were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1β secretion in mice.
- Agarwal, Sameer,Sasane, Santosh,Shah, Hardik A.,Pethani, Jignesh P.,Deshmukh, Prashant,Vyas, Vismit,Iyer, Pravin,Bhavsar, Harsh,Viswanathan, Kasinath,Bandyopadhyay, Debdutta,Giri, Poonam,Mahapatra, Jogeswar,Chatterjee, Abhijit,Jain, Mukul R.,Sharma, Rajiv
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supporting information
p. 414 - 418
(2020/03/13)
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- Mn(III)-based oxidative radical ring-expansion reaction using squarate derivatives: Selective synthesis of bis(butenolide)s and the acetate monomers
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The Mn(III)-based oxidation of phenyl- and alkyl-substituted hydroxycyclobutenones selectively produced the bis(butenolide)s or the acetate monomers via the 5-endo radical cyclization depending upon the concentration of the reaction. A similar reaction of hydroxycyclobutenones bearing an alkenyl and alkynyl substituent did not produce any bis(butenolide)s or acetate monomers, but the 5-exo and 6-endo radical cyclization products including the unsaturated group. The oxidation of the hydroxycyclobutenones having an unsaturated substituent in the presence of alkenes afforded radical coupling products during the 5-exo radical cyclization. The reaction details, structure determination of the products, and the mechanism for the formation of the products are described.
- Sasaki, Jun-Ichi,Kobayashi, Makoto,Ibe, Y?suke,Nishino, Hiroshi
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p. 958 - 988
(2019/08/01)
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- The base-catalysed Tamura cycloaddition reaction: Calculation, mechanism, isolation of intermediates and asymmetric catalysis
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A combined experimental and computational investigation has revealed that the base-catalysed Tamura cycloaddition between homophthalic anhydride and activated alkenes/alkynes-a reaction previously thought of as a Diels-Alder type process-proceeds via a stepwise mechanism involving conjugate addition and ring closure; which allowed the first catalytic asymmetric α-substitution reactions to be demonstrated with up to >99% ee.
- Lockett-Walters, Bruce,Trujillo, Cristina,Twamley, Brendan,Connon, Stephen
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supporting information
p. 11283 - 11286
(2019/09/30)
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- Dynamic kinetic resolution of bis-aryl succinic anhydrides: Enantioselective synthesis of densely functionalised γ-butyrolactones
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The efficient Dynamic Kinetic Resolution (DKR) of disubstituted anhydrides has been shown to be possible for the first time. Using an ad hoc designed organocatalyst and an enantio- and diastereoselective cycloaddition process with aldehydes, stereochemically complex γ-butyrolactone derivatives can be obtained-with control over three contiguous stereocentres, one of which is all carbon quaternary.
- Claveau, Romain,Twamley, Brendan,Connon, Stephen J.
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supporting information
p. 3231 - 3234
(2018/04/05)
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- Protecting-Group-Free Total Synthesis and Biological Evaluation of 3-Methylkealiiquinone and Structural Analogues
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The modular protecting-group-free total synthesis of 3-methylkealiiquinone, an analogue of the marine alkaloid kealiiquinone, was accomplished in seven steps. A regioselectively constructed functionalized arylbenzimidazolone moiety and dimethyl squarate were used as the only two building blocks. A thermal ring expansion via 6π-conrotatory ring closure to build the quinone fragment gave rise to the desired linear analogue of the natural compound along with a nondescribed structurally attractive angular naphtho[1,2-d]imidazole regioisomer. The IC50 values for the compounds were determined on three cancer cell lines.
- Ramadoss, Velayudham,Alonso-Castro, Angel Josabad,Campos-Xolalpa, Nimsi,Solorio-Alvarado, César R.
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p. 10627 - 10635
(2018/09/06)
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- Total synthesis of kealiiquinone: the regio-controlled strategy for accessing its 1-methyl-4-arylbenzimidazolone core
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A practical, concise and straightforward total synthesis of kealiiquinone 1, a naphtho[2,3-d]imidazole alkaloid obtained from the Micronesian marine sponge Leucetta sp. was accomplished. The squaric acid chemistry to construct the 1,4-quinoid ring and the regioselective N-methylation through a benzo[c][1,2,5]selenadiazolium heterocycle are the key features in this report. The full details of the representative approaches involving the different attempted synthetic strategies are also presented. Finally a successful total synthesis of this complex secondary metabolite is described.
- Ramadoss, Velayudham,Alonso-Castro, Angel J.,Campos-Xolalpa, Nimsi,Ortiz-Alvarado, Rafael,Yahuaca-Juárez, Berenice,Solorio-Alvarado, César R.
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p. 30761 - 30776
(2018/09/13)
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- Squarate-based carbocyclic nucleosides: Syntheses, computational analyses and anticancer/antiviral evaluation
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Squaric acid and its derivatives are versatile synthons and have demonstrated applications in medicinal chemistry, notably as non-classical bioisosteric replacements for functional groups such as carboxylic acids, alpha-amino acids, urea, guanidine, peptide bonds and phosphate/pyrophosphate linkages. Surprisingly, no reports have appeared concerning its possible application as a nucleobase substitute in nucleosides. A preliminary investigation of such an application is reported herein. 3-Amino-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione, 3-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-4-methoxycyclobut-3-ene-1,2-dione, and 3-hydroxy-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione sodium salt were synthesized. Computational analyses of their structures and preliminary antitumor and antiviral screening results are reported.
- Lu, Meijun,Lu, Qing-Bin,Honek, John F.
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supporting information
p. 282 - 287
(2016/12/27)
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- Total Syntheses of Pyroclavine, Festuclavine, Lysergol, and Isolysergol via a Catalytic Asymmetric Nitro-Michael Reaction
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A catalytic enantioselective construction of vicinal stereocenters is reported. The reaction takes advantage of thiourea-catalyzed intramolecular nitronate addition onto α,β-unsaturated ester to afford exceptional levels of enantioselectivity (up to 97 % ee) with moderate diastereoselectivity (up to 4:1). Using this method, a cross-conjugated ester was synthesized in few steps, from which a 6-endo-trig cyclisation led to the formation of all required functionalities for total syntheses of ergot alkaloids. The strategy not only offers first total syntheses of ergot alkaloids, festuclavine (1 c), and pyroclavine (1 e), and but also an efficient and general approach to other congeners such as, lysergol (1 b), and isolysergol (1 d).
- Bhunia, Subhajit,Chaudhuri, Saikat,Bisai, Alakesh
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supporting information
p. 11234 - 11238
(2017/08/26)
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- Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS
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Elevation of reactive oxygen species (ROS) is both a consequence and driver of the upregulated metabolism and proliferation of transformed cells. The resulting increase in oxidative stress is postulated to saturate the cellular antioxidant machinery, leaving cancer cells susceptible to agents that further elevate their intracellular oxidative stress. Several small molecules, including the marine natural product cribrostatin 6, have been demonstrated to trigger apoptosis in cancer cells by increasing intracellular ROS. Here, we report the modular synthesis of a series of cribrostatin 6 derivatives, and assessment of their activity in a number of cell lines. We establish that placing a phenyl ring on carbon 8 of cribrostatin 6 leads to increased potency, and observe a window of selectivity towards cancer cells. The mechanism of activity of this more potent analogue is assessed and demonstrated to induce apoptosis in cancer cells by increasing ROS. Our results demonstrate the potential for targeting tumors with molecules that enhance intracellular oxidative stress.
- Asby,Radigois,Wilson,Cuda,Chai,Chen,Bienemann,Light,Harrowven,Tavassoli
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p. 9322 - 9330
(2016/10/13)
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- Synthesis of an Isotopically Labeled Naphthalene Derivative That Supports a Long-Lived Nuclear Singlet State
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The synthesis of an octa-alkoxy substituted isotopically labeled naphthalene derivative, shown to have excellent properties in singlet NMR experiments, is described. This highly substituted naphthalene system, which incorporates an adjacent 13C spin pair, is readily accessed from a commercially available 13C2-labeled building block via sequential thermal alkynyl- and arylcyclobutenone rearrangements. The synthetic route incorporates a simple desymmetrization approach leading to a small difference in the chemical shifts of the 13C spin pair, a design constraint crucial for accessing nuclear singlet order. (Chemical Equation Presented).
- Hill-Cousins, Joseph T.,Pop, Ionut-Alexandru,Pileio, Giuseppe,Stevanato, Gabriele,H?kansson, P?r,Roy, Soumya S.,Levitt, Malcolm H.,Brown, Lynda J.,Brown, Richard C. D.
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supporting information
p. 2150 - 2153
(2015/05/13)
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- Synthesis and evaluation of cationic norbornanes as peptidomimetic antibacterial agents
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A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 μg mL-1 against Streptococcus pneumoniae, Enterococcus faecalis and several strains of Staphylococcus aureus, including multi-resistant methicillin resistant (mMRSA), glycopeptide-intermediate (GISA) and vancomycin-intermediate (VISA) S. aureus.
- Hickey, Shane M.,Ashton, Trent D.,Khosa, Simren K.,Robson, Ryan N.,White, Jonathan M.,Li, Jian,Nation, Roger L.,Yu, Heidi Y.,Elliott, Alysha G.,Butler, Mark S.,Huang, Johnny X.,Cooper, Matthew A.,Pfeffer, Frederick M.
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supporting information
p. 6225 - 6241
(2015/06/08)
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- Catalytic asymmetric tamura cycloadditions
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In the presence of a novel, tert-butyl-substituted squaramide-based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products of significant synthetic interest with excellent enantio- and diastereocontrol. The methodology is of wide scope and encompasses both homophthalic and glutaconic anhydride derivatives, which lead to structurally diverse products. Glutaconic acid-derived anhydrides undergo a clean post-cyclization decarboxylation process which is not a feature of reactions involving homophthalic acid-derived anhydrides. The unusual influence of reaction temperature on diastereocontrol has been probed, with reactions occurring at 30 °C and -30 °C delivering products epimeric at one stereocenter only, in near optical purity. Squared away: The first strategy for bringing about enantioselective Tamura reactions is reported. In the presence of a squaramide-based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products with excellent enantio- and diastereocontrol. The methodology is of wide scope and leads to structurally diverse products.
- Manoni, Francesco,Connon, Stephen J.
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supporting information
p. 2628 - 2632
(2014/03/21)
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- Organoytterbium ate complexes extend the value of cyclobutenediones as isoprene equivalents
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Changing course: While organolithium and Grignard reagents favor addition to C1 of A (R=Me), the corresponding organoytterbium reagents add to C2 (R=tBu). Computational studies provide insights into the nature of organoytterbium species and their reactivity, and a total synthesis of (-)-mansonone B illustrates the utility of the method in terpenoid synthesis. Tf=trifluoromethanesulfonyl.
- Packard, Emma,Pascoe, David D.,Maddaluno, Jacques,Goncalves, Theo P.,Harrowven, David C.
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supporting information
p. 13076 - 13079
(2014/01/06)
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- New insights into cyclobutenone rearrangements: A total synthesis of the natural ROS-generating anti-cancer agent cribrostatin 6
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Aryl- and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous-flow conditions. The former shows a Hammett correlation with σI providing strong evidence that electrocyclisation is the rate-determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti-neoplastic and anti-microbial agent, provides a topical demonstration of the value of this method.
- Mohamed, Mubina,Gon?alves, Théo P.,Whitby, Richard J.,Sneddon, Helen F.,Harrowven, David C.
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supporting information; experimental part
p. 13698 - 13705
(2012/01/05)
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- New syntheses and ring expansion reactions of cyclobutenimines
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Two routes are reported for the synthesis of iminocyclobutenones having N-(het)aryl substitution: an addition/substitution sequence starting with cyclobutenediones and an aza-Wittig method. A new synthetic route to N-alkyl derivatives is also presented. This involves O-alkylation of 3-alkylamino-1,2-cyclobutenediones using Meerwein's reagent and subsequent deprotonation under non-hydrolytic conditions. Lithium organyls were found to add to the remaining carbonyl group. The resulting tertiary alcohols undergo ring enlargement on heating in xylene to give 4-aminophenols, 4-amino-1-naphthols, or cyclopenta-annulated quinolines from 4-vinyl, 4-aryl, and 4-alkynyl derivatives, respectively. CSIRO 2010.
- Schaumann, Ernst,Oppermann, Gerrit,Stranberg, Michael,Moore, Harold W.
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scheme or table
p. 1656 - 1664
(2011/09/16)
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- PROCESS FOR CONTROLLED CRYSTAL SIZE IN 1,2-SUBSTITUTED 3,4-DIOXO-1-CYCLOBUTENE COMPOUNDS
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This application discloses a novel process for the preparation of 2-Hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide, which has utility, for example, in the treatment of CXC chemokine-mediated diseases.
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Page/Page column 20-21
(2009/03/07)
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- PROCESS AND INTERMEDIATES FOR THE SYNTHESIS OF 1,2-SUBSTITUTED 3,4-DIOXO-1-CYCLOBUTENE COMPOUNDS
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This application discloses a novel process for the preparation of 1.2 - substituted 3, 4 - dioxo - 1 - cyclobutene compounds of formula (A), which have utility, for example, in the treatment of CXC chemokine -mediated diseases, and intermediates useful in the synthesis thereof.
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Page/Page column 30-31
(2009/03/07)
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- Structural effects on interconversion of oxygen-substituted bisketenes and cyclobutenediones
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(Graph Presented) Cyclobutenediones 5 disubstituted with HO (a), MeO (b), EtO (c), i-PrO (d), t-BuO (e), PhO (f), 4-MeOC6H4O (g), 4-O2NC6H4O (h), and 3,4-bridging OCH 2CH2O (i) substituents upon laser flash photolysis gave the corresponding bisketenes 6a-i, as detected by their distinctive doublet IR absorptions between 2075 and 2106 and 2116 and 2140 cm-1. The reactivities in ring closure back to the cyclobutenediones were greatest for the group 6b-e, with the highest rate constant of 2.95 ×107 s -1 at 25°C for 6e (RO = t-BuO) in isooctane, were less for 6a (RO = OH, k = 2.57 × 106 s-1 in CH3CN), while 6f- i were the least reactive, with the lowest rate constant of 3.8 × 104 s-1 in CH3CN for 6h (RO = 4-O 2NC6H4O). The significantly reduced rate constants for 6f-i are attributed to diminution of the electron-donating ability of oxygen to the cyclobutenediones 5f-h by the ArO substituents compared to alkoxy groups and to angle strain in the bridged product cyclobutenedione 5i. The reactivities of the ArO-substituted bisketenes 6f-h in CH3CN varied by a factor of 50 and gave an excellent correlation of the observed rate constants log k with the σp constants of the aryl substituents. Computational studies at the B3LYP/6-31G(d) level of ring-closure barriers are consistent with the measured reactivities. Photolysis of squaric acid (5a) in solution provides a convenient preparation of deltic acid (7).
- Fu, Nanyan,Allen, Annette D.,Kobayashi, Shinjiro,Tidwell, Thomas T.,Vukovic, Sinisa,Matsuoka, Takeshi,Mishima, Masaaki
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p. 1768 - 1773
(2008/09/18)
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- 3,4-DI-SUBSTITUTED CYCLOBUTENE-1,2-DIONES AS CXC-CHEMOKINE RECEPTOR LIGANDS
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Disclosed are novel cyclobutenedione Compounds comprising a cycloclobutenedione ring, a substituted phenyl ring, and a -CH(C2H5)-furan moiety. The phenyl ring and the -CH(C2H5)-furan moiety are each bound to the
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Page/Page column 74-75
(2008/06/13)
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- An efficient general synthesis of squarate esters
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An efficient and general method for the synthesis of alkyl squarates is presented. This involves the reactions of squaric acid with the desired alcohol in the presence of an orthoformate. This was applicable for the synthesis of dimethyl-, diethyl-, diisopropyl, di-n-butyl and di-t-butyl squarates in yields ranging from 77-97%. It is a convenient and safe method that can be accomplished on a multigram scale.
- Liu, Hiu,Tomooka, Craig S.,Moore, Harold W.
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p. 2177 - 2180
(2007/10/03)
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- Synthesis of 4-Substituted-3-alkoxy-3-cyclobutene-1,2-diones
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4-Substituted-3-alkoxycyclobutenediones 3 were obtained from dialkoxycyclobutenediones (dialkyl squarates) 1 by the addition of organolithium reagents followed by hydrolysis of the resulting hydroxycyclobutenone 2.A particularly useful one-pot procedure i
- Reed, Michael W.,Pollart, Daniel J.,Perri, Steven T.,Foland, Lafayette D.,Moore, Harold W.
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p. 2477 - 2482
(2007/10/02)
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- 3,4-Bis(4-substituted piperazinyl)-3-cyclobutene-1,2-diones and related compounds
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3,4-bis(4-substituted piperazinyl)-3-cyclobutene-1,2-diones and related compounds having antiviral activity are described herein. The subject compounds can be prepared by reacting 3,4-dimethoxy-3-cyclobutene-1,2-dione with the appropriate substituted piperazine.
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