Studies in asymmetric and heterocyclic synthesis: I. chiral ketones II. Quinolones III. Trifluoromethylated pyrones

This thesis is split into three sections based on three different areas of research. In the first section, investigations into the α-alkylation of ketones using a novel chiral auxiliary is reported. This chiral auxiliary was synthesised containing a pyrrolidine ring in the chiral arm and was applied in the preparation of α-alkylated ketones which were obtained in up to 92% ee and up to 63% yield over two steps. Both 3-pentanone and propiophenone based ketones were used in the investigation with a variety of both alkyl and benzyl based electrophiles. The novel chiral auxiliary was also successful when applied to Michael and aldol reactions. A diamine precursor en route to the chiral auxiliary was also applied as an organocatalyst in a Michael reaction, with the product obtained in excellent enantioselectivity. In the second section, investigations into potential anti-quorum sensing molecules are reported. The bacteria Pseudomonas aeruginosa is an antibiotic-resistant pathogen that demonstrates cooperative behaviours and communicates using small chemical molecules in a process termed quorum sensing. A variety of C-3 analogues of the quorum sensing molecules used by P. aeruginosa were synthesised. Expanding upon previous research within the group, investigations were carried out into alternative protecting group strategies of 2-heptyl-4-(1H)- quinolone with the aim of improving the yields of products of cross-coupling reactions. In the third section, investigations into fluorination and trifluoromethylation of 2-pyrones, pyridones and quinolones is reported. The incorporation of a fluorine atom or a trifluoromethyl group into a molecule is important in pharmaceutical drug discovery programmes as it can lead to increased lipophilicity and bioavailability, however late-stage incorporation is rarely reported. Both direct fluorination and trifluoromethylation were attempted. Eight trifluoromethylated 2-pyrones, five trifluoromethylated 2-pyridones and a trifluoromethylated 2-quinolone were obtained in a late-stage synthesis from their respective iodinated precursors using methyl fluorosulfonyldifluoroacetate as a trifluoromethylating reagent.

The application of aryne chemistry and use of α-diazo carbonyl derivatives in indazole synthesis with biological evaluation

This thesis outlines the synthetic chemistry involved in the preparation of a range of novel indazole compounds and details the subsequent investigation into their potential as biologically active agents. The synthetic route utilised in this research to form the indazole structure was the [3+2] dipolar cycloaddition of diazo carbonyl compounds with reactive aryne intermediates generated in situ. The preparation of further novel indazole derivatives containing different functional groups and substituents was performed by synthesising alternative 1,3- dipole and dipolarophile analogues and provided additionally diverse compounds. Further derivatisation of the indazole product was made possible by deacylation and alkylation methods. Transformation reactions were performed on alkenecontaining ester side chains to provide novel epoxide, aldehyde and tertiary amine derivatives. The first chapter is a review of the literature beginning with a short overview on the structure, reactivity and common synthetic routes to diazo carbonyl derivatives. More attention is given to the use of diazo compounds as 1,3-dipoles in cycloaddition reactions or where the diazo group is incorporated into the final product. A review of the interesting background, structure and reactivity of aryne intermediates is also presented. In addition, some common syntheses of indazole compounds are presented as well as a brief discussion on the importance of indazole compounds as therapeutic agents. The second chapter discusses the synthetic routes employed towards the synthesis of the range of indazoles. Initially, the syntheses of the diazo carbonyl and aryne precursors are described. Next, the synthetic methods to prepare the indazole compounds are provided followed by discussion on derivatisation of the indazole compounds including N-deacylation, N-benzylation and ester side-chain transformation of some alkene-containing indazoles. A series of novel indazole derivatives were submitted for anti-cancer screening at the U.S National Cancer Institute (NCI). A number of these derivatives were identified as hit compounds, with excellent growth inhibition. The results obtained from biological evaluation from the NCI are provided with further results pending from the Community for Open Antimicrobial Drug Discovery. The third chapter details the full experimental procedures, including spectroscopic and analytical data for all the compounds prepared during this research.

Amélioration des propriétés pharmacocinétiques de peptides par différentes alkylations N-terminales

Modélisations moléculaires réalisés avec le logiciel HyperChem 8.

Synthèse de sulfilimines et de sulfoximines catalysée par les métaux de transition

Les sulfilimines et les sulfoximines sont des motifs structuraux dont l’intérêt synthétique est grandissant, notamment du fait de leurs applications en chimie médicinale et en agrochimie. Les travaux rapportés dans cet ouvrage décrivent le développement de nouvelles méthodes de synthèse efficaces pour la production de ces unités atypiques. Ces méthodes sont basées sur la réactivité d’une source d’azote électrophile, vis-à-vis de thioéthers et de sulfoxydes. L’utilisation d’un complexe métallique introduit en quantité catalytique a permis de favoriser le processus réactionnel. En tirant bénéfice de l’expertise de notre groupe de recherche sur le développement de réactions d’amination stéréosélectives de liaisons C-H et d’aziridination de styrènes, nous avons d’abord étudié la réactivité des N-mésyloxycarbamates comme source d’azote électrophile. Après avoir optimisé sa synthèse sur grande échelle, ce réactif chiral a été utilisé dans des réactions d’amination de thioéthers et de sulfoxydes, catalysées par un dimère de rhodium (II) chiral. Un processus diastéréosélectif efficace a été mis au point, permettant de produire des sulfilimines et des sulfoximines chirales avec d’excellents rendements et sélectivités. Au cours de l’optimisation de cette méthode de synthèse, nous avons pu constater l’effet déterminant de certains additifs sur la réactivité et la sélectivité de la réaction. Une étude mécanistique a été entreprise afin de comprendre leur mode d’action. Il a été observé qu’une base de Lewis telle que le 4-diméthylaminopyridine (DMAP) pouvait se coordiner au dimère de rhodium(II) et modifier ses propriétés structurales et redox. Les résultats que nous avons obtenus suggèrent que l’espèce catalytique active est un dimère de rhodium de valence mixte Rh(II)/Rh(III). Nous avons également découvert que l’incorporation de sels de bispyridinium avait une influence cruciale sur la diastéréosélectivité de la réaction. D’autres expériences sur la nature du groupe partant du réactif N-sulfonyloxycarbamate nous ont permis de postuler qu’une espèce nitrénoïde de rhodium était l’intermédiaire clé du processus d’amination. De plus, l’exploitation des techniques de chimie en débit continu nous a permis de développer une méthode d’amination de thioéthers et de sulfoxydes très performante, en utilisant les azotures comme source d’azote électrophile. Basée sur la décompositon photochimique d’azotures en présence d’un complexe de fer (III) simple et commercialement disponible, nous avons été en mesure de produire des sulfilimines et des sulfoximines avec d’excellents rendements. Le temps de résidence du procédé d’amination a pu être sensiblement réduit par la conception d’un nouveau type de réacteur photochimique capillaire. Ces améliorations techniques ont permis de rendre la synthèse plus productive, ce qui constitue un élément important d’un point de vue industriel.

Amélioration des propriétés pharmacocinétiques de peptides par différentes alkylations N-terminales

Modélisations moléculaires réalisés avec le logiciel HyperChem 8.

Towards the total synthesis of amphidinolides C and F

The amphidinolides are marine macrolides extracted from dinoflagellates of the genus Amphidinium. To date, 37 amphidinolides have been isolated and identified, most of them possessing cytotoxicity against human cancer cell lines. Among these, amphidinolides C, F, C2 and C3 represent synthetic targets of interest owing to their scarcity, structural complexity and promising biological activities. This thesis describes the work realised towards the total synthesis of amphidinolides C and F, with a focus on the different strategies investigated and the key fragments synthesised. In the first approach, the C18−C29 fragment of amphidinolide F was prepared using an intramolecular etherification of an epoxide under acidic catalysis to produce the 2,5-trans-disubstituted tetrahydrofuran ring featured in the natural product. Unfortunately, dithiane alkylation with the C1−C17 iodide counterpart generated the desired coupling product in low yield. A second approach proposing to build the C17−C18 bond by a silicon-tethered RCM proved unsuccessful, because the requisite diene could not be obtained. It was then envisioned to form the C18−C19 bond by displacement of a triflate with an alkyne and install the ketone at C18 by a protoborylation/oxidation sequence. To this end, the C19−C29 triflate precursor was synthesised. Displeasingly, the C1−C18 alkyne counterpart (work by Dr Filippo Romiti) could not be prepared and coupling of the two fragments was not attempted. In the latest approach, the C10−C29 fragment of amphidinolide F was obtained employing a boron-mediated aldol condensation and a dithiane alkylation to form the C13−C14 and C18−C19 bonds. Several endgame strategies were examined including the successful Yamaguchi esterification of the C13-epi C10−C29 fragment and the C1−C9 acid. A challenging Stille crosscoupling was then effected to close the macrocycle but only yielded the desired macrolactone in trace amounts after global desilylation.

Synthèse de sulfilimines et de sulfoximines catalysée par les métaux de transition

Les sulfilimines et les sulfoximines sont des motifs structuraux dont l’intérêt synthétique est grandissant, notamment du fait de leurs applications en chimie médicinale et en agrochimie. Les travaux rapportés dans cet ouvrage décrivent le développement de nouvelles méthodes de synthèse efficaces pour la production de ces unités atypiques. Ces méthodes sont basées sur la réactivité d’une source d’azote électrophile, vis-à-vis de thioéthers et de sulfoxydes. L’utilisation d’un complexe métallique introduit en quantité catalytique a permis de favoriser le processus réactionnel. En tirant bénéfice de l’expertise de notre groupe de recherche sur le développement de réactions d’amination stéréosélectives de liaisons C-H et d’aziridination de styrènes, nous avons d’abord étudié la réactivité des N-mésyloxycarbamates comme source d’azote électrophile. Après avoir optimisé sa synthèse sur grande échelle, ce réactif chiral a été utilisé dans des réactions d’amination de thioéthers et de sulfoxydes, catalysées par un dimère de rhodium (II) chiral. Un processus diastéréosélectif efficace a été mis au point, permettant de produire des sulfilimines et des sulfoximines chirales avec d’excellents rendements et sélectivités. Au cours de l’optimisation de cette méthode de synthèse, nous avons pu constater l’effet déterminant de certains additifs sur la réactivité et la sélectivité de la réaction. Une étude mécanistique a été entreprise afin de comprendre leur mode d’action. Il a été observé qu’une base de Lewis telle que le 4-diméthylaminopyridine (DMAP) pouvait se coordiner au dimère de rhodium(II) et modifier ses propriétés structurales et redox. Les résultats que nous avons obtenus suggèrent que l’espèce catalytique active est un dimère de rhodium de valence mixte Rh(II)/Rh(III). Nous avons également découvert que l’incorporation de sels de bispyridinium avait une influence cruciale sur la diastéréosélectivité de la réaction. D’autres expériences sur la nature du groupe partant du réactif N-sulfonyloxycarbamate nous ont permis de postuler qu’une espèce nitrénoïde de rhodium était l’intermédiaire clé du processus d’amination. De plus, l’exploitation des techniques de chimie en débit continu nous a permis de développer une méthode d’amination de thioéthers et de sulfoxydes très performante, en utilisant les azotures comme source d’azote électrophile. Basée sur la décompositon photochimique d’azotures en présence d’un complexe de fer (III) simple et commercialement disponible, nous avons été en mesure de produire des sulfilimines et des sulfoximines avec d’excellents rendements. Le temps de résidence du procédé d’amination a pu être sensiblement réduit par la conception d’un nouveau type de réacteur photochimique capillaire. Ces améliorations techniques ont permis de rendre la synthèse plus productive, ce qui constitue un élément important d’un point de vue industriel.

Síntese estereosseletiva da naftotectona

Tese (doutorado)—Universidade de Brasília, Instituto de Química, 2016.

Hidrocarbonetos policíclicos aromáticos em sedimentos de fundo do estuário do rio Potengi, região da grande Natal (RN): implicações ambientais

Estuaries are environments prone to the input of chemical pollutants of various kinds and origins, including polycyclic aromatic hydrocarbons (PAHs). Anthropogenic PAHs may have two possible sources: pyrolytic (with four or more aromatic rings and low degree of alkylation) and petrogenic (with two and three aromatic rings and high degree of alkylation). This study aimed to evaluate the levels, distribution and possible sources of polycyclic aromatic hydrocarbons in the estuary of the Potengi river, Natal, Brazil. Samples of bottom sediments were collected in the final 12 km of the estuary until its mouth to the sea, where the urbanization of the Great Natal is more concentrated. Sampling was performed on 12 cross sections, with three stations each, totaling 36 samples, identified as T1 to T36. The non alkylated and alkylated PAHs were analyzed by gas chromatography coupled to mass spectrometry (GC / MS). PAHs were detected in all 36 stations with total concentration on each varying 174-109407 ng g-1. These values are comparable to those of several estuarine regions worldwide with high anthropogenic influence, suggesting the record of diffuse contamination installed in the estuary. PAHs profiles were similar for most stations. In 32 of the 36 stations, low molecular weight PAHs (with 2 and 3 ring: naphthalene, phenanthrene and their alkylated homologues) prevailed, which ranged from 54% to 100% of the total PAH, indicating that leaks, spills and combustion fuels are the dominant source of PAH pollution in the estuary. The level of contamination by PAHs in most stations suggests that there is potential risk of occasional adverse biological effects, but in some stations adverse impacts on the biota may occur frequently. The diagnostic ratios could differentiate sources of PAHs in sediments of the estuary, which were divided into three groups: petrogenic, pyrolytic and mixing of sources. The urban concentration of the Great Natal and the various industrial activities associated with it can be blamed as potential sources of PAHs in bottom sediments of the estuary studied. The data presented highlight the need to control the causes of existing pollution in the estuary

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.

Exploring the scope of asymmetric synthesis of β-Hydroxy-γ-lactams via Noyori-type reductions

Enantio- and diastereoselective hydrogenation of β-keto-γ-lactams with a ruthenium–BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to β-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired β-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while β-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.

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.

Novel catalytic systems and methidologies for organocatalysis and photocatalysis

The thesis is divided into two main parts. In the first one organocatalysis is briefly introduced. Then, new enantiopure trityl pyrrolidines modified with an ionic tag are described. All the catalysts are tested in the benchmark Michael addition reaction to prove their activity and stereoselectivity. In the second part, photocatalysis is first introduced. Then, four different research projects are described. At first, the construction of a hybrid metal-organo-photoredox catalyst is described. The hybrid photocatalysts obtained were employed in the benchmark photoredox alkylation of aldehydes. Then, the use of visible light and a photocatalytic system for the cyclization of iodoaryl vinyl derivatives to tetrahydroquinoline structures is described. In addition, the reaction can also be performed using flow-chemistry. Finally, a mechanistic proposal based on some mechanistic studies is described. Third, a new photoredox catalyzed transformation for the synthesis of 2,3-dihydrofurans is reported. Depending on the involved starting materials, different pathways have arisen. A mechanistic proposal based on reported literatures and experimental data is described. At last, a new photoredox catalyzed transformation for the synthesis of 2-aminofurans is described. Electrophilic radical addition on allenamides and subsequential intramolecular cyclization are exploited. The reaction proceeds under very mild conditions and in 2-aminofurans are obtained in good to high yield. It represents one of the few applications of allenamides in photoredox catalysis. A mechanistic proposal is described. Finally, preliminary investigations on the applicability of the developed transformation under flow chemistry conditions.

Synthesis of manganese organometallic complexes

Il presente lavoro di tesi si inserisce in un progetto di ricerca volto alla sintesi di nuovi complessi di metalli di transizione per lo sviluppo di catalizzatori da impiegare in reazioni di catalisi omogenea. In particolare il mio progetto si è concentrato sulla sintesi di complessi organometallici di manganese con leganti carbenici N-eterociclici (NHC). La scelta dei leganti è stata effettuata in modo tale da poter avere leganti chelanti NHC di tipo MIC (mesoionic carbene) sintetizzati tramite cicloaddizione tra un alchino ed un azide catalizzata da rame (CuAAC) e N-alchilazione. Lo studio di questi complessi a base di manganese è ancora tutt’oggi agli albori, leganti NHC vengono molto utilizzati grazie alla possibilità di variarne le proprietà steriche ed elettroniche e alla possibilità di formare legami forti con quasi tutti i metalli. Il manganese è stato scelto poiché un elemento abbondante, poco tossico e poco costoso. The present thesis work is part of a research project aimed at the synthesis of new transition metal complexes to be used in homogeneous catalysis reactions. In particular my project focused on the synthesis of manganese organometallic complexes with N-heterocyclic carbene ligands (NHC). The choice of ligands was carried out to have NHC chelating ligands of the class of MIC (mesoionic carbene). These ligands are synthesized by cycloaddition between alkyl and azide with a copper-catalyzed reaction (CuAAC) and N-alkylation in order to obtain MIC after deprotonation. The study of these manganese-based complexes is still in its infancy today, NHC ligands are widely used thanks to the possibility of varying their steric and electronic properties and the possibility of forming strong bonds with almost all metals. The choice of manganese was made because is an abundant, low-toxic and inexpensive element.

Photoredox Catalysis and Nucleophilic Organometallic Reagents – Application in Organic Synthesis

The main purpose of my PhD was the combination of the principles of transition metal catalysis with photoredox catalysis. We focused our attention on the development of novel dual catalytic protocols for the functionalization of carbonyl compounds through the generation of transient nucleophilic organometallic species. Specifically, we focused on the development of new methodologies combining photoredox catalysis with titanium and nickel in low oxidation state. Firstly, a Barbier-type allylation of aromatic and aliphatic aldehydes –catalytic in titanium– in the presence of a blue photon-absorbing dye was developed. Parallelly, we were pleased to observe that the developed methodology could also be extended to the propargylation of aldehydes under analogous conditions. After an extensive re–optimization of all the reaction parameters, we developed an enantioselective and diastereoselective pinacol coupling of aromatic aldehydes promoted by non-toxic, cheap and easy to synthetize titanium complexes. The key feature, that allows the complete (dia)stereocontrol played by titanium, is the employment of a red-absorbing organic dye. The tailored (photo)redox properties of the red-absorbing organic dye [nPr–DMQA+][BF4–] promote the selective reduction of Ti(IV) to Ti(III). Moreover, even if the major contribution in dual photoredox and nickel catalysis is devoted to the realization of cross-coupling-type reactions, we wanted to evaluate different possible scenarios. Our focus was on the possibility of exploiting intermediates arising from the oxidative addition of nickel complexes as transient nucleophilic species. The first topic considered regarded the possibility to perform allylation of aldehydes by dual photoredox and nickel catalysis. In the first instance, a non–stereocontrolled version of the reaction was presented. Finally, after a long series of drastic modification of the reaction conditions, a highly enantioselective variant of the protocol was also reported. All the reported methodologies are supported by careful photophysical analysis and, in some cases, computational modelling.