- Synthesis of 3-geranyl- and 3-prenyl-2,4,6-trihydroxybenzophenone
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Biologically active phenyl[3-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl]methanone (2) and phenyl[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl]methanone (3) were synthesized by an efficient and convenient synthetic sequence. The reaction steps of this synthesis included methylation, Friedel-Crafts acylation, demethylation and geranylation steps.
- Mzozoyana, Vuyisa,van Heerden, Fanie R.
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- Biomimetic total synthesis of (±)-garcibracteatone
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The polycyclic polyprenylated acylphloroglucinol natural product garcibracteatone has been synthesized in four steps from phloroglucinol, using a strategy based on biosynthetic speculation. The key biomimetic transformation is a cascade of 7-endo-trig and 5-exo-trig radical cyclizations followed by a terminating aromatic substitution reaction.
- Pepper, Henry P.,Lam, Hiu C.,Bloch, Witold M.,George, Jonathan H.
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- Synthesis of fluorine-containing prenylated benzophenones
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In this study, an effective route to synthesize fluorine-containing prenylated benzophenones was developed. Friedel–Crafts acylation and electrophilic aromatic substitution reactions were the key reactions of this synthesis to achieve these fluorinated prenylated benzophenones. The use of DBU in the prenylation step achieved only the C-prenylated benzophenones, whereas K2CO3 produced the C- and O-prenylated benzophenones.
- Mzozoyana, Vuyisa,van Heerden, Fanie R.
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supporting information
p. 2226 - 2235
(2020/07/09)
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- Expedient Synthesis of Lupulones and Their Derivatization to 2,8-7H-Dihydrochromen-7-ones
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A convenient and improved method for the synthesis of beta acids or lupulones, which are known to possess e. g. anti-cancer, anti-inflammatory, anti-oxidative and antimicrobial activity, has been developed successfully. Further derivatization of these complex structures to the corresponding dihydrochromen-7-ones, including the natural product machuone, was realized to simplify their analysis and to confirm their molecular structure. In addition to practical and safe laboratory procedures, the advantages associated with this new approach involve the use of water as a solvent and the direct crystallization of lupunones from acetonitrile, rendering our strategy more efficient and benign as compared to available methods.
- Blondeel, Eline,D'hooghe, Matthias,Decuyper, Lena,Depetter, Yves,Kaur, Gurkirat,Van Hecke, Kristof,Versyck, Charlotte
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p. 442 - 444
(2020/10/02)
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- The Natural Product Elegaphenone Potentiates Antibiotic Effects against Pseudomonas aeruginosa
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Natural products represent a rich source of antibiotics that address versatile cellular targets. The deconvolution of their targets via chemical proteomics is often challenged by the introduction of large photocrosslinkers. Here we applied elegaphenone, a largely uncharacterized natural product antibiotic bearing a native benzophenone core scaffold, for affinity-based protein profiling (AfBPP) in Gram-positive and Gram-negative bacteria. This study utilizes the alkynylated natural product scaffold as a probe to uncover intriguing biological interactions with the transcriptional regulator AlgP. Furthermore, proteome profiling of a Pseudomonas aeruginosa AlgP transposon mutant provided unique insights into the mode of action. Elegaphenone enhanced the elimination of intracellular P. aeruginosa in macrophages exposed to sub-inhibitory concentrations of the fluoroquinolone antibiotic norfloxacin.
- Zhao, Weining,Cross, Ashley R.,Crowe-McAuliffe, Caillan,Weigert-Munoz, Angela,Csatary, Erika E.,Solinski, Amy E.,Krysiak, Joanna,Goldberg, Joanna B.,Wilson, Daniel N.,Medina, Eva,Wuest, William M.,Sieber, Stephan A.
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supporting information
p. 8581 - 8584
(2019/05/28)
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- Total synthesis of acylphloroglucinols and their antibacterial activities against clinical isolates of multi-drug resistant (MDR) and methicillin-resistant strains of Staphylococcus aureus
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Bioassay-directed drug discovery efforts focusing on various species of the genus Hypericum led to the discovery of a number of new acylphloroglucinols including (S,E)-1-(2-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-4,6-dihydroxyphenyl)-2-methylbutan-1-one (6, olympicin A) from H. olympicum, with MICs ranging from 0.5 to 1 mg/L against a series of clinical isolates of multi-drug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) strains. The promising activity and interesting chemistry of olympicin A prompted us to carry out the total synthesis of 6 and a series of analogues in order to assess their structure-activity profile as a new group of antibacterial agents. Following the synthesis of 6 and structurally-related acylphloroglucinols 7–15 and 18–24, their antibacterial activities against a panel of S. aureus strains were evaluated. The presence of an alkyloxy group consisting of 8–10 carbon atoms ortho to a five-carbon acyl substituent on the phloroglucinol core are important structural features for promising anti-staphylococcal activity.
- Rahman, M. Mukhlesur,Shiu, Winnie K.P.,Gibbons, Simon,Malkinson, John P.
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supporting information
p. 255 - 262
(2018/06/20)
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- Friedel-Crafts Alkylation of Acylphloroglucinols Catalyzed by a Fungal Indole Prenyltransferase
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Naturally occurring prenylated acylphloroglucinol derivatives are plant metabolites with diverse biological and pharmacological activities. Prenylation of acylphloroglucinols plays an important role in the formation of these intriguing natural products and is catalyzed in plants by membrane-bound enzymes. In this study, we demonstrate the prenylation of such compounds by a soluble fungal prenyltransferase AnaPT involved in the biosynthesis of prenylated indole alkaloids. The observed activities of AnaPT toward these substrates are much higher than that of a microsomal fraction containing an overproduced prenyltransferase from the plant hop.
- Zhou, Kang,Ludwig, Lena,Li, Shu-Ming
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p. 929 - 933
(2015/05/05)
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- Synthesis and biological evaluation of novel myrtucommulones and structural analogues that target mPGES-1 and 5-lipoxygenase
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The natural acylphloroglucinol myrtucommulone A (1) inhibits microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), and induces apoptosis of cancer cells. Starting from 1 as lead, 28 analogues were synthesized following a straightforward modular strategy with high yielding convergent steps. Major structural variations concerned (I) replacement of the syncarpic acid moieties by dimedone or indandione, (II) cyclization of the syncarpic acid with the acylphloroglucinol core, and (III) substitution of the methine bridges and the acyl residue with isopropyl, isobutyl, n-pentyl or phenyl groups, each. The potency for mPGES-1 inhibition was improved by 12.5-fold for 43 (2-(1-(3-hexanoyl-2,4,6-trihydroxy-5-(1-(3-hydroxy-1-oxo-1H-inden-2-yl)-2-methylpropyl)phenyl)-2-methylpropyl)-3-hydroxy-1H-inden-1-one) with IC50 Combining double low line 0.08 μM, and 5-LO inhibition was improved 33-fold by 47 (2-((3-hexanoyl-2,4,6-trihydroxy-5-((3-hydroxy-1-oxo-1H-inden-2-yl) (phenyl)methyl)phenyl) (phenyl)methyl)-3-hydroxy-1H-inden-1-one) with IC50 Combining double low line 0.46 μM. SAR studies revealed divergent structural determinants for induction of cell death and mPGES-1/5-LO inhibition, revealing 43 and 47 as non-cytotoxic mPGES-1 and 5-LO inhibitors that warrant further preclinical assessment as anti-inflammatory drugs.
- Wiechmann, Katja,Müller, Hans,Huch, Volker,Hartmann, David,Werz, Oliver,Jauch, Johann
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p. 133 - 149
(2015/07/07)
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- Rapid preparation of (methyl)malonyl coenzyme A and enzymatic formation of unusual polyketides by type III polyketide synthase from Aquilaria sinensis
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(Methyl)malonyl coenzyme A was rapidly and effectively synthesized by a two-step procedure involving preparation of N-hydroxysuccinimidyl (methyl)malonate from (methyl)Meldrum's acid, and followed by transesterification with coenzyme A. The synthesized (methyl)malonyl coenzyme A could be well accepted and assembled to 4-hydroxy phenylpropionyl coenzyme A by type III polyketide synthase from Aquilaria sinensis to produce dihydrochalcone and 4-hydroxy-3,5-dimethyl-6-(4-hydroxyphenethyl)-2H-pyrone as well as 4-hydroxy-3,5-dimethyl-6-(5-(4-hydroxyphenyl)-3-oxopentan-2-yl)-2H-pyrone.
- Gao, Bo-Wen,Wang, Xiao-Hui,Liu, Xiao,Shi, She-Po,Tu, Peng-Fei
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supporting information
p. 1279 - 1283
(2015/03/14)
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- Asymmetric, stereodivergent synthesis of (-)-clusianone utilizing a biomimetic cationic cyclization
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We report a stereodivergent, asymmetric total synthesis of (-)-clusianone in six steps from commercial materials. We implement a challenging cationic cyclization forging a bond between two sterically encumbered quaternary carbon atoms. Mechanistic studies point to the unique ability of formic acid to mediate the cyclization forming the clusianone framework. Aim for selectivity: (-)-Clusianone was produced by a stereodivergent asymmetric total synthesis in six steps from commercial materials. The synthesis utilizes a challenging formic acid-mediated cationic cyclization forging a bond between two sterically encumbered quaternary carbon atoms.
- Boyce, Jonathan H.,Porco, John A.
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supporting information
p. 7832 - 7837
(2014/08/05)
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- Biomimetic total synthesis of (±)-doitunggarcinone A and (+)-garcibracteatone
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A full account of our oxidative radical cyclization approach to the synthesis of garcibracteatone and doitunggarcinone A is presented. This includes the first enantioselective synthesis of garcibracteatone, which allowed the absolute configuration of the natural compound to be determined. The first synthesis of doitunggarcinone A is also described, which confirms our reassignment of the relative configuration of this molecule. Novel syntheses of monoterpene fragments used to construct the target molecules are also reported.
- Pepper, Henry P.,Tulip, Stephen J.,Nakano, Yuji,George, Jonathan H.
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p. 2564 - 2573
(2014/04/17)
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- Rapid synthesis of polyprenylated acylphloroglucinol analogs via dearomative conjunctive allylic annulation
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Polyprenylated acylphloroglucinols (PPAPs) are structurally complex natural products with promising biological activities. Herein, we present a biosynthesis-inspired, diversity-oriented synthesis approach for rapid construction of PPAP analogs via double decarboxylative allylation (DcA) of acylphloroglucinol scaffolds to access allyl-desoxyhumulones followed by dearomative conjunctive allylic alkylation (DCAA).
- Grenning, Alexander J.,Boyce, Jonathan H.,Porco, John A.
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supporting information
p. 11799 - 11804
(2014/10/16)
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- Facile formation of methylenebis(chalcone)s through unprecedented methylenation reaction. Application to antiparasitic and natural product synthesis
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The formation of methylenebis(chalcone)s has been discovered during deprotection with methoxymethyl groups from trihydroxychalcones. Studies on this methylenation reaction led to a mechanism hypothesis that was extended to other chalcones and to dihydrochalcone, acetophenone, benzophenone and flavone derivatives. This new method was applied to the rapid synthesis of natural product piperanduncin C. These original methylenebis compounds were also evaluated for their antiparasitic activity. Copyright
- Thevenin, Marion,Mouray, Elisabeth,Grellier, Philippe,Dubois, Joelle
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p. 2986 - 2992
(2014/05/20)
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- Cloning and structure-function analyses of quinolone- and acridone-producing novel type III polyketide synthases from citrus microcarpa
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Background:Type III polyketide synthases (PKSs) synthesize various polyketide and alkaloid scaffolds. Results:QNS synthesizes quinolone as the single product, whereas ACS produces acridone as the major product. Conclusion:QNS and ACS are novel quinolone- and acridone-producing type III PKSs, respectively. Significance:Structure-function analyses of QNS and ACS provide insights into molecular bases for alkaloid biosyntheses.
- Mori, Takahiro,Shimokawa, Yoshihiko,Matsui, Takashi,Kinjo, Keishi,Kato, Ryohei,Noguchi, Hiroshi,Sugio, Shigetoshi,Morita, Hiroyuki,Abe, Ikuro
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p. 28845 - 28858
(2013/10/22)
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- Biomimetic total synthesis of (±)-garcibracteatone
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The polycyclic polyprenylated acylphloroglucinol natural product garcibracteatone has been synthesized in four steps from phloroglucinol, using a strategy based on biosynthetic speculation. The key biomimetic transformation is a cascade of 7-endo-trig and 5-exo-trig radical cyclizations followed by a terminating aromatic substitution reaction.
- Pepper, Henry P.,Lam, Hiu C.,Bloch, Witold M.,George, Jonathan H.
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supporting information
p. 5162 - 5164
(2013/01/15)
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- Synthesis and evaluation of antibacterial activities of 5,7-dihydroxycoumarin derivatives
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This study examines the synthesis and antibacterial activities of 5,7-dihydroxycoumarin derivatives, whose structures were confirmed using analytical and spectral data. Twenty compounds were tested for their antibacterial activities against five microbial species such as E. coli, S. aureus, K. pneumonia, P. aeruginosa, and S. typhimurium were studied. Compounds 5 and 12 exhibited the most potent activity against Staphylococcus aureus with a MIC value of 2.5 μg/mL for each of the compounds. Copyright
- Chin, Yi-Ping,Huang, Wei-Jan,Hsu, Feng-Lin,Lin, Mei-Hsiang,Lin, Yuh-Ling
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experimental part
p. 386 - 393
(2012/01/11)
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- Evaluation of polyhydroxybenzophenones as α-glucosidase inhibitors
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This experiment was designed to synthesize 18 kinds of polyhydroxybenzophenones by using Friedel-Crafts reaction, and to measure the inhibitory activity on α-glucosidase with p-nitrophenyl-β-D- galactopyranoside (PNPG) as a substrate. Here, acarbose (IC50a= a1674.75aaμmolaL-1) was used as the reference inhibitor. The results demonstrated that most of the target compounds had remarkable inhibitory activities on α-glucosidase. Among all these compounds, 2,4,4′,6-butahydroxydiphenylketone (11) was found to be the most potent α-glucosidase inhibitor with an IC50 value of 10.62aaμmolaL-1. In addition, we found these compounds were competitive inhibitors through the kinetic analysis. The results suggested that such compounds might be utilized for the development of new candidates for diabetes treatment. A series of polyhydroxybenzophenones was synthesized and evaluated as α-glucosidase inhibitors. Compound 11 was found to be the most potent inhibitor. Copyright
- Hu, Xuesen,Xiao, Yang,Wu, Jianlong,Ma, Lin
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experimental part
p. 71 - 77
(2011/09/21)
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- Synthesis and biological evaluation of polyhydroxy benzophenone as mushroom tyrosinase inhibitors
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A series of polyhydroxy benzophenone were synthesized and evaluated as mushroom tyrosinase inhibitors. The results demonstrated that most of the target compounds had remarkable inhibitory activities on mushroom tyrosinase. Among all these compounds, 2,3,4,3′,4′,5′-hexahydroxy-diphenylketone 10 was found to be the most potent tyrosinase inhibitor with IC50 value of 1.4 μM. In addition, the inhibition kinetics analyzed by Lineweaver-Burk plots revealed that such compounds were competitive inhibitors. These results suggested that such compounds might be utilized for the development of new candidate for treatment of dermatological disorders.
- Wu, Jianlong,Hu, Xuesen,Ma, Lin
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experimental part
p. 449 - 452
(2012/01/04)
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- A facile phenol-driven intramolecular diastereoselective thermal/base-catalyzed dipolar [2 + 2] annulation reactions: An easy access to complex bioactive natural and unnatural benzopyran congeners
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The complex bioactive natural and unnatural benzopyran congeners have been synthesized using one-/two-step approaches in very good yields from the reactions of two different dihydroxyphthalides, natural resorcyclic acid derivative, and trihydroxybenzophenone with citral and/or farnesal, via the phenol-driven intramolecular diastereoselective thermal/base-catalyzed dipolar [2 + 2] cycloaddition reactions and three different thermal intramolecular cyclization reactions. The effects of the nature and the position of phenolic groups in the starting materials on the course of these cycloaddition reactions have also been described. Depending upon the absence or presence of intramolecular hydrogen bonding of the phenolic group with the carbonyl moiety in the starting materials, these phenol-driven intramolecular thermal/base-catalyzed dipolar [2 + 2] cycloaddition reactions either furnished the kinetically controlled products or directly formed the thermodynamically controlled rearranged products, respectively.
- Mondal, Mukulesh,Puranik, Vedavati G.,Argade, Narshinha P.
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p. 2068 - 2076
(2007/10/03)
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- Sulfonium salts as prenyl, geranyl, and isolavandulyl transfer agents towards benzoylphloroglucinol derivatives
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In search for new methods aiming biomimetic synthesis of polyprenylated acylphloroglucinols (PPAPs), we now report the results of an evaluation of sulfonium salts as prenyl, geranyl, and isolavandulyl transfer agents towards benzoylphloroglucinol derivatives, in neutral conditions. As a result, conditions were found for rather efficient C-prenylation of these compounds. The corresponding trimethyl ether gave the best results, but the reaction was accompanied by a deacylation process. Geranyl transfer was also observed, but in low yield, and, interestingly, an isolavandulyl group could be introduced with an appreciable yield.
- Brajeul, Solenn,Delpech, Bernard,Marazano, Christian
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p. 5597 - 5600
(2008/03/11)
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- 6-Acyl-4-aryl/alkyl-5,7-dihydroxycoumarins as anti-inflammatory agents
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A series of coumarin derivatives were synthesized in two steps from phloroglucinol. The anti-inflammatory activities of these derivatives were evaluated by means of inhibiting NO production in LPS-induced RAW 264.7 cells. Derivatives 3, 8, 10, 11, and 13 exhibited low micromolar levels of anti-inflammatory activities, and these derivatives also protected DNA against hydroxyl radical attack. Coumarin derivative 8 was the most potent derivative among those tested herein against NO production in LPS-induced RAW 264.7 cells with an IC50 value of 7.6 μM, and it effectively reduced the hydroxyl radical production by 50% at 100 μM in the electron spin resonance study.
- Lin, Chun-Mao,Huang, Sheng-Tung,Lee, Fu-Wei,Kuo, Hsien-Saw,Lin, Mei-Hsiang
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p. 4402 - 4409
(2007/10/03)
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- A test for homology: Photoactive crystalline assemblies involving linear templates based on a homologous series of phloroglucinols
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(Chemical Equation Presented) Cocrystallization of trans-1,2-bis(4-pyridyl) ethylene (4,4′-bpe) with eight members of a homologous series of phloroglucinols 1a-h yields molecular solids 2(1a-h)·2(4,4′-bpe) with components held together by four O-H...N hydrogen bonds. In each case, the molecules assemble to form a discrete four-component assembly with olefins preorganized for a [2 + 2] photodimerization. UV irradiation of each member in the series of solids produces rctt-tetrakis(4-pyridyl)cyclobutane (4,4′-tpcb), stereospecifically, in up to 100% yield.
- Friscic, Tomislav,Drab, David M.,MacGillivray, Leonard R.
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p. 4647 - 4650
(2007/10/03)
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- Thermal cross fries acyl and benzoyl migrations from aromatic diesters to phenols
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A study of boron trifluoride etherate catalyzed thermal cross Fries reaction is reported in this paper. Acyl and benzoyl migrations from various aromatic diesters to phenols in dry benzene as solvent takes place selectively and in this, way offers an alternative route to the preparation of different hydroxy acetophenones and benzophenones.
- Thapliyal,Aggarwal
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p. 706 - 708
(2007/10/03)
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- Radiation-sensitive resin composition
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The radiation-sensitive resin composition, containing an alkali-soluble resin, comprises 1,1-bis(4-hydroxyphenol)-1-phenylethane, 1,1,1-tris(4-hydroxyphenyl)ethane or a compound selected from a polyhydroxy compound having the following formula: and quinonediazidesulfonates of the polyhydroxy compound, and the like. The radiation-sensitive resin composition is suitable for use as a positive type photoresist which has such excellent developability as to inhibit effectively the generation of scum in the formation of a photoresist pattern, has high sensitivity and is excellent in heat resistance and remained thickness ratio upon development.
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- Synthesis of Vismiaphenone-B: A Naturally Occurring Prenylated Benzophenone
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Vismiaphenone-B, 5-C-prenyl-2,6-dihydroxy-6'',6''-dimethylchromenobenzophenone (II), has been synthesised starting from 2,4,6-trihydroxybenzophenone (V).V on prenylation with prenyl bromide in the presence of methanolic sodium methoxide yields three products, viz. 3,5-di-C-prenyl-2,4,6-trihydroxybenzophenone (VI), 2,6-dihydroxy-4-O-prenylbenzophenone (VII) and a brown oil, which could not be characterised.VI on cyclodehydrogenation with DDQ affords II, identical in all respects (UV, IR and PMR) with a natural sample.
- Pathak, V. P.,Khanna, R. N.
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p. 253 - 254
(2007/10/02)
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