- Hydrogenative Cyclopropanation and Hydrogenative Metathesis
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The unusual geminal hydrogenation of a propargyl alcohol derivative with [CpXRuCl] as the catalyst entails formation of pianostool ruthenium carbenes in the first place; these reactive intermediates can be intercepted with tethered alkenes to give either cyclopropanes or cyclic olefins as the result of a formal metathesis event. The course of the reaction is critically dependent on the substitution pattern of the alkene trap.
- Peil, Sebastian,Guthertz, Alexandre,Biberger, Tobias,Fürstner, Alois
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- Cationic Au(I)- and Pt(II)-catalyzed silylation of alcohols using allylsilanes
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The silylation of alcohols using allylsilanes was catalyzed by cationic Au(I) and Pt(II) species, which were prepared in situ from the metal chlorides ([AuCl(PPh3)], PtCl2) and a silver salt. TBS-, TES-, and TIPS-protections of vario
- Shibata, Takanori,Kanda, Kazumasa,Ueno, Yasunori,Fujiwara, Ryo
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- Unlocking a Diazirine Long-Lived Nuclear Singlet State via Photochemistry: NMR Detection and Lifetime of an Unstabilized Diazo-Compound
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Diazirines are important for photoaffinity labeling, and their photoisomerization is relatively well-known. This work shows how hyperpolarized NMR spectroscopy can be used to characterize an unstable diazo-compound formed via photoisomerization of a 15N2-labeled silyl-ether-substituted diazirine. This diazirine is prepared in a nuclear spin singlet state via catalytic transfer of spin order from para-hydrogen. The active hyperpolarization catalyst is characterized to provide insight into the mechanism. The photochemical isomerization of the diazirine into the diazo-analogue allows the NMR invisible nuclear singlet state of the parent compound to be probed. The identity of the diazo-species is confirmed by trapping with N-phenyl maleimide via a cycloaddition reaction to afford bicyclic pyrazolines that also show singlet state character. The presence of singlet states in the diazirine and the diazo-compound is validated by comparison of experimental nutation behavior with theoretical simulation. The magnetic state lifetime of the diazo-compound is determined as 12 ± 1 s in CD3OD solution at room temperature, whereas its chemical lifetime is measured as 100 ± 5 s by related hyperpolarized NMR studies. Indirect evidence for the generation of the photoproduct para-N2 is presented.
- Procacci, Barbara,Roy, Soumya S.,Norcott, Philip,Turner, Norman,Duckett, Simon B.
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- Incorporation of β-Silicon-β3-Amino Acids in the Antimicrobial Peptide Alamethicin Provides a 20-Fold Increase in Membrane Permeabilization
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Incorporation of silicon-containing amino acids in peptides is known to endow the peptide with desirable properties such as improved proteolytic stability and increased lipophilicity. In the presented study, we demonstrate that incorporation of β-silicon-β3-amino acids into the antimicrobial peptide alamethicin provides the peptide with improved membrane permeabilizing properties. A robust synthetic procedure for the construction of β-silicon-β3-amino acids was developed and the amino acid analogues were incorporated into alamethicin at different positions of the hydrophobic face of the amphipathic helix by using SPPS. The incorporation was shown to provide up to 20-fold increase in calcein release as compared with wild-type alamethicin.
- Madsen, Julie L. H.,Hj?rringgaard, Claudia U.,Vad, Brian S.,Otzen, Daniel,Skrydstrup, Troels
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- Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing an Intermediate for Squalestatin Synthesis
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Studies on both the propensity for intramolecular cycloaddition between diazo and alkene functionality, and the tolerance of α-substituted α-diazoesters towards ozone in the presence of an alkene, led to chemoselective alkene ozonolysis of an ?-unsaturated-α-diazoester to give a key racemic diazoketone for the synthesis of 6,7-dideoxysqualestatin H5.
- Almohseni, Hasanain A. A.,Arif, Tanzeel,Fegheh-Hassanpour, Younes,Hodgson, David M.
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Read Online
- Hydrogenative metathesis of enynes via piano-stool ruthenium carbene complexes formed by alkyne gem-hydrogenation
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The only recently discovered gem-hydrogenation of internal alkynes is a fundamentally new transformation, in which both H atoms of dihydrogen are transferred to the same C atom of a triple bond while the other position transforms into a discrete metal carbene complex. [Cp?RuCl]4 is presently the catalyst of choice: the resulting piano-stool ruthenium carbenes can engage a tethered alkene into either cyclopropanation or metathesis, and a prototypical example of such a reactive intermediate with an olefin ligated to the ruthenium center has been isolated and characterized by X-ray diffraction. It is the substitution pattern of the olefin that determines whether metathesis or cyclopropanation takes place: a systematic survey using alkenes of largely different character in combination with a computational study of the mechanism at the local coupled cluster level of theory allowed the preparative results to be sorted and an intuitive model with predictive power to be proposed. This model links the course of the reaction to the polarization of the double bond as well as to the stability of the secondary carbene complex formed, if metathesis were to take place. The first application of "hydrogenative metathesis"to the total synthesis of sinularones E and F concurred with this interpretation and allowed the proposed structure of these marine natural products to be confirmed. During this synthesis, it was found that gem-hydrogenation also provides opportunities for C-H functionalization. Moreover, silylated alkynes are shown to participate well in hydrogenative metathesis, which opens a new entry into valuable allylsilane building blocks. Crystallographic evidence suggests that the polarized [Ru-Cl] bond of the catalyst interacts with the neighboring R3Si group. Since attractive interligand Cl/R3Si contacts had already previously been invoked to explain the outcome of various ruthenium-catalyzed reactions, including trans-hydrosilylation, the experimental confirmation provided herein has implications beyond the present case.
- Peil, Sebastian,Bistoni, Giovanni,Goddard, Richard,Fürstner, Alois
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supporting information
p. 18541 - 18553
(2020/11/17)
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- BENZIMIDAZOLONE DERIVED INHIBITORS OF BCL6
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The present invention relates to compounds of Formula I that function as inhibitors of BCL6 (B-cell lymphoma 6) activity: wherein X1, X2, R1, R2 and R3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6 activity is implicated.
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Paragraph 00390
(2018/12/13)
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- Deoxyalkoxyamination of Alcohols for the Synthesis of N-Alkoxy-N-alkylbenzenesulfonamides
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A novel protocol for the deoxyalkoxyamination of alcohols has been developed, using N-alkoxybenzenesulfonimide (NOSI) as both a sulfonyl transfer reagent and an alkoxyamine source, accessing a diverse range of N-alkoxy-N-alkylbenzenesulfonamides with excellent isolated yields. This method is characterized by metal-free reaction, scalability, and waste-balance. Chiral substrates are converted with excellent levels of stereochemical inversion. NOSI could be generated in situ during the reaction as a stable reagent if a three-component one-pot reaction was designed. Exploiting this approach to run intramolecular reactions offered various N-protected isoxazolidines. In addition, valuable O-alkyl hydroxylamines (or isoxazolidines) were obtained through a neutral strategy of desulfonylation of the products.
- Sun, Qi-An,Lu, Ze-Hai,Pu, Xiao-Qiu,Hu, Hui-Lian,Zhang, Jia-heng,Yang, Xian-Jin
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supporting information
p. 3920 - 3927
(2018/07/31)
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- Stereoselective Synthesis of a Highly Oxygenated δ-Lactone Related to the Core Structure of (-)-Enterocin
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The title compound was prepared in a concise route starting from an appropriately protected (S)-glyceraldehyde. A highly diastereoselective (d.r. >95:5) Mukaiyama aldol reaction of an acetoacetate-derived silyl enol ether served as the initial step of the synthetic sequence. It was found that protection of the glyceraldehyde as a butane-2,3-dione acetal is required to achieve the desired diastereoselectivity. Upon lactonization, a Tsuji-Trost allylation and a subsequent one-pot reaction cascade including an ozonolysis and an α-hydroxylation gave diastereoselective access to the desired α-hydroxy-β-oxo-δ-lactone. Alternative synthetic approaches are discussed and proof for the configuration of the product is presented.
- Wegmann, Marcus,Bach, Thorsten
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supporting information
p. 209 - 217
(2016/12/24)
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- ISOXAZOLE DERIVATIVE AS MUTATED ISOCITRATE DEHYDROGENASE 1 INHIBITOR
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It has been found that a compound of the general formula (I) having an isoxazole skeleton has excellent inhibitory activity against mutant IDH1 protein and inhibits the production of 2-HG by this protein, while the compound is also capable of effectively inhibiting the growth of various tumors expressing the protein. In the formula, R1, R2, R3, Y, and Z are as defined in claim 1.
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Paragraph 0256; 0257
(2018/02/06)
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- Alcohol, Aldehyde, and Ketone Liberation and Intracellular Cargo Release through Peroxide-Mediated α-Boryl Ether Fragmentation
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α-Boryl ethers, carbonates, and acetals, readily prepared from the corresponding alcohols that are accessed through ketone diboration, react rapidly with hydrogen peroxide to release alcohols, aldehydes, and ketones through the collapse of hemiacetal intermediates. Experiments with α-boryl acetals containing a latent fluorophore clearly demonstrate that cargo can be released inside cells in the presence of exogenous or endogenous hydrogen peroxide. These experiments show that this protocol can be used for drug activation in an oxidative environment without generating toxic byproducts.
- Hanna, Ramsey D.,Naro, Yuta,Deiters, Alexander,Floreancig, Paul E.
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supporting information
p. 13353 - 13360
(2016/10/22)
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- Gold-catalyzed spiro-N,O-ketal synthesis
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An efficient method for the synthesis of spiro-N,O-ketals with 5- and 6-membered rings was developed via a gold-catalyzed spiroamidoketalization of alkynyl amidoalcohols under mild conditions. This methodology has been successfully applied to the synthesis of a spiro-N,O-ketal analogue of marineosin A. This journal is
- Grammatikopoulou,Thysiadis,Sarli
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p. 1169 - 1178
(2015/03/04)
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- Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability
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The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.
- Kang, Soosung,Watanabe, Mizuki,Jacobs,Yamaguchi, Masaya,Dahesh, Samira,Nizet, Victor,Leyh, Thomas S.,Silverman, Richard B.
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p. 448 - 461
(2015/04/16)
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- Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes by Rh(III)-Catalyzed C-H Activation
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α,β-Unsaturated oxime pivalates are proposed to undergo reversible C(sp2)-H insertion with cationic Rh(III) complexes to furnish five-membered metallacycles. In the presence of 1,1-disubstituted olefins, these species participate in irreversible migratory insertion to give, after reductive elimination, 2,3-dihydropyridine products in good yields. Catalytic hydrogenation can then be used to convert these molecules into piperidines, which are important structural components of numerous pharmaceuticals.
- Romanov-Michailidis, Fedor,Sedillo, Kassandra F.,Neely, Jamie M.,Rovis, Tomislav
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supporting information
p. 8892 - 8895
(2015/08/03)
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- Synthesis of mevalonate-and fluorinated mevalonate prodrugs and their in vitro human plasma stability
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The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro-and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro-and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.
- Kang, Soosung,Watanabe, Mizuki,Jacobs,Yamaguchi, Masaya,Dahesh, Samira,Nizet, Victor,Leyh, Thomas S.,Silverman, Richard B.
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p. 448 - 461
(2016/10/19)
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- PRODRUGS OF FLUORINATED MEVALONATES TO INHIBIT THE MEVALONATE PATHWAY OF STREPTOCOCCUS PNEUMONIAE
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Fluorinated prodrug compounds as can be used for selective streptococcal mevalonate pathway inhibition.
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Paragraph 0055
(2013/09/12)
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- Syntheses of structurally-simplified and fluorescently-labeled neovibsanin derivatives and analysis of their neurite outgrowth activity in PC12 cells
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The syntheses of several neovibsanin derivatives were carried out in order to elucidate the simple structure required for displaying neurite outgrowth activity. In addition, a fluorescent probe molecule was synthesized and the analysis of its behavior in the PC12 cell line showed that the neovibsanins accumulate on the outer edge of the cell at the site of formation of prominences.
- Imagawa, Hiroshi,Saijo, Hayato,Yamaguchi, Hitomi,Maekawa, Ken,Kurisaki, Takahiro,Yamamoto, Hirofumi,Nishizawa, Mugio,Oda, Masataka,Kabura, Michiko,Nagahama, Masahiro,Sakurai, Jun,Kubo, Miwa,Nakai, Megumi,Makino, Kosho,Ogata, Mitsuko,Takahashi, Hironobu,Fukuyama, Yoshiyasu
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supporting information; experimental part
p. 2089 - 2093
(2012/04/17)
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- Synthesis of sequentially deuterated 1-n-Butyl-3-methylimidazolium ionic liquids
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Deuterium isotopologues of the ionic liquid (IL) 1-n-butyl-3- methylimidazolium chloride ([C4mim]Cl) sequentially labeled on the C-1″, C-1′, C-2′, C-3′, and C-4′ positions of the N-alkyl groups were prepared following a strategy that minimizes
- Khrizman, Alexander,Cheng, Hiu Yan,Moyna, Guillermo
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experimental part
p. 401 - 407
(2012/07/13)
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- Flow ozonolysis using a semipermeable Teflon AF-2400 membrane to effect gas - Liquid contact
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(Figure Presented) A flow-through chemistry apparatus has been developed which allows gases and liquids to contact via a semipermeable Teflon AF-2400 membrane. In this preliminary investigation, the concept was proven by application to the ozonolysls of a series of alkenes.
- O'Brien, Matthew,Baxendale, Ian R.,Ley, Steven V.
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supporting information; experimental part
p. 1596 - 1598
(2010/06/16)
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- Synthesis and anti-HCV activity of 3′,5′-cyclic SATE phosphonodiester nucleoside as a novel prodrug
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A novel 2′,4′-dimethyl carbocyclic adenosine 5′-phosphonic acid analogue (20) was prepared using acyclic stereoselective route from commercially available 4-hydroxybutan-2-one (4). To improve cellular permeability and enhance the anti-HCV activity of this phosphonic acid, a 3′,5′-cyclic SATE phosphonodiester nucleoside prodrug (22) was prepared. The synthesized phosphonic nucleoside analogues, (20) and (22), were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line.
- Liu, Lian Jin,Seo, Rac Seok,Yoo, Seung Won,Choi, Jin,Hong, Joon Hee
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experimental part
p. 915 - 920
(2010/10/21)
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- Design and synthesis of dually branched 5′-norcarbocyclic adenosine phosphonodiester analogue as a new anti-HIV prodrug
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A novel 3′,4′-dimethyl-5′-norcarbocyclic adenosine phosphonic acid was prepared using acyclic stereoselective route from 4-hydroxybutan-2-one (4). To improve the cellular permeability and enhance the anti-HIV activity of this phosphonic acid, a (bis)SATE
- Oh, Chang Hyun,Liu, Lian Jin,Hong, Joon Hee
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experimental part
p. 721 - 733
(2011/05/03)
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- Indium(III) trifluoromethanesulfonate as an efficient catalyst for the deprotection of acetals and ketals
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(Chemical Equation Presented) Acetals and ketals are readily deprotected under neutral conditions in the presence of acetone and catalytic amounts of indium(III) trifluoromethanesulfonate (0.8 mol %) at room temperature or mild microwave heating conditions to give the corresponding aldehydes and ketones in good to excellent yields.
- Gregg, Brian T.,Golden, Kathryn C.,Quinn, John F.
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p. 5890 - 5893
(2008/02/09)
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- Compatible injection and detection systems for studying the kinetics of excess electron transfer
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A design for fast kinetic studies of electron transfer in radical anions is reported. α-Hydroxy radicals formed by 355 nm laser flash photolysis of α-phenacyl alcohols are deprotonated under basic conditions to give ketyl radical anions that serve as elec
- Xu, Libin,Jin,Lal, Mukul,Daublain, Pierre,Newcomb, Martin
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p. 1837 - 1840
(2008/02/02)
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- Stereochemical analysis of isopentenyl diphosphate isomerase type II from Staphylococcus aureus using chemically synthesized (S)- and (R)-[2- 2H]Isopentenyl diphosphates
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(Chemical Equation Presented) To study the catalysis of isopentenyl diphosphate (IPP) isomerase type II from Staphylococcus aureus, which is a flavoprotein catalyzing the interconversion of IPP and dimethylallyl diphosphate, we have chemically synthesized (S)- and (R)-[2-2H]IPP and carried out stereochemical analysis of the reaction. Our results show that the C-2 deprotonation of IPP by this enzyme is pro-R stereospecific, suggesting a similar stereochemical course as the type I enzyme.
- Kao, Chai-Lin,Kittleman, William,Zhang, Hua,Seto, Haruo,Liu, Hung-Wen
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p. 5677 - 5680
(2007/10/03)
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- Development and comparison of the substrate scope of Pd-catalysts for the aerobic oxidation of alcohols
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(Chemical Equation Presented) Three catalysts for aerobic oxidation of alcohols are discussed and the effectiveness of each is evaluated for allylic, benzylic, aliphatic, and functionalized alcohols. Additionally, chiral nonracemic substrates as well as chemoselective and diastereoselective oxidations are investigated. In this study, the most convenient system for the Pd-catalyzed aerobic oxidation of alcohols is Pd(OAc)2 in combination with triethylamine. This system functions effectively for the majority of alcohols tested and uses mild conditions (3 to 5 mol % of catalyst, room temperature). Pd(IiPr)(OAc)2(H2O) (1) also successfully oxidizes the majority of alcohols evaluated. This system has the advantage of significantly lowering catalyst loadings but requires higher temperatures (0.1 to 1 mol % of catalyst, 60°C). A new catalyst is also disclosed, Pd(IiPr)(OPiv)2 (2). This catalyst operates under very mild conditions (1 mol %, room temperature, and air as the O2 source) but with a more limited substrate scope.
- Schultz, Mitchell J.,Hamilton, Steven S.,Jensen, David R.,Sigman, Matthew S.
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p. 3343 - 3352
(2007/10/03)
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- Studies of intramolecular alkylidene carbene reactions; an approach to heterocyclic nucleoside bases
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A series of investigations into the applications of intramolecular cyclisations of alkylidene carbenes are described. The insertion reaction of the carbene generated from 1,4-di(tert-butyldimethylsilyloxy)-3-benzyloxy-butane-2-one to the benzylic position
- Hobley, Gerard,Stuttle, Keith,Wills, Martin
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p. 4739 - 4748
(2007/10/03)
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- Construction of the diene moiety (C9-C18) of amphidinolide B, a 26- membered macrolide
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The diene moiety (C9-C18) of amphidinolide B, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been synthesized by a coupling reaction of an alkynyl anion of 5 and the aldehyde 7, followed by Michael addition and methylenation.
- Ohi, Katsuhide,Nishiyama, Shigeru
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p. 571 - 572
(2007/10/03)
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- Deprotection of Acetals and Silyl Ethers by DDQ. Is DDQ a Neutral Catalyst ?
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2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ) in wet ethyl acetate at room temperature catalytically hydrolyzed acyclic acetals effectively and selectively among ethereal functional groups such as dioxoranes, 1,3-dioxanes, oxiranes, TMS- and TBDMS ethers.The mechanism is discussed on the basis of the function of DDQ as a Lewis acid in a wet solvent. 1890
- Oku, Akira,Kinugasa, Motoharu,Kamada, Tohru
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p. 165 - 168
(2007/10/02)
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- Cross Aldol Products from α-Haloalkoxysilanes and Silyl Enol Ethers
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α-Haloalkoxysilanes have been prepared by cleavage of the C-S bond in O,S-acetals with sulfuryl chloride, and by cleavage of C-Sn bond in α-silyloxystannanes by bromine.The α-haloalkoxysilanes, both after isolation or after preparation in situ react with silyl enol ethers to yield silyl-protected cross aldol products.The reaction is catalyzed by Lewis acids.
- Antonsen, Oeyvind,Benneche, Tore,Gundersen, Lise-Lotte,Undheim, Kjell
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p. 172 - 177
(2007/10/02)
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