- Total synthesis, molecular editing and evaluation of a tripyrrolic natural product: The case of "butylcycloheptylprodigiosin"
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Conflicting reports are found in the literature on whether the ortho-pyrrolophane derivative 6, which has been named " butylcycloheptylprodigiosin" even though it is a cyclononane derivative, is a natural product or merely a mis-assigned structure. This dispute has now been resolved by an unambiguous total synthesis of this complex alkaloid which confirms the initial structure assignment. The chosen approach is largely catalysis-based, featuring the first application of a "Narasaka-Heck" reaction in natural product chemistry. This palladium-catalyzed transformation allows the unsaturated oxime ester 26 to be converted into the bicyclic dihydropyrrole 27. Other notable reactions of the reported approach to 6 are a regioselective Tsuji-Trost reaction of the doubly allylic acetate 21 with methyl acetoacetate. a base-induced aromatization of 27 to the corresponding pyrrole 28. a chemoselective oxidation of the benzylic methyl group in 33 with cerium ammonium nitrate in a biphasic reaction medium that does not affect the labile pyrrole nucleus, and a Suzuki cross-coupling for the completion of the heterocyclic domain. Diversification in the latter step leads to a set of analogues that differ from the natural product in the terminal (hetero)arene ring. This structural modification results in complete loss of the very pronounced ability of the parent compound 6 to induce oxidative cleavage in double stranded DNA in the presence of Cu11. Several cyclononane-, cyclononene- and cyclononadiene derivatives prepared en route to 6 have been characterized by crystal structure analysis, allowing the conformational behavior of nine-membered carbocycles to be studied.
- Fuerstner, Alois,Radkowski, Karin,Peters, Hartwig,Seidel, Guenter,Wirtz, Conny,Mynott, Richard,Lehmann, Christian W.
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- Synthetic Entry to Polyfunctionalized Molecules through the [3+2]-Cycloaddition of Thiocarbonyl Ylides
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Here we present a comprehensive study on the [3+2]-cycloaddition of thiocarbonyl ylides with a wide variety of alkenes and alkynes. The obtained dihydro- and tetrahydrothiophene products serve as exceptionally versatile intermediates providing access to thiophenes, dienes, dendralenes, and vic-quarternary carbon centers. The use of high-pressure conditions enables thermally unstable, sterically encumbered or moderately reactive substrates to undergo the cycloaddition under mild conditions, thereby increasing the yield by up to 58percent. In addition, we showcase its utility by the formal syntheses of the pharmaceuticals NGB 4420 and tenilapine.
- Habiger, Christoph,Haut, Franz-Lucas,Korber, Johannes Nepomuk,Müller, Thomas,Magauer, Thomas,Mayer, Peter,Speck, Klaus,Wurst, Klaus
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- Synthesis of Cyclic Peptide Mimetics by the Successive Ring Expansion of Lactams
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A successive ring-expansion protocol is reported that enables the controlled insertion of natural and non-natural amino acid fragments into lactams. Amino acids can be installed into macrocycles via an operationally simple and scalable iterative procedure, without the need for high dilution. This method is expected to be of broad utility, especially for the synthesis of medicinally important cyclic peptide mimetics.
- Stephens, Thomas C.,Lodi, Mahendar,Steer, Andrew M.,Lin, Yun,Gill, Matthew T.,Unsworth, William P.
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p. 13314 - 13318
(2017/10/05)
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- Structure-reactivity relationship for alcohol oxidations via hydride transfer to a carbocationic oxidizing agent
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Second-order rate constants were determined for the oxidation of 27 alcohols (R1R2CHOH) by a carbocationic oxidizing agent, 9-phenylxanthylium ion, in acetontrile at 60°C. Alcohols include open-chain alkyl, cycloalkyl, and unsaturated alcohols. Kinetic isotope effects for the reaction of 1-phenylethanol were determined at three H/D positions of the alcohol (KIEα-D=3.9, KIEβ-D3=1.03, KIE OD=1.10). These KIE results are consistent with those we previously reported for the 2-propanol reaction, suggesting that these reactions follow a hydride-proton sequential transfer mechanism that involves a rate-limiting formation of the α-hydroxy carbocation intermediate. Structure-reactivity relationship for alcohol oxidations was deeply discussed on the basis of the observed structural effects on the formation of the carbocationic transition state (Cδ+-OH). Efficiencies of alcohol oxidations are largely dependent upon the alcohol structures. Steric hindrance effect and ring strain relief effect win over the electronic effect in determining the rates of the oxidations of open-chain alkyl and cycloalkyl alcohols. Unhindered secondary alkyl alcohols would be selectively oxidized in the presence of primary and hindered secondary alkyl alcohols. Strained C7-C11 cycloalkyl alcohols react faster than cyclohexyl alcohol, whereas the strained C5 and C12 alcohols react slower. Aromatic alcohols would be efficiently and selectively oxidized in the presence of aliphatic alcohols of comparable steric requirements. This structure-reactivity relationship for alcohol oxidations via hydride-transfer mechanism is hoped to provide a useful guidance for the selective oxidation of certain alcohol functional groups in organic synthesis. Copyright
- Lu, Yun,Bradshaw, Joshua,Zhao, Yu,Kuester, William,Kabotso, Daniel
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p. 1172 - 1178
(2013/01/12)
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- Oxidation catalytic system and oxidation process using the same
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A substrate (e.g., a cycloalkane, a polycyclic hydrocarbon, an aromatic compound having a methyl group or methylene group adjacent to an aromatic ring) is oxidized with oxygen in the presence of an oxidation catalyst comprising an imide compound of the following formula (1) (e.g., N-hydroxyphthalimide), and a co-catalyst (except phosphovanadomolybdic acid) containing an element selected from the group consisting of Group 2A elements of the Periodic Table of Elements, transition metals (Group 3A to 7A elements, Group 8 elements, Group 1B elements and Group 2B elements of the Periodic Table of Elements) and Group 3B elements of the Periodic Table of Elements, for the formation of an oxide (e.g., a ketone, an alcohol, a carboxylic acid): STR1 wherein R1 and R2 represent a substituent such as a hydrogen atom or a halogen atom, or R1 and R2 may together form a double bond or an aromatic or nonaromatic 5- to 12-membered ring, X is O or OH, and n is 1 to 3.
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- Cascade rearrangement of spiroepoxymethyl radicals into 2-oxocycloalkyl radicals: Evaluation of a two-carbon cycloalkanone ring expansion
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Series of 2-bromomethyl- and 2-hydroxymethyl-1-oxaspiro[2.n]alkanes were prepared from cycloalkanones by initial Wadsworth-Horner-Emmons methodology to afford ester-substituted methylenecycloalkanes. The latter were selectively reduced to hydroxymethylmethylenecycloalkanes which were epoxidised with peroxyacetic acid. Homolytic reactions were studied by EPR spectroscopy which enabled transient 3-oxoalk-1-enyl radicals, and their cyclisation products, 2-oxocycloalkyl and 2-oxocycloalkylmethyl radicals, to be characterised. This evidence, together with end product analyses of organotin hydride reductions of the 2-bromomethyl-1-oxaspiro[2.n]alkanes, established that the initial spiroepoxymethyl radicals rearranged by a three-stage cascade of two consecutive β-scissions followed by a cyclisation. Cyclisations of the 3-oxoalk-1-enyl radicals took place mainly in the endo-mode to afford 2-oxocycloalkyl radicals, except for the 5-oxohept-6-enyl radical for which exo-cyclisation to generate the 2-oxocyclohexylmethyl radical was preferred. Kinetic data for the exo-and endo-cyclisations of the 4-oxohex-5-enyl radical were obtained from tributyltin hydride mediated reactions of 2-bromomethyl-1-oxaspiro[2.3]hexane.
- Afzal, Mohammad,Walton, John C.
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p. 937 - 945
(2007/10/03)
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- Preparation, Properties, and Reactions of Metal-Containing Heterocycles, XCVI. Mono-, Di- and Trinuclear Metallacycloalkanes of the Iron-Triad
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The reaction of the bis(triflates) with Na2 in dimethyl ether affords the osmacycloalkanes 2a, 2b and 2f-i (m = 5, 6, 10, 12, 14, 16), diosmacycloalkanes 3a-i (m = 5-10, 12, 14, 16), and triosmacycloalkanes 4a-i (m = 5-10, 12, 14, 16).The structure of 3f was investigated by an X-ray structural analysis.This 22-membered diosmacycle crystallizes in the space group P1/ with Z = 1.If the unsaturated cis-4-octen-1,8-diyl bis(trifluoromethanesulfonate) (5) is treated with Na2 the diosmacyclooctadeca-5,14- diene 6 is obtained.By treating the bis(triflates) 1a, d with Na2 the corresponding ferracycloalkanes are formed only in situ.Insertion of carbon monoxide into the M-C ? bonds leads to the cyclic ketones 7a, d and to the diketone 8d. - Keywords: Metallacycloalkanes; Metallacycloalkenes; Osmium; Iron; Cyclic ketones; Metallacycles
- Lindner, Ekkehard,Leibfritz, Thomas,Fawzi, Riad,Steimann, Manfred
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p. 347 - 356
(2007/10/03)
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- Photoinduced Molecular Transformations. Part 155. General Synthesis of Macrocyclic Ketones based on a Ring Expansion involving a Selective β-Scission of Alkoxyl Radicals, its Applications to a New Synthesis of (+/-)-Isocaryophyllene and (+/-)-Caryophyllene, and a Conformational Analy...
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The method used for a general synthesis of macrocyclic ketones based on a ring expansion involving a selective β-scission of alkoxyl radicals devised by Suginome and Yamada was extended and modified.Thus, cycloalkanones were transformed into the corresponding α-(ω-iodoalkyl)-cycloalkanones by alkylation of the corresponding lithium enolates with either 1,3-diiodopropane or 1,4-diiodobutane.Treatment of these α-iodoalkyl cyclic ketones with samarium iodide gave bicyclic tertiary alcohols.The generation of the alkoxyl radicals from the bicyclic alcohols by irradiation of the corresponding hypoiodites generated with mercury(II) oxide - iodine - pyridine in benzene resulted in a selective β-scission of their ring-junction bond to give high yields of macrocyclic ketones carrying an iodine which can be removed with tributyltin hydride.The method was then applied to new syntheses of (+/-)-isocaryophyllene and (+/-)-caryophyllene.Thus, ω-iodopropylation of ethyl 7,7-dimethyl-2-oxobicyclooctane-3-carboxylate, followed by cyclization of the resulting α-(ω-iodoalkyl)cycloalkanone with samarium diiodide, gave cis-transoid-cis-ethyl 1-hydroxy-4,4-dimethyltricyclo2,5>undecane-8-carboxylate (69percent).The ethoxycarbonyl group of this tricyclic alcohol was transformed into a methyl group by the standard method.Irradiation of a solution of the hypoiodite, prepared by the method mentioned above, with Pyrex-filtered light gave the corresponding cis-bicycloundecenone (15percent), its exomethylene isomer (2,5>undecan-1-ol mentioned above were correlated with the three products.
- Suginome, Hiroshi,Kondoh, Takahiko,Gogonea, Camelia,Singh, Vishwakarma,Goto, Hitoshi,Osawa, Eiji
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- 1-Alkenylcycloalkoxy Radical Chemistry. A Two-Carbon Ring Expansion Methodology
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The exploitation of alkoxy radicals derived from 1-ethenylcycloalkanols for use in a two-carbon ring expansion protocol was proposed.Direct one-pot alkoxy radical-mediated fragmentation-cyclization was not feasible since the reactive intermediate was quenched by iodine in the reaction mixture.However, via the use of iodo epoxides 3, the tandem fragmentation-cyclization sequence could be accomplished.This afforded ring-expanded products via an endo mode of cyclization, although in one example product from an exo mode of cyclization was also isolated.This methodologywas shown to be valid for large ring compounds as well.The intermediary of iodo epoxides 3 also afforded improved yields as compared to the direct cyclization of iodo enones 4.These results are the first examples of radical cyclization to medium-sized carbocycles.
- Galatsis, Paul,Millan, Scott D.,Faber, Tim
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p. 1215 - 1220
(2007/10/02)
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- Oxidation of Secondary Alcohols with t-Butyl Hypochlorite in the Presence of Pyridine
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When treated with t-butyl hypochlorite and pyridine in methylene dichloride, secondary alcohols give the corresponding ketones in very high yield.The relative reactivities of a number of p-substituted 1-phenylethanols containing electron-donating and -withdrawing substituents were investigated.Oxidation of cis- and trans-4-t-butylcyclohexanol, as well as some other cycloalkanols, proceeds with the same relative rate.On the basis of this and other data a cyclic transition state and loss of α-hydrogen of the starting alcohols as hydride ion are proposed as characteristics of the reaction mechanism.
- Milovanovic, Jovan N.,Vasojevic, Miorad,Gojkovic, Svetislav
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p. 533 - 536
(2007/10/02)
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- Ring Enlargement of Boracyclanes via Sequential One-Carbon Homologation. The First Synthesis of Boracyclanes in the Strained Medium Ring Range.
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We explored the Matteson homologation procedure as a means of enlarging the size of the ring in B-methoxyboracyclanes.
- Brown, Herbert C.,Phadke, Avinash S.,Rangaishenvi, Milind V.
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p. 6263 - 6264
(2007/10/02)
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- Synthesis of Medium and Large Rings, XVI: Boat-shaped Arenes - Synthesis, Structure, and Properties of Paracyclophanes and (1,4)Naphthalinophanes
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A preparative synthesis of the compounds 2, 5, 7, and 11 starting from cyclononanone is described.Key steps are the conversion of 5,6,7,8,9,10-hexahydro-4H-cyclononafuran to the β,β'-heptanooxepines 1, which can be desoxygenated.The NMR spectra of the new cyclophanes are discussed in detail.The deformation angles α of the boat-shaped heptano-bridged benzene rings were determined for 5 and 11 by X-ray analysis.Values between 13.6 degree and 15.9 degree are found.In several respects heptano-bridged ansa compounds are interesting borderline cases: The oxepines 9 and 15 probably exist in a valence tautomeric equilibrium with the corresponding cyclophane oxides 10 and 16.The bis(acetoxymethyl)paracyclophane 2c still adds chlorine under mild conditions. 12 does not exist as β-naphthol but as "non-enolized" ketone.
- Hunger, Juergen,Wolff, Christian,Tochtermann, Werner,Peters, Eva-Maria,Peters, Karl,Schnering, Hans Georg von
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p. 2698 - 2722
(2007/10/02)
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- Medium-ring Ketone Synthesis. Synthesis of Eight- to Twelve-membered Cyclic Ketones based on the Intramolecular Cyclization of Large-Membered Lactam Sulfoxides or Sulfones
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An effective general method for the construction of medium-ring ketones from the corresponding ω-bromocarboxylic acids is described.When the diamide disulfide 10 was treated with NaBH4 and NaH in 2-propanol, reductive cleavage of the sulfur-sulfur bond and concomitant intramolecular coupling of the resulting thiolate anion with the terminal bromide took place and the large-ring lactam sulfide 7, which was the key intermediate for the synthesis of medium-ring ketones, was obtained.Although lithium diisopropyl amide (LDA) treatment of 11 followed by reductive desulfurization provided cycloundecanone (13d) in only 19.5percent yield, intramolecular cyclization of the α-methylated analogues 17 with LDA proceeded smoothly and the keto sulfoxides 18 were obtained in quantitative yields.In the case of the lactam sulfones 21, tert-BuOK was effective as a base for the intramolecular cyclization, affording the keto sulfones 22 in quantitative yields.The keto sulfoxides 18 and sulfones 22 were subjected to reductive desulfurization with Al-Hg to yield medium-ring ketones 19 and 13, respectively, in high yields.Keywords - medium-ring ketone; intramolecular cyclization; large-ring lactam sulfide; bis(2-methylaminophenyl) disulfide; 2-methylaminobenzenethiol; reductive desulfurization; sulfur-stabilized carbanion; active methylene
- Ohtsuka, Yasuo,Oishi, Takeshi
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p. 454 - 465
(2007/10/02)
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- Kinetics and Thermodynamics of Keto-Enol Tautomerism of Simple Carbonyl Compounds: An Approach Based on a Kinetic Study of Halogenation at Low Halogen Concentrations
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Kinetic data for bromination and/or iodination of cycloalkanones and aryl-substituted acetophenones in water, using very low halogen concentrations (10-7 - 10 -5 M) (i.e., when the rate limiting step is not enolization but partly halogen addition to enol) provide the hydronium-catalyzed enolization rate coefficients (k1) and the apparent second-order rate coefficients kII = KHSSHk2 (where KHSSH is the keto-enol equilibrium constant and k2 the enol halogenation rate constant).As previously suggested, the rate of enol halogenation is usually encounter controlled.This makes it possible to estimate k2 and calculate KHSSH from data on kII.The enol ketonization rate coefficients are deduce and compared with those for methyl and ethyl enol ether hydrolysis.It is shown that the ratio enol ketonization/enol ether hydrolysis of parent compounds varies in the range 15-150 and depends on enol structure.For the different rate and equilibrium coefficients which intervene in the two-step mechanism of keto-enol interconversion of acetophenones, a variety of linear free-energy relationships are established, using the Young-Jencks modified Yukawa-Tsuno equation.A Broensted relation is observed by plotting the rate constants for enol formation from the conjugated acids of acetophenones vs. the CH acidity constants of these ions.The Broensted exponent, α = 0.4, is in agreement with a transition state model in which the proton is less than half-transferred.Data on entalpy and enthropy of activation for enolization of cycloalkanones, compared with those for keto-enol equilibrium, are also in favor with an early transition state.
- Dubois, Jaques-Emile,El-Alaoui, Mohiedine,Toullec, Jean
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p. 5393 - 5401
(2007/10/02)
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- 186. Steric Effects on Reaction Rates. Rate and Equilibrium Constants for Oxidation of Cyclanols
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Equilibrium constants for oxidations of cyclanols by cyclohexanone in benzene have been determined in the presence of aluminium isopropoxide.The free energies of the equilibrium (ΔGox) are correlated with equilibrium constants for dissociation of cyanohydrins, rate constants for cyclanol oxidation with chromic acid, ketone reduction with sodium borohydride and trifluoroethanolysis of tosylates.
- Paul, Mueller,Blanc, Jacky
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p. 1759 - 1766
(2007/10/02)
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