- Synthesis of boron-containing cholesterol derivatives for incorporation into unilamellar liposomes and evaluation as potential agents for BNCT
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Four carborane-containing derivatives of cholesterol were prepared for incorporation into the bilayer of unilamellar liposomes and evaluation as potential agents for boron neutron capture therapy. The derivatives enable the evaluation of the linker moiety and the type of carborane head group on the bilayer stability and ultimate in vivo tumor specificity.
- Feakes, Debra A.,Spinler, Jennifer K.,Harris, Fred R.
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- A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling
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Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background.
- Lin, Hong-Yu,Haegele, Joseph A.,Disare, Michael T.,Lin, Qishan,Aye, Yimon
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- 18-iodooctadeca-(8Z,11Z)-dienoic acid as useful intermediate for the synthesis of special lipoxygenase substrates bearing bulky substituents at the ω-position
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18-Iodooctadeca-(8Z, 11Z)-dienoic acid (7) was synthesized in five steps starting from methyl 10-bromodec-7-ynoate (2) in an overall yield of 53%. The synthetic procedure involves Cu(I)-catalyzed cross-coupling of propargylic bromide 2 with 7-octyn-1-ol (3), followed by hydrogenation of the coupling product 4 to Z,Z-diene 5 on Lindlar's catalyst and subsequent substitution of the OH- group of 5 with iodine. Coupling of the resulting iodide 7 with low- order organic cuprates [t-Bu2CuLi or (PhCH2)2CuMgCl] leads to 19,19- dimethyl-eicosa-(8Z, 11Z)-dienoic acid (1a) and 19-phenylnonadeca-(8Z, 11Z)- dienoic acid (1b), respectively. (C) 2000 Elsevier Science Ltd.
- Ivanov, Igor V.,Groza, Nataliya V.,Romanov, Stepan G.,Kuhn, Hartmut,Myagkova, Galina I.
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- Design and synthesis of potential mechanism-based inhibitors of the aminotransferase BioA involved in biotin biosynthesis
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BioA, a pyridoxal 5′-phosphate (PLP) dependent aminotransferase, catalyzes the second step of biotin biosynthesis, converting 7-keto-8-aminopelargonic acid (KAPA) into 7,8-diaminopelargonic acid (DAPA). Amiclenomycin (ACM) isolated from cultures of different Streptomyces strains is a potent mechanism-based inhibitor of BioA that operates via an aromatization mechanism, irreversibly labeling the PLP cofactor. However, ACM is plagued by inherent chemical stability. Herein we describe the synthesis of four inhibitors, inspired by ACM but containing an allylic amine as the chemical warhead, designed to both improve stability and operate via a complementary Michael addition-pathway upon enzymatic oxidation of the allylic amine substrate to an enimine. Acyclic analogue M-1 contains a terminal olefin as the pro-Michael acceptor. The synthesis of M-1 features an alkyne-zipper reaction and the Overman rearrangement as key synthetic operations. The cyclic analogues M-2/3/4 contain either an endocyclic or exocyclic olefin as the pro-Michael acceptor. These were all prepared using a common strategy employing DIBAL reduction of a precursor bicyclic lactam, followed by in situ Horner-Wadsworth-Emmons (HWE) olefination as the key synthetic steps.
- Shi, Ce,Aldrich, Courtney C.
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- Total synthesis of the cytotoxic enehydrazide natural products hydrazidomycins A and B by a carbazate addition/peterson olefination approach
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The first total syntheses of two natural antitumor enehydrazide compounds (hydrazidomycins A and B) and a related positional isomer of hydrazidomycin B (elaiomycin B) have been accomplished in a rapid and stereocontrolled fashion using a Peterson elimination approach. A regioselective silyl epoxide ring opening reaction with Boc-carbazate followed by base-mediated Peterson siloxide elimination stereospecifically installed the key Z-enehydrazide functionality. The use of Boc-carbazate allowed for the differential functionalization of the hydrazide nitrogens.
- Beveridge, Ramsay E.,Batey, Robert A.
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- Click-Connected 2-(Hydroxyimino)aldehydes for the Design of UV-Responsive Functional Molecules
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Click chemistry is used to functionalize simple lipophilic and water-soluble molecules, a complex PEGylated phospholipid (DSPE-PEG2000), and two benzylic substrates with the 2-(hydroxyimino)aldehyde (HIA) group. To this end, two terminal alkynes bearing the HIA moiety were synthesized and coupled to different azides through copper(I)-catalyzed azide alkyne cycloaddition (CuAAC). Norrish–Yang photoisomerization (λ= 365 nm, LED source) is successfully obtained, with no interference by the triazole linker, except when the forbidden n-π* carbonyl transition is screened by a remote substituent such as salicylaldehyde. UV-Vis spectrometry suggests a specific interaction of HIAs with Cu(II), whereas no such evidence is found with Cu(I). We thereby show that the CuAAC methodology can be used successfully to obtain HIA-based UV-responsive hydrophilic or lipophilic ligands, phospholipidic components for the construction of liposomes, and macrocycle precursors.
- Carbonaro, Linda,Cort, Antonella Dalla,D'Acunzo, Francesca,Di Sabato, Antonio,Filippini, Dario,Gentili, Patrizia,Leonelli, Francesca,Mancini, Laura
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supporting information
p. 289 - 294
(2020/12/17)
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- Enantioselective Rhodium-Catalyzed Dimerization of ω-Allenyl Carboxylic Acids: Straightforward Synthesis of C2-Symmetric Macrodiolides
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Herein, we report on the first enantioselective and atom-efficient catalytic one-step dimerization method to selectively transform ω-allenyl carboxylic acids into C2-symmetric 14- to 28-membered bismacrolactones (macrodiolides). This convenient asymmetric access serves as an attractive route towards multiple naturally occuring homodimeric macrocyclic scaffolds and demonstrates excellent efficiency to construct the complex, symmetric core structures. By utilizing a rhodium catalyst with a modified chiral cyclopentylidene-diop ligand, the desired diolides were obtained in good to high yields, high diastereoselectivity, and excellent enantioselectivity.
- Steib, Philip,Breit, Bernhard
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p. 6572 - 6576
(2018/05/08)
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- Bola type ribavirin compound, and preparation method and application thereof
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The invention relates to a Bola type ribavirin compound. A structure is shown as a general formula I. Through studying the characteristics of the special structure of the Bola type amphiphilic molecules, the structure optimization is performed by aiming at 1, 2, 4-ribavirin; the water solubility and the cancer cell growth inhibition rate of the compound are improved. Further, the compound has the capability of forming nanometer scale particles through self assembly in a water solution, so that the compound can be more easily gathered into the tumor tissues to realize the targeted medication through high permeability of the solid tumor and the retention effect. Meanwhile, as a nanometer medicine carrier, the compound can also encapsulate and seal other micromolecular medicine to reach the combined medication effect. In the general formula, n, R1, R2, R3 and R4 are defined as the patent claim. The formula I is shown as the accompanying drawing.
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- Total Synthesis and Structural Elucidation of Two Unusual Non-Methylene-Interrupted Fatty Acids in Ovaries of the Limpet Cellana toreuma
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In our previous study, unusual odd-numbered dienoic acids with a terminal olefin were found as minor components in ovaries of the Japanese limpet Cellana toreuma, and the synthetic interests have been focused onto their structural confirmation and the inspection into their potential biological activity. Here, we describe an efficient and stereoselective total synthesis of two new unusual dienoic acids, 19:2?7,18 and 21:2?7,20, through a common pathway involving the strategic combination of alkyne-zipper reaction and Lindlar hydrogenation for the construction of their unique carbon chains. In our synthetic study, 2-propyn-1-ol was at first subjected to alkylation and alkyne-zipper reaction to form the two fragments, and the subsequent carbon chain elongation was achieved by the usual coupling reaction to obtain the C-19 and C-21 products bearing an internal acetylenic group. Then, the internal acetylenic group of these products was subjected to Lindlar hydrogenation to form a Z-alkenyl moiety, and the subsequent deprotection of the products was carried out under an acidic condition without isomerization of the internal Z-alkenyl group. Total synthesis of target fatty acids, 19:2?7,18 and 21:2?7,20, was finally accomplished by two-step oxidation of the resulting alcohols into carboxylic acids in a highly chemoselective manner, and the structures of these unusual natural fatty acids were finally elucidated by identifying the GC–MS spectra of the methyl esters of authentic and synthetic fatty acids.
- Shimada, Kazuaki,Sugawara, Ayako,Korenaga, Toshinobu,Kawashima, Hideki
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p. 1019 - 1032
(2017/10/07)
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- Catalysis of Michael Additions by Covalently Modified G-Quadruplex DNA
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Enantioselective catalysis utilizing G-quadruplex DNA-based artificial metalloenzymes has emerged as a new approach in the field of aqueous-phase homogeneous catalysis. Recently, a catalytic asymmetric Michael addition employing a covalently modified G-quadruplex in combination with CuII ions has been reported. Here we assess, by systematic chemical variation and using various spectrometric techniques, a variety of parameters that govern rate acceleration and stereoselectivity of the reaction, such as the position of modification, the topology of the quadruplex, the nature of the ligand, the length of the linker between ligand and DNA, the chemical identity of monovalent ions and transition metal complexes. The DNA quadruplex modified at position 10 (dU10) with hexynyl-linked bpy ligand showed twice the initial reaction rate as compared with the DNA strand derivatized at position 12 (dU12). The strikingly different dependence of the stereoselectivity on the linker length, and their different spectroscopic properties indicate large differences in the architecture of the catalytic centers between the dU10-derivatized and the dU12-modified quadruplexes. Upon addition of CuII, both types of bpy-derivatized DNA strands form defined 1:1 Cu–DNA complexes stable enough for mass spectrometric analysis, while the underivatized strands exhibit weak and unspecific binding, correlated with much lower catalytic rate acceleration. Both dU10- and dU12-derivatized quadruplexes could be reused ten times without reduction of stereoselectivity.
- Dey, Surjendu,Rühl, Carmen L.,J?schke, Andres
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p. 12162 - 12170
(2017/09/14)
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- Discovery of a Fluorinated Enigmol Analog with Enhanced in Vivo Pharmacokinetic and Anti-Tumor Properties
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The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous in vivo settings. However, as no Enigmol analog with enhanced potency in vitro has been identified, a new strategy to improve efficacy in vivo by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF3-Enigmol and CF2-Enigmol, are reported. Each analog was equipotent to Enigmol in vitro, but achieved higher plasma and tissue levels than Enigmol in vivo. Although plasma and tissue exposures were anticipated to trend with fluorine content, CF2-Enigmol absorbed into tissue at strikingly higher concentrations than CF3-Enigmol. Using mouse xenograft models of prostate cancer, we also show that CF3-Enigmol underperformed Enigmol-mediated inhibition of tumor growth and elicited systemic toxicity. By contrast, CF2-Enigmol was not systemically toxic and demonstrated significantly enhanced antitumor activity as compared to Enigmol.
- Miller, Eric J.,Mays, Suzanne G.,Baillie, Mark T.,Howard, Randy B.,Culver, Deborah G.,Saindane, Manohar,Pruett, Sarah T.,Holt, Jason J.,Menaldino, David S.,Evers, Taylor J.,Reddy, G. Prabhakar,Arrendale, Richard F.,Natchus, Michael G.,Petros, John A.,Liotta, Dennis C.
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supporting information
p. 537 - 542
(2016/06/01)
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- The synthesis and biological evaluation of a kabiramide C fragment modified with a WH2 consensus actin-binding motif as a potential disruptor of the actin cytoskeleton
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The F-actin depolymerisation potency of a fragment of kabiramide C was increased when modified with a WH2 consensus actin-binding motif LKKV. Despite its low affinity for actin monomers, a shorter analogous fragment not bearing LKKV was identified as a potent inhibitor of actin polymerisation and a promoter of its depolymerisation, resulting in a loss of actin stress fibres in cells.
- Tetlow, Daniel J.,Winder, Steve J.,A?ssa, Christophe
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supporting information
p. 807 - 810
(2016/01/12)
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- Synthesis of a pH-Sensitive Hetero[4]Rotaxane Molecular Machine that Combines [c2]Daisy and [2]Rotaxane Arrangements
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The synthesis of a novel pH-sensitive hetero[4]rotaxane molecular machine through a self-sorting strategy is reported. The original tetra-interlocked molecular architecture combines a [c2]daisy chain scaffold linked to two [2]rotaxane units. Actuation of the system through pH variation is possible thanks to the specific interactions of the dibenzo-24-crown-8 (DB24C8) macrocycles for ammonium, anilinium, and triazolium molecular stations. Selective deprotonation of the anilinium moieties triggers shuttling of the unsubstituted DB24C8 along the [2]rotaxane units.
- Waelès, Philip,Riss-Yaw, Benjamin,Coutrot, Frédéric
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supporting information
p. 6837 - 6845
(2016/05/11)
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- Chemoproteomic Evaluation of the Polyacetylene Callyspongynic Acid
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Polyacetylenes are a class of alkyne-containing natural products. Although potent bioactivities and thus possible applications as chemical probes have already been reported for some polyacetylenes, insights into the biological activities or molecular mode of action are still rather limited in most cases. To overcome this limitation, we describe the application of the polyacetylene callyspongynic acid in the development of an experimental roadmap for characterizing potential protein targets of alkyne-containing natural products. To this end, we undertook the first chemical synthesis of callyspongynic acid. We then used in situ chemical proteomics methods to demonstrate extensive callyspongynic acid-mediated chemical tagging of endoplasmic reticulum-associated lipid-metabolizing and modifying enzymes. We anticipate that an elucidation of protein targets of natural products may serve as an effective guide to the development of subsequent biological assays that aim to identify chemical phenotypes and bioactivities.
- Nickel, Sabrina,Serwa, Remigiusz A.,Kaschani, Farnusch,Ninck, Sabrina,Zweerink, Susanne,Tate, Edward W.,Kaiser, Markus
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supporting information
p. 10721 - 10728
(2015/07/20)
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- Identification of a novel NAMPT inhibitor by combinatorial click chemistry and chemical refinement
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The identification of compounds able to inhibit the NAD salvage pathway is experiencing a growing popularity as it has been proposed to be a novel target for antitumoral and anti-inflammatory drugs. In this manuscript, we used the copper-catalyzed [3+2] cycloaddition between azides and alkynes (click chemistry) to identify novel NAMPT inhibitors with a triazole-containing tail group. 720 compounds were synthesized in the first round, allowing the identification of 17 hit compounds. The second round of optimization brought about the discovery of compound 43 which displayed a cytotoxicity of 20 nM on neuroblastoma cancer cells and an inhibition of NAMPT of 114 nM.
- Theeramunkong,Galli,Grolla,Caldarelli,Travelli,Massarotti,Troiani,Alisi,Orsomando,Genazzani,Tron
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p. 1891 - 1897
(2015/10/20)
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- Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists
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Abstract We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds.
- Kajita, Daisuke,Nakamura, Masaharu,Matsumoto, Yotaro,Ishikawa, Minoru,Hashimoto, Yuichi,Fujii, Shinya
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supporting information
p. 3350 - 3354
(2015/07/08)
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- In situ proteome profiling of C75, a covalent bioactive compound with potential anticancer activities
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A library of cell-permeable, minimally tagged C75 analogues was synthesized and used to uncover biological targets in human liver cancer cells. Known targets of C75, namely FASN and CPT1A, together with other unknown targets, including PDIA3, TFRC, and GAPDH, were thus identified.
- Cheng, Xiamin,Li, Lin,Uttamchandani, Mahesh,Yao, Shao Q.
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supporting information
p. 1414 - 1417
(2014/04/03)
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- N-Substituted 2-aminoimidazole inhibitors of MRSA biofilm formation accessed through direct 1,3-bis(tert-butoxycarbonyl)guanidine cyclization
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Antibiotic resistance is a significant problem and is compounded by the ability of many pathogenic bacteria to form biofilms. A library of N-substituted derivatives of a previously reported 2-aminoimidazole/triazole (2-AIT) biofilm modulator was constructed via α-bromoketone cyclization with 1,3-bis(tert-butoxycarbonyl)guanidine, followed by selective substitution. Several compounds exhibited the ability to inhibit biofilm formation by three strong biofilm forming strains of methicillin resistant Staphylococcus aureus (MRSA). Additionally, a number of members of this library exhibited synergistic activity with oxacillin against planktonic MRSA. Compounds with this type of dual activity have the potential to be used as adjuvants with conventional antibiotics. The Royal Society of Chemistry.
- Yeagley, Andrew A.,Su, Zhaoming,McCullough, Kára D.,Worthington, Roberta J.,Melander, Christian
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p. 130 - 137
(2013/02/22)
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- A flexible approach to 1,4-di-substituted 2-aminoimidazoles that inhibit and disperse biofilms and potentiate the effects of β-lactams against multi-drug resistant bacteria
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The pyrrole-imidazole alkaloids are a 2-aminoimidazoles containing family of natural products that possess anti-biofilm activity. A library of 1,4-di-substituted 2-aminoimidazole/triazoles (2-AITs) was synthesized, and its anti-biofilm activity as well as oxacillin resensitization efficacy toward methicillin resistant Staphylococcus aureus (MRSA) was investigated. These 2-AITs were found to inhibit biofilm formation by MRSA with low micromolar IC50 values. Additionally, the most active compound acted synergistically with oxacillin against MRSA lowering the minimum inhibitory concentration (MIC) 4-fold.
- Furlani, Robert E.,Yeagley, Andrew A.,Melander, Christian
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- Tandem br?nsted acid promoted and nazarov carbocyclizations of enyne acetals to hydroazulenones
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Ring the changes: Enyne acetals were easily converted into hydroazulene skeletons by a new and efficient metal-free route involving a Br?nsted acid promoted carbocyclization and a subsequent stereospecific Nazarov cyclization (see scheme). The versatility of this transformation also allowed assembly of interesting heteroaromatic tricyclic systems. Copyright
- Escalante, Luz,González-Rodríguez, Carlos,Varela, Jesús A.,Saá, Carlos
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supporting information
p. 12316 - 12320
(2013/02/25)
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- Fused ring aziridines as a facile entry into triazole fused tricyclic and bicyclic heterocycles
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The intramolecular dipolar cycloaddition of an azide with an alkyne has provided a useful entry into triazole fused tricyclic heterocycles containing both the triazole ring and the oxazolidin-2-one ring system. The requisite azido-alkynes have been prepared via a two-step sequence from fused ring aziridines. A series of 6-12 membered rings containing both the oxazolidinone and triazole rings have been prepared. These ring systems have been designed as conformationally restrained analogs of RNA-binding oxazolidinones. The Royal Society of Chemistry 2012.
- Fang, Fang,Vogel, Megan,Hines, Jennifer V.,Bergmeier, Stephen C.
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scheme or table
p. 3080 - 3091
(2012/05/07)
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- Inhibition of Acinetobacter baumannii biofilm formation on a methacrylate polymer containing a 2-aminoimidazole subunit
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A polymeric composite containing a 2-aminoimidazole derivative was synthesized. It was found that this polymer was resistant to biofilm colonization by Acinetobacter baumannii, no leaching of the 2-aminoimidazole derivative was observed after 2 weeks of treatment with deionized water, and the resulting polymer was not hemolytic.
- Peng, Lingling,Desousa, Joseph,Su, Zhaoming,Novak, Bruce M.,Nevzorov, Alexander A.,Garland, Eva R.,Melander, Christian
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supporting information; experimental part
p. 4896 - 4898
(2011/06/10)
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- Synthesis and biological activity of 2-aminoimidazole triazoles accessed by Suzuki-Miyaura cross-coupling
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A pilot library of 2-aminoimidazole triazoles (2-AITs) was synthesized and assayed against Acinetobacter baumannii and methicillin-resistant Staphylococus aureus (MRSA). Results from these studies show that these new derivatives have improved biofilm dispersal activities as well as antibacterial properties against A. baumannii. With MRSA biofilms they are found to possess biofilm inhibition capabilities at low micromolar concentrations.
- Reyes, Samuel,Huigens Iii, Robert W.,Su, Zhaoming,Simon, Michel L.,Melander, Christian
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experimental part
p. 3041 - 3049
(2011/06/09)
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- Very contracted to extended co -conformations with or without oscillations in two- and three-station ['2]daisy chains
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The syntheses of various two- and three-station mannosyl [c2]daisy chains, based on a dibenzo-24-crown-8 macrocyclic moiety and an ammonium, a triazolium, and a mono- or disubstituted pyridinium amide station, are reported. The ability of these molecules to act as molecular machine based mimetics has been further studied by 1H NMR studies. In all the protonated ammonium states, the interwoven rotaxane dimers adopt an extended co-conformation. However, carbamoylation of the ammonium station led to many different other [c2]daisy chain co-conformations, depending on the other molecular stations belonging to the axle. In the two-station [c2]daisy chains containing an ammonium and a mono- or disubstituted pyridinium amide station, two large-amplitude relative movements of the interwoven components were noticed and afforded either an extended and a contracted or very contracted state with, in the latter case, an impressive chairlike conformational flipping of the mannopyranose from 1C4 to 4C1. In the case of the three-station-based [c2]daisy chains containing an ammonium, a triazolium, and disubstituted pyridinium amide, an extended and a half-contracted molecular state could be obtained because of the stronger affinity of the dibenzo-24-crown-8 part for, respectively, the ammonium, the triazolium, and the disubstituted pyridinium amide. Eventually, with axles comprising an ammonium, a triazolium, and a monosubstituted pyridinium amide, an extended conformation was noticed in the protonated state whereas a continuous oscillation between half-contracted and contracted states, in fast-exchange on the NMR time scale, was triggered by carbamoylation. Variations of the solvent or the temperature allow the modification of the population of each co-conformer. Thermodynamic data provided a small free Gibbs energy δG of 2.1 kJ·mol -1 between the two translational isomers at 298 K.
- Romuald, Camille,Busseron, Eric,Coutrot, Frederic
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supporting information; experimental part
p. 6516 - 6531
(2010/12/24)
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- Synthesis and activity of polyacetylene substituted 2-hydroxy acids, esters, and amides against microbes of clinical importance
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A series of novel polyacetylene substituted 2-hydroxy acids and derivatives were prepared and characterized. Alkylation of butane-2,3-diacetal (BDA) protected glycolic acid with iodoalkyl substituted polyacetylene compounds gave the corresponding diacetal protected polyacetylene substituted 2-hydroxy acids. Diacetal deprotection through acid mediated hydrolysis, transesterification or aminolysis afforded the 2-hydroxy-polyacetylenic acid, ester or amide derivatives. Twenty one of these novel compounds were tested against 10 microbes of clinical importance and several of them showed good antimicrobial activity, in particular against Pseudomonas aeruginosa.
- Kyi, Stella,Wongkattiya, Nalin,Warden, Andrew C.,O'Shea, Michael S.,Deighton, Margaret,MacReadie, Ian,Graichen, Florian H.M.
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supporting information; experimental part
p. 4555 - 4557
(2010/09/16)
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- Modulating the development of E. coli biofilms with 2-aminoimidazoles
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The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC50 of 13 μM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400 μM.
- Reed, Catherine S.,Huigens III, Robert W.,Rogers, Steven A.,Melander, Christian
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scheme or table
p. 6310 - 6312
(2010/11/18)
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- 6,6′-Dimethyl-2,2′-bipyridine-4-ester: A pivotal synthon for building tethered bipyridine ligands
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We describe an efficient and scalable synthesis of 4-carbomethoxy-6,6′-dimethyl-2,2′-bipyridine starting from easily available substituted 2-halopyridines and based on the application of modified Negishi cross-coupling conditions. This compound is a versatile starting material for the synthesis of 4-functionalized 2,2′-bipyridines bearing halide, alcohol, amine, and other functionalities, suitable for conjugation to biological material (2a-c, 3a-g). The utility of this compound in the construction of more complex architectures was further demonstrated by the synthesis of two bifunctional lanthanide chelators; an open chain ligand based on one 2,2′-bipyridine unit and a cryptand based on three 2,2′-bipyridine units [N2(bpy)3COOMe]. In the field of luminophoric biolabels, the photophysical properties of the corresponding Eu(III) cryptate are reported.
- Havas, Fabien,Leygue, Nadine,Danel, Mathieu,Mestre, Béatrice,Galaup, Chantal,Picard, Claude
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experimental part
p. 7673 - 7686
(2009/12/06)
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- Cyclization reactions through DDQ-mediated vinyl oxazolidinone oxidation
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Vinyl oxazolidinones react with DDQ to form α,β-unsaturated acyliminium ions in a new method for forming electrophiles under oxidative conditions. Appended nucleophiles undergo 1,4-addition reactions with these intermediates to form cyclic vinyl oxazolidinones with good levels of diastereocontrol, highlighting a new approach to utilizing oxidative carbon-hydrogen bond functionalization to increase molecular complexity.
- Liu, Lei,Floreancig, Paul E.
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supporting information; scheme or table
p. 3152 - 3155
(2009/12/05)
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- CONJUGATED UNSATURATED COMPOUNDS
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The present invention relates to a class of conjugated unsaturated compounds, to a method of preparing such compounds, and to the polymerisation and bio-active uses of such compounds including their use as antimicrobial agents. The invention particularly relates to compounds containing three conjugated unsaturated moieties, at least two of which are yne moieties.
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Page/Page column 51-52
(2009/10/22)
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- Synthesis of (4R,15R,16R,21S)-rollicosin and its 4S epimer
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(4R,15R,16R,21S)-Rollicosin (2) was synthesized by palladium-catalyzed coupling of two building blocks 4 and 5. Lactone 4 was synthesized from 1-heptyne and terminal acetylene 5 was prepared from lactone 6 and allyl iodide or (S)-epichlorohydrin. (4S,15R,16R,21S)-Rollicosin (3) was also synthesized from (R)-epichlorohydrin by the same synthetic pathway. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Wu, Ming-Jung,Lee, Cheng-Lin,Wu, Yang-Chang,Chen, Chiao-Pei
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experimental part
p. 854 - 861
(2009/04/11)
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- ANTIBACTERIAL AGENTS
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Compounds of formula (I) have antibacterial activity wherein R represents hydrogen or 1, 2 or 3 optional substituents; W is =C(R1)- or =N-; R1 is hydrogen or an optional substituent and R2 is hydrogen, methyl, or fluorine; or R1 and R2 taken together are -CH2-, -CH2CH2-, -O-, or, in either orientation, -O- CH2- Or -OCH2CH2-; R3 is a radical of formula -(Alk1)m-(Z)p-(Alk2)n-Q wherein m, p and n are independently 0 or 1, provided that at least one of m, p and n is 1, Z is -O-, -S-, -S(O)-, -S(O2)-, -NH-, -N(CH3)-, -N(CH2CH3)-, -C(=O)-, -O-(C=O)-, -C(=O)-O-, or an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted divalent bicyclic heterocyclic radical having 5 to 10 ring atoms; Alk1 and Alk2 are optionally substituted C1C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radicals, which may optionally terminate with or be interrupted by -O-, -S-, -S(O)-, -S(O2)-, -NH-, -N(CH3)-, or -N(CH2CH3)-; and Q is hydrogen, halogen, nitrile, or hydroxyl or an optionally substituted monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted bicyclic heterocyclic radical having 5 to 10 ring atoms.
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Page/Page column 44
(2010/11/28)
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- Synthesis and spectral properties of amphophilic lipids with linear conjugated polyene and phenylpolyene fluorescent groups
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Lipophilic fluorescent groups with a chain-like linear conformation emitting in the visible range and with high photostability are presently unavailable. These structures would be of great interest as labels for long-chain fatty acids and phospholipids lacking intrinsic fluorescent groups. With this aim in mind, we report the synthesis and the spectroscopic characterization of a series of emitting amphiphilic lipids that may approach that ideal fluorescent tag. Each lipid was constructed by attaching a linear, all-(E) conjugated pentaene, tetraenyne, ω-phenyltetraene, or ω-phenyltrienyne chromophore to a hydrophilic head-group through a polymethylene chain spacer. The key steps of the synthesis were the Pd 0-mediated cross-coupling reaction between bromopolyenes and terminal acetylenic compounds, yielding tetraenynes or ω-phenyltrienynes, and the subsequent triple-bond partial reduction, producing the corresponding pentaenes or ω-phenyltetraenes in good overall yields. This method represents a further successful example of the so-called "acetylenic approach" to the indirect high-yield synthesis of polyene systems. In the case of ω-phenyltrienynes, a higher proportion of the all-(E) isomer was obtained using an alternative method based on the reaction of an ω- phenyldienylphosphonate with an α-acetylenic aldehyde. Some of the resulting compounds exhibit spectral and photochemical properties that warrant their use as emitting lipophilic tags. Thus, the cophenyltetraene and ω-phenyltrienyne members of the series show intense absorption bands in the 320-370 nm range with fluorescence emission centered at 475 nm and quantum yields up to 0.25. These parameters are appropriate for the applications noted above. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Quesada, Ernesto,Delgado, Javier,Hornillos, Valentin,Acuna, A. Ulises,Amat-Guerri, Francisco
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p. 2285 - 2295
(2008/02/06)
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- Sequential ring-closing metathesis/Pd-catalyzed, Si-assisted cross-coupling reactions: General synthesis of highly substituted unsaturated alcohols and medium-sized rings containing a 1,3-cis-cis diene unit
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A sequential ring-closing metathesis/silicon-assisted cross-coupling protocol has been developed. Alkenyldimethylsilyl ethers of allylic, homoallylic and bis(homoallylic) alcohols undergo facile ring closure with Schrock's catalyst to afford 5-, 6-, and 7-membered cycloalkenylsiloxanes, respectively, in some cases with substituents on both alkenyl carbons. These siloxanes are highly effective coupling partners that afford styrenes and dienes (with various aryl and alkenyl halides) in high yield and specificity as well as good functional group compatibility. The siloxanes bearing a Z-iodoalkenyl tether undergo an intramolecular coupling process in the presence of [allylPdCl] 2 which constitutes a powerful method for the construction of medium-sized rings with an internal 1,3-cis-cis diene unit. The formation of 9-, 10-, 11-, and 12-membered carbocyclic dienes is achieved in good yield. Extension to the synthesis of 9-membered ring unsaturated ethers has also been accomplished. Noteworthy features of this process include: (1) highly stereospecific intramolecular coupling, (2) flexible positioning of the revealed hydroxy group, and (3) potential extension to other medium-sized carbocycles and heterocycles. Graphical Abstract.
- Denmark, Scott E.,Yang, Shyh-Ming
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p. 9695 - 9708
(2007/10/03)
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- Applications of size-selective macrolactonizations to the synthesis of benzolactone-enamide core structures
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By utilizing Stille cross-coupling reactions four benzoic acid derivatives (18, 32, 46, 66) were prepared that carry a side chain with two secondary hydroxy groups. It could be shown that the hydroxy functions can be distinguished by size-selective macrolactonization reactions. Thus, 12-membered lactones 19 and 33 are favored over their 11-membered lactone counterparts 20 and 34, respectively, albeit with a low (60:40-70:30) ratio. The selectivity is much more pronounced if there is a competition between a 12- and 10-membered lactone. This could be shown with the two lactones 47 and 67. The 12-membered lactones 33, 47, and 67 represent core structures for analogs of the benzolactone enamides. The macrolactonization reactions were performed under Yamaguchi conditions.
- Petri, Andreas F.,Kuehnert, Sven M.,Scheufler, Frank,Maier, Martin E.
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p. 940 - 955
(2007/10/03)
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- Method of DNA sequencing
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Disclosed are methods for determining DNA nucleotide sequences comprising reacting ribonucleoside 5′-triphosphates and 3′-dNTP derivatives in the presence of an RNA polymerase modified so as to enhance its ability for incorporating the 3′-dNTP derivatives and a DNA fragment containing a promoter sequence for the RNA polymerase to obtain a nucleic acid transcription product, separating the resulting nucleic acid transcription product, and determining a nucleic acid sequence from the resulting separated fraction. These methods can produce a transcription product of a long chain and afford more accurate sequence data where fluctuation of signals from labeled deoxyribonucleotides is reduced.
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- Intramolecular silicon-assisted cross-coupling reactions: General synthesis of medium-sized rings containing a 1,3-cis-cis diene unit
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The combination of ring-closing metathesis and Pd-catalyzed, silicon-assisted intramolecular cross-coupling has been developed to provide an effective and powerful method for construction of medium-sized rings with an internal 1,3-cis-cis diene unit. Allylic alcohols bearing a Z-iodoalkenyl tether can be silylated with chlorodimethylvinylsilane and subjected to Mo-catalyzed ring-closing metathesis to form unsaturated siloxanes. Activation of the siloxane with tetrabutylammonium fluoride in the presence of [allylPdCl]2 leads to high yielding ring-closing reactions to form 9-, 10-, 11- and 12-membered rings. Extension to the synthesis of 9-membered ring unsaturated ethers has also been accomplished. Noteworthy features of this process include: (1) a highly stereospecific intramolecular coupling process, (2) flexible positioning of the hydroxy group, and (3) potential extension to other medium-sized carbocycles and heterocycles. Copyright
- Denmark, Scott E.,Yang, Shyh-Ming
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p. 2102 - 2103
(2007/10/03)
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- 3'-Deoxyribonucleotide derivatives
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Disclosed are 3′-deoxyribonucleotide derivatives represented by the following general formula [I]: Q—V—(CH2)n—NH—R??[I] wherein Q represents a 3′-deoxyribonucleotide residue, n represents an integer not less than 4, V represents —C≡C— or —CH═CH—, and R represents a fluorescent group. The above 3′-deoxyribonucleotide derivatives are derivatives with improved rates for incorporation using RNA polymerases, which are useful as terminators in the DNA sequence determination methods utilizing RNA polymerases.
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- Synthesis of polyacetylenic acids isolated from Heisteria acuminata
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matrix presented Four linear polyacetylenic compounds were synthesized. Pentadeca-6,8,10-triynoic acid 1 and octadeca-8,10,12-triynoic acid 2 were synthesized by using acetylene coupling reactions. The syntheses of (Z)-hexadec-11-en-7,9-diynoic acid 3 and (Z)-octadec-12-en-7,9-diynoic acid 4 by using vinylic telluride coupling reactions were accomplished.
- Zeni, Gilson,Panatieri, Rodrigo B.,Lissner, Eliseo,Menezes, Paulo H.,Braga, Antonio L.,Stefani, Helio A.
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p. 819 - 820
(2007/10/03)
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- Regioselective palladium-catalyzed cross-coupling reactions in the synthesis of novel 2,3-disubstituted thiophene derivatives
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A reactivity optimization study of the palladium-catalyzed cross-coupling reactions of 2,3-dibromothiophene and organometallic reagents has been conducted. Regioselective coupling at the C2 position, accomplished most notably by Suzuki coupling, was combined with a Stille reaction at C3 using Fu's modification, to afford the 2,3-disubstituted thiophene derivatives.
- Pereira, Raquel,Iglesias, Beatriz,De Lera, Angel R
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p. 7871 - 7881
(2007/10/03)
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- Synthesis of cyclo-1,3-dien-5-ynes
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Cyclo-1,3-dien-5-ynes with ring sizes from 10 to 14 (6a-e) have been prepared for the first time by using a five-step synthesis starting from the alkynols 7a-e. The final ring-closure was achieved by McMurry coupling of the α,ω-dialdehydes 12a-e with the complex TiCl3(DME)1.5. Thermal isomerization of the cyclodienynes leads to the corresponding benzocycloalkenes, and it has been shown that the ring size has a considerable influence on the temperature necessary for thermocylization.
- Hopf, Henning,Krueger, Anke
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p. 4378 - 4385
(2007/10/03)
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- Synthesis of pyrinodemins A and B. Assignment of the double bond position of pyrinodemin A
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Condensation of aldehyde 3a with hydroxylamine 4b afforded nitrone 2, which underwent an intramolecular cycloaddition to give 1b, the proposed structure of pyrinodemin A. A similar condensation of aldehyde 3a and hydroxylamine 4a provided pyrinodemin A (1a), which has the double bond one carbon further away from the isoxazolidine. An analogous sequence gave pyrinodemin B (21).
- Snider, Barry B.,Shi, Bo
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p. 1639 - 1642
(2007/10/03)
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- Studies toward an asymmetric synthesis of CP-263,114 and CP-225,917
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An enantioselective approach to construction of the complex framework of the CP compounds is presented. The synthesis relies on initial elaboration of the two sidechains. The "upper" appendage was asymmetrically dihydroxylated with both AD-mix reagents in order to lend flexibility to the scheme and provide the necessary handle for evolving the additional stereogenic centers. These fragments were linked to benzoic acid via Birch reduction-alkylation and subsequent cuprate addition. A series of functionalization reactions including dissolving metal reduction, Claisen rearrangement, iodolactonization, regioselective epoxide cleavage-oxidation, and intramolecular Wadsworth-Emmons cyclization took advantage of highly efficient stereocontrol. However, this flexibility was thwarted when deprotonation of a penultimate intermediate failed to be regioselective in the proper direction.
- Devaux, Jean-Francois,O'Neil, Steven V.,Guillo, Nathalie,Paquette, Leo A.
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p. 490 - 510
(2007/10/03)
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- Total syntheses of (-)-grandinolide and (-)-sapranthin by the sharpless asymmetric dihydroxylation of methyl trans-3-pentenoate: Elucidation of the stereostructure of (-)-sapranthin
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Methyl trans-3-pentenoate (7) was converted into the cis-substituted γ- lactone 8 in a single step with 78% ee. The derived enolate dilithio-8 was alkylated trans-selectively with primary iodoalkanes with 1-iodobutane dilithio-8 afforded, after esterification with isovaleroyl chloride, the epi- blastmycinone 9. Dilithio-8 gave (-)-grandinolide (II) with 1-iodo-19- phenylnonadecane (20). A third trans-selective alkylation of dilithio-8 was undertaken with 16-iodo-1,5-hexadecadiene-7,9-diyne (21). This gave the γ- 1actone 12, which had the published relative configuration of (-)-sapranthin but different spectroscopic data. When the OH group of lactone 8 was inverted (to hydroxylactone 40) and the derived enolate dilithio-40 alkylated with iodide 21, lactone 41 resulted. Its 1H and 13C NMR spectra and the sign and value of optical rotation coincide with the data of natural sapranthin. These findings establish that (-)-sapranthin possesses the relative and absolute configuration of stereoformula 41. The synthesis of iodide 21 was performed via the dienoic carboxylic ester trans-23 which stemmed from the Claisen-Ireland rearrangement (27 → 28/29)/esterification (28/29 → 26)/Cope rearrangement (26 → 23) sequence shown in Scheme 5.
- Harcken, Christian,Brueckner, Reinhard,Rank, Elisabeth
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p. 2342 - 2352
(2007/10/03)
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- Pyridine compounds for treating leukotriene-related diseases
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STR1 This invention relates to compounds of formula (I) which are useful as leukotriene antagonists.
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- Synthesis of polyunsaturated constituents of phenolic lipids
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The diene, (ZZ)-[(8,11)-pentadecadienyl]salicylic acid, (or 2-hydroxy-6-[(ZZ)-pentadeca-8,11-dienyl] acid), has been synthesised by two routes. In the first, the key intermediate methyl or ethyl 2-hydroxy-6-(7-bromoheptyl)benzoate has been converted to methyl or ethyl 2-hydroxy-6-(10-hydroxydec-8-ynyl)benzoate and thence by reaction of the corresponding bromide with 1-pentynylmagnesium bromide to methyl or ethyl 2-hydroxy-6-(pentadeca-8,11-diynyl)benzoate. Selective reduction afforded methyl or ethyl 2-hydroxy-6-[(ZZ)-pentadeca-8,11-dienyl]benzoate. An attempt to employ the Grignard reagent from methyl 2-methoxy-6-(non-8-ynyl)benzoate and reaction with 1-bromohex-2-yne was ineffective because of a side reaction of the former with ethylmagnesium bromide to give a ketone. In the third approach ethyl 2-methoxy-6-methylbenzoate was alkylated with 1-iodotetradeca-7,10-diyne and the product selectively reduced as before to the O-methyl ether ethyl ester. A variety of C14 intermediates has been prepared for the derivation of the 8(E),11(E), 8(E),11(Z) and 8(Z),11(E) stereoisomers by the alkylation procedure. A similar methodology of alkylation can be adopted for obtaining corresponding trienes in which some progress has been made commencing with the synthesis of the 8(Z),11(Z),14 compound.
- Tyman, John H.P.,Visani
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p. 157 - 174
(2007/10/03)
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- Short and stereoselective syntheses of pheromone components of Aproaerema modicella
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Efficient syntheses of pheromone components of Aproaerema modicella starting from a common intermediate 7-octyn-1-ol is described.
- Yadav,Chandrasekhar,Kache
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p. 4035 - 4043
(2007/10/03)
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- Synthesis of (R,S)-10-methyloctadecanoic acid (tuberculostearic acid) and key chiral 2-methyl branched intermediates
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Tuberculostearic acid (R)-10-methyloctadecanoic acid, is a characteristic component of pathogenic mycobacteria and related organisms.Sensitive detection of this acid infected material allows rapid detection of mycobacterial disease.A novel, convergent synthesis of tuberculostearic acid and key chiral intermediates is described in this communication, to provide a reference compound.Racemic and (R)- and (S)-1-iodo-2-methyldecanes were synthesised from 1-octanal and 1-carboethoxyethylidenetriphenylphosphorane as initial starting materials. 1-Hydroxyoct-7-yne was made from 1,6-hexanediol by two alternative methods and coupled with the above racemic iodide.Hydrogenation and oxidation of the resulting (R,S)-10-methyloctadec-7-yn-1-ol gave racemic tuberculostearic acid. Keywords: Mycobacterium tuberculosis; Tuberculostearic acid; Acetylene coupling; (R,S)-10-methyloctadecanoic acid; Chiral 2-methyl branched fatty acids
- Wallace, Paul A.,Minnikin, David E.,McCrudden, Katharine,Pizzarello, Andrea
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p. 145 - 162
(2007/10/02)
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- (E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl]oxy]-2- pyridinyl]-methyl]thio]methyl]benzoic acid and related compounds: High affinity leukotriene B4 receptor antagonists
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(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl]oxy]-2- pyridinyl]-methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The placement of an additional methylene unit in the sulfur containing chain linking the pyridine and benzoic acid moieties of lead compound 8 (K(i) = 80 nM) resulted in a greater than 10-fold increase in receptor affinity. Additionally, in this new series of compounds, the oxidation state of the sulfur was found to be critical to the activity, i.e., the sulfoxide and sulfone showed substantially lower affinity for the LTB4 receptor. Compound 11 competitively inhibits the binding of [3H]LTB4 to LTB4 receptors on human polymorphonuclear leukocutes with a K(i) of 7.1 nM and blocks both the LTB4-induced calcium mobilization and the LTB4-induced degranulation responses in these cells with IC50 values of 131 and 271 nM, respectively. Compound 11 demonstrated oral LTB4 antagonist activity as well as topical antiinflammatory activity in the mouse.
- Daines,Chambers,Eggleston,Foley,Griswold,Haltiwanger,Jakas,Kingsbury,Martin,Pendrak,Schmidt,Tzimas,Sarau
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p. 3327 - 3336
(2007/10/02)
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- First Total Synthesis of Niphatesines A-D and Assignment of Absolute Configuration
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Regio/Enantioselective synthesis of niphatesines A-D is achieved making use of Pd(0) assisted 3-alkylation of pyridine as the key step.Absolute configuration of niphatesines C and D is established.
- Rao, A. V. Rama,Reddy, Gongiti Ravindra
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p. 8329 - 8332
(2007/10/02)
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