- First total synthesis and assignment of the stereochemistry of crispatenine
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(Figure Presented) The first racemic and enantioselective synthesis of crispatenine 1 has been achieved, which involved a few steps, enabling the assignment of the absolute and relative configurations.
- Bourdron, Julien,Commeiras, Laurent,Audran, Gerard,Vanthuyne, Nicolas,Hubaud,Parrain, Jean-Luc
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Read Online
- Stereochemical Effects in the Gas-Phase Pinacol Rearrangement. 2. Ring Contraction versus Methyl Migration in cis- and trans-1,2-Dimethylcyclohexane-1,2-diol
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The gas-phase pinacol rearrangement of cis- and trans-1,2-dimethylcyclohexane-1,2-diols, promoted by D3+, CH5+/C2H5+ and t-C4H9+ ions, was studied by mass spectrometric and radiolytic methods in the pressure range 0.5-760 Torr.When product isomerization is inhibited, by using N(CH3)3 as a trapping reagent at high pressure, mixtures of 2,2-dimethylcyclohexanone and 1-acetyl-1-methylcyclopentane were recovered from the reaction.In methane, the trend of measured relative rates for ring contraction (k5), methyl or hydroxyl group migration (k6) versus the rearrangement rate of pinacol itself (kp), is k6(trans) = k5(trans) > k5(cis) > k6(cis) > kp.No evidence for the formation of an intermediate carbenium ion was found.Stereochemical aspects of the mechanism are discussed and compared with solution data.
- Petris, Giulia de,Giacomello, Pierluigi,Pizzabiocca, Adriano,Renzi, Gabriele,Speranza, Maurizio
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- 11-Step Total Synthesis of (-)-Maoecrystal v
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An expedient, practical, and enantioselective route to the highly congested ent-kaurane diterpene maoecrystal V is presented. This route, which has been several years in the making, is loosely modeled after a key pinacol shift in the proposed biosynthesis. Only 11 steps, many of which are strategic in that they build key skeletal bonds and incorporate critical functionalities, are required to access (-)-maoecrystal V. Several unique and unexpected maneuvers are featured in this potentially scalable pathway. Reevaluation of the biological activity calls into question the initial exuberance surrounding this natural product.
- Cernijenko, Artiom,Risgaard, Rune,Baran, Phil S.
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- Sequential hydroformylation/aldol addition reactions of β,γ- unsaturated ketones and their derivatives
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Novel rhodium(I) complex catalysed tandem hydroformylation/aldol reactions of a β,γ-unsaturated ketone 1 or its silyl enol ethers 4 in a one-pot procedure are presented to give varying cyclisation products depending on the reaction conditions.
- Hollmann, Christoph,Eilbracht, Peter
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- Stereoselective Synthesis of 1-Tuberculosinyl Adenosine; A Virulence Factor of Mycobacterium tuberculosis
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Despite its status as one of the world's most prevalent and deadly bacterial pathogens, Mycobacterium tuberculosis (Mtb) infection is not routinely diagnosed by rapid and highly reliable tests. A program to discover Mtb-specific biomarkers recently identified two natural compounds, 1-tuberculosinyl adenosine (1-TbAd) and N6-tuberculosinyl adenosine (N6-TbAd). Based on their association with virulence, the lack of similar compounds in nature, the presence of multiple stereocenters, and the need for abundant products to develop diagnostic tests, synthesis of these compounds was considered to be of high value but challenging. Here, a multigram-scale stereoselective synthesis of 1-TbAd and N6-TbAd is described. As a key-step, a chiral auxiliary-mediated Diels-Alder cycloaddition was developed, introducing the three stereocenters with a high exo endo ratio (10:1) and excellent enantioselectivity (>98% ee). This constitutes the first entry into the stereoselective synthesis of diterpenes with the halimane skeleton. Computational studies explain the observed stereochemical outcome.
- Buter, Jeffrey,Heijnen, Dorus,Wan, Ieng Chim,Bickelhaupt, F. Matthias,Young, David C.,Otten, Edwin,Moody, D. Branch,Minnaard, Adriaan J.
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- Total Synthesis of the Alleged Structure of Crenarchaeol Enables Structure Revision**
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Crenarchaeol is a glycerol dialkyl glycerol tetraether lipid produced exclusively in Archaea of the phylum Thaumarchaeota. This membrane-spanning lipid is undoubtedly the structurally most sophisticated of all known archaeal lipids and an iconic molecule in organic geochemistry. The 66-membered macrocycle possesses a unique chemical structure featuring 22 mostly remote stereocenters, and a cyclohexane ring connected by a single bond to a cyclopentane ring. Herein we report the first total synthesis of the proposed structure of crenarchaeol. Comparison with natural crenarchaeol allowed us to propose a revised structure of crenarchaeol, wherein one of the 22 stereocenters is inverted.
- Cunha, Ana V.,Havenith, Remco W. A.,Holzheimer, Mira,Minnaard, Adriaan J.,Schouten, Stefan,Sinninghe Damsté, Jaap S.
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supporting information
p. 17504 - 17513
(2021/07/06)
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- 5-MEMBERED HETEROARYLAMINOSULFONAMIDES FOR TREATING CONDITIONS MEDIATED BY DEFICIENT CFTR ACTIVITY
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The invention relates to heteroaryl compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof. Also described herein are compositions and the use of such compounds in methods of treating diseases and conditions mediated by deficient CFTR activity, in particular cystic fibrosis.
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Page/Page column 366
(2021/05/21)
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- POLYORGANOSILOXANE COMPOSITIONS CONTAINING A 2-SUBSTITUTED-1-ALKYNYL-1-CYCLOHEXANOL USEFUL AS A HYDROSILYLATION REACTION INHIBITOR
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A hydrosilylation curable composition includes a new 2-substituted-1-alkynyl-1-cyclohexanol as an inhibitor. The hydrosilylation curable composition is useful for preparing release coatings for packaging applications.
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Paragraph 0104; 0110
(2019/05/10)
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- (Poly)cationic λ3-Iodane-Mediated Oxidative Ring Expansion of Secondary Alcohols
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Herein, a simplified approach to the synthesis of medium-ring ethers through the electrophilic activation of secondary alcohols with (poly)cationic λ3-iodanes (N-HVIs) is reported. Excellent levels of selectivity are achieved for C–O bond migration over established α-elimination pathways, enabled by the unique reactivity of a novel 2-OMe-pyridine-ligated N-HVI. The resulting hexafluoroisopropanol (HFIP) acetals are readily derivatized with a range of nucleophiles, providing a versatile functional handle for subsequent manipulations. The utility of this methodology for late-stage natural product derivatization was also demonstrated, providing a new tool for diversity-oriented synthesis and complexity-to-diversity (CTD) efforts. Preliminary mechanistic investigations reveal a strong effect of alcohol conformation on the reactive pathway, thus providing a predictive power in the application of this approach to complex molecule synthesis.
- Walters, Jennifer C.,Tierno, Anthony F.,Dubin, Aimee H.,Wengryniuk, Sarah E.
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supporting information
p. 1460 - 1464
(2018/04/06)
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- Catalyst-controlled aliphatic C—H oxidations
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The invention provides simple small molecule, non-heme iron catalyst systems with broad substrate scope that can predictably enhance or overturn a substrate's inherent reactivity preference for sp3-hybridized C—H bond oxidation. The invention also provides methods for selective aliphatic C—H bond oxidation. Furthermore, a structure-based catalyst reactivity model is disclosed that quantitatively correlates the innate physical properties of the substrate to the site-selectivities observed as a function of the catalyst. The catalyst systems can be used in combination with oxidants such as hydrogen peroxide to effect highly selective oxidations of unactivated sp3 C—H bonds over a broad range of substrates.
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Page/Page column 36-37; 47-48
(2018/04/20)
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- Platinum-catalyzed α,β-unsaturated carbene formation in the formal syntheses of frondosin B and liphagal
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Formal syntheses of tetracyclic terpenoids frondosin B and liphagal are described. Both synthetic routes rely on the use of platinum-catalyzed α,β-unsaturated carbene formation for the key C-C bond forming transformations. The successful route toward frondosin B utilizes a formal (4 + 3) cycloaddition, while the liphagal synthesis features the vinylogous addition of an enol nucleophile as a key step. Both synthetic routes are discussed, revealing insights into structural requirements in the catalytic a,β-unsaturated carbene reaction manifold.
- Huynh, Khoi Q.,Seizert, Curtis A.,Ozumerzifon, Tarik J.,Allegretti, Paul A.,Ferreira, Eric M.
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supporting information
p. 294 - 297
(2017/11/28)
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- Isotope-labeled methyl ketofuran, intermediate and method for preparing same
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The invention discloses isotopically labeled methyl furanone, an intermediate and a preparation method of isotopically labeled methyl furanone. The invention provides isotopically labeled methyl furanone 6. The invention further provides a preparation method of isotopically labeled methyl furanone 6, and the preparation method comprises the following steps: performing removal of a hydroxy protecting group and isomerization reaction on a compound 20 in the presence of an acid. The method provided by the invention comprises short reaction steps, labeling loci are stable, are labeled on a common D ring of a strigolactone type compound family and are successfully butted with ABC rings of strigolactone type compounds to obtain a variety of isotopically labeled strigolactone type compounds with different isotopic abundances which are more than 99% respectively, and the isotopically labeled methyl furanone is applicable to wide substances, is used as an internal source standard matter for GC-MS and LC-MS/MS analysis and has high detection sensitivity and good accuracy, thereby having broad market application prospects.
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Paragraph 0125; 0126; 0127
(2016/10/09)
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- Catalytic Multisite-Selective Acetoxylation Reactions at sp2 vs sp3 C-H Bonds in Cyclic Olefins
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The first Pd-catalyzed multisite-selective acetoxylation reactions are disclosed at an unactivated alkene sp2 C-H bond versus secondary allylic sp3 C-H bond in cyclic olefins via the modulation of directing groups. The different directing groups overcome the key challenge in differentiating C-H bonds and provide a new controlling approach for site-specific C-H activation. A wide variety of substrates are readily acetoxylated under operationally simple conditions. Mechanistic studies suggest that different Pd (IV) intermediates were involved in the multisite-selective acetoxylation reactions.
- Zang, Zhong-Lin,Zhao, Sheng,Karnakanti, Shuklachary,Liu, Cheng-Lin,Shao, Pan-Lin,He, Yun
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supporting information
p. 5014 - 5017
(2016/10/14)
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- Readily Accessible Bulky Iron Catalysts exhibiting Site Selectivity in the Oxidation of Steroidal Substrates
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Bulky iron complexes are described that catalyze the site-selective oxidation of alkyl C-H bonds with hydrogen peroxide under mild conditions. Steric bulk at the iron center is introduced by appending trialkylsilyl groups at the meta-position of the pyridines in tetradentate aminopyridine ligands, and this effect translates into high product yields, an enhanced preferential oxidation of secondary over tertiary C-H bonds, and the ability to perform site-selective oxidation of methylenic sites in terpenoid and steroidal substrates. Unprecedented site selective oxidation at C6 and C12 methylenic sites in steroidal substrates is shown to be governed by the chirality of the catalysts.
- Font, David,Canta, Mercè,Milan, Michela,Cussó, Olaf,Ribas, Xavi,Klein Gebbink, Robertus J. M.,Costas, Miquel
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supporting information
p. 5776 - 5779
(2016/05/09)
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- Trapping a Highly Reactive Nonheme Iron Intermediate That Oxygenates Strong C-H Bonds with Stereoretention
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An unprecedentedly reactive iron species (2) has been generated by reaction of excess peracetic acid with a mononuclear iron complex [FeII(CF3SO3)2(PyNMe3)] (1) at cryogenic temperatures, and characterized spectroscopically. Compound 2 is kinetically competent for breaking strong C-H bonds of alkanes (BDE ≈ 100 kcal·mol-1) through a hydrogen-atom transfer mechanism, and the transformations proceed with stereoretention and regioselectively, responding to bond strength, as well as to steric and polar effects. Bimolecular reaction rates are at least an order of magnitude faster than those of the most reactive synthetic high-valent nonheme oxoiron species described to date. EPR studies in tandem with kinetic analysis show that the 490 nm chromophore of 2 is associated with two S = 1/2 species in rapid equilibrium. The minor component 2a (~5% iron) has g-values at 2.20, 2.19, and 1.99 characteristic of a low-spin iron(III) center, and it is assigned as [FeIII(OOAc)(PyNMe3)]2+, also by comparison with the EPR parameters of the structurally characterized hydroxamate analogue [FeIII(tBuCON(H)O)(PyNMe3)]2+ (4). The major component 2b (~40% iron, g-values = 2.07, 2.01, 1.95) has unusual EPR parameters, and it is proposed to be [FeV(O)(OAc)(PyNMe3)]2+, where the O-O bond in 2a has been broken. Consistent with this assignment, 2b undergoes exchange of its acetate ligand with CD3CO2D and very rapidly reacts with olefins to produce the corresponding cis-1,2-hydroxoacetate product. Therefore, this work constitutes the first example where a synthetic nonheme iron species responsible for stereospecific and site selective C-H hydroxylation is spectroscopically trapped, and its catalytic reactivity against C-H bonds can be directly interrogated by kinetic methods. The accumulated evidence indicates that 2 consists mainly of an extraordinarily reactive [FeV(O)(OAc)(PyNMe3)]2+ (2b) species capable of hydroxylating unactivated alkyl C-H bonds with stereoretention in a rapid and site-selective manner, and that exists in fast equilibrium with its [FeIII(OOAc)(PyNMe3)]2+ precursor.
- Serrano-Plana, Joan,Oloo, Williamson N.,Acosta-Rueda, Laura,Meier, Katlyn K.,Verdejo, Bego?a,García-Espa?a, Enrique,Basallote, Manuel G.,Münck, Eckard,Que, Lawrence,Company, Anna,Costas, Miquel
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supporting information
p. 15833 - 15842
(2016/01/09)
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- Total synthesis of (+/-)-frondosin B and (+/-)-5-epi-liphagal by using a concise (4+3) cycloaddition approach
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A recently developed (4+3) cycloaddition between dienes and furfuryl alcohols, as precursors of oxyallyl-type cations, has been used as a key step in the racemic syntheses of two natural products: frondosin B and liphagal. This work demonstrates the synthetic potential of this cycloaddition reaction, and offers a short synthetic route to an interesting family of natural products. A full account of these synthetic studies is presented, further illustrating the mechanism, scope, and limitations of this straightforward synthetic method for seven-membered rings. Cycloheptanes: Furfuryl alcohols serve as effective three-carbon dienophiles for a wide range of dienes in stereoselective cycloaddition reactions. This efficient reaction has been used to prepare two cycloheptanoid natural products, offering a conceptually straightforward and short synthetic entry into a biologically interesting class of polycyclic meroterpenoids (see scheme; TFA = trifluoroacetic acid). Copyright
- Laplace, Duchan R.,Verbraeken, Bart,Van Hecke, Kristof,Winne, Johan M.
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supporting information
p. 253 - 262
(2014/01/17)
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- Photocatalytic degradation of water taste and odour compounds in the presence of polyoxometalates and TiO2: Intermediates and degradation pathways
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Geosmin (GSM) and 2-methylisoborneol (MIB) are produced by several species of cyanobacteria and actinomycetes. These compounds can taint water and fish causing undesirable taste and odours. Studies have shown that GSM/MIB are resistant in standard water treatments. Polyoxometalates (POM) are efficient photocatalysts in the degradation and mineralization of a great variety of organic pollutants, presenting similar behaviour with the widely published titanium dioxide (TiO2). Photocatalytic degradation of GSM and MIB under UV-A light in the presence of a characteristic POM photocatalyst, SiW 12O404-, in aqueous solution has been studied and compared with the photodegradation by TiO2 suspensions. GSM and MIB are effectively degraded in the presence of both photocatalysts. Addition of OH radical scavengers (KBr and tertiary butyl alcohol, TBA) retards the photodegradation rates of both compounds, suggesting that photodegradation mechanism takes place via OH radicals. Intermediates identified using GC-MS in the case of GSM and MIB, are mainly identical in the presence of both photocatalysts, also suggesting a common reaction mechanism. Possible photocatalytic degradation pathway for both GSM and MIB is proposed.
- Fotiou, Theodora,Triantis, Theodoros M.,Kaloudis, Triantafyllos,Papaconstantinou, Elias,Hiskia, Anastasia
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- The iron(II) complex [Fe(CF3SO3)2(mcp)] as a convenient, readily available catalyst for the selective oxidation of methylenic sites in alkanes
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The efficient and selective oxidation of secondary C-H sites of alkanes is achieved by using low catalyst loadings of a non-expensive, readily available iron catalyst [Fe(II)(CF3SO3)2(mcp)], {Fe-mcp, [mcp=N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)cyclohexane-trans-1,2-diamine]}, and hydrogen peroxide (H2O2) as oxidant, via a simple reaction protocol. Natural products are selectively oxidized and isolated in synthetically amenable yields. The easy access to large quantities of the catalyst and the simplicity of the C-H oxidation procedure make this system a particularly convenient tool to carry out alkane C-H oxidation reactions on the preparative scale, and in short reaction times.
- Canta, Merce,Font, David,Gomez, Laura,Ribas, Xavi,Costas, Miquel
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supporting information
p. 818 - 830
(2014/04/03)
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- OPSIN-BINDING LIGANDS, COMPOSITIONS AND METHODS OF USE
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Compounds are disclosed that are useful for treating ophthalmic conditions caused by or related to production of toxic visual cycle products that accumulate in the eye, such as dry adult macular degeneration, as well as conditions caused by or related to the misfolding of mutant opsin proteins and/or the mis-localization of opsin proteins. Compositions of these compounds alone or in combination with other therapeutic agents are also described, along with therapeutic methods of using such compounds and/or compositions. Methods of synthesizing such agents are also disclosed.
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- C-H oxidation by H2O2 and O2 catalyzed by a non-heme iron complex with a sterically encumbered tetradentate N-donor ligand
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The compound N,N′-dineopentyl-N,N′-bis(2-pyridylmethyl)-1,2- ethanediamine (dnbpn) and its ferrous complex [Fe(dnbpn)(OTf)2] were synthesized. The Fe(II) complex was used to catalyze the oxidation of hydrocarbons by H2O2 and O2. Although the catalyzed alkane oxidation by H2O2 displays a higher preference for secondary over tertiary carbons than those associated with most previously reported nonheme iron catalysts, the catalytic activity is markedly inferior. In addition to directing the catalyzed oxidation toward the less sterically congested C-H bonds of the substrates, the neopentyl groups destabilize the metal-based oxidants generated from H2O2 and the Fe(II) complex. The presence of benzylic substrates with weak C-H bonds stabilizes an intermediate which we have tentatively assigned as a high-spin ferric hydroperoxide species. The oxidant generated from O2 reacts with allylic and benzylic C-H bonds in the absence of a sacrificial reductant; less substrate dehydrogenation is observed than with related previously described systems that use O2 as a terminal oxidant.
- Zhang, Qiao,Gorden, John D.,Goldsmith, Christian R.
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p. 13546 - 13554
(2014/01/06)
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- Catalyst-controlled aliphatic c-h oxidations with a predictive model for site-selectivity
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Selective aliphatic C-H bond oxidations may have a profound impact on synthesis because these bonds exist across all classes of organic molecules. Central to this goal are catalysts with broad substrate scope (small-molecule-like) that predictably enhance or overturn the substrate's inherent reactivity preference for oxidation (enzyme-like). We report a simple small-molecule, non-heme iron catalyst that achieves predictable catalyst-controlled site-selectivity in preparative yields over a range of topologically diverse substrates. A catalyst reactivity model quantitatively correlates the innate physical properties of the substrate to the site-selectivities observed as a function of the catalyst.
- Gormisky, Paul E.,White, M. Christina
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supporting information
p. 14052 - 14055
(2013/10/21)
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- Regioselective oxidation of nonactivated alkyl C-H groups using highly structured non-heme iron catalysts
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Selective oxidation of alkyl C-H groups constitutes one of the highest challenges in organic synthesis. In this work, we show that mononuclear iron coordination complexes Λ-[Fe(CF3SO3) 2((S,S,R)-MCPP)] (Λ-1P), Δ-[Fe(CF3SO 3)2((R,R,R)-MCPP)] (Δ-1P), Λ-[Fe(CF 3SO3)2((S,S,R)-BPBPP)] (Λ-2P), and Δ-[Fe(CF3SO3)2((R,R,R)-BPBPP)] (Δ-2P) catalyze the fast, efficient, and selective oxidation of nonactivated alkyl C-H groups employing H2O2 as terminal oxidant. These complexes are based on tetradentate N-based ligands and contain iron centers embedded in highly structured coordination sites defined by two bulky 4,5-pinenopyridine donor ligands, a chiral diamine ligand backbone, and chirality at the metal (Λ or Δ). X-ray diffraction analysis shows that in Λ-1P and Λ-2P the pinene rings create cavity-like structures that isolate the iron site. The efficiency and regioselectivity in catalytic C-H oxidation reactions of these structurally rich complexes has been compared with those of Λ-[Fe(CF3SO3) 2((S,S)-MCP)] (Λ-1), Λ-[Fe(CF3SO 3)2((S,S)-BPBP)] (Λ-2), Δ-[Fe(CF 3SO3)2((R,R)-BPBP)] (Δ-2), Λ-[Fe(CH3CN)2((S,S)-BPBP)](SbF6) 2 (Λ-2SbF6), and Δ-[Fe(CH3CN) 2((R,R)-BPBP)](SbF6)2 (Δ-2SbF 6), which lack the steric bulk introduced by the pinene rings. Cavity-containing complexes Λ-1P and Λ-2P exhibit enhanced activity in comparison with Δ-1P, Δ-2P, Λ-1, Λ-2, and Λ-2SbF6. The regioselectivity exhibited by catalysts Λ-1P, Λ-2P, Δ-1P, and Δ-2P in the C-H oxidation of simple organic molecules can be predicted on the basis of the innate properties of the distinct C-H groups of the substrate. However, in specific complex organic molecules where oxidation of multiple C-H sites is competitive, the highly elaborate structure of the catalysts allows modulation of C-H regioselectivity between the oxidation of tertiary and secondary C-H groups and also among multiple methylene sites, providing oxidation products in synthetically valuable yields. These selectivities complement those accomplished with structurally simpler oxidants, including non-heme iron catalysts Λ-2 and Λ-2SbF6.
- Gómez, Laura,Canta, Merceì,Font, David,Prat, Irene,Ribas, Xavi,Costas, Miquel
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p. 1421 - 1433
(2013/03/29)
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- An iron catalyst for oxidation of alkyl C-H bonds showing enhanced selectivity for methylenic sites
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Many are called but few are chosen: A nonheme iron complex catalyzes the oxidation of alkyl C-H bonds by using H2O2 as the oxidant, showing an enhanced selectivity for secondary over tertiary C-H bonds (see scheme). Copyright
- Prat, Irene,Gomez, Laura,Canta, Merce,Ribas, Xavi,Costas, Miquel
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supporting information
p. 1908 - 1913
(2013/03/14)
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- Site-selective oxidation of unactivated C sp 3-H bonds with hypervalent iodine(III) reagents
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By design: The site-selective oxidation of unactivated secondary C sp 3-H bonds was accomplished with hypervalent iodine(III) reagents and tert-butyl hydroperoxide (see scheme). The preparation and derivatization of the hypervalent iodine(III) reagent are simple, thus allowing the rational design of these reagents to optimize the site selectivity of the oxidation. Copyright
- Moteki, Shin A.,Usui, Asuka,Zhang, Tiexin,Solorio Alvarado, Cesar R.,Maruoka, Keiji
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supporting information
p. 8657 - 8660
(2013/09/12)
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- Combined effects on selectivity in Fe-catalyzed methylene oxidation
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Methylene C-H bonds are among the most difficult chemical bonds to selectively functionalize because of their abundance in organic structures and inertness to most chemical reagents. Their selective oxidations in biosynthetic pathways underscore the power of such reactions for streamlining the synthesis of molecules with complex oxygenation patterns. We report that an iron catalyst can achieve methylene C-H bond oxidations in diverse natural-product settings with predictable and high chemo-, site-, and even diastereoselectivities. Electronic, steric, and stereoelectronic factors, which individually promote selectivity with this catalyst, are demonstrated to be powerful control elements when operating in combination in complex molecules. This small-molecule catalyst displays site selectivities complementary to those attained through enzymatic catalysis.
- Chen, Mark S.,White, M. Christina
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scheme or table
p. 533 - 571
(2010/10/05)
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- Spiro compounds as perfuming ingredients
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The present invention relates to the perfumery industry. It concerns more particularly an alcohol, ester, ether or ketone derivative having a spiro-type skeleton, the latter being substituted by short alkyl groups. The invention also relates to the use of the invention compounds as perfuming ingredients, able to impart a woody and/or aromatic, as well as to the perfumed articles or perfuming compositions comprising as active ingredient a compound of formula (I).
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- GUANIDINE DERIVATIVES AND USE THEREOF AS NEUROPEPTIDE FF RECEPTOR ANTAGONISTS
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The invention relates to guanidine derivatives of formula (I) where: A = a chain of 3-c6 carbon atoms, one of which can be replaced by -N(R')- or -O- and R' = H or a substituent, where the ring skeleton only contains both double bonds of the thiazole component, the pharmaceutically-acceptable acid addition salts of basic compounds of formula (I), the pharmaceutically-acceptable salts of compounds of formula (I),, comprising acid groups, with bases, the pharmaceutically-acceptable esters of hydroxy or carboxyl group containing compounds of formula (I) and the solvates or hydrates thereof, which are partly known and partly novel and exhibit a neuropeptide FF receptor antagonist effect. The above are suitable for the treatment of pain and hyperalgesia, withdrawal symptoms in alcohol, psychotropic and nicotine dependencies, for improvement or cure of said dependencies, for regulation of insulin excretion, food intake, memory functions, blood pressure, electrolyte and energy management and for treatment of urinary incontinence. The above can be produced using generally used methods and processed to give medicaments.
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- Reactions of β-trimethylstannylcyclohexanones with peracids: Investigations into the stannyl-directed Baeyer-Villiger reaction
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The trimethylstannyl subsituent raises the migratory aptitude of a primary β-carbon to be above that of a not otherwise activated secondary or tertiary carbon. This is apparent from the exclusive formation of the alkene acids 9-11 from Baeyer-Villiger reaction of the β-stannyl cyclohexanones 3-5. The stereoelectronic requirements of the stannyl-directed Baeyer-Villiger reaction were investigated using the axial β-trimethylstannlcyclohexanone 20.
- Horvat, Sonia,Karallas, Panagoitis,White, Jonathan M.
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p. 2151 - 2154
(2007/10/03)
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- SUBSTITUTED TETRAHYDROBENZOPYRROLYL-FURANOIC ACID DERIVATIVES AS PHOSPHOLIPASE A2 INHIBITORS
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Compounds of the formula wherein R is hydrogen, alkyl1-8, geminal alkyl1-3, un-substituted or substituted aryl; X is alkylene, ?CR1=CR2? (E and/or Z), carbonyl, oxygen or sulfur, wherein one of Ri and R2 is alkyli.3 and the other is hydrogen; Y is unsubstituted alkyh-n or substituted by one or more alkyl1-3 groups, or unsubstituted or substituted phenylalkyl 1-3; or a salt thereof with a pharmaceutically acceptable base, are described. The compound of formula I are potent inhibitors of phospholipase A2 (PLA2) and are therefore useful in the treatment of inflammatory diseases, such as, psoriasis, inflammatory bowel disease, asthma, allergy, arthritis, dermatitis, gout, pulmonary, myocardial ischemia and trauma induced inflammation, such as, spinal cord injury
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- Synthesis and Biological Activity of 7'-, 8'-, and 9'-Alkyl Analogues of Abscisic Acid
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In order to examine the hypothesis of pseudo-symmetry in the abscisic acid (ABA) molecule, (+/-)-7'-,8'-, and 9'-methyl, and (+/-)-7'-, 8'-, and 9'-ethyl analogues of abscisic acid, whose pseudo-symmetry is decreased, weresynthesized and, after optical resolution, tested for their inhibitory activity in four bioassays.The correlation of the decrease in the activity of (-)-7'- and 9'-alkyl-ABAs with that of (+)-9'- and 7'-alkyl-ABAs, respectively, seemed to agree with the hypothesis.The decrease in activity by alkylating C-8' of (+)-ABA was smaller than that by alkylating C-7' and C-9' of (+)-ABA, indicating that the activity was relatively unaffected by the bulky group at C-8' of (+)-ABA.Alkylation of C-8' and C-9', especially that of C-8', of (-)-ABA markedly reduced the activity.If the high activity of unnatural (-)-ABA is attributable to the pseudo-symmetry of the molecule, C-8' of (-)-ABA would occupy the space facing the re-face of C-2' in natural (+)-ABA.The low activity of (-)-8'-alkyl-ABA suggests the presence of a strict steric requirement of the binding sites to occupy the re-face of C-2' in (+)-ABA.
- Nakano, Sei-ichi,Todoroki, Yasushi,Hirai, Nobuhiro,Ohigashi, Hajime
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p. 1699 - 1706
(2007/10/02)
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- Et3GeNa-YCl3 complex as a new strong base
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The complex Et3GeNa-YCl3 (3:1) as a new strong base reacted with a variety of ketones to yield the corresponding enolate anions in good yields.Keywords: Germanium; Yttrium; Germyl anion; Base
- Yokoyama, Yasuo,Mochida, Kunio
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- Highly Regioselective Monoalkylation of Ketones via Manganese Enolates. Prepared from Lithium Enolates
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Li-enolates are readily converted to Mn-enolates by treatment with manganese halides.In THF, the reaction is easily and economically performed with manganese chloride at room temperature.Mn-enolates can then be regioselectively monoalkylated in good yields.The formation of di and polyalkylated products is never observed (1percent).
- Cahiez, Gerard,Chau, Khi,Clery, Patrick
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p. 3069 - 3072
(2007/10/02)
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- β-copper(II) ketones. Generation, coupling, and highly stereoselective trapping by electron-deficient acetylenes
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The generation and the reaction of β-copper(II) ketones via electrophilic ring opening of siloxycyclopropanes with copper(II) tetrafluoroborate (Cu(BF4)2) were studied. Treatment of siloxycyclopropane with Cu(BF4)2 resulted in desilylative dimerization to give a 1,6-diketone in good yield. The ring opening took place regioselectively across the bond between the methylene and siloxy carbons. The reaction is reasonably interpreted by assuming the electrophilic ring opening by cupric ion to form β-copper(II) ketone and trimethylsilylfluoride, followed by dimerization. With dimethyl acetylene dicarboxylate (DMAD) and water, β-(acyl)alkyls were captured to give dimethyl 2-(3-oxoalkyl)-maleate with high degree of stereoselectivity. The stereoselective transfer of β-(acyl)alkyl arises from syn addition across the triple bond followed by in situ protonation of the resulting vinylcopper species with retention of configuration. The stereoselective transfer of β-(acyl)alkyls to acetylenic sulfones, which gives β-(acyl)alkylated vinylic sulfones, was also successful.
- Ryu, Ilhyong,Matsumoto, Koichi,Kameyama, Yasuhiro,Ando, Masato,Kusumoto, Nobuo,Ogawa, Akiya,Kambe, Nobuaki,Murai, Shinji,Sonoda, Noboru
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p. 12330 - 12339
(2007/10/02)
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- α-Methylation of ketones via manganese-enolates: Absence of undesired polyalkylation
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The transmetalation of ketone lithium-enolates using MnBr2 generates manganese-enolates which react with CH3I to provide α-methylated ketones with essentially no undesired polyalkylated byproducts.
- Reetz, Manfred T.,Haning, Helmut
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p. 7395 - 7398
(2007/10/02)
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- Dependence of the Lewis Acid-Induced Reaction of β-Stannyl Ketones upon Substitution Pattern: Cyclopropanation versus 1,2-Alkyl Migration
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3-Stannylcyclohexanones fully substituted at 2 and 3 positions underwent a 1,2-aklyl migration, along with the cyclopropanation.The balance of the reactions depended upon the steric environment and migratory aptitude of the alkyl groups.
- Fujiwara, Jun,Sato, Tadashi
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p. 1258 - 1264
(2007/10/02)
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- A Regioselective and Stereospecific Synthesis of Allylsilanes from Secondary Allylic Alcohol Derivatives
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Primary and secondary allylic acetates and benzoates react with the dimethyl(phenyl)silyl-cuprate reagent to give allylsilanes, provided that the THF in which the cuprate is prepared is diluted with ether before addition of the allylic ester.The reaction is reasonably regioselective in some cases: (i) when the allylic system is more-substituted at one end than the other, as in the reactions 4->5 and 9->10; (ii) when the steric hindrance at one end is neopentyl-like, as in the reactions 15->16; and (iii) when the disubstituted double bond has the Z configuration, as in th e reactions Z-19->E-21 or, better, because the silyl group is becoming attached to the less-sterically hindered end of the allylic system, Z-20->E-22.The regioselectivity is better if a phenyl carbamate is used in place of the ester, and a three-step protocol assembling the mixed cuprate on the leaving group is used, as in the reactions 23->24 and E- or Z-29->E-21, or, best of all, because the silyl group is again becoming attached to the less-sterically hindered end of the allylic system, E- or Z-30->E-22.This sequence works well to move the silyl group onto the more substituted end of an allyl system, but only when the move is from a secondary allylic carbamate to a tertiary allylsilane, as in the reaction 38->39.Allyl(trimethyl)silanes can be made using alkyl- or aryl-cuprates on trimethylsilyl-containing allylic esters and carbamates, as in the reactions 40->41, and 43->44.The reaction of the silyl-cuprate with allylic esters and the three-step sequence with the allylic carbamates are stereochemically complementary, the former being stereospecifically anti and the latter stereospecifically syn.Homochiral allylsilanes can be ma de by these methods with high levels of stereospecificity, as shown by the synthesis of the allylsilanes 54, 58 and 59.
- Fleming, Ian,Higgins, Dick,Lawrence, Nicholas J.,Thomas, Andrew P.
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p. 3331 - 3350
(2007/10/02)
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- Electroorganic Chemistry. 124. Electroreductive Intramolecular Coupling of α-(ω-Bromoalkyl) β-Keto Esters
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Intramolecular coupling occurs when cyclic α-(bromomethyl) β-keto esters are electrochemically reduced in the presence of trimethylsilyl chloride and one-carbon ring-enlarged products are obtained in reasonable yields.Electroreduction of α-(γ-bromopropyl) β-keto esters also affords the corresponding five-membered cyclized products and/or the corresponding ring-opened compounds.The ease of ring opening of the cyclized products is highly influenced by their stereoconfiguration.Electroreduction of α-(β-bromoethyl) β-keto ester gives the product formed by the reductive elimination of the bromoethyl group whereas α-(δ-bromobutyl) β-keto ester yields the product of the reductive elimination of bromine.This electroreductive intramolecular coupling is initiated by the reduction of the carbon-bromine bond and proceeds through a carbanion intermediate.
- Shono, Tatsuya,Kise, Naoki,Uematsu, Nobuyuki,Morimoto, Shinji,Okazaki, Eiichi
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p. 5037 - 5041
(2007/10/02)
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- α-ALKYLATION AND α-ALKYLIDENATION OF CARBONYL COMPOUNDS BY O-SILYLATED ENOLATE PHENYLTHIOALKYLATION
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For many reactions next to a carbonyl group, the use of O-silylated enolate chemistry offers improvements in yield and selectivity over the corresponding reactions of Group I metal enolates.In the case of α-alkylation of carbonyl compounds, Lewis acid (TiCl4 or ZnBr2) promoted phenylthioalkylation of O-silylated enolates 3 by α-chlorosulphides 4 (R3=H, Me, Prn, Pri, Bui, and Me3Si), followed by reductive sulphur removal by Raney nickel, 5->6, is found to be a reliable method for this synthetically important C-C bond forming step.An alternative sulphur elimination pathway via the sulphoxide, 5->7, allows the regio- and stereocontrolled α-alkylidenation of carbonyl compounds.The phenylthioalkylation reaction is applicable to ketones, aldehydes, esters, and lactones.
- Paterson, Ian
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p. 4207 - 4220
(2007/10/02)
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- Original Syntheses of Carbonyl Compounds and gem-Dihalocyclopropanes from β-Hydroxylalkylselenides
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β-hydroxyalkylselenides possessing two alkyl substituents on the carbon bearing the selenyl moiety react with dihalocarbenes generated from haloforms and thallous ethoxide or under phase transfer catalysis to produce ring enlarged ketones as the sole product in the first case, as the main product in the second.The reaction takes another course when the dihalocarbenes generated from haloforms and tBuOK or from trihalomethylphenylmercury are employed and leads inter alias to dihalocyclopropanes.
- Krief,A.,Laboureur, J. L.,Dumont, W.
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p. 1549 - 1552
(2007/10/02)
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- The UV absorption and HeI and HeII photoelectron spectra of some (E)- and (Z)-α-oxo oxime O-methyl ethers and related compounds
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The HeI and HeII photoelectron spectra, as well as the UV absorption spectra, of a series of α-oxo oxime O-methyl ethers have been measured and assigned with the help a qualitative molecular orbital model, including through-bond and through-space interaction between lone-pair-type orbitals on the separate chromophore moieties.The observed dependence of the UV absorption frequency of both the n->?* and ?->?* transitions on the intercarbonyl-iminyl dihedral angle Φ is explained in terms of the angular dependence of occupied and unoccupied molecular orbitals.
- Buys, Theo S. V.,Cerfontain, Hans,Stunnenberg, Frank,Louwen, Jaap N.
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- A Study of the Diels-Alder Regioselectivity of Substituted Vinyl Cyclohexenes
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The regioselectivity of dienes 6a and 6b in Diels-Alder reactions with ethylenic and acetylenic dienophilic was examined and found to be good-excellent.An improved synthesis of diene 6a via a CuSO4 mediated dehydration of the vinyl carbinol precursor is described.
- Tanis, Steven P.,Abdallah, Yousef M.
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p. 251 - 260
(2007/10/02)
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- Ring Contraction of 2-Chlorocyclohexanone with Grignard Reagents
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The reaction of 2-chlorocyclohexanone with phenylmagnesium bromide in refluxing tetrahydrofuran unexpectedly afforded the ring-contracted product, cyclopentyl phenyl ketone, as the main product in moderate yield.The reactivities of several cyclic 2-haloketones were examined.Keywords - 2-chlorocyclohexanone; Grignard reaction; ring contraction; cyclopentyl phenyl ketone; solvent effect; THF; conformational isomer
- Hori, Mikio,Kataoka, Tadashi,Shimizu, Hiroshi,Imai, Eiji,Iwamura, Tatsunori,Maeda, Kaori
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p. 3599 - 3605
(2007/10/02)
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- ALKYLATION DIRECTE DE CETONES ET D'ALDEHYDES EN PRESENCE DE POTASSE SOLIDE EN SUSPENSION
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Dehydrated solid KOH, suspended in aprotic solvents, is used as a base for ketone and aldehyde alkylation.The best solvent as regards yields and selectivity is DME.The quantity of KOH depends on the carbonyl compound acidity.This method gives as good results as less convenient homogeneous conditions.
- Artaud, I.,Torossian, G.,Viout, P.
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p. 5031 - 5038
(2007/10/02)
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- α-HYDROXYLATION OF β-DICARBONYL COMPOUNDS
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Various β-dicarbonyl compounds can be hydroxylated as their silyl enol ethers by m-chloroperbenzoic acid (MCPBA).
- Andriamialiosa, R. Z.,Langlois, N.,Langlois, Y.
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p. 3563 - 3566
(2007/10/02)
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- Branched amides of L-aspartyl-D-amino acid dipeptides
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Amides of L-aspartyl-D-amino acid dipeptides of the formula STR1 and physiologically acceptable cationic and acid addition salts thereof wherein Ra is CH2 OH or CH2 OCH3 ; R is a branched member selected from the group consisting of fenchyl, diisopropylcarbinyl, d-methyl-t-butylcarbinyl, d-ethyl-t-butylcarbinyl, di-t-butylcarbinyl, 2-methylthio-2,4-dimethylpentan-3-yl, STR2 where at least one of R3, R4, R5, R6 is alkyl having from one to four carbon atoms and the remainder are hydrogen or alkyl having from one to four carbon atoms, X is O, S, SO, SO2, C=O or CHOH; m is zero or 1-4, n and p are each zero, 1, 2 or 3 where the sum of n+p is not greater than 3 and the sum of the carbon atoms in R3, R4, R5 and R6 is not greater than six, and when both of R3 and R4 or R5 and R6 are alkyl they are methyl or ethyl, STR3 where one of R7, R8, R9 is alkyl having from one to four carbon atoms and the remainder are hydrogen or alkyl having from one to four carbon atoms and the sum of the carbon atoms in R7, R8 and R9 is not greater than six, m and q are the same or different and each have the values previously defined for m; STR4 where each of R12 and R13 are methyl or ethyl, or R12 is hydrogen and R13 is alkyl having from one to four carbon atoms, Z is O or NH and t is 1 or 2, STR5 where W is 1-4, R14 and R16 are each alkyl having from one to four carbon atoms, R15 is H, OH, methyl or ethyl and the sum of the carbon atoms in R14, R15 and R16 is not greater than six and when both of R14 and R15 are alkyl they are methyl or ethyl, and STR6 where R17 and R19 are alkyl having from one to four carbon atoms, R18 and R20 are H or alkyl having one to two carbon atoms, A is OH and B is H, OH or CH3 and taken together A and B are STR7 where the sum of the carbon atoms in R17, R18, R19 and R20 is not greater than six and when both of R17 and R18 or R19 and R20 are alkyl they are methyl or ethyl; said amides are potent sweeteners having advantages over the prior art, edible compositions containing them, methods for their use in edible compositions and novel amide intermediates useful in their production.
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- Acetylenic retinals form functional bacteriorhodopsins but do not form bovine rhodopsins
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Three acetylenic retinals bearing a triple bond between the carbon atoms 7 and 8, and carrying no, two, or three methyl groups on the cyclohexene ring, were synthesized and various isomers obtained by illumination and subsequent chromatographic separation. The introduction of the acetylenic bond leads to a different geometrical arrangement of the cyclohexene ring with respect to the polyene side chain. Attempts to reconstitute rhodopsins and isorhodopsins with any of these compounds failed. Bacteriorhodopsins formed with the 13-cis and the all-trans isomers of all three acetylenic retinals showing absorption maxima between 490 and 530 nm. The increasing number of methyl groups on the ring correlated with an increasing red shift of the absorption maximum of the chromoproteins. This same correlation was found for the proton-pumping activity of the acetylenic bacteriorhodopsins. The results are in agreement with the fact that in rhodopsin a covalent binding at the carbonyl group (Schiff's base formation) and also a fixation at the cyclohexene ring of retinal occurs. The changed geometry of the acetylenic retinals, therefore, prevents binding. In bacteriorhodopsin, which lacks a specific cyclohexene ring binding site, the acetylenic retinals form active molecules. However, the contribution of the ring and its substituents to the function of bacteriorhodopsin is significant.
- Gartner,Oesterhelt,Seifer-Schiller,et al.
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p. 5654 - 5659
(2007/10/02)
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- HIGHLY REGIOSELECTIVE GENERATION OF "THERMODYNAMIC" ENOLATES AND THEIR DIRECT CHARACTERIZATION BY NMR
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Addition of 2-methylcyclohexanone to 1.05 equiv of KH suspended in THF, followed by treatment with 1.25 equiv of BEt3 gives potassium enoxyborate 2a as a 90-95percent regioisomerically pure species, as judged by its 1H and 13C NMR as well as by GLC analysis of the silylated products, while the use of KN(SiMe3)2 in place of KH gives 1a as a 90-95percent pure substance.The KH-BEt3 procedure also gives 4 and 5 as 91 and 85percent regiochemically pure species, respectively.
- Negishi, Ei-ichi,Chatterjee, Sugata
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p. 1341 - 1344
(2007/10/02)
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- NEW METHOD FOR THE RING ENLARGEMENT OF CYCLIC KETONES
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A simple two step procedure which allows the ring enlargement of cyclic ketones is disclosed which takes advantage of the high nucleophilicity of α-selenoalkyllithiums towards carbonyl compounds and of a novel transposition reaction which occurs on the resulting β-hydroxyselenides.
- Labar, D.,Laboureur, J. L.,Krief, A.
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p. 983 - 986
(2007/10/02)
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