420 research outputs found
Dihydrogen activation at non-metallic centers
No full textThe work presented in this thesis was dedicated to the development of novel systems based on pyridinium salts for the heterolytic dihydrogen activation and evaluation of their suitability as catalysts for catalytic hydrogenation. These systems contain a pyridinium salt as hydride acceptor and a basic nitrogen or oxygen function as proton acceptor. Initially, an intramolecular system was envisioned, in which the pyridinium salt is linked with a basic amine and the hydrogen cleavage should occur through a concerted transition state. Due to the low stability of the starting materials, mainly decomposition products were observed after test reactions at high temperatures and hydrogen pressures ranging from 50-100 bar.
As a next step, a bimolecular system based on pyridinium salts and sterically hindered alcoxides was evaluated. For this purpose, electrophilic N-acyl ammonium salts and phenolates derived from commercially available BHT derivatives were prepared. However, in the presence of hydrogen gas no reaction was observed and starting materials were recovered.
ITAMI and co-workers demonstrated the formation of pyridylidenes from pyridinium salts in the presence of a strong base. These highly reactive intermediates could then undergo formal addition of H2. Known pyridinium salt/dihydropyridine systems are Hantzsch esters and nicotinamide derivatives. Both classes of pyridinium salts were tested for H2 activation reactions. Although the formation of the corresponding dihydropyridines was observed, deuteration experiments proved that the reaction did not proceed via dihydrogen splitting. Furthermore, the ability of these N protected pyridinium salts to reduce selected substrates was rather poor.
Finally, the activation of dihydrogen was achieved by reaction of a pyridinium salt as described by ITAMI in the presence of base. First, a 1,3,5 triarylpyridinium salt was synthesized, which could be transformed into the corresponding pyridylidene in the presence of LiHMDS. This intermediate was trapped by quenching with S8. Reaction with H2 led to its activation and the corresponding 1,2 dihydropyridine was formed.
Dihydrogen activation was confirmed by reaction with deuterium gas, as the 2H NMR spectra showed the signal of the corresponding CD2 group. Studies towards catalytic applications of that system showed that imine 255 was reduced to the corresponding amine in the presence of stoichiometric amounts of base and 20 mol% of catalyst loading
Data Quality in Predictive Toxicology: Identification of Chemical Structures and Calculation of Chemical Descriptors
No full textEvery technique for toxicity prediction and for the detection of structure–activity relationships relies on the accurate estimation and representation of chemical and toxicologic properties. In this paper we discuss the potential sources of errors associated with the identification of compounds, the representation of their structures, and the calculation of chemical descriptors. It is based on a case study where machine learning techniques were applied to data from noncongeneric compounds and a complex toxicologic end point (carcinogenicity). We propose methods applicable to the routine quality control of large chemical datasets, but our main intention is to raise awareness about this topic and to open a discussion about quality assurance in predictive toxicology. The accuracy and reproducibility of toxicity data will be reported in another paper
Unfolding presence: an interpretative phenomenological analysis of photography
No full textNote: This record first appeared under the author\u27s less commonly used primary name of Emma Helena Sawatzky. In order to match the information contained in the thesis itself, the name in the record has been changed to the author\u27s regular name of Helma Sawatzky
Iridium-catalyzed asymmetric hydrogenation of furan derivatives and thiophene 1,1-dioxides
No full textThe main focus of the research presented in this dissertation was to broaden the substrate scope of the iridium-catalyzed asymmetric hydrogenation of heterocyclic compounds. In view of the fact that a widely applicable hydrogenation system for the reduction of structurally diverse furans and benzofurans is to date not available, a thorough investigation of furan, benzofuran and thiophene 1,1-dioxide derivatives was carried out. Mono- and disubstituted furan derivatives were synthesized and submitted to iridium-catalyzed hydrogenation reactions. While 3-substituted furans were reduced using a catalyst based on a cyclopentane-annulated bicyclic pyridine-phosphine ligand with high enantiomeric excess (95–99% ee) and conversion (83–99%), 2-substituted counterparts proved to be less reactive (80–97% conv., 65–82% ee) with the same catalyst. Asymmetric hydrogenation of 2,4-disubstituted furans proved to be challenging for several reasons, not least because of the problem of controlling the cis/trans selectivity. Surprisingly, in the iridium-catalyzed hydrogenation of 3-substituted benzofurans only one catalyst, based on the cyclohexane-annulated pyridine-phosphinite ligand, showed high activity and enantioselectivity (75–89% conv., 91–92% ee), whereas the five-membered ring analog suffered from moderate activity and enantioselectivity. In contrast, the 2-alkyl substituted benzofurans gave superior results (99% conv., 97–99% ee). Disubstituted thiophene 1,1-dioxides were also investigated in the iridium-catalyzed asymmetric hydrogenation. The hydrogenation of 3,4 disubstituted thiophene 1,1 dioxides using a catalyst based on a cyclopentane-annulated bicyclic pyridine-phosphine ligand gave inferior results to those obtained with their 2,5 disubstituted counterparts
Author Correction: A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity (Nature Communications, (2022), 13, 1, (5104), 10.1038/s41467-022-3
No full textIn the author list of this article, the names of the authorswere incorrectly listed with initials and family name only. The incorrect author list read as “C. Kedor, H. Freitag, L. Meyer-Arndt, K. Wittke, L. G. Hanitsch, T. Zoller, F. Steinbeis, M. Haffke, G. Rudolf, B. Heidecker, T. Bobbert, J. Spranger, H. D. Volk, C. Skurk, F. Konietschke, F. Paul, U. Behrends, J. Bellmann-Strobl and C. Scheibenbogen”. The author list has now been amended to include the given and family names in the HTML and PDF versions of the article. The corrected author list reads as “Claudia Kedor, Helma Freitag, Lil Meyer-Arndt, Kirsten Wittke, Leif G. Hanitsch, Thomas Zoller, Fridolin Steinbeis, Milan Haffke, Gordon Rudolf, Bettina Heidecker, Thomas Bobbert, Joachim Spranger, Hans- Dieter Volk, Carsten Skurk, Frank Konietschke, Friedemann Paul, Uta Behrends, Judith Bellmann-Strobl and Carmen Scheibenbogen”
Latent Structure Pattern Mining
No full textPattern mining methods for graph data have largely been restricted to ground features, such as frequent or correlated subgraphs. Kazius et al. have demonstrated the use of elaborate patterns in the biochemical domain, summarizing several ground features at once. Such patterns bear the potential to reveal latent information not present in any individual ground feature. However, those patterns were handcrafted by chemical experts. In this paper, we present a data-driven bottom-up method for pattern generation that takes advantage of the embedding relationships among individual ground features. The method works fully automatically and does not require data preprocessing (e.g., to introduce abstract node or edge labels). Controlling the process of generating ground features, it is possible to align them canonically and merge (stack) them, yielding a weighted edge graph. In a subsequent step, the subgraph features can further be reduced by singular value decomposition (SVD). Our experiments show that the resulting features enable substantial performance improvements on chemical datasets that have been problematic so far for graph mining approaches. © 2010 Springer-Verlag Berlin Heidelber
Strategies for peptide-induced formation of noble-metal nanoparticles and investigation of their antibacterial efficacy
No full textNoble-Metal Nanoparticle formation in defined sizes and shapes is still a great challenge. Peptides
have shown potential for offering the generation of such nanoparticles. However, still limited is the
knowledge for identifying the appropriate peptides. To fulfill this requirement, we used colorimetric
on-bead screening of encoded one-bead-one-peptide libraries and successfully identified a variety
of simple tripeptides which are able to induce the formation of AgNPs in different size on solid
support. Furthermore, in this thesis we demonstrate how short peptides identified within the
encoded one-bead-one-peptide libraries could be used to generate highly stable AgNPs of different
size and shape in solution. In this regard, the effect of pH, peptide/Ag+ ratio and the role of the
linker between the amino acids were evaluated. Also accompanying this account, are the
exceptional antibacterial activities of our peptide-AgNPs as determined by Isothermal Micro
Calorimetric studies
Palladium and copper-catalysed (C-C)-bond formation
No full textCopper-Catalysed Conjugate Additions:
Conjugate 1,4-additions of carbon nucleophiles to α,β-unsaturated ketones are valuable C-C bond forming reactions that furthermore allow introduction of stereogenic centers.(1) Copper-catalysed reactions have been successfully employed in a variety of syntheses, for example for (-)-solavetivone(2) or prostaglandins.(3) Improvement of enantioselectivity through design of more effective ligands is thus highly desirable.
The ligands depicted below were synthesised and tested, with excellent enantioselectivities on selected substrates.
Muscone Synthesis:
Musk odorants are a family of molecules possessing a very nice smell, of central importance for the fragrance industry. Application of the methodology developed for the copper-catalysed conjugate addition to the synthesis of (S)-muscone allowed the obtaining of product 90 in high yield and excellent enantiomeric purity.
Multicomponent Heck-Allylic substitution Reaction:
Synthetic methodology which allows for a rapid increase in molecular complexity is extremely valuable in organic chemistry, particularly if it generates more than one new carbon-carbon bond at a time, accommodates considerable functionality and is broad in scope.
Design of a reaction sequence involving a Heck reaction followed by an allylic substitution allowed the obtaining of compound 141 depicted below
Development and evaluation of chiral catalysts for asymmetric C-C and C-H bond forming reactions
No full textThis work was dedicated to the development and evaluation of new chiral catalysts for asymmetric C-C and C-H bond forming reactions. In this context ESI-MS was used as a powerful tool for reactivity- and selectivity-studies.
In the first part an ESI-MS screening method is described, which allows the determination of the selectivity of a chiral catalyst in the palladium catalyzed asymmetric allylic alkylation by testing its racemic form. It was shown that, by reacting a racemic mixture of the with a scalemic mixture of quasi-enantiomeric mass-labeled substrates, the selectivity of the chiral catalyst can be calculated from the ratio of the formed mass-labeled reaction intermediates. The value of this new method was demonstrated when different new aryl-PHOX-type ligands, which are not easily accessible in enantiopure form, were synthesized and evaluated in the allylic alkylation reaction. In this way a more selective member of this class was found compared to the previously reported phenyl-PHOX ligand.
Since PHOX ligands are suitable ligands in the iridium-catalyzed asymmetric hydrogenation of C-C and C-N double bonds, the new PHOX ligands were then tested as well in the iridium-catalyzed asymmetric hydrogenation of different unsaturated compounds. Although low activities and selectivities were found in most cases, one ligand showed some promising results in the hydrogenation of allylic alcohols and imines.
Furthermore air- and moisture-stable secondary phosphine oxide (SPO) containing bidentate ligands were tested in the palladium-catalyzed asymmetric allylic alkylation reaction. SPO,N-ligands bearing a PHOX type backbone were inactive in this transformation as they tend to form inactive palladium-bis-ligand complexes stabilized by hydrogen-bonding between the two ligands. SPO,P ligands however, were able to promote the desired reaction in a highly selective fashion although only low activities were found.
During this work as well a new organo-catalyst, based on the structure of 2,3-dihydrobenzo[1,4]oxazine, was developed which allows for the asymmetric transfer-hydrogenation of alpha, beta-unsaturated aldehydes. Especially in the reduction of beta, beta-diaryl acrylaldehydes very good activities and high enantioselectivities were achieved. It was shown that for this particular substrate this catalyst outperformed the previously described ones. Thus it proved to be a useful extension to the limited known catalysts for this reaction and especially for this interesting class of products, which can act as precursors for many natural products or drugs.
Another organo-catalyzed reaction which was studied in this work was the conjugate addition reaction catalyzed by a tripeptidic organo-catalyst. As in the literature two different mechanistically pathways were hypothesized, via an enamine- or via an enol-intermediate, ESI-MS studies were carried out to clarify the actual mechanism for this transformation. All reaction intermediates which are postulated for the enamine-pathway could be found in both the forward- and the back-reaction. Furthermore the enantioselectivity of enamine-attack onto a nitroolefin was determined by an ESI-MS screening and it was shown that this enantioselectivity equals the selectivity of the preparative reaction. All of these findings strongly support the suggestion of an enamine-catalysis mechanism to be true in this reaction.
The last part of this work aimed for the asymmetric alpha-allylation of carbonyl compounds by a tandem-catalysis approach. An intensive screening of both the organo-catalyst and the palladium-ligand led to reaction conditions which allowed for the selective mono-allylation of ketones in high yields. The formation of a quaternary center by alpha-allylation of
alpha-branched aldehydes was also achieved. However, only low enantiomeric excesses were obtained in this transformation for the different catalyst systems tested
Peptide catalyzed conjugate addition reactions of aldehydes to nitroolefins
No full textAbstract
In this thesis mechanistic investigations into the peptide catalyzed conjugate addition reaction between aldehydes and nitroolefins are described. Additionally, the extension of this reaction to special reaction conditions as well as challenging substrate combinations is presented. The tripeptide H-D-Pro-Pro-Glu-NH2 is an excellent catalyst for conjugate addition reactions between aldehydes and beta-nitroolefins. Mechanistic investigations comparing the tripeptide H-D-Pro-Pro-Glu-NH2 with its methyl ester analogue H-D-Pro-Pro-Glu(OCH3)-NH2 revealed that the reaction pathway and thus the rate determining steps of the reaction depend on the presence or absence of a suitably positioned carboxylic acid moiety within the catalyst. These findings have important implications for future catalyst design and optimization and offer an explanation why the peptide H-D-Pro-Pro-Glu-NH2 bearing an intramolecular carboxylic acid moiety is such a successful catalyst for this reaction. Further mechanistic studies were directed at the elucidation whether an enamine or an enol is the active nucleophile in the peptide catalyzed conjugate addition reactions. ESI-MS back reaction screening using mass-labeled quasi-enantiomeric substrate mixtures revealed that in the presence of several peptides of the type Pro-Pro-Xaa (Xaa = variable amino acid bearing a carboxylic acid group) the selectivity of the attack of the enamine onto the nitroolefin equals the selectivity of the preparative reaction. Thus, an enamine is involved in the selectivity determining step of reactions in the presence of such peptidic catalysts.
In the second part of this thesis, amphiphilic analogues of H-D-Pro-Pro-Glu-NH2 were examined as catalysts for conjugate addition reactions between aldehydes and nitroolefins in aqueous reaction media. Introduction of a hydrophobic alkyl chain to the C-terminus gave the peptide H-D-Pro-Pro-Glu-NH-C12H25 as an excellent catalyst. This amphiphilic peptide serves as both, catalyst for the reaction as well as a detergent stabilizing an emulsion of the substrates in the aqueous environment.
Finally, peptides of the type Pro-Pro-Xaa were examined as catalysts for conjugate addition reactions between aldehydes and alpha,beta-disubstituted nitroolefins, a much more challenging and far less examined substrate class than their beta-mono-substituted counterparts. The testing of a small collection of peptides led to the identification of H-Pro-Pro-D-Gln-OH and H-Pro-Pro-Asn-OH as effective catalysts allowing for addition reactions between different combinations of aldehydes and alpha,beta-disubstituted nitroolefins. The resulting gamma-nitroaldehydes bearing three consecutive stereogenic centres were obtained in good yields and excellent stereoselectivities. Chiral pyrrolidines as well as fully substituted gamma-butyrolactams and gamma-amino acids were easily accessible from the gamma-nitroaldehydes.
The results described within this thesis not only highlight the value of peptides of the type Pro-Pro-Xaa as successful catalysts in enamine catalysis but might also pave the way for future research into addition reactions of carbonyl compounds to other challenging electrophiles or the application of peptidic catalysts under physiological conditions in a cellular environment.---------- Zusammenfassung:
In der vorliegenden Arbeit werden mechanistische Untersuchungen zu peptidkatalysierten 1,4-Additionen von Aldehyden an Nitroolefine beschrieben. Zusätzlich wird die Erweiterung der Reaktion auf spezielle Reaktionsbedingungen sowie schwierige Substratkombinationen dargestellt. Das Tripeptid H-D-Pro-Pro-Glu-NH2 ist ein exzellenter Katalysator für 1,4 Additionsreaktionen zwischen Aldehyden und beta-Nitroolefinen. Mechanistische Untersuchungen, in welchen das Peptid H-D-Pro-Pro-Glu-NH2 mit seinem Methylester Analog H-D-Pro-Pro-Glu(OCH3)-NH2 verglichen wurde, zeigten dass der Reaktionsweg sowie die geschwindigkeitsbestimmenden Schritte von der Gegenwart einer günstig positionierten Carbonsäuregruppe innerhalb der Katalysatorstruktur abhängen. Diese Erkenntnisse haben wichtige Auswirkungen auf die zukünftige Katalysatorenentwicklung und erklären weshalb das Peptid H-D-Pro-Pro-Glu-NH2, welches eine intramolekulare Säuregruppe trägt, ein derart erfolgreicher Katalysator ist. Weitere mechanistische Arbeiten dienten der Aufklärung ob ein Enamin oder ein Enol als aktives Nukleophil in 1,4 Additionsreaktionen zwischen Aldehyden und Nitroolefinen involviert ist. ESI-MS Studien der Rückreaktion mittels quasi-enantiomerer Substrate ergaben dass in Gegenwart von Peptiden des Typs Pro-Pro-Xaa (Xaa = variable säurehaltige Aminosäure) die Selektivität der Reaktion zwischen Enamin und Nitroolefin der Selektivität der präparativen Reaktion entspricht. Dies zeigt dass ein Enamin im Selektivitätsbestimmenden Schritt involviert ist.
Im zweiten Teil dieser Arbeit wurden amphiphile Analoga des Peptids H-D-Pro-Pro-Glu-NH2 als Katalysatoren für 1,4-Additionsreaktionen zwischen Aldehyden und Nitroolefinen in einem wässrigen Reaktionsmedium untersucht. Einführung einer hydrophoben Alkylkette ergab den erfolgreichen Katalysator H-D-Pro-Pro-Glu-NH-C12H25. Dabei dient dieses amphiphile Peptid sowohl als Katalysator für die Reaktion als auch als Detergens, welches eine Emulsion der Substrate im wässrigen Medium stabilisiert.
Letztendlich wurden Peptide der Art Pro-Pro-Xaa als Katalysatoren untersucht für 1,4-Additionen zwischen Aldehyden und alpha,beta-disubstituierten Nitroolefinen, eine bedeutend anspruchsvollere und viel seltener benutzte Substratklasse als beta-mono-substituierte Analoga. Aus einer kleinen Katalysatorensammlung wurden die beiden Peptide H-Pro-Pro-D-Gln-OH sowie H-Pro-Pro-Asn-OH identifiziert, welche effektive Katalysatoren für Additionsreaktionen verschiedener Kombinationen von Aldehyden und alpha,beta-disubstituierten Nitroolefinen darstellen. Die resultierenden gamma-Nitroaldehyde mit drei aufeinanderfolgenden Stereozentren wurden in guten Ausbeuten und hervorragenden Stereoselektivitäten erhalten und konnten zu chiralen Pyrrolidinen sowie gamma-Butyrolaktonen und gamma-Aminosäuren umgesetzt werden.
Die vorliegenden Resultate dieser Arbeit heben nicht nur hervor dass Peptide der Art Pro-Pro-Xaa wertvolle Enaminkatalysatoren darstellen sondern ebnen ebenfalls den Weg für die zukünftige Erforschung von Additionsreaktionen zwischen Carbonylverbindungen und anderen anspruchsvollen Elektrophilen oder die Anwendung von Peptidkatalysatoren unter physiologischen Bedingungen innerhalb einer Zelle
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