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1.
Biochemistry ; 56(38): 5134-5146, 2017 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-28858522

RESUMEN

Histone deacetylases (HDACs) are validated targets for treatment of certain cancer types and play numerous regulatory roles in biology, ranging from epigenetics to metabolism. Small molecules are highly important as tool compounds for probing these mechanisms as well as for the development of new medicines. Therefore, detailed mechanistic information and precise characterization of the chemical probes used to investigate the effects of HDAC enzymes are vital. We interrogated Nature's arsenal of macrocyclic nonribosomal peptide HDAC inhibitors by chemical synthesis and evaluation of more than 30 natural products and analogues. This furnished surprising trends in binding affinities for the various macrocycles, which were then exploited for the design of highly potent class I and IIb HDAC inhibitors. Furthermore, thorough kinetic investigation revealed unexpected inhibitory mechanisms of important tool compounds as well as the approved drug Istodax (romidepsin). This work provides novel inhibitors with varying potencies, selectivity profiles, and mechanisms of inhibition and, importantly, affords insight into known tool compounds that will improve the interpretation of their effects in biology and medicine.


Asunto(s)
Productos Biológicos/química , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Compuestos Macrocíclicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Células HeLa , Inhibidores de Histona Desacetilasas/administración & dosificación , Histona Desacetilasas/metabolismo , Humanos , Cinética , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Profármacos/farmacología , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Zinc/metabolismo
2.
J Biol Chem ; 291(13): 7128-41, 2016 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-26861872

RESUMEN

Protein lysine posttranslational modification by an increasing number of different acyl groups is becoming appreciated as a regulatory mechanism in cellular biology. Sirtuins are class III histone deacylases that use NAD(+)as a co-substrate during amide bond hydrolysis. Several studies have described the sirtuins as sensors of the NAD(+)/NADH ratio, but it has not been formally tested for all the mammalian sirtuinsin vitro To address this problem, we first synthesized a wide variety of peptide-based probes, which were used to identify the range of hydrolytic activities of human sirtuins. These probes included aliphatic ϵ-N-acyllysine modifications with hydrocarbon lengths ranging from formyl (C1) to palmitoyl (C16) as well as negatively charged dicarboxyl-derived modifications. In addition to the well established activities of the sirtuins, "long chain" acyllysine modifications were also shown to be prone to hydrolytic cleavage by SIRT1-3 and SIRT6, supporting recent findings. We then tested the ability of NADH, ADP-ribose, and nicotinamide to inhibit these NAD(+)-dependent deacylase activities of the sirtuins. In the commonly used 7-amino-4-methylcoumarin-coupled fluorescence-based assay, the fluorophore has significant spectral overlap with NADH and therefore cannot be used to measure inhibition by NADH. Therefore, we turned to an HPLC-MS-based assay to directly monitor the conversion of acylated peptides to their deacylated forms. All tested sirtuin deacylase activities showed sensitivity to NADH in this assay. However, the inhibitory concentrations of NADH in these assays are far greater than the predicted concentrations of NADH in cells; therefore, our data indicate that NADH is unlikely to inhibit sirtuinsin vivo These data suggest a re-evaluation of the sirtuins as direct sensors of the NAD(+)/NADH ratio.


Asunto(s)
Histona Desacetilasas/química , Lisina/análogos & derivados , NAD/química , Procesamiento Proteico-Postraduccional , Sirtuinas/química , Acilación , Bioensayo , Cromatografía Líquida de Alta Presión , Cumarinas/química , Colorantes Fluorescentes/química , Humanos , Hidrólisis , Isoenzimas/química , Cinética , Espectrometría de Masas , Simulación de Dinámica Molecular , Oligopéptidos/química , Proteínas Recombinantes/química , Soluciones
3.
Chemistry ; 23(43): 10235-10243, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28423204

RESUMEN

The deoxydehydration (DODH) reaction remains one of the most efficient methods of reducing the oxygen content of biomass while keeping important functionality in place. This reaction is traditionally catalysed by high-valent oxo-rhenium species. Recent research into heterogeneous rhenium-based catalysts for DODH demonstrates their ability to rival and in some cases surpass their homogeneous counterparts. Furthermore, catalysts based on the metals molybdenum and vanadium show great potential as inexpensive alternatives to rhenium catalysts. In this Minireview, we detail the recent developments within the field of DODH with particular emphasis on discoveries outside the realms of rhenium.

4.
J Org Chem ; 82(11): 5890-5897, 2017 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-28499339

RESUMEN

The hydroxide-mediated cleavage of ketones into alkanes and carboxylic acids has been reinvestigated and the substrate scope extended to benzyl carbonyl compounds. The transformation is performed with a 0.05 M ketone solution in refluxing xylene in the presence of 10 equiv of potassium hydroxide. The reaction constitutes a straightforward protocol for the synthesis of certain phenyl-substituted carboxylic acids from 2-phenylcycloalkanones. The mechanism was investigated by kinetic experiments which indicated a first order reaction in hydroxide and a full negative charge in the rate-determining step. The studies were complemented by a theoretical investigation where two possible pathways were characterized by DFT/M06-2X. The calculations showed that the scission takes place by nucleophilic attack of hydroxide on the ketone followed by fragmentation of the resulting oxyanion into the carboxylic acid and a benzyl anion.

5.
Angew Chem Int Ed Engl ; 56(10): 2599-2603, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28128488

RESUMEN

Enolonium species/iodo(III)enolates of carbonyl compounds have been suggested to be intermediates in a wide variety of hypervalent iodine induced chemical transformations of ketones, including α-C-O, α-C-N, α-C-C, and α-carbon-halide bond formation, but they have never been characterized. We report that these elusive umpoled enolates may be made as discrete species that are stable for several minutes at -78 °C, and report the first spectroscopic identification of such species. It is shown that enolonium species are direct intermediates in C-O, C-N, C-Cl, and C-C bond forming reactions. Our results open up chemical space for designing a variety of new transformations. We showcase the ability of enolonium species to react with prenyl, crotyl, cinnamyl, and allyl silanes with absolute regioselectivity in up to 92 % yield.

6.
Chemistry ; 22(46): 16621-16631, 2016 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-27723128

RESUMEN

The molybdate-catalysed transfer hydrodeoxygenation (HDO) of benzyl alcohol to toluene driven by oxidation of the solvent isopropyl alcohol to acetone has been investigated by using a combination of experimental and computational methods. A Hammett study that compared the relative rates for the transfer HDO of five para-substituted benzylic alcohols was carried out. Density-functional theory (DFT) calculations suggest a transition state with significant loss of aromaticity contributes to the lack of linearity observed in the Hammett study. The transfer HDO could also be carried out in neat PhCH2 OH at 175 °C. Under these conditions, PhCH2 OH underwent disproportionation to yield benzaldehyde, toluene, and significant amounts of bibenzyl. Isotopic-labelling experiments (using PhCH2 OD and PhCD2 OH) showed that incorporation of deuterium into the resultant toluene originated from the α position of benzyl alcohol, which is in line with the mechanism suggested by the DFT study.

7.
J Org Chem ; 81(20): 9931-9938, 2016 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-27685175

RESUMEN

Primary alcohols have been reacted with hydroxide and the ruthenium complex [RuCl2(IiPr)(p-cymene)] to afford carboxylic acids and dihydrogen. The dehydrogenative reaction is performed in toluene, which allows for a simple isolation of the products by precipitation and extraction. The transformation can be applied to a range of benzylic and saturated aliphatic alcohols containing halide and (thio)ether substituents, while olefins and ester groups are not compatible with the reaction conditions. Benzylic alcohols undergo faster conversion than other substrates, and a competing Cannizzaro reaction is most likely involved in this case. The kinetic isotope effect was determined to be 0.67 using 1-butanol as the substrate. A plausible catalytic cycle was characterized by DFT/B3LYP-D3 and involved coordination of the alcohol to the metal, ß-hydride elimination, hydroxide attack on the coordinated aldehyde, and a second ß-hydride elimination to furnish the carboxylate.

8.
Chemistry ; 21(8): 3435-42, 2015 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-25588805

RESUMEN

The mechanism of the molybdenum-catalyzed deoxydehydration (DODH) of vicinal diols has been investigated using density functional theory. The proposed catalytic cycle involves condensation of the diol with an Mo(VI) oxo complex, oxidative cleavage of the diol resulting in an Mo(IV) complex, and extrusion of the alkene. We have compared the proposed pathway with several alternatives, and the results have been corroborated by comparison with the molybdenum-catalyzed sulfoxide reduction recently published by Sanz et al. and with experimental observations for the DODH itself. Improved understanding of the mechanism should expedite future optimization of molybdenum-catalyzed biomass transformations.

9.
J Org Chem ; 80(16): 8142-9, 2015 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-26244379

RESUMEN

The first reported twisted bis-lactam, a racemic Tröger's base (TB) analogue (2), was resolved into its enantiomers on a chiral stationary phase HPLC column. The absolute configuration of (+)-2 was determined to be (R,R)-2 by comparing experimental and calculated vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectra. The absolute configuration of (-)-2 was determined by comparing experimental and calculated electronic circular dichroism (ECD) spectra. The corresponding theoretical spectra were calculated using the lowest energy conformation of (R,R)-2 and (S,S)-2 at the B3LYP/6-31G(d,p) level of theory. The absolute configuration of (+)-2 was also determined to (R,R)-2 by anomalous X-ray diffraction (AXRD) in a chiral space group P212121 using Cu-irradiation resulting in a very low Flack parameter of -0.06(3), despite the heaviest element being an oxygen atom, thus unambiguously confirming the results from the spectroscopic studies. We conclude that, for the Tröger's base (TB) analogue (2), we may rank the reliability of the individual methods for AC determination as AXRD ≫ VCD > ECD, while the synergy of all three methods provides very strong confidence in the assigned ACs of (+)-(R,R)-2 and (-)-(S,S)-2.

10.
Inorg Chem ; 54(22): 11031-6, 2015 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-26517008

RESUMEN

Mononuclear, coordinatively unsaturated rhenium(V) dioxo species of the type XReO2 (X = Me, substituted cyclopentadienyl) have long been postulated as intermediates in rhenium-catalyzed deoxydehydration, but their characterization was precluded because of aggregation into dimeric or oligomeric structures. Using the bulky 1,2,4-tri-tert-butylcyclopentadienyl (Cp(ttt)) ligand, the rhenium(V) dioxo species (Cp(ttt))ReO2 could now be observed, in equilibrium with the dimeric form [(Cp(ttt))Re(O)µ-O]2, and characterized by NMR, IR, and UV-vis spectroscopies, as well as electrospray ionization mass spectrometry. (Cp(ttt))ReO2 is shown to be the primary product of reduction of the rhenium(VII) complex (Cp(ttt))ReO3 with PPh3 and demonstrated to react with ethylene glycol significantly faster than its dimeric counterpart, supporting its role as an intermediate in rhenium-catalyzed deoxydehydration reactions.

11.
Org Biomol Chem ; 12(44): 8930-41, 2014 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-25271821

RESUMEN

The first generation of an organic nanotube based on the enantiomerically pure bicyclo[3.3.1]nonane framework is presented. The helical tube synthesised is the longest to date having its aromatic systems oriented parallel to the axis of propagation (length ∼26 Å and inner diameter ∼11 Å according to molecular dynamics simulations in chloroform). The synthesis of the tube, a heptamer, is based on a series of Friedländer condensations and the use of pyrido[3,2-d]pyrimidine units as masked 2-amino aldehydes, as a general means to propagate organic tubular structures and the introduction of a methoxy group for modification toward solubility and functionalization are described. The electronic CD spectra of the tube and molecular intermediates are correlated with theoretical spectra calculated with time-dependent density functional theory to characterize the chirality of the tube. Both experimental (NMR-titrations) and theoretical (molecular dynamics simulations) techniques are used to investigate the use of the tube as a receptor for the acetylcholine and guanidinium cations, respectively.

12.
J Am Chem Soc ; 135(7): 2835-44, 2013 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-23343406

RESUMEN

Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, the ß-peptoids (N-alkyl-ß-alanines), has found use in a variety of biologically active compounds but has been sparsely studied with respect to folding propensity. Thus, we here report an investigation of the effect of structural variations on the cis-trans amide bond rotamer equilibria in a selection of monomer model systems. In addition to various side chain effects, which correlated well with previous studies of α-peptoids, we present the synthesis and investigation of cis-trans isomerism in the first examples of peptoids and ß-peptoids containing thioamide bonds as well as trifluoroacetylated peptoids and ß-peptoids. These systems revealed an increase in the preference for cis-amides as compared to their parent compounds and thus provide novel strategies for affecting the folding of peptoid constructs. By using NMR spectroscopy, X-ray crystallographic analysis, and density functional theory calculations, we present evidence for the presence of thioamide-aromatic interactions through C(sp(2))-H···S(amide) hydrogen bonding, which stabilize certain peptoid conformations.


Asunto(s)
Amidas/química , Peptoides/química , Acetilación , Acrilamida/química , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Estructura Molecular , Estereoisomerismo
13.
Chemistry ; 19(44): 14963-9, 2013 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-24105657

RESUMEN

The synthesis of an orthogonal topological pentamer analogue of helicene is presented. This analogue forms a tubular structure with its aromatic systems directed parallel to the axis of propagation, which creates a cavity with the potential to function as a host molecule. The synthetic strategy reported, based on a series of repeating Friedländer condensations that utilize pyrido[3,2-d]pyrimidine moieties as protected amino aldehydes, allows for the facile access of higher generations of helical, tubular structures. As a result of the synthetic strategy, only a helical isomer of the pentamer is possible. The structure and absolute configuration of the pentamer were elucidated from a combination of NMR spectroscopic data, optical properties, X-ray structures, and by comparison of an experimental electronic circular dichroism spectrum to a calculated spectrum.

14.
Phys Chem Chem Phys ; 15(36): 15062-77, 2013 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-23925839

RESUMEN

In order to describe possible reaction mechanisms involving amino acids, and the evolution of the protonation state of amino acid side chains in solution, a reactive force field (ReaxFF-based description) for peptide and protein simulations has been developed as an expansion of the previously reported glycine parameters. This expansion consists of adding to the training set more than five hundred molecular systems, including all the amino acids and some short peptide structures, which have been investigated by means of quantum mechanical calculations. The performance of this ReaxFF protein force field on a relatively short time scale (500 ps) is validated by comparison with classical non-reactive simulations and experimental data of well characterized test cases, comprising capped amino acids, peptides, and small proteins, and reaction mechanisms connected to the pharmaceutical sector. A good agreement of ReaxFF predicted conformations and kinetics with reference data is obtained.


Asunto(s)
Glicina/química , Péptidos/química , Proteínas/química , Teoría Cuántica , Cinética , Conformación Proteica , Soluciones
15.
Chemistry ; 18(49): 15683-92, 2012 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-23070855

RESUMEN

The mechanism of the ruthenium-N-heterocyclic-carbene-catalyzed formation of amides from alcohols and amines was investigated by experimental techniques (Hammett studies, kinetic isotope effects) and by a computational study with dispersion-corrected density functional theory (DFT/M06). The Hammett study indicated that a small positive charge builds-up at the benzylic position in the transition state of the turnover-limiting step. The kinetic isotope effect was determined to be 2.29(±0.15), which suggests that the breakage of the C-H bond is not the rate-limiting step, but that it is one of several slow steps in the catalytic cycle. Rapid scrambling of hydrogen and deuterium at the α position of the alcohol was observed with deuterium-labeled substrates, which implies that the catalytically active species is a ruthenium dihydride. The experimental results were supported by the characterization of a plausible catalytic cycle by using DFT/M06. Both cis-dihydride and trans-dihydride intermediates were considered, but when the theoretical turnover frequencies (TOFs) were derived directly from the calculated DFT/M06 energies, we found that only the trans-dihydride pathway was in agreement with the experimentally determined TOFs.

16.
Org Biomol Chem ; 10(13): 2569-77, 2012 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-22349189

RESUMEN

The [Cp*IrCl(2)](2)-catalysed alkylation of amines with alcohols was investigated using a combination of experimental and theoretical methods. A Hammett study involving a series of para-substituted benzyl alcohols resulted in a line with a negative slope. This clearly documents that a positive charge is built up in the transition state, which in combination with the measurement of a significant kinetic isotope effect determines hydride abstraction as being the selectivity-determining step under these conditions. A complementary Hammett study using para-substituted anilines was also carried out. Again, a line with a negative slope was obtained suggesting that nucleophilic attack on the aldehyde is selectivity-determining. A computational investigation of the entire catalytic cycle with full-sized ligands and substrates was performed using density functional theory. The results suggest a catalytic cycle where the intermediate aldehyde stays coordinated to the iridium catalyst and reacts with the amine to give a hemiaminal which is also bound to the catalyst. Dehydration to the imine and reduction to the product amine also takes place without breaking the coordination to the catalyst. The fact that the entire catalytic cycle takes place with all the intermediates bound to the catalyst is important for the further development of this synthetic transformation.


Asunto(s)
Alcoholes/química , Aminas/química , Iridio/química , Alquilación , Catálisis , Iminas/química , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción
17.
Chemistry ; 17(5): 1456-64, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21268148

RESUMEN

The dehydration of glucose and other hexose carbohydrates to 5-(hydroxymethyl)furfural (HMF) was investigated in imidazolium-based ionic liquids with boric acid as a promoter. A yield of up to 42% from glucose and as much as 66% from sucrose was obtained. The yield of HMF decreased as the concentration of boric acid exceeded one equivalent, most likely as a consequence of stronger fructose-borate chelate complexes being formed. Computational modeling with DFT calculations confirmed that the formation of 1:1 glucose-borate complexes facilitated the conversion pathway from glucose to fructose. Deuterium-labeling studies elucidated that the isomerization proceeded via an ene-diol mechanism, which is different to that of the enzyme-catalyzed isomerization of glucose to fructose. The introduced non-metal system containing boric acid provides a new direction in the search for catalyst systems allowing efficient HMF formation from biorenewable sources.


Asunto(s)
Ácidos Bóricos/química , Furaldehído/análogos & derivados , Glucosa/química , Líquidos Iónicos/química , Catálisis , Furaldehído/química , Estructura Molecular
18.
Chemistry ; 17(10): 2885-96, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21294194

RESUMEN

The Pd-catalyzed intramolecular allylic alkylation of unsaturated amides to give γ- and δ-lactams has been studied in the presence of chiral ligands. Ligand (R)-3,5-tBu-MeOBIPHEP (MeOBIPHEP = 6,6'-dimethoxybiphenyl-2,2-diyl)bis(diphenylphosphine)) afforded the best results and allowed the cyclization reactions to take place in up to 94:6 enantiomeric ratio. A model Pd-allyl complex has been prepared and studied through NMR spectroscopic analysis, which provided insight into the processes responsible for the observed enantiomeric ratios. DFT studies were used to characterize the diastereomeric reaction pathways. The calculated energy differences were in good agreement with the experimentally observed enantiomeric ratios.

19.
J Chem Inf Model ; 51(12): 3262-74, 2011 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-22035233

RESUMEN

Histamine receptors (HRs) are excellent drug targets for the treatment of diseases, such as schizophrenia, psychosis, depression, migraine, allergies, asthma, ulcers, and hypertension. Among them, the human H(3) histamine receptor (hH(3)HR) antagonists have been proposed for specific therapeutic applications, including treatment of Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), epilepsy, and obesity. However, many of these drug candidates cause undesired side effects through the cross-reactivity with other histamine receptor subtypes. In order to develop improved selectivity and activity for such treatments, it would be useful to have the three-dimensional structures for all four HRs. We report here the predicted structures of four HR subtypes (H(1), H(2), H(3), and H(4)) using the GEnSeMBLE (GPCR ensemble of structures in membrane bilayer environment) Monte Carlo protocol, sampling ∼35 million combinations of helix packings to predict the 10 most stable packings for each of the four subtypes. Then we used these 10 best protein structures with the DarwinDock Monte Carlo protocol to sample ∼50 000 × 10(20) poses to predict the optimum ligand-protein structures for various agonists and antagonists. We find that E206(5.46) contributes most in binding H(3) selective agonists (5, 6, 7) in agreement with experimental mutation studies. We also find that conserved E5.46/S5.43 in both of hH(3)HR and hH(4)HR are involved in H(3)/ H(4) subtype selectivity. In addition, we find that M378(6.55) in hH(3)HR provides additional hydrophobic interactions different from hH(4)HR (the corresponding amino acid of T323(6.55) in hH(4)HR) to provide additional subtype bias. From these studies, we developed a pharmacophore model based on our predictions for known hH(3)HR selective antagonists in clinical study [ABT-239 1, GSK-189,254 2, PF-3654746 3, and BF2.649 (tiprolisant) 4] that suggests critical selectivity directing elements are: the basic proton interacting with D114(3.32), the spacer, the aromatic ring substituted with the hydrophilic or lipophilic groups interacting with lipophilic pockets in transmembranes (TMs) 3-5-6 and the aliphatic ring located in TMs 2-3-7. These 3D structures for all four HRs should help guide the rational design of novel drugs for the subtype selective antagonists and agonists with reduced side effects.


Asunto(s)
Diseño de Fármacos , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/química , Secuencia de Aminoácidos , Agonistas de los Receptores Histamínicos/química , Agonistas de los Receptores Histamínicos/farmacología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Método de Montecarlo , Conformación Proteica , Receptores Histamínicos/química , Receptores Histamínicos/metabolismo , Receptores Histamínicos H3/metabolismo , Alineación de Secuencia , Relación Estructura-Actividad
20.
Molecules ; 16(1): 951-69, 2011 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-21258300

RESUMEN

The atom-efficiency of one of the most widely used catalytic reactions for forging C-C bonds, the Tsuji-Trost reaction, is limited by the need of preoxidized reagents. This limitation can be overcome by utilization of the recently discovered palladium-catalyzed C-H activation, the allylic C-H alkylation reaction which is the topic of the current review. Particular emphasis is put on current mechanistic proposals for the three reaction types comprising the overall transformation: C-H activation, nucleophilic addition, and re-oxidation of the active catalyst. Recent advances in C-H bond activation are highlighted with emphasis on those leading to C-C bond formation, but where it was deemed necessary for the general understanding of the process closely related C-H oxidations and aminations are also included. It is found that C-H cleavage is most likely achieved by ligand participation which could involve an acetate ion coordinated to Pd. Several of the reported systems rely on benzoquinone for re-oxidation of the active catalyst. The scope for nucleophilic addition in allylic C-H alkylation is currently limited, due to demands on pK(a) of the nucleophile. This limitation could be due to the pH dependence of the benzoquinone/hydroquinone redox couple. Alternative methods for re-oxidation that does not rely on benzoquinone could be able to alleviate this limitation.


Asunto(s)
Paladio/química , Alquilación , Catálisis
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