Negishi cross-coupling of organotellurium compounds: synthesis of biaryls, aryl-, and diaryl acetylenes

A functional group tolerant palladium-catalyzed Negishi coupling of diaryl tellurides with organozinc has been developed. This methodology permits efficient preparation of biaryls, aryl acetylenes and diaryl acetylenes in moderate to good yields. A preliminary study to gain further insight into the reaction was performed using in situ ReactIR technology. (C) 2011 Elsevier Ltd. All rights reserved.

4-Organochalcogenoyl-1H-1,2,3-triazoles: synthesis and functionalization by a nickel-catalyzed Negishi cross-coupling reaction

A general method for the synthesis of triazoles containing selenium and tellurium was accomplished via a CuCAAC reaction between organic azides and a terminal triple bond, generated by in situ deprotection of the silyl group. The reaction tolerates alkyl and arylazides, with alkyl and aryl substituents directly bonded to the chalcogen atom. The products were readily functionalized by a nickel-catalyzed Negishi cross-coupling reaction, furnishing the aryl-heteroaryl products at the 4-position in good yields. (C) 2012 Elsevier Ltd. All rights reserved.

Iridium and rhodium analogues of the Shilov cycle catalyst; and the investigation and applications of the Reduction-Coupled Oxo Activation (ROA) mechanistic motif towards alkane upgrading

This dissertation will cover several disparate topics, with the overarching theme centering on the investigation of organometallic C-H activation and hydrocarbon transformation and upgrading. Chapters 2 and 3 discuss iridium and rhodium analogues of the Shilov cycle catalyst for methane to methanol oxidation, and Chapter 4 on the recently discovered ROA mechanistic motif in catalysts for various alkane partial oxidation reactions. In addition, Chapter 5 discusses the mechanism of nickel pyridine bisoxazoline Negishi catalysts for asymmetric and stereoconvergent C-C coupling, and the appendices discuss smaller projects on rhodium H/D exchange catalysts and DFT method benchmarking.

Applications of a Concise and General Strategy for the Syntheses of Transtaganolide and Basiliolide Natural Products

Herein are described the total syntheses of all members of the transtaganolide and basiliolide natural product family. Utilitzation of an Ireland–Claisen rearrangement/Diels–Alder cycloaddition cascade (ICR/DA) allowed for rapid assembly of the transtaganolide and basiliolide oxabicyclo[2.2.2]octane core. This methodology is general and was applicable to all members of the natural product family.

A brief introduction outlines all the synthetic progress previously disclosed by Lee, Dudley, and Johansson. This also includes the initial syntheses of transtaganolides C and D, as well as basiliolide B and epi-basiliolide B accomplished by Stoltz in 2011. Lastly, we discuss our racemic synthesis of basililide C and epi-basiliolide C, which utilized an ICR/DA cascade to constuct the oxabicyclo[2.2.2]octane core and formal [5+2] annulation to form the ketene-acetal containing 7-membered C-ring.

Next, we describe a strategy for an asymmetric ICR/DA cascade, by incorporation of a chiral silane directing group. This allowed for enantioselective construction of the C8 all-carbon quaternary center formed in the Ireland–Claisen rearrangement. Furthermore, a single hydride reduction and subsequent translactonization of a C4 methylester bearing oxabicyclo[2.2.2]octane core demonstrated a viable strategy for the desired skeletal rearrangement to obtain pentacyclic transtaganolides A and B. Application of the asymmetric strategy culminated in the total syntheses of (–)-transtaganolide A, (+)-transtaganolide B, (+)-transtaganolide C, and (–)-transtaganolide D. Comparison of the optical rotation data of the synthetically derived transtaganolides to that from the isolated counterparts has overarching biosynthetic implications which are discussed.

Lastly, improvement to the formal [5+2] annulation strategy is described. Negishi cross-coupling of methoxyethynyl zinc chloride using a palladium Xantphos catalyst is optimized for iodo-cyclohexene. Application of this technology to an iodo-pyrone geranyl ester allowed for formation and isolation of the eneyne product. Hydration of the enenye product forms natural metabolite basiliopyrone. Furthermore, the eneyne product can undergo an ICR/DA cascade and form transtaganolides C and D in a single step from an achiral monocyclic precursor.

Anomalous scattering factor determined by semicircle fitting near the K-absorption edge of Ge

It is shown that the locus of the f' + if '' plot in the complex plane, f' being determined from measured f '' by using the dispersion relation, looks like a semicircle very near the absorption edge of Ge. The semicircular locus is derived from a quantum theory of X-ray resonant scattering when there is a sharp isolated peak in f '' just above the K-absorption edge. Using the semicircular behavior, an approach is proposed to determine the anomalous scattering factors in a crystal by fitting known calculated values based on an isolated-atom model to a semicircular focus. The determined anomalous scattering factors f' show excellent agreement with the measured values just below the absorption edge. In addition, the phase determination of a crystal structure factor has been considered by using the semicircular behavior.

Precise determination of anomalous scattering factors of Ge by using X-ray resonant scattering

Variations of peak position of the rocking curve in the Bragg case are measured from a Ge thin crystal near the K-absorption edge. The variations are caused by a phase change of the real part of the atomic scattering factor. Based on the measurement, the values of the real part are determined with an accuracy of better than 1%. The values are the most reliable ones among those reported values so far as they are directly determined from the normal atomic scattering factors.

Monohalogénocyclopropanations stéréosélectives à l'aide de carbénoïdes de zinc, couplages croisés de cyclopropylsilanols, cyclisations d'iodures d'alkyle catalysées par le nickel

Les cyclopropanes sont des unités qui sont très importantes en raison de leur présence dans de nombreux produits naturels, dans certaines molécules synthétiques ayant une activité biologique, ainsi que dans plusieurs intermédiaires synthétiques. Les travaux décrits dans cet ouvrage portent sur l’halogénocyclopropanation stéréosélective d’alcools allyliques en présence d’un ligand chiral stœchiométrique de type dioxaborolane et de carbénoïdes de zinc substitués dérivés de composés organozinciques et d’haloformes. Nous avons ainsi développé des conditions pour l’iodo-, la chloro- et la fluorocyclopropanation stéréosélective. Une étude mécanistique portant sur la nature des carbénoïdes alpha-chlorés et alpha-bromés a révélé qu’il y a un échange des halogènes portés par ces carbénoïdes. Lors de la chlorocyclopropanation, le carbénoïde le plus réactif (alpha-chloré) réagit de façon prédominante en vertu du principe de Curtin-Hammet. Les iodocyclopropanes énantioenrichis ont pu être fonctionnalisés via une réaction d’échange lithium-iode suivie du traitement avec des électrophiles, ou via une réaction de transmétallation au zinc suivie d’un couplage de Negishi. Ainsi, toute une gamme de cyclopropanes 1,2,3-substitués énantioenrichis a pu être synthétisée. Dans l’optique de développer de nouvelles méthodologies de fonctionnalisation des cyclopropanes, nous nous sommes par la suite tournés vers le couplage croisé de type Hiyama-Denmark des cyclopropylsilanols. Dans cette voie synthétique, le groupement silanol a deux fonctions : il sert de groupement proximal basique lors de la cyclopropanation de Simmons-Smith et il subit la transmétallation au cours du couplage croisé. Dans l’étape du couplage croisé, la nature des ligands liés à l’atome de silicium s’est avérée cruciale au bon déroulement de la réaction. Ainsi, l’échange de ligands avec le diéthyl éthérate de trifluoroborane générant le cyclopropyltrifluorosilane in situ est requis pour obtenir de bons rendements. Le dernier volet de cet ouvrage porte sur la cyclisation d’iodures d’alkyle par substitution aromatique par voie homolytique catalysée par le nickel. Une série de composés de type tétrahydronaphtalène et thiochromane ont été préparés selon cette méthode. Une étude mécanistique a confirmé la nature radicalaire de cette réaction et suggère fortement l’action catalytique du nickel. De plus, des études de spectrométrie RMN DOSY ont montré une association entre le complexe de nickel et le substrat ainsi que la base employés dans cette réaction.

Synthèse stéréosélective de pipéridines et activation électrophile chimiosélective d’amides en présence de dérivés de la pyridine

L’importance des produits naturels dans le développement de nouveaux médicaments est indéniable. Malheureusement, l’isolation et la purification de ces produits de leurs sources naturelles procure normalement de très faibles quantités de molécules biologiquement actives. Ce problème a grandement limité l’accès à des études biologiques approfondies et/ou à une distribution sur une grande échelle du composé actif. Par exemple, la famille des pipéridines contient plusieurs composés bioactifs isolés de sources naturelles en très faible quantité (de l’ordre du milligramme). Pour pallier à ce problème, nous avons développé trois nouvelles approches synthétiques divergentes vers des pipéridines polysubstituées contenant une séquence d’activation/désaromatisation d’un sel de pyridinium chiral et énantioenrichi. La première approche vise la synthèse de pipéridines 2,5-disubstituées par l’utilisation d’une réaction d’arylation intermoléculaire sur des 1,2,3,4-tétrahydropyridines 2-substituées. Nous avons ensuite développé une méthode de synthèse d’indolizidines et de quinolizidines par l’utilisation d’amides secondaires. Cette deuxième approche permet ainsi la synthèse formelle d’alcaloïdes non-naturels à la suite d’une addition/cyclisation diastéréosélective et régiosélective sur un intermédiaire pyridinium commun. Finalement, nous avons développé une nouvelle approche pour la synthèse de pipéridines 2,6-disubstituées par l’utilisation d’une réaction de lithiation dirigée suivie d’un couplage croisé de Negishi ou d’un parachèvement avec un réactif électrophile. Le développement de transformations chimiosélectives et versatiles est un enjeu crucial et actuel pour les chimistes organiciens. Nous avons émis l’hypothèse qu’il serait possible d’appliquer le concept de chimiosélectivité à la fonctionnalisation d’amides, un des groupements le plus souvent rencontrés dans la structure des molécules naturelles. Dans le cadre précis de cette thèse, des transformations chimiosélectives ont été réalisées sur des amides secondaires fonctionnalisés. La méthode repose sur l’activation de la fonction carbonyle par l’anhydride triflique en présence d’une base faible. Dans un premier temps, l’amide ainsi activé a été réduit sélectivement en fonction imine, aldéhyde ou amine en présence d’hydrures peu nucléophiles. Alternativement, un nucléophile carboné a été employé afin de permettre la synthèse de cétones ou des cétimines. D’autre part, en combinant un amide et un dérivé de pyridine, une réaction de cyclisation/déshydratation permet d’obtenir les d’imidazo[1,5-a]pyridines polysubstituées. De plus, nous avons brièvement appliqué ces conditions d’activation au réarrangement interrompu de type Beckmann sur des cétoximes. Une nouvelle voie synthétique pour la synthèse d’iodures d’alcyne a finalement été développée en utilisant une réaction d’homologation/élimination en un seul pot à partir de bromures benzyliques et allyliques commercialement disponibles. La présente méthode se distincte des autres méthodes disponibles dans la littérature par la simplicité des procédures réactionnelles qui ont été optimisées afin d’être applicable sur grande échelle.

Strain longitudinal global para la detección de estenosis coronaria significativa en pacientes con infarto agudo del miocardio

Introducción: La evaluación de la función miocárdica global y regional juega una papel crítico en el diagnóstico y manejo de los pacientes con enfermedad coronaria con importantes implicaciones pronosticas, las nuevas técnicas ecocardiográficas como la evaluación del STRAIN han sido validadas como una herramienta objetiva, comprehensiva y precisa para evaluar dichos parámetros. Objetivo: Determinar la capacidad del strain global longitudinal para la detección de estenosis coronaria significativa, número de territorios comprometidos y territorio anatómico del vaso culpable; en pacientes sin antecedentes de enfermedad coronaria previa con infarto agudo del miocardio. Diseño: estudio de pruebas diagnósticas retrospectivo en el que se utilizó como gold estándar la angiografía coronaria, se seleccionaron 64 pacientes con ecocardiograma transtorácico previo a la angiografía coronaria. Resultados: Se demostró una exactitud intermedia del strain global longitudinal para detectar estenosis coronaria por análisis de curvas ROC, con un área bajo la curva de 0,78 p= 0,000 (IC 0,6; 1,0), Una sensibilidad de 96.5% (91.7%, 101.3%), especificidad 40.0% (9.6%, 70.4%) y una prevalencia real del enfermedad coronaria de 85.1% (76.5%, 93.6%) Conclusiones: La medición de la función global y regional por medio del strain global longitudinal identifica pacientes con infarto agudo del miocardio que tienen estenosis coronaria significativa, número de territorios afectados, y la distribución anatómica de los posibles vasos culpables, sin embargo hay que tener precaución en su uso que sólo se limite a escenarios en donde pueda ser interpretado adecuadamente. Palabras clave: strain global bidimensional, detección de estenosis coronaria significativa, infarto del miocardio.

Mecánica ventricular izquierda en pacientes con infarto agudo del miocardio

RESUMEN Introducción El papel de las nuevas técnicas ecocardiográficas para el diagnóstico de infarto agudo del miocardio se encuentra en desarrollo y la realización de mecánica ventricular izquierda podría sugerir la presencia de enfermedad coronaria hemodinámicamente significativa. Objetivos Determinar si en pacientes con infarto agudo del miocardio la medición de strain longitudinal global y regional sirve para predecir la presencia de enfermedad coronaria significativa. Métodos Es un estudio de pruebas diagnósticas en el que se evaluaron las características operativas de la mecánica ventricular izquierda para la detección de enfermedad coronaria significativa comparado contra el cateterismo cardiaco, considerado el patrón de oro. Se analizaron 54 pacientes con infarto agudo del miocardio llevados a cateterismo cardiaco, a quienes se les realizó un ecocardiograma transtorácico con medición de strain longitudinal global y regional. Resultados De los 54 pacientes analizados, el 83% tenía enfermedad coronaria significativa. El hallazgo de un strain longitudinal global < -17.5 tuvo una sensibilidad del 85% y una especificidad del 78% para predecir la presencia de enfermedad coronaria; para la arteria descendente anterior un strain longitudinal regional < – 17.4 tuvo una sensibilidad de 82% y una especificidad de 44%, para la arteria circunfleja una sensibilidad del 87% y una especificidad del 37% y para la arteria coronaria derecha una sensibilidad de 73% y una especificidad de 32%. Conclusiones La realización de ecocardiografía con mecánica ventricular en pacientes con infarto agudo del miocardio es útil para predecir la presencia de enfermedad coronaria hemodinámicamente significativa.

Seawater carbonate chemistry and net dissolution rate for experiment of Shiraho reef

Acidification of the oceans by increasing anthropogenic CO2 emissions will cause a decrease in biogenic calcification and an increase in carbonate dissolution. Previous studies have suggested that carbonate dissolution will occur in polar regions and in the deep sea where saturation state with respect to carbonate minerals (Omega) will be <1 by 2100. Recent reports demonstrate nocturnal carbonate dissolution of reefs, despite a Omega a (aragonite saturation state) value of >1. This is probably related to the dissolution of reef carbonate (Mg-calcite), which is more soluble than aragonite. However, the threshold of Omega for the dissolution of natural sediments has not been clearly determined. We designed an experimental dissolution system with conditions mimicking those of a natural coral reef, and measured the dissolution rates of aragonite in corals, and of Mg-calcite excreted by other marine organisms, under conditions of Omega a > 1, with controlled seawater pCO2. The experimental data show that dissolution of bulk carbonate sediments sampled from a coral reef occurs at Omega a values of 3.7 to 3.8. Mg-calcite derived from foraminifera and coralline algae dissolves at Omega a values between 3.0 and 3.2, and coralline aragonite starts to dissolve when Omega a = 1.0. We show that nocturnal carbonate dissolution of coral reefs occurs mainly by the dissolution of foraminiferans and coralline algae in reef sediments.

The Syk and ZAP-70 SH2-containing tyrosine kinases are implicated in pre-T cell receptor signaling

An early stage in thymocyte development, after rearrangement of the β chain genes of the T cell receptor (TCR), involves expression of the pre-TCR complex and accompanying differentiation of CD4−CD8− double negative (DN) cells to CD4+CD8+ double positive (DP) cells. The ZAP-70 and Syk tyrosine kinases each contain two N-terminal SH2 domains that bind phosphorylated motifs in antigen receptor subunits and are implicated in pre-T receptor signaling. However, mice deficient in either ZAP-70 or Syk have no defect in the formation of DP thymocytes. Here we show that, in mice lacking both Syk and ZAP-70, DN thymocytes undergo β chain gene rearrangement but fail to initiate clonal expansion and are incapable of differentiating into DP cells after expression of the pre-TCR. These data suggest that the ZAP-70 and Syk tyrosine kinases have crucial but overlapping functions in signaling from the pre-TCR and hence in early thymocyte development.

Interaction of pigeon cytochrome c-(43–58) peptide analogs with either T cell antigen receptor or I-Ab molecule

We determined that a pigeon cytochrome c-derived peptide, p43–58, possesses two anchor residues, 46 and 54, for binding with the I-Ab molecule that are compatible to the position 1 (P1) and position 9 (P9) of the core region in the major histocompatibility complex (MHC) class II binding peptides, respectively. In the present study to analyze each binding site between P1 and P9 of p43–58 to either I-Ab or T cell antigen receptor (TCR), we investigated T cell responses to a series of peptides (P2K, P3K, P4K, P5K, P6K, P7K, and P8E) that sequentially substituted charged amino acid residues for the residues at P2 to P8 of p43–58. T cells from C57BL/10 (I-Ab) mice immunized with P4K or P6K did not mount appreciable proliferative responses to the immunogens, but those primed with other peptides (P2K, P3K, P5K, P7K, and P8E) showed substantial responses in an immunogen-specific manner. It was demonstrated by binding studies that P1 and P9 functioned as main anchors and P4 and P6 functioned as secondary anchors to I-Ab. Analyses of Vβ usage of T cell lines specific for these analogs suggested that P8 interacts with the complementarity-determining region 1 (CDR1)/CDR2 of the TCR β chain. Furthermore, sequencing of the TCR on T cell hybridomas specific for these analogs indicated that P5 interacts with the CDR3 of the TCR β chain. The present findings are consistent with the three-dimensional structure of the trimolecular complex that has been reported for TCR/peptide/MHC class I molecules.

Human SULT1A genes: Cloning and activity assays of the SULT1A promoters

The three human SULT1A sulfotransferase enzymes are closely related in amino acid sequence (>90%), yet differ in their substrate preference and tissue distribution. SULT1A1 has a broad tissue distribution and metabolizes a range of xenobiotics as well as endogenous substrates such as estrogens and iodothyronines. While the localization of SULT1A2 is poorly understood, it has been shown to metabolize a number of aromatic amines. SULT1A3 is the major catecholamine sulfonating form, which is consistent with it being expressed principally in the gastrointestinal tract. SULT1A proteins are encoded by three separate genes, located in close proximity to each other on chromosome 16. The presence of differential 5′-untranslated regions identified upon cloning of the SULT1A cDNAs suggested the utilization of differential transcriptional start sites and/or differential splicing. This chapter describes the methods utilized by our laboratory to clone and assay the activity of the promoters flanking these different untranslated regions found on SULT1A genes. These techniques will assist investigators in further elucidating the differential mechanisms that control regulation of the human SULT1A genes. They will also help reveal how different cellular environments and polymorphisms affect the activity of SULT1A gene promoters.

Developing of Germyldesulonylation and Thiodesulfonylation Reactions for the Synthesis of Novel Nucleoside Analogues. Efficient Synthesis of Novel (α-Fluoro)vinyl Sulfides

S-adenosyl-L-homocysteine (AdoHcy) hydrolase effects hydrolytic cleavage of AdoHcy to produce both adenosine and L-homocysteine and is a feedback inhibitor of S-adenosyl- L-methionine (SAM). Nucleoside analogues bearing an alkenyl or fluoroalkenyl chain between sulfur and C5' utilizing Negishi coupling reactions were synthesized. Palladium-catalyzed cross-coupling between the 5'-deoxy-5'-(iodomethylene) nucleosides and alkylzinc bromides gives analogues with the alkenyl unit. Palladium-catalyzed selective monoalkylation of 5'-(bromofluoromethylene)-5'-deoxy-adenosine with alkylzinc bromide afford adenosylhomocysteine analogues with a 6'-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-L-homocysteine hydrolases. Stannydesulfonylation reaction is a critical step in the synthesis of E-fluorovinyl cytidine (Tezacitabine) a ribonucleoside reductase inhibitor with a potent anticancer activity. The synthesis involves the removal of the sulfonyl group by a radical-mediated stannyldesulfonylation reaction using tributyltin hydride. In order to eliminate the toxicity of tin, I developed a radical-mediated germyldesulonylation utilizing less toxic germane hydrides. Treatment of the protected (E)-5'-deoxy-5'-[(p-toluenesulfonyl)-methylene]uridine and adenosine derivatives with tributyl- or triphenylgermane hydride effected radical-mediated germyldesulfonylations to give 5'-(tributyl- or triphenylgermyl)methylene-5'-deoxynucleoside derivatives as single (E)-isomers. Analogous treatment of 2'-deoxy-2'-[(phenylsulfonyl)methylene]uridine with Ph3GeH afforded the corresponding vinyl triphenylgermane product. Stereoselective halodegermylation of the (E)-5'-(tributylgermyl)-methylene-5'-deoxy nucleosides with NIS or NBS provided the Wittig-type (E)-5'-deoxy-5'-(halomethylene) nucleosides quantitatively. Radical-mediated thiodesulfonylation of the readily available vinyl and (α-fluoro) vinyl sulfones with aryl thiols in organic or aqueous medium to provide a bench and environmentally friendly protocol to access (α-fluoro)vinyl sulfides were developed. Methylation of the vinyl or (α-fluoro)vinyl phenyl sulfide gave access to the corresponding vinyl or (α-fluoro)vinyl sulfonium salts. These sulfonium ions were tested as possible methyl group donors during reactions with thiols, phenols or amino groups which are commonly present in natural amino acids.