- Concerning synthesis of ring-A fluorinated anthracyclines. The dioxirane shunt
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In a key step of the synthesis of 8-fluoro anthracycline aglycones such as 7, epoxidation of the electron-poor C8-C9 double bond moiety presented by the 8-acetyl-6,11-dimethoxy-7,10-dihydronaphthacene-5,12-dione starting material can be achieved in high yield and ease of operations using methyl(trifluoromethyl)dioxirane (1b).
- D'Accolti, Lucia,Fusco, Caterina,Rella, M. Rosaria,Curci, Ruggero
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- A simple protocol for the generation of methyl(trifluoromethyl)dioxirane
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Methyl(trifluoromethyl)dioxirane, generated from an aqueous solution of 1,1,1-trifluoroacetone hydrate, sodium bicarbonate and peroxomonosulfate, is removed from the reaction mixture by the evolved gases and applied to the oxidation of substrates placed in a second reaction zone. The method is simple and robust, and allows for the application of methyl(trifluoromethyl)dioxirane in oxidation reactions on a preparative scale. Georg Thieme Verlag Stuttgart.
- Mello, Rossella,González-Nú?ez, Maria Elena,Asensio, Gregorio
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- Direct synthesis of 3-aryl-1,2,4,5-tetrazine N-1-oxides by the oxidation with methyl(trifluoromethyl)dioxirane
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1,2,4,5-Tetrazines are oxidized by methyl(trifluoromethyl)dioxirane (TFD) to their hitherto unknown N-oxides in excellent yields. A detailed NMR study (1H, 13C, 15N) shows that the N-1 atom of 3-aryl-1,2,4,5-tetrazines 1 is oxidized regioselectively. A Hammett plot (r2 = 0.970) affords a ρ value of -1.53. The correlation of the logarithm of the reaction rates versus the ionization potentials, which were calculated by AM1, is much worse for ionization out of the aromatic system (IP(π); r2 = 0.804) than for ionization out of the higher-energy nitrogen lone pairs (IP(N:); r2 = 0.940). This implies that an electron transfer mechanism is unlikely and an S(N)2 attack by the nitrogen lone pair of the tetrazine on the dioxirane peroxide bond appears to operate.
- Adam, Waldemar,Van Barneveld, Claus,Golsch, Dieter
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- Synthesis and Neurotrophic Activity Studies of Illicium Sesquiterpene Natural Product Analogues
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Neurotrophic natural products hold potential as privileged structures for the development of therapeutic agents against neurodegeneration. However, only a few studies have been conducted to investigate a common pharmacophoric motif and structure–activity relationships (SARs). Here, an investigation of structurally more simple analogues of neurotrophic sesquiterpenes of the illicium family is presented. A concise synthetic route enables preparation of the carbon framework of (±)-Merrilactone A and (±)-Anislactone A/B on a gram scale. This has allowed access to a series of structural analogues by modification of the core structure, including variation of oxidation levels and alteration of functional groups. In total, 15 derivatives of the natural products have been synthesized and tested for their neurite outgrowth activities. Our studies indicate that the promising biological activity can be retained by structurally simpler natural product analogues, which are accessible by a straightforward synthetic route.
- Richers, Johannes,P?thig, Alexander,Herdtweck, Eberhardt,Sippel, Claudia,Hausch, Felix,Tiefenbacher, Konrad
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- Deciphering Reactivity and Selectivity Patterns in Aliphatic C-H Bond Oxygenation of Cyclopentane and Cyclohexane Derivatives
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A kinetic, product, and computational study on the reactions of the cumyloxyl radical with monosubstituted cyclopentanes and cyclohexanes has been carried out. HAT rates, site-selectivities for C-H bond oxidation, and DFT computations provide quantitative information and theoretical models to explain the observed patterns. Cyclopentanes functionalize predominantly at C-1, and tertiary C-H bond activation barriers decrease on going from methyl- and tert-butylcyclopentane to phenylcyclopentane, in line with the computed C-H BDEs. With cyclohexanes, the relative importance of HAT from C-1 decreases on going from methyl- and phenylcyclohexane to ethyl-, isopropyl-, and tert-butylcyclohexane. Deactivation is also observed at C-2 with site-selectivity that progressively shifts to C-3 and C-4 with increasing substituent steric bulk. The site-selectivities observed in the corresponding oxidations promoted by ethyl(trifluoromethyl)dioxirane support this mechanistic picture. Comparison of these results with those obtained previously for C-H bond azidation and functionalizations promoted by the PINO radical of phenyl and tert-butylcyclohexane, together with new calculations, provides a mechanistic framework for understanding C-H bond functionalization of cycloalkanes. The nature of the HAT reagent, C-H bond strengths, and torsional effects are important determinants of site-selectivity, with the latter effects that play a major role in the reactions of oxygen-centered HAT reagents with monosubstituted cyclohexanes.
- Martin, Teo,Galeotti, Marco,Salamone, Michela,Liu, Fengjiao,Yu, Yanmin,Duan, Meng,Houk,Bietti, Massimo
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supporting information
p. 9925 - 9937
(2021/06/30)
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- Direct Oxidation of Csp3?H bonds using in Situ Generated Trifluoromethylated Dioxirane in Flow
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A fast, scalable, and safer Csp3?H oxidation of activated and un-activated aliphatic chains can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platform allows the in situ generation of TFDO gas and its rapid reactivity toward tertiary and benzylic Csp3?H bonds. The process exhibits a broad scope and good functional group compatibility (28 examples, 8–99 %). The scalability of this methodology is demonstrated on 2.5 g scale oxidation of adamantane.
- Lesieur, Mathieu,Battilocchio, Claudio,Labes, Ricardo,Jacq, Jér?me,Genicot, Christophe,Ley, Steven V.,Pasau, Patrick
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supporting information
p. 1203 - 1207
(2019/01/04)
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- A six-step total synthesis of α-thujone and: D 6-α-thujone, enabling facile access to isotopically labelled metabolites
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The short synthesis of α-thujone relies on the functionalization of the readily available dimethylfulvene. Furthermore, the three main metabolites of the natural product were also synthesized. Since d6-acetone can be used as a starting material, the route developed allows for the facile incorporation of isotopic labels which are required for detecting and quantifying trace amounts via GC/MS analysis.
- Thamm, Irene,Richers, Johannes,Rychlik, Michael,Tiefenbacher, Konrad
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supporting information
p. 11701 - 11703
(2016/10/04)
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- Alkoxide-directed hydride addition to D,E-unsaturated sultones
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Seven- and eight-membered E,J-unsaturated sultones were readily prepared by ring closing metathesis. Epoxidation of these sultones and of an analogous six-membered sultone furnished the corresponding E,J-epoxy sultones efficiently. Treatment of these epoxides with a suitable base gave D,E-unsaturated J-hydroxy sultones in high yields. Reduction of both the D,E-unsaturated sultones and the epoxy sultones by Red-Al is likely to proceed in a hydroxyl-directed fashion via a mixed aluminate as the reactive intermediate.
- Dawood, Kamal M.,Bramborg, Andrea,Darweesh, Ahmed F.,Spinde, Katrin,Rogachev, Victor,J?ger, Anne,Metz, Peter
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p. 723 - 736
(2017/04/01)
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- Evaluating the thermal vinylcyclopropane rearrangement (VCPR) as a practical method for the synthesis of difluorinated cyclopentenes: Experimental and computational studies of rearrangement stereospecificity
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Vinyl cyclopropane rearrangement (VCPR) has been utilised to synthesise a difluorinated cyclopentene stereospecifically and under mild thermal conditions. Difluorocyclopropanation chemistry afforded ethyl 3-(1'(2'2'-difluoro-3'-phenyl)cyclopropyl) propenoate as all four stereoisomers (18a, 18b, 22a, 22b) (all racemic). The trans-E isomer (18a), prepared in 70% yield over three steps, underwent near quantitative VCPR to difluorocyclopentene 23 (99 %). Rearrangements were monitored by 19F NMR (100-180 °C). While cis/trans cyclopropane stereoisomerisation was facile, favouring trans-isomers by a modest margin, no E/Z alkene isomerisation was observed even at higher temperatures. Neither cis nor trans Z-alkenoates underwent VCPR, even up to much higher temperatures (180 °C). The cis-cyclopropanes underwent [3,3]-rearrangement to afford benzocycloheptadiene species. The reaction stereospecificity was explored by using electronic structure calculations, and UB3LYP/6-31G methodology allowed the energy barriers for cyclopropane stereoisomerisation, diastereoisomeric VCPR and [3,3]-rearrangement to be ranked in agreement with experiment.
- Orr, David,Percy, Jonathan M.,Tuttle, Tell,Kennedy, Alan R.,Harrison, Zo A.
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supporting information
p. 14305 - 14316
(2015/02/05)
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- Studies of new indole alkaloid coupling methods for the synthesis of haplophytine
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The two novel bisindole alkaloid structures shown can be synthesized in a few steps from the canthiphytine derivative 9.
- Rege, Pankaj D.,Tian, Yuan,Corey
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p. 3117 - 3120
(2007/10/03)
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- Synthesis and NMR studies of 13C-labeled vitamin D metabolites
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Isotope-labeled drug molecules may be useful for probing by NMR spectroscopy the conformation of ligand associated with biological hosts such as membranes and proteins. Triple-labeled [7,9,19-13C3]-vitamin D3 (56), its 25-hydroxylated and 1α,25-dihydroxylated metabolites (58 and 68, respectively), and other labeled materials have been synthesized via coupling of [9-13C]-Grundmann's ketone 39 or its protected 25-hydroxy derivative 43 with labeled A ring enyne fragments 25 or 26. The labeled CD-ring fragment 39 was prepared by a sequence involving Grignard addition of [13C]-methylmagnesium iodide to Grundmann's enone 28, oxidative cleavage, functional group modifications leading to seco-iodide 38, and finally a kinetic enolate SN2 cycloalkylation. The C-7,19 double labeling of the A-ring enyne was achieved by the Corey-Fuchs/Wittig processes on keto aldehyde 11. By employing these labeled fragments in the Wilson-Mazur route, the C-7,9,19 triple-13C-labeled metabolites 56, 58, and 68 as well as other 13C-labeled metabolites have been prepared. In an initial NMR investigation of one of the labeled metabolites prepared in this study, namely [7,9,19-13C3]-25-hydroxyvitamin D3 (58), the three 13C-labeled carbons of the otherwise water insoluble steroid could be clearly detected by 13C NMR analysis at 0.1 mM in a mixture of CD3OD/D2O (60/40) or in aqueous dimethylcyclodextrin solution and at 2 mM in 20 mM sodium dodecyl sulfate (SDS) aqueous micellar solution. In the SDS micellar solution, a double half-filter NOESY experiment revealed that the distance between the H19Z and H7 protons is significantly shorter than that of the corresponding distance calculated from the solid state (X-ray) structure of the free ligand. The NMR data in micelles reveals that 58 exists essentially completely in the α-conformer with the 3β-hydroxyl equatorially oriented, just as in the solid state. The shortened distance (H19Z-H7) in micellar solutions as compared to that in the solid state is most easily rationalized on the basis that the 5(10)-torsion angle in 58 is decreased in micellar solutions as compared to that in the solid state.
- Okamura, William H.,Zhu, Gui-Dong,Hill, David K.,Thomas, Richard J.,Ringe, Kerstin,Borchardt, Daniel B.,Norman, Anthony W.,Mueller, Leonard J.
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p. 1637 - 1650
(2007/10/03)
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- On the formation of dioxiranes and of singlet oxygen by the ketone-catalysed decomposition of Caro's acid
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Measurements of the infrared phosphorescence of singlet molecular oxygen (1O2) at 1270 nm have been used to demonstrate the formation of 1O2 by the ketone-catalysed decomposition of peroxymonosulfuric acid (Caro's acid).The kinetics of the ketone-catalysed decomposition of Caro's acid have been studied by this technique and the rate law was found to be of first order for HSO5-, for ketone and for a pH-dependent factor F = KW/(+> + Ka2).Eleven ketones were chosen to determine kDI, the third-order rate constant for the formation of the corresponding dioxirane.The values of kDI depend on ketone structure and vary over a wide range.For both the acetone- and cyclohexanone-catalysed decomposition of Caro's acid measurements have been performed at different temperatures.The apparent activation energies Eaa were determined to be Eaa(acetone) = 47.8 kJ mol-1 and Eaa(cyclohexanone) = 36.0 kJ mol-1, respectively.For the uncatalysed self-decomposition of Caro's acid the second-order rate constant was determined to be k2 = 5.9 * 10-2 dm3 mol-1 s-1.
- Lange, Andreas,Brauer, Hans-Dieter
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p. 805 - 812
(2007/10/03)
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- Oxidations by Methyl(trifluoromethyl)dioxirane. 2. Oxyfunctionalization of Saturated Hydrocarbons
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The reaction of methyl(trifluoromethyl)dioxirane (1b), a novel dioxirane species, with two open-chain, four cyclic, and five polycyclic saturated hydrocarbons and two aralkyl hydrocarbons in CH2Cl2/1,1,1-trifluoropropanone has been studied; under mild conditions (-22 to 0 deg C), it gives alcohols and/or ketones (deriving from further oxidation of secondary alcohols) in high yields and within very short reaction times.Primary C-H bonds are not appreciably oxidized and high regioselectivities were determined for attack at tertiary over secondary C-H bonds, with theexception of norbornane, which showed opposite regioselectivity.The reaction is also highly stereoselective, since hydroxylations of cis- and trans-decalin and of cis- and trans-1,2-dimethylcyclohexane were found to be in each case stereospecific with retention.From kinetic data, Ea = 14.3 kcal mol-1 and log A = 9.9 were estimated for cyclohexane oxidation.Relative rates change in the order cyclohexane (0.78) octane (9.2) adamantane (146); cis-1,2-dimethylcyclohexane was observed to be 7-fold more reactive than its trans isomer, demonstrating remarkable discrimination for equatorial vs axial C-H attack (also noticed in the case of cis- and trans-decalin).The relative rate of oxidation of cumene vs ethylbenzene was found to be ca. 3.1 (after statistical correction), i.e., in sharp excess over values usually recorded in classical radical H-atom abstraction from benzylic position.Rate constants determined for the reactions of cumene and of ethylbenzene show the title dioxirane (1b) is more reactive than dimethyldioxirane (1a) by factors of ca. 600 and over 700, respectively.The whole of theobservations is better accommodated by an "oxenoid" mechanism, involving concerted O-atom insertion by dioxirane into C-H bonds of hydrocarbons.
- Mello, Rossella,Fiorentino, Michele,Fusco, Caterina,Curci, Ruggero
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p. 6749 - 6757
(2007/10/02)
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- OXIDATIONS BY METHYL TRIFLUOROMETHYL DIOXIRANE. EPOXIDATION OF ENOL ETHERS
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Isolated methyl trifluoromethyl dioxirane 4b has been employed to achieve the rapid, low temperature epoxidation of enol ethers, such as alkoxy(aryl)methylidene adamantanes 1a-e and methoxy(2-naphtyl)methylidene 2-bornane 1f, affording the corresponding spirooxiranes in excellent (92-97percent) yields.
- Troisi, Luigino,Cassidei, Luigi,Lopez, Luigi,Mello, Rossella,Curci, Ruggero
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p. 257 - 260
(2007/10/02)
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