1,721,115 research outputs found
Reactivity of trifluoromethyl aldimines with active methylene compounds
Full text linkIn this thesis the reactivity of N-protected trifluoromethyl (E)-aldimines towards different active methylene compounds in the Mannich-type and aza-Reformatsky reactions was studied.
At first, suitable trifluoromethyl aldimines were reacted with β-dicarbonyl compounds, including diethyl malonate and several β-keto esters. The presence of a trifluoromethyl group, lowering both nitrogen basicity and carbon electrophilicity of the imine C=N group, greatly affects the Mannich-type addition of β-dicarbonyl compounds. In fact, the most common organic or inorganic bases, such as some organocatalysts (cinchonidine, L-proline or their derivatives), frequently used to promote Mannich-type reactions between aromatic aldimines and β-dicarbonyl compounds,1 did not give the expected results.
Excellent results were obtained only through a Lewis acid catalysis, indeed an efficient solvent-free Zr-catalyzed Mannich-type reaction has been developed for the synthesis of fluorinated β-amino β-dicarbonyl compounds starting from N-protected trifluoromethyl aldimines and cyclic or acyclic β-keto esters bearing different ester residues.
The presence of an alkyl substituent on the nucleophilic carbon and the use of Zr as coordinating metal lead to a high stereoselective control of reactions. Instead, contrary to what reported in the literature for similar reaction, the ester residue did not affect the reaction outcome: in fact, no difference in reactivity was found by changing the ester moiety. Then, in order to develop a catalytic asymmetric Mannich-type reaction, failing all attempts using an added chiral catalyst, we successfully developed a new asymmetric Zr-catalyzed Mannich-type reaction at low cost starting from the optically pure aldimine derived by the inexpensive chiral (R)-α-methylbenzylamine. A complete facial and geometric stereoselective induction with formation of a chiral quaternary center was so obtained, the same chiral
substrate acting as chiral ligand. The nucleophilic attack takes place only on the sterically less hindered prochiral Re face of optically pure aldimine, giving R,R,S pure diastereomeric compounds bearing a quaternary chiral center. In addition, the diastereoselective catalytic Mannich-type reaction represents, thanks to a diastereoselective decarboxylation reaction of the new obtained β-keto esters, a valid approach to obtain optically active trifluoromethyl β-amino ketones. Extending my studies, the interest has been directed towards the possibility to synthesize attractive trifluoromethylated 2-imidazolines by Mannich-type addition/cyclization cascade reaction of isocyano acetates on trifluoromethyl aldimines. Silver(I) oxide is turned out to be a very efficient catalyst for the reaction performed under solvent-free conditions between methyl 2-isocyanoacetate and trifluoromethyl aldimines. High cis/trans stereoselective control was obtained, the reaction affording only trans imidazolines. Subsequently, the study has been extended to the reactivity of α-isocyano esters bearing a tertiary carbon center. Though the silver(I) catalysis appeared once again to be a good reaction catalyst, the use of dichloromethane as solvent was required and the total loss of geometric selectivity was recorded because of the steric hindrance on the nucleophilic site. Excellent stereoselectivity was obtained starting from the trifluoromethyl (E)- aldimines deriving from L-α-amino esters, leading to the formation of the only optically pure trans isomers. To explain the high diastereoselectivity observed and the stereochemical outcome, a transition state can be proposed in which the coordination of the imine ester group to the silver promotes the enolate attack preferentially to the Re imine face, obtaining enantiopure valuable trifluoromethyl imidazolines enriched by an α-amino ester residue. As a further and last class of active methylene compounds, α-bromo esters have been considered in the aza-Reformatsky reactions, always with different trifluoromethyl aldimines. The reactions were studied under two different conditions: heterogeneous conditions, using activated metal zinc as catalyst, and homogenous conditions,
using Et2Zn as source of the metal. Working under heterogeneous conditions, only β-lactams in good yields and high trans geometric selectivity were achieved when the reactions were performed starting from α-bromo esters. However, adding (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol as chiral ligand no enantioselective control was obtained. Even the presence of a chiral center on the aldimine does not seem able to control the facial attack selectivity. Then, we moved on to study the homogeneous reaction outcome. Under optimal conditions, the additions lead to the only β-amino esters, in good isolated yields and high geometric selectivity, the syn or anti isomer formation depending from the R substituent. In fact, while a complete syn selectivity was achieved starting from methyl substituted α-bromo ester, the anti β-amino ester was obtained starting from phenyl substituted α-bromo ester. Subsequently, the first example of a convenient enantioselective aza- Reformatsky reaction on trifluoromethyl aldimines has been successfully developed. Using diethyl zinc and substoichiometric amount of (1R,2S)-1-phenyl-2-(1- pyrrolidinyl)propan-1-ol as chiral ligand, trifluoromethyl enantioenriched β-amino esters in good yields and enantioselectivities (up to 91% ee) were synthesized. β-Amino esters, keto esters, and malonates obtained through aza-Reformatsky and Mannich type-reactions respectively, allow to approach, through appropriate chemical transformations, new ψ[CH(CF3)NH]-peptidomimetics. In fact, the [CH(CF3)] group is a known isoster of the carbonyl group.
Similarly, the synthesis of bioisoster has been the aim of the project carried out at the University of Oxford (UK) under the supervision of Professor Darren J. Dixon and in collaboration with the SGC (Structural Genomics Consortium). I have turned the attention on the development of potential epigenetic probes, characterized by a portion of acetyl lysine bioisoster, in order to draw conclusions about the binding elements, which are important for affinity with the bromodomain module of PCAF. A library of 20 compounds was developed and improvements in terms of affinity, compared to the lead compound, were obtained
DNA binding and oxidative DNA damage induced by climacostol–copper(II) complexes: Implications for anticancer properties
No full textClimacostol is a natural toxin isolated from the freshwater ciliated protozoan Climacostomum virens and belongs to the group of resorcinolic lipids. Climacostol exerts a potent antimicrobial activity against a panel of bacterial and fungal pathogens. In addition it inhibits the growth of tumor cell lines in a dose-dependent manner by inducing programmed cell death via intrinsic pathway. In this work, we investigated the possibility that climacostol exerts a prooxidant effect, inducing plasmid DNA strand breakage and eukaryotic DNA damage in presence of Cu(II) ions. Inhibition of DNA breakage using SOD, catalase and neocuproine confirmed the involvement of reactive oxygen species and Cu(I) ions in the DNA damage. UV–visible absorption changes and mass spectrometric analysis identified a product of reaction as a deprotonated form of climacostol. Study of the interaction with DNA, using fluorescence spectroscopic techniques, showed that climacostol binds with DNA. Given the structure–activity relationship of this compound and the mechanism of its prooxidant effect, we propose that the Cu(II)-mediated oxidative DNA damage by climacostol could explain its antimicrobial and antiproliferative activity
Crucial Role of Elusive Isomeric h-Complexes in Gas-Phase Electrophilic Aromatic Alkylations
No full textThe kinetics and stereochem. of the protonation-induced unimol. isomerization of (R)-1-D1-3-(p-fluorophenyl)butane have been investigated in the gas phase at 40-100 C and 70-760 Torr. This process leads to the formation of the relevant meta and ortho isomers with partial racemization of the migrating sec-Bu moiety. Complete racemization is obsd., instead, when the isomerization reaction involves a 1,2-H shift in the moving alkyl group. These results, together with the relevant activation parameters, fully confirm the previous evidence of the occurrence in the alkyl cation/arene PES of noncovalent .eta.-type intermediates of defined structure and stability, lying well below the classical .pi.-complexes, as confirmed by ab initio calcns. Their crucial role in detg. the positional selectivity of gas-phase electrophilic arom. substitutions clearly emerges from the comparison of the present results with the site selectivity measured in the corresponding bimol. arene alkylation carried out at the same temps. and pressures
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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