- Kinetic isotope effects implicate two electrophilic oxidants in cytochrome P450-catalyzed hydroxylations
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Intramolecular kinetic isotope effects (KIEs) were determined for cytochrome P450-catalyzed hydroxylation reactions of methyl-dideuterated trans-2-phenylcyclopropylmethane-d2 (1-d2), which gives two products from oxidation of the methyl group, trans-2-phenylcyclopropylmethanol (2) and 1-phenyl-3-buten-1ol (3). In oxidations of each enantiomer of 1-d2 with three P450 enzymes (CYP2B1, CYPΔ2E1, and CYPΔ2E1 T303A), the apparent intramolecular KIEs were different for products 2 and 3 in all cases and different for each enzyme-substrate combination. In oxidations of each enantiomer of undeuterated 1-d0 and trideuteriomethyl 1-d3 by CYP2B1 and CYPΔ2E1, the ratio of products 2/3 decreased for 1-d3 in comparison to 1-d0 in all cases. The results require multiple pathways for P450-catalyzed hydroxylation and are consistent with the two-oxidants model, where hydroxylation is effected by both the hydroperoxy-iron species and the iron-oxo species. The results are not consistent with predictions of the two-states model for P450-catalyzed hydroxylations, where oxidations occur from a low-spin state and a high-spin state of iron-oxo. Copyright
- Newcomb, Martin,Aebisher, David,Shen, Runnan,Chandrasena, R. Esala P.,Hollenberg, Paul F.,Coon, Minor J.
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Read Online
- Donor-Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates: Synthesis and Reactions with 4-Phenyl-1,2,4-triazoline-3,5-dione and Terminal Acetylenes
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The bicyclopropyl system activated by incorporation of donor and acceptor groups in the presence of Lewis acids was used as a synthetic equivalent of 1,6-zwitterions. Opening of both cyclopropane rings in 2′-aryl-1,1′-bicyclopropyl-2,2-dicarboxylates (D-A bicyclopropyl, ABCDs) in the presence of GaI3 + Bu4N+GaI4- results in 5-iodo-5-arylpent-2-enylmalonates as products of HI formal 1,6-addition to the bicyclopropyl system. The use of GaCl3 or GaBr3 as a Lewis acid and terminal aryl or alkyl acetylenes as 1,6-zwitterion interceptors allows the alkyl substituent to be grown to give the corresponding acyclic 7-chloro(bromo)-hepta-2,6-dienylmalonates. The reaction of ABCDs with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) catalyzed by Yb(OTf)3 also results in the opening of both cyclopropane rings. The reaction products are tetrahydropyridazine derivatives - (7,9-dioxo-1,6,8-triazabicyclo[4.3.0]non-3-en-2-ylmethyl)malonates - containing one more PTAD moiety in the malonyl group.
- Potapov, Konstantin V.,Denisov, Dmitry A.,Glushkova, Valeriia V.,Novikov, Roman A.,Tomilov, Yury V.
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p. 15562 - 15576
(2020/11/30)
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- 5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors
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A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.
- Peese, Kevin M.,Allard, Christopher W.,Connolly, Timothy,Johnson, Barry L.,Li, Chen,Patel, Manoj,Sorensen, Margaret E.,Walker, Michael A.,Meanwell, Nicholas A.,McAuliffe, Brian,Minassian, Beatrice,Krystal, Mark,Parker, Dawn D.,Lewis, Hal A.,Kish, Kevin,Zhang, Ping,Nolte, Robert T.,Simmermacher, Jean,Jenkins, Susan,Cianci, Christopher,Naidu, B. Narasimhulu
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p. 1348 - 1361
(2019/02/24)
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- Titanium(III)-Catalyzed Reductive Decyanation of Geminal Dinitriles by a Non-Free-Radical Mechanism
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A titanium-catalyzed mono-decyanation of geminal dinitriles is reported. The reaction proceeds under mild conditions, tolerates numerous functional groups, and can be applied to quaternary malononitriles. A corresponding desulfonylation is demonstrated as well. Mechanistic experiments support a catalyst-controlled cleavage without the formation of free radicals, which is in sharp contrast to traditional stoichiometric radical decyanations. The involvement of two TiIII species in the C?C cleavage is proposed, and the beneficial role of added ZnCl2 and 2,4,6-collidine hydrochloride is investigated.
- Weweler, Jens,Younas, Sara L.,Streuff, Jan
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supporting information
p. 17700 - 17703
(2019/11/13)
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- Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases
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Ene reductases from the Old Yellow Enzyme (OYE) family reduce the C=C double bond in α,β-unsaturated compounds bearing an electron-withdrawing group, for example, a carbonyl group. This asymmetric reduction has been exploited for biocatalysis. Going beyond its canonical function, we show that members of this enzyme family can also catalyze the formation of C?C bonds. α,β-Unsaturated aldehydes and ketones containing an additional electrophilic group undergo reductive cyclization. Mechanistically, the two-electron-reduced enzyme cofactor FMN delivers a hydride to generate an enolate intermediate, which reacts with the internal electrophile. Single-site replacement of a crucial Tyr residue with a non-protic Phe or Trp favored the cyclization over the natural reduction reaction. The new transformation enabled the enantioselective synthesis of chiral cyclopropanes in up to >99 % ee.
- Heckenbichler, Kathrin,Schweiger, Anna,Brandner, Lea Alexandra,Binter, Alexandra,Toplak, Marina,Macheroux, Peter,Gruber, Karl,Breinbauer, Rolf
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supporting information
p. 7240 - 7244
(2018/06/15)
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- Lewis Acid Catalyzed Annulation of Cyclopropane Carbaldehydes and Aryl Hydrazines: Construction of Tetrahydropyridazines and Application Toward a One-Pot Synthesis of Hexahydropyrrolo[1,2- b]pyridazines
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In this report, a facile synthesis of tetrahydropyridazines via a Lewis acid catalyzed annulation reaction of cyclopropane carbaldehydes and aryl hydrazines has been demonstrated. Moreover, the generated tetrahydropyridazine further participated in a cycloaddition reaction with donor-acceptor cyclopropanes to furnish hexahydropyrrolo[1,2-b]pyridazines. We also performed these two steps in one pot in a consecutive manner. In addition, a monodecarboxylation reaction of hexahydropyrrolo[1,2-b]pyridazine was achieved with a good yield.
- Dey, Raghunath,Kumar, Pankaj,Banerjee, Prabal
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p. 5438 - 5449
(2018/05/28)
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- Olefin-Migrative Cleavage of Cyclopropane Rings through the Nickel-Catalyzed Hydrocyanation of Allenes and Alkenes
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A nickel-catalyzed hydrocyanation triggered by hydronickelation of the carbon-carbon double bonds of allenes followed by cyclopropane cleavage is described. The observed regio- and stereochemistries in the products are strongly influenced by the initial hydronickelation step, and allenyl- and methylenecyclopropanes reacted smoothly to promote the cleavage of cyclopropane. In contrast, this cleavage was not observed with vinylidenecyclopropanes, because the initial hydronickelation does not give a suitable intermediate for cleavage of the cyclopropanes. (Figure presented.).
- Hori, Hiroto,Arai, Shigeru,Nishida, Atsushi
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supporting information
p. 1170 - 1176
(2017/04/13)
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- Temporary Generation of a Cyclopropyl Oxocarbenium Ion Enables Highly Diastereoselective Donor-Acceptor Cyclopropane Cycloaddition
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A novel formal [3+2] cycloaddition of cyclopropylacetals and aldehydes was developed, and the resulting trisubstituted tetrahydrofurans display three new chiral centers formed with highly diastereoselectivity. This method is stereocomplementary to most previously reported cycloadditions of malonate diesters, relies on the transient generation of cyclopropyl oxocarbenium ions, proceeds under mild conditions, and is based on the concept of temporary activation of an otherwise inert protecting group. Hide-and-seek with a dipole: A novel formal [3+2] cycloaddition of cyclopropylacetals and aldehydes was developed. This reaction affords trisubstituted tetrahydrofurans displaying three newly formed chiral centers with high diastereoselectivity. The reaction relies on the transient generation of cyclopropyl oxocarbenium ions under mild conditions and is based on the concept of temporary activation of an otherwise inert protecting group.
- Sabbatani, Juliette,Maulide, Nuno
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supporting information
p. 6780 - 6783
(2016/06/08)
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- Lewis Basic Sulfide Catalyzed Electrophilic Bromocyclization of Cyclopropylmethyl Amide
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A Lewis basic sulfide catalyzed electrophilic bromocyclization of cyclopropylmethyl amide has been developed. The catalytic protocol is applicable to both 1,1- and 1,2-substituted cyclopropylmethyl amides, giving oxazolines and oxazines in good yields and excellent diastereoselectivity.
- Wong, Ying-Chieh,Ke, Zhihai,Yeung, Ying-Yeung
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supporting information
p. 4944 - 4947
(2015/11/03)
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- A Novel Cathode Material for Cathodic Dehalogenation of 1,1-Dibromo Cyclopropane Derivatives
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Leaded bronze turned out to be an excellent cathode material for the dehalogenation reaction of cyclopropanes without affecting the strained molecular entity. With this particular alloy, beneficial properties of lead cathodes are conserved, whereas the corrosion of cathode is efficiently suppressed. The solvent in the electrolyte determines whether a complete debromination reaction is achieved or if the process can be selectively stopped at the monobromo cyclopropane intermediate. The electroorganic conversion tolerates a variety of functional groups and can be conducted at rather complex substrates like cyclosporine A. This approach allows the sustainable preparation of cyclopropane derivatives.
- Gütz, Christoph,Selt, Maximilian,B?nziger, Markus,Bucher, Christoph,R?melt, Christina,Hecken, Nadine,Gallou, Fabrice,Galv?o, Tomás R.,Waldvogel, Siegfried R.
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p. 13878 - 13882
(2015/09/28)
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- Copper-catalyzed regio- and stereoselective intermolecular three-component oxyarylation of allenes
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A copper(II)-catalyzed intermolecular three-component oxyarylation of allenes using arylboronic acids as a carbon source and TEMPO as an oxygen source is described. The reaction proceeded under mild conditions with high regio- and stereoselectivity and functional group tolerance. A plausible reaction mechanism is proposed, involving carbocupration of allenes, homolysis of the intervening allylcopper(II), and a radical TEMPO trap.
- Itoh, Taisuke,Shimizu, Yohei,Kanai, Motomu
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supporting information
p. 2736 - 2739
(2014/06/09)
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- Improved zinc-catalyzed simmons-smith reaction: Access to various 1,2,3-trisubstituted cyclopropanes
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The Simmons-Smith reaction of zinc carbenoids with alkenes is a powerful method to access cyclopropanes containing various substitution patterns. This work exploits the high reactivity of aryldiazomethanes toward zinc halides to generate aryl-substituted carbenoids catalytically. These carbenoids are able to cyclopropanate various alkenes diastereoselectively, including unfunctionalized substrates such as styrenes. The zinc catalyst can be modified to tolerate the use of free allylic alcohols.
- Levesque, Eric,Goudreau, Sebastien R.,Charette, Andre B.
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p. 1490 - 1493
(2014/04/03)
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- Synergistic effect of additives on cyclopropanation of olefins
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An efficient cyclopropanation of olefins with Zn(CH2I) 2, a catalytic amount of CCl3CO2H, and 1,2-dimethoxyethane at room temperature is described. A wide variety of olefins, including acid-sensitive substrates,
- Cheng, Donghao,Huang, Deshun,Shi, Yian
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supporting information
p. 5588 - 5591
(2013/09/12)
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- Synthesis of highly functionalized cyclohexenone rings: Rhodium-catalyzed 1,3-acyloxy migration and subsequent [5+1] cycloaddition
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Lead Rh-ole: Highly substituted cyclohexenones were prepared from cyclopropyl-substituted propargyl esters by using a [{Rh(CO)2Cl} 2] catalyst. This metal catalyst promoted the 1,3-acyloxy migration of propargyl esters and a subsequent [5+1] cycloaddition of the resulting allenylcyclopropanes in the presence of CO with high regioselectivity.
- Shu, Dongxu,Li, Xiaoxun,Zhang, Min,Robichaux, Patrick J.,Tang, Weiping
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supporting information; scheme or table
p. 1346 - 1349
(2011/04/22)
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- Catalytic oxidation of aromatic oxygenates by the heterogeneous catalyst Co-ZIF-9
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The catalytic activity of Co-ZIF-9, a zeolitic imidazolate framework of sodalite topology, in the oxidation of small aromatic molecules including phthalan, vanillyl alcohol, guaiacol, syringol, veratryl alcohol, and cinnamyl alcohol by molecular oxygen has been investigated. Co-ZIF-9 selectively oxidized the substrates and thus represents a promising heterogeneous catalyst for the oxidation of small aromatic substrates. Phthalan was converted to three different products, i.e. phthalide, phthalaldehyde, and small amounts of phthalic acid. In addition to phthalan, the alcohol functionality of vanillyl alcohol, veratryl alcohol, and cinnamyl alcohol was also similarly oxidized to yield the corresponding aldehydes in high yields and excellent selectivity. The effect of solvent, temperature and NaOH addition on the Co-ZIF-9 catalytic system has been studied. The presence of NaOH in the solution greatly enhanced the oxidation activity. The structure and stability of the heterogeneous catalyst was probed by UV-vis diffuse reflection spectroscopy, confirming the coordination geometry of cobalt in the catalyst framework, thermal gravimetric analysis, establishing the thermal stability of the structure, and XRD to monitor crystallinity of the catalyst. The heterogeneous nature of the catalyst was established by a hot filtration experiment, ICP analysis of the liquid phase, and by UV-vis absorption spectroscopy on the hot filtered reaction mixture.
- Zakzeski, Joseph,Dbczak, Agnieszka,Bruijnincx, Pieter C.A.,Weckhuysen, Bert M.
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experimental part
p. 79 - 85
(2011/12/16)
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- Preparation of a storable zinc carbenoid species and its application in cyclopropanation, chain extension, and [2,3]-sigmatropic rearrangement reactions
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(Chemical Equation Presented) The formation of a new phosphate carbenoid (n-BuO)2P(O)OZnCH2I and its application in organozinc-mediated reactions is described. This carbenoid undergoes very slow degradation in solution and can be stored for several weeks at -20 °C. Its reactivity was tested with many representative alkenes and was determined to be a powerful cyclopropanating reagent, giving the corresponding cyclopropanes in 72-99% yield. The use of this carbenoid in the chain extension of 1,3-diketones and [2,3]-sigmatropic rearrangement reactions is also described. 2010 American Chemical Society.
- Voituriez, Arnaud,Zimmer, Lucie E.,Charette, Andre B.
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experimental part
p. 1244 - 1250
(2010/04/26)
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- In situ generation of zinc carbenoids from diazo compounds and zinc salts: Asymmetric synthesis of 1,2,3-substituted cyclopropanes
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(Chemical Equation Presented) The first enantioselective cyclopropanation of alkenes using zinc carbenoids generated in situ from diazo compounds and zinc salts is reported. This new method allows the highly enantioand diastereoselective synthesis of 1,2,
- Goudreau, Sebastien R.,Charette, Andre B.
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supporting information; experimental part
p. 15633 - 15635
(2010/01/29)
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- Mechanistic studies on au(I)-catalyzed [3,3]-sigmatropic rearrangements using cyclopropane probes
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A comparative study of the Au(I)-catalyzed [3,3]-sigmatropic rearrangement of propargylic esters and propargyl vinyl ethers is described. Stereochemically defined cyclopropanes are employed as mechanistic probes to provide new synthetic and theoretical data concerning the reversibility of this type of rearrangement. Factors controlling the structure-reactivity relationship of Au(I)-coordinated allenes have been examined, therebyallowing for controlled access to orthogonal reactivity.
- Mauleon, Pablo,Krinsky, Jamin L.,Toste, F. Dean
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supporting information; experimental part
p. 4513 - 4520
(2009/09/30)
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- Iodomethylzinc phosphates: Powerful reagents for the cyclopropanation of alkenes
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A new family of zinc carbenoids derived from phosphoric acids was developed and used in the cyclopropanation of allylic alcohols and ethers and also of unfunctionalized olefins. The use of the chiral phosphoric acid of a 3,3′-disubstituted BINOL leads to efficient stereocontrol, affording the cyclopropanes of allylic and homoallylic ethers with complete conversions and up to 93% ee. A catalytic version of this reaction using 10 mol % of the chiral phosphate reagent is also disclosed. Copyright
- Lacasse, Marie-Christine,Poulard, Cyril,Charette, Andre B.
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p. 12440 - 12441
(2007/10/03)
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- Construction of a cis-Cyclopropane via Reductive Radical Decarboxylation. Enantioselective Synthesis of cis- and trans-1-Arylpiperazyl-2-phenylcyclopropanes Designed as Antidopaminergic Agents
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(1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a, 3, and ent-3, respectively), which were designed as conformationally restricted analogues of haloperidol (1), a clinically effective antipsychotic agent, were synthe
- Yamaguchi, Kazuya,Kazuta, Yuji,Abe, Hiroshi,Matsuda, Akira,Shuto, Satoshi
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p. 9255 - 9262
(2007/10/03)
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- Hydroxamic acid and N-hydroxyurea derivatives and their use
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Certain novel hydroxamic acid derivatives having the structure inhibit the enzyme lipoxygenase. These compounds, and the pharmaceutically acceptable salts thereof, are useful in the treatment or alleviation of inflammatory diseases, allergic conditions and cardiovascular diseases in mammals and as the active ingredient in pharmaceutical compositions for treating such conditions.
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- Kinetic enzymatic resolution of cyclopropane derivatives
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The kinetic enzymatic resolution of cyclopropane acetates was systematically investigated utilizing 16 different hydrolases. Best results were obtained with hydrolyses in the presence of Candida antarctica B lipase.
- Pietruszka, J?rg,Wilhelm, Thorsten,Witt, Andreas
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p. 1981 - 1983
(2007/10/03)
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- N,N-disubstituted amic acid derivatives
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A compound represented by general formula (I) or a pharmaceutically acceptable salt or ester thereof: [wherein each of Ar1, Ar2, Ar3 and Ar4 is an aryl group or an aromatic heterocyclic group; A1 is a
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- Magnesium promoted cyclopropanation reactions of allylic alcohols
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Treatment of allylic alcohols 1 with various magnesium reagents in the presence of alkyl dihalides affords the corresponding cyclopropyl alcohols 2. Reactions occur under mild conditions, and excellent diastereoselectivities have been achieved.
- Bolm, Carsten,Pupowicz, Doris
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p. 7349 - 7352
(2007/10/03)
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- The intramolecular electron transfer reactions of N-Alkylcyclopropyl phthalimides
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N-Alkylcyclopropyl phthalimides 5 and 6 were photolyzed to afford spiro lactams 17, 18 and 20-24. These products arise via an intramolecular electron transfer reaction between the phthalimide and the phenylcyclopropane portions of the molecule. The result
- Weidner-Wells, Michele A.,Oda, Kazuaki,Mazzocchi, Paul H.
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p. 3475 - 3486
(2007/10/03)
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- Stereochemistry of the thermal isomerizations of (1S,2R)-1-(E-styiyl)-2-phenylcyclopropane to 3,4-diphenylcyclopentenes
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One stereoisomer of 1-(E-styryl)-2-phenylcyclopropane undergoes reversible thermal stereomutations to equilibrate with three other stereoisomers and gives more slowly the four isomers of 3,4-diphenylcyclopentene. Appropriate kinetic data and analyses have
- Asuncion, Lisa A.,Baldwin, John E.
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p. 10672 - 10677
(2007/10/03)
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- Diastereoselective synthesis of bicyclopropanes
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Diastereoselective cyclopropanation of a trans-substituted vinyl cyclopropane was studied. The stereochemistry of the major and minor isomers was assigned by diastereoselective synthesis of the two isomers.
- Theberge, Cory R.,Zercher, Charles K.
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p. 9181 - 9184
(2007/10/02)
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- Transmission of Electronic Effects through 2--1--Cyclopropane
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The through-ring conjugation between ?-donor and attractor substituents on vicinal carbons of cyclopropane with the direct participation of the ring was assessed using proton and 13C NMR.Appropriate 1H NMR correlations were obtained between ?p and δH of the trimethylene protons.However, aryl through-space field effects were found to obscure individual conjugative effects.Conversely, the 13C NMR data implied the occurrence of competitive conjugation of ?-groups with the ring but gave no proof for the existence of the actual transmission of conjugative effects through the C-1-C-2 bond of the ring.
- Alonso, Miguel E.,Pekerar, Sarah V.,Borgo, Maria L.
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p. 956 - 962
(2007/10/02)
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- ARYLCYCLOPROPANE PHOTOCHEMISTRY. UNUSUAL AROMATIC SUBSTITUENT EFFECTS ON THE PHOTOCHEMICAL REARRANGEMENT OF (2-ARYLCYCLOPROPYL)METHYL ACETATES TO 1-ARYLHOMOALLYL ACETATES.
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Irradiation of trans(2-arylcyclopropyl)methyl acetates a 4-butenyl-1-arylacetate (7a,b,d-h) via an ionic mechanism from the singlet state. Similar rearrangements occurred with exo-(1,1a,6,6a-tetrahydrocycloprop left bracket a right bracket inden-1-yl)methyl acetate and the 4-cyano derivative. Excited state reaction rate constants were determined from reactant fluorescence lifetimes and product quantum yields. It is concluded that the rate-determining step involves conversion of the initially formed aromatic excited state to a reactive cyclopropane excited state and that cyclopropane to aromatic ring charge transfer enhances this process.
- Hixson,Franke,Gere,Xing
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p. 3601 - 3610
(2007/10/02)
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