I. Synthetic Studies Toward the Total Synthesis of Polycyclic Natural Products – Communesin F, Perophoramidine and Ineleganolide. II. Nickel Catalyzed Intramolecular C–O Bond Formation

Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Finally, a previously unknown mild and efficient deprotection protocol for the o-nitrobenzyl group is disclosed – this serendipitous discovery permitted a concise endgame for the formal syntheses of both communesin F and perophoramidine.

In addition, the atroposelective synthesis of PINAP ligands has been accomplished via a palladium-catalyzed C–P coupling process through dynamic kinetic resolution. These catalytic conditions allow access to a wide variety of alkoxy- and benzyloxy-substituted PINAP ligands in high enantiomeric excess.

An efficient and exceptionally mild intramolecular nickel-catalyzed carbon–oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step.

Finally, synthetic studies toward polycyclic ineleganolide are described. The entire fragmented carbon framework has been constructed from this work. Highly (Z)-selective olefination was achieved by the method by the Ando group.

Obtenção de álcool alílico (PROP-2-EN-1-OL) a partir da glicerina derivada do biodiesel de óleo de mamona

In this work, biodiesel was produced from castor oil that was a byproduct glycerin. The molar ratio between oil and alcohol, as well as the use of (KOH) catalyst to provide the chemical reaction is based on literature. The best results were obtained using 1 mol of castor oil (260g) to 3 moles of methyl alcohol (138g), using 1.0% KOH as catalyst at a temperature of 260 ° C and shaken at 120 rpm. The oil used was commercially available, the process involves the reaction of transesterification of a vegetable oil with methyl alcohol. The product of this reaction is an ester, biodiesel being the main product and the glycerin by-product which has undergone treatment for use as raw material for the production of allyl alcohol. The great advantage of the use of glycerin to obtain allyl alcohol is that its use eliminates the large amount of waste of the biodiesel and various forms of insult to the environment. The reactions for the formation of allyl alcohol was conducted from formic acid and glycerin in a ratio 1/1, at a temperature of 260oC in a heater blanket, being sprayed by a spiral condenser for a period of 2 hours and the product obtained contains mostly the allylic alcohol .. The monitoring of reactions was performed by UV-Visible Spectrophotometer: FTIR Fourier transform, the analysis showed that these changes occur spectrometer indicating the formation of the product allylic alcohol (prop-2-en-1-ol) in the presence of water, This alcohol was appointed Alcohol GL. The absorption bands confirms that the reaction was observed in (υ C = C) 1470 -1600 cm -1 and (υ CO), 3610-3670 attributed to C = C groups and OH respectively. The thermal analysis was carried out in a thermogravimetric analyzer SDT Q600, where the mass and temperature are displayed against time, that allows checking the approximate rate of heating. The innovative methodology developed in the laboratory (LABTAM, UFRN), was able to treat the glycerine produced by transesterification of castor oil and used as raw material for production of allyl alcohol, with a yield of 80%, of alcohol, the same is of great importance in the manufacture of polymers, pharmaceuticals, organic compounds, herbicides, pesticides and other chemicals

Complexes cationiques POCOP de nickel : synthèse, caractérisation, réactivité et étude catalytique

Ce mémoire traite de la chimie des complexes pinceurs de nickel (II) cationiques ayant un ligand de type POCOP. Elle se divise en deux parties. La première traite de la synthèse, de la caractérisation et de la réactivité des complexes cationiques pinceurs de Ni(II) de type POCOP (POCOP = 1,3-bis(phosphinitobenzene), où C fait partie d’un cycle benzénique et est lié au métal, et P est un ligand phosphoré aussi lié au métal). Ces complexes ont un ligand acétonitrile coordonné au centre métallique et sont du type [(R-POCOPR’)Ni(NCMe)][OSO2CF3], où R est un substituant du cycle benzénique et R’ est un substituant sur le ligand phosphoré (R’ = iPr: R = H (1), p-Me(2), p-OMe(3), p-CO2Me(4), p-Br(5), m,m-tBu2(6), m-OMe(7), m-CO2Me(8); R’ = t-Bu : R = H (9), p-CO2Me(10)). Les complexes cationiques sont préparés en faisant réagir le dérivé Ni(II) neutre correspondant R-(POCOPR’)Ni-Br avec Ag(OSO2CF3¬) dans l’acétonitrile à température ambiante. L’impact des groupements R et R’ du ligand POCOP sur la structure et sur les propriétées électroniques du complexe a été étudié par spectroscopies RMN, UV-VIS et IR, analyse électrochimique, et diffraction des rayons X. Les valeurs de fréquence du lien C≡N (ν(C≡N)) augmentent avec le caractère électroattracteur du complexe, dans l’ordre 7 < 3 ~ 2 ~ 6 < 1 < 5 ~ 8 < 4 et 9 < 10. Ces résultats sont en accord avec le fait qu’une augmentation du caractère électrophile du centre métallique devrait résulter en une augmentation de la donation σ MeCN→Ni. De plus, les complexes cationiques montrent tous un potentiel d’oxydation Ni(II)/Ni(III) plus élevé que leurs analogues neutres Ni-Br. Ensuite, une étude d’équilibre entre un complexe neutre (R-POCOPR’)NiBr et un complexe cationique [(R-POCOPR’)Ni(NCMe)][OSO2CF3] démontre l’échange facile des ligands MeCN et Br. La deuxième partie de ce mémoire consiste en deux chapitres. Le premier (Chapitre 3) est une étude structurelle permettant une meilleure compréhension du mécanisme d’hydroamination des oléfines activées promue par les complexes présentés au chapitre 1, suivi de tentatives de synthèse de nouveaux composés POCOP cationiques comportant un ligand amine et nitrile, et de déplacement du groupement amine par un groupement nitrile. Le deuxième chapitre (4) décrit la réactivité et la cinétique de la réaction d’hydroamination et d’hydroalkoxylation d’oléfines activées, qui permet ainsi de mieux comprendre l’impact des différentes variables du système (groupements R et R’, température, substrats, solvent, etc.) sur la réactivité catalytique.

Complexes cationiques POCOP de nickel : synthèse, caractérisation, réactivité et étude catalytique

Ce mémoire traite de la chimie des complexes pinceurs de nickel (II) cationiques ayant un ligand de type POCOP. Elle se divise en deux parties. La première traite de la synthèse, de la caractérisation et de la réactivité des complexes cationiques pinceurs de Ni(II) de type POCOP (POCOP = 1,3-bis(phosphinitobenzene), où C fait partie d’un cycle benzénique et est lié au métal, et P est un ligand phosphoré aussi lié au métal). Ces complexes ont un ligand acétonitrile coordonné au centre métallique et sont du type [(R-POCOPR’)Ni(NCMe)][OSO2CF3], où R est un substituant du cycle benzénique et R’ est un substituant sur le ligand phosphoré (R’ = iPr: R = H (1), p-Me(2), p-OMe(3), p-CO2Me(4), p-Br(5), m,m-tBu2(6), m-OMe(7), m-CO2Me(8); R’ = t-Bu : R = H (9), p-CO2Me(10)). Les complexes cationiques sont préparés en faisant réagir le dérivé Ni(II) neutre correspondant R-(POCOPR’)Ni-Br avec Ag(OSO2CF3¬) dans l’acétonitrile à température ambiante. L’impact des groupements R et R’ du ligand POCOP sur la structure et sur les propriétées électroniques du complexe a été étudié par spectroscopies RMN, UV-VIS et IR, analyse électrochimique, et diffraction des rayons X. Les valeurs de fréquence du lien C≡N (ν(C≡N)) augmentent avec le caractère électroattracteur du complexe, dans l’ordre 7 < 3 ~ 2 ~ 6 < 1 < 5 ~ 8 < 4 et 9 < 10. Ces résultats sont en accord avec le fait qu’une augmentation du caractère électrophile du centre métallique devrait résulter en une augmentation de la donation σ MeCN→Ni. De plus, les complexes cationiques montrent tous un potentiel d’oxydation Ni(II)/Ni(III) plus élevé que leurs analogues neutres Ni-Br. Ensuite, une étude d’équilibre entre un complexe neutre (R-POCOPR’)NiBr et un complexe cationique [(R-POCOPR’)Ni(NCMe)][OSO2CF3] démontre l’échange facile des ligands MeCN et Br. La deuxième partie de ce mémoire consiste en deux chapitres. Le premier (Chapitre 3) est une étude structurelle permettant une meilleure compréhension du mécanisme d’hydroamination des oléfines activées promue par les complexes présentés au chapitre 1, suivi de tentatives de synthèse de nouveaux composés POCOP cationiques comportant un ligand amine et nitrile, et de déplacement du groupement amine par un groupement nitrile. Le deuxième chapitre (4) décrit la réactivité et la cinétique de la réaction d’hydroamination et d’hydroalkoxylation d’oléfines activées, qui permet ainsi de mieux comprendre l’impact des différentes variables du système (groupements R et R’, température, substrats, solvent, etc.) sur la réactivité catalytique.

PROLINE-BASED CHIRAL STATIONARY PHASES: INSIGHTS INTO THE MECHANISM OF CHIRAL SELECTIVITY

Proline (Pro) is a unique amino acid that has been examined previously as a potential chiral selector for high-performance liquid chromatography. In recent years, a new class of promising Pro based enantioselective stationary phases has been studied and the longer peptides were found to be competitive with commercial chiral stationary phases (CSPs). Here, we aim to perform a comprehensive examination of a t-butoxycarbonyl- (t-Boc-) terminated monoproline selector. This selector was grafted through an amide linkage to an aminopropyl siloxane-terminated Si (111) wafer and to a silicon atomic force microscopy tip. To ensure a flat, homogeneous overlayer of selectors suitable for force spectrometric measurements, the prepared surfaces were characterized using XPS, AFM and contact angle measurements. Chemical force spectrometry (CFS) has been used to examine the chiral discrimination in our monoproline CSP by measuring the interaction forces between two D- or L-monoproline monolayers in water and in the presence of a series of amino acids in solution to explore the degree to which binding of amino acids impacts self-selectivity. Chemical force titration (CFT) has been used to observe the influence of variations in pH on the binding interaction of proline modified chiral surfaces. Here we aim to explore the connection between side-chain hydrophobicity and differences in the nature of the binding between different ionic forms of amino acids and the t-Boc-Pro interface, and thereby to gain insight into the mechanism of chiral selectivity. The CFS results show several trends for different proline selector/amino acid combinations and indicate that the binding characteristics of amino acid to the proline surface is strongly dependent on the amino acid side chain where hydrophilic side chain amino acids exhibit a selectivity opposite to that seen for those with hydrophobic side chains. The CFT studies also provide valuable insights into interactions between the proline selector and the amino acids under a wide range of pH conditions, indicating that protonated amine groups of alanine and serine are closely involved in the binding mechanism to proline surfaces. On the other hand, the presence of the second carboxylic group in aspartic acid plays an important role while interacting with proline.

Synthetic studies towards the total synthesis of hexacyclinic acid

In the first chapter of this thesis, published works found in the literature about hexacyclinic acid and FR182877 are reported and commented. A quick summary of the previous work done in the Prunet group is also described. In the second and third chapter, a more detailed account of the work undertaken during this PhD was given. Firstly, syntheses of two ABC tricycles incorporating tert-butyl and (trimethylsilyl)ethyl esters were undertaken. These syntheses include two key steps previously developed in the group, a diastereoselective Michael addition and a Snider cyclisation. Multiple conditions for the hydrolysis of the esters were attempted but none of them gave the desired product. The main part of this work is focused on the synthesis of a CDEF model and in particular about the development of the key step, the formation of a nine-membered ring. Several DEF fragments were synthesised in short synthetic sequences and as single isomers. Six different synthetic pathways were developed in total and a novel method, a Michael/elimination reaction, was found to be a very efficient way to close the desired medium-size ring. From the nine-membered ring, regioselective reduction and palladiumcatalysed allylic substitution led to the formation of the CDF tricycle. Final steps of the synthesis were fruitless and led only to decomposition. A synthesis of a chiral C-ring was also developed during this PhD. II Finally, another project was undertaken, not related to hexacyclinic acid. Methodology developed in the group for the diastereoselective formation of trisubstituted alkenes employing a temporary silicon-tethered ring-closing metathesis was extended to homoallylic alcohols. The first steps of the method were similar to the previous methodology but the end-game had to be modified in favour of an oxidation/reduction sequence to successfully obtain the desired products with the correct geometry. In the fourth chapter, procedures and analytical data for the synthesised compounds previously described are reported.

Estudio molecular en dos hermanas afectadas por ictiosis congénita autosómica recesiva : descripción de una nueva mutación causal en TGM1

Se describe la variante homocigota c.320-2A>G de TGM1 en dos hermanas con ictiosis congénita autosómica recesiva. El clonaje de los transcritos generados por esta variante permitió identificar tres mecanismos moleculares de splicing alternativos.

Adenine as an organocatalyst for the ring-opening polymerization of lactide: scope, mechanism and access to adenine-functionalized polylactide

Nucleobase-functionalized polymers are widely used in the fields of supramolecular chemistry and self-assembly, and their development for biomedical applications is also an area of interest. They are usually synthesized by tedious multistep procedures. In this study, we assess adenine as an organoinitiator/ organocatalyst for the ring-opening polymerization of lactide. L-Lactide can be quantitatively polymerized in the presence of adenine. Reaction conditions involving short reaction times and relatively low temperatures enable the access to adenine end-capped polylactide in a simple one-step procedure, in bulk, without additional catalyst. DFT calculations show that the polymerization occurs via hydrogen bond catalysis. The mechanism involves (i) a hydrogen bond between the NH9 of adenine and the carbonyl moiety of lactide, leading to an electron deficient carbon atom, and (ii) a second hydrogen bond between the N3 of adenine and the NH2 of a second adenine molecule, followed by a nucleophilic attack of the latter activated amine on the former electron deficient carbon on the monomer. For longer reaction times and higher temperatures, macrocyclic species are formed, and a mechanism involving the imidazole ring of adenine is proposed based on literature studies. Depending on the reaction conditions, adenine can thus be considered as an organoinitiator or an organocatalyst for the ring-opening polymerization of lactide.

Adenine as an organocatalyst for the ring-opening polymerization of lactide: scope, mechanism and access to adenine-functionalized polylactide

Nucleobase-functionalized polymers are widely used in the fields of supramolecular chemistry and self-assembly, and their development for biomedical applications is also an area of interest. They are usually synthesized by tedious multistep procedures. In this study, we assess adenine as an organoinitiator/organocatalyst for the ring-opening polymerization of lactide. L-Lactide can be quantitatively polymerized in the presence of adenine. Reaction conditions involving short reaction times and relatively low temperatures enable the access to adenine end-capped polylactide in a simple one-step procedure, in bulk, without additional catalyst. DFT calculations show that the polymerization occurs via hydrogen bond catalysis. The mechanism involves (i) a hydrogen bond between the NH9 of adenine and the carbonyl moiety of lactide, leading to an electron deficient carbon atom, and (ii) a second hydrogen bond between the N3 of adenine and the NH2 of a second adenine molecule, followed by a nucleophilic attack of the latter activated amine on the former electron deficient carbon on the monomer. For longer reaction times and higher temperatures, macrocyclic species are formed, and a mechanism involving the imidazole ring of adenine is proposed based on literature studies. Depending on the reaction conditions, adenine can thus be considered as an organoinitiator or an organocatalyst for the ring-opening polymerization of lactide.

DFT STUDIES ON THE MECHANISM OF RING-OPENING POLYMERIZATION OF LACTIDE WITH ADENINE

The use of organic molecules as catalysts for the ring-opening polymerization (ROP) of cyclic esters has gained much interest last years.[1] The use of a molecule of biological interest, able to initiate ROP of cyclic esters without any cocatalyst is even more interesting, as the resulting material will not contain any catalytic residue. Nucleobase-polymer conjugates development is thus an emerging area envisaging biomedical applications.[2] However, they are usually synthesized by tedious multistep procedures. Recently, adenine was used as organoinitiator for the ROP of L-lactide.[3] Reaction conditions involving short reaction times and relatively low temperatures enable the access to adenine-polylactide(Adn-PLA)conjugates in a simple one-step procedure, without additional catalyst and in the absence of solvent. In this study, computational investigations with density functional theory (DFT) were performed in order to clarify the reaction mechanism leading to the desired Adn-PLA. The results show that a hydrogen bond catalytic mechanism, involving a nucleophilic attack of the activated amine group of adenine onto the carbonyl group of lactide, seem to be plausible.

Synthesis, Characterization and Conformational Studies of Modified Carbazole-bis-aryl-boranes

During this project we have synthetized different compounds belonging to the class of amino-boranes for the study of bis-aryl-B=N system. We have decided to keep unchanged the aryl components and change only the amine to observe the effect of that on the B=N bond. The used amines are modified carbazoles with functional groups chosen to amplify or disempower the steric and the conjugation effect. We have found that the evaluation of steric barrier was possible studying the gearing aryls rotation around the C-B bonds, while the conjugation barrier is instead given by the energy needed to break the formal double bond B=N and allow the amine rotation. The work started with a proposed synthesis, improved for every reaction, then the products are characterized by NMR, fluorometric spectroscopy, mass spectrometry and X-Ray diffraction on single crystal. The following study on rotational energy barrier was possible theoretically through DFT calculation and experimentally with techniques like Dynamic NMR and EXSY. The fluorometric analysis was done for the study of the solvatochromic propriety of the products.

Cadmium Telluride Magic-Sized Clusters and Superstructures

The aim of the present work is to gain new insights into the formation mechanism of CdTe magic-sized clusters (MSCs) at low temperatures, as well as on their evolution towards 1D and 2D nanostructures and assemblies thereof, under mild reaction conditions. The reaction system included toluene as solvent, octylamine as primary alkylamine, trioctylphosphine-Te as chalcogenide precursor and Cd(oleate)2 as metal precursor. UV-Vis absorption spectroscopy and transmission electron microscopy (TEM) were used to analyze samples containing concentrations of octylamine of 0.2, 0.8 and 2 M: well-defined, sharp absorption peaks were observed, with peaks maxima at 449, 417 and 373 nm respectively, and 1D structures with a string-like appearance were displayed in the TEM images. Investigating peaks growth, step-wise peaks shift to lower energies and reverse, step-wise peak shift to higher energies allowed to propose a model to describe the system, based on interconnected [CdTe]x cluster units originating an amine-capped, 1-dimensional, polymer-like structure, in which different degrees of electronic coupling between the clusters are held responsible for the different absorption transitions. The many parameters involved in the synthesis procedure were then investigated, starting from the Cd:Te ratio, the role of the amine, the use of different phosphine-Te and Cd precursors. The results allowed to gain important information of the reaction mechanism, as well as on the different behavior of the species featuring the sharp absorption peaks in each case. Using Cd(acetate)2 as metal precursor, 2D structures were found to evolve from the MSCs solutions over time, and their tendency to self-assemble was then analyzed employing two amines of different alkyl chain length, octylamine (C-8) and oleylamine (C-18). Their co-presence led to the formation of free-floating triangular nanosheets, which tend to readily aggregate if only octylamine is present in solution.

Computational study on the asymmetric aminocatalysed Michael addition reaction of cyclohexanone to trans–β–nitrostyrene

Asymmetric organocatalysed reactions are one of the most fascinating synthetic strategies which one can adopt in order to induct a desired chirality into a reaction product. From all the possible practical applications of small organic molecules in catalytic reaction, amine–based catalysis has attracted a lot of attention during the past two decades. The high interest in asymmetric aminocatalytic pathways is to account to the huge variety of carbonyl compounds that can be functionalized by many different reactions of their corresponding chiral–enamine or –iminium ion as activated nucleophile and electrophile, respectively. Starting from the employment of L–Proline, many useful substrates have been proposed in order to further enhance the catalytic performances of these reaction in terms of enantiomeric excess values, yield, conversion of the substrate and turnover number. In particular, in the last decade the use of chiral and quasi–enantiomeric primary amine species has got a lot of attention in the field. Contemporaneously, many studies have been carried out in order to highlight the mechanism through which these kinds of substrates induct chirality into the desired products. In this scenario, computational chemistry has played a crucial role due to the possibility of simulating and studying any kind of reaction and the transition state structures involved. In the present work the transition state geometries of primary amine–catalysed Michael addition reaction of cyclohexanone to trans–β–nitrostyrene with different organic acid cocatalysts has been studied through different computational techniques such as density functional theory based quantum mechanics calculation and force–field directed molecular simulations.

Electrochemiluminescence: insights into the mechanisms and nanomaterial-based applications

Biomarkers are biological indicators of human health conditions. Their ultra-sensitive quantification is of paramount importance in clinical monitoring and early disease diagnosis. Biosensors are simple and easy-to-use analytical devices and, in their world, electrochemiluminescence (ECL) is one of the most promising analytical techniques that needs an ever-increasing sensitivity for improving its clinical effectiveness. Scope of this project was the investigation of the ECL generation mechanisms for enhancing the ECL intensity also through the identification of suitable nanostructures. The combination of nanotechnologies, microscopy and ECL has proved to be a very successful strategy to improve the analytical efficiency of ECL in one of its most promising bioanalytical approaches, the bead-based immunoassay. Nanosystems, such as [Ru(bpy)3]2+-dye-doped nanoparticles (DDSNPs) and Bodipy Carbon Nanodots, have been used to improve the sensitivity of ECL techniques thanks to their advantageous and tuneable properties, reaching a signal increase of 750% in DDSNPs-bead-based immunoassay system. In this thesis, an investigation of size and distance effects on the ECL mechanisms was carried out through the innovative combination of ECL microscopy and electrochemical mapping of radicals. It allowed the discovery of an unexpected and highly efficient mechanistic path for ECL generation at small distances from the electrode surface. It was exploited and enhanced through the addition of a branched amine DPIBA to the usual coreactant TPrA solution for enhancing the ECL efficiency until a maximum of 128%. Finally, a beads-based immunoassay and an immunosensor specific for cardiac Troponin I were built exploiting previous results and carbon nanotubes features. They created a conductive layer around beads enhancing the signal by 70% and activating an ECL mechanism unobserved before in such systems. In conclusion, the combination of ECL microscopy and nanotechnology and the deep understanding of the mechanisms responsible for the ECL emission led to a great enhancement in the signal.

Chemical looping reforming from methane to syngas: investigation on CeO2 oxygen carrier lifetime and optimal process times

Emissions of CO2 are constantly growing since the beginning of industrial era. Interruption of the production of major emitters sectors (energy and agriculture) is not a viable way and reducing all the emission through carbon capture and storage (CCS) is not economically viable and little publicly accepted, therefore, it becomes fundamentals to take actions like retrofitting already developed infrastructure employing cleanest resources, modify the actual processes limiting the emissions, and reduce the emissions already present through direct air capture. The present thesis will deeply discuss the aspects mentioned in regard to syngas and hydrogen production since they have a central role in the market of energy and chemicals. Among the strategies discussed, greater emphasis is given to the application of looping technologies and to direct air capture processes, as they have been the main point of this work. Particularly, chemical looping methane reforming to syngas was studied with Aspen Plus thermodynamic simulations, thermogravimetric analysis characterization (TGA) and testing in a fixed bed reactor. The process was studied cyclically exploiting the redox properties of a Ce-based oxide oxygen carrier synthetized with a simple forming procedure. The two steps of the looping cycles were studied isothermally at 900 °C and 950° C with a mixture of 10 %CH4 in N2 and of 3% O2 in N2, for carrier reduction and oxidation, respectively. During the stay abroad, in collaboration with the EHT of Zurich, a CO2 capture process in presence of amine solid sorbents was investigated, studying the difference in the performance achievable with the use of contactors of different geometry. The process was studied at two concentrations (382 ppm CO2 in N2 and 5.62% CO2 in N2) and at different flow rates, to understand the dynamics of the adsorption process and to define the mass transfer limiting step.