No description available.

Biaryl atropisomers are common structural motifs in natural products but most importantly they are used as chiral ligands in asymmetric catalysis. Despite their utility, current methods to synthesise them are limited and lack generality. Often ligands such as QUINAP have to be synthesised as the racemate and are resolved using stoichiometric palladium which is expensive and time consuming. Biocatalytic synthesis of biaryl atropisomers offers a new alternative greener route to their production. A biocatalytic redox desymmetrisation of symmetrical biaryl diols using a mutant of galactose oxidase (M3-5) is reported. Desymmetrised biaryl atropisomers were produced in good to excellent ee and yield for a range of substrates. After the desymmetrisation a partial kinetic resolution increased the ee further as the minor enantiomer was converted to the dialdehyde. The first example of biocatalytic dynamic kinetic resolution to synthesise atropisomers asymmetrically has been developed. Freely rotating biaryl N-oxide aldehydes underwent reduction using a ketoreductase enzyme to give biaryl N-oxide products in excellent ee (96-99%). These products were found to be novel Lewis base organocatalysts for the asymmetric allylation of benzaldehyde derivatives.

No description available.

This thesis describes the first total synthesis of ancistrotanzanine A, a member of the naphthylisoquinoline class of natural products. In Chapter 1 the synthetic challenges presented by the naphthylisoquinoline alkaloids are discussed and strategies that have been adopted in previous syntheses of naphthylisoquinoline alkaloids overviewed. Chapter 2 describes the preparation of the key 5,3'-biaryl linkage via the Pinhey-Barton reaction. Studies into forming the linkage atropselectively were investigated using chiral hydrobenzoin acetal auxiliaries. This was found to have limited success with an atropisomeric ratio of 65:35 obtained. Changing the base from the achiral pyridine to the chiral brucine was also investigated and found to give no enhancement in the diastereoselectivity. From the results presented in Chapter 2, it was concluded that hydrobenzoin acetal auxiliaries were not appropriate for the diastereoselective synthesis of the key biaryl linkage of ancistrotanzanine A. As the chiral acetal strategy outlined in Chapter 2 failed to yield an atropselective process, efforts were re-focused on a new approach to the naphthylisoquinolines. In Chapter 3, an overview of all the methods available for the synthesis of chiral 3,4-dihydroisoquinolines is provided. From this, it was decided to apply the alkylation of o-tolylnitriles with chiral sulfinimines, as originally developed by Davis, to the synthesis of naphthylisoquinolines. Synthesis of the o-tolylnitrile lead reagent was readily achieved, but it was found that the amount of lead tetraacetate had to be carefully controlled to avoid side-reactions in the Pinhey-Barton reaction. After careful optimisation, the key 5,3'-biaryl linkage was prepared in high yield. Application of the Davis methodology to the MOM protected biaryl failed, with no reaction resulting. After much experimentation, it was established that the reaction was very sensitive to steric hindrance. A successful reaction was finally achieved by changing the base to lithium diethylamide. However, it was found the diastereoselection of the alkylation was quite low when p-tolyl sulfinimine was used. The use of the t-butane sulfinimine meant that the diastereoselection was significantly improved, with a ratio of 85:15 being obtained. After 3 more steps, the total synthesis was completed and ancistrotanzanine A was obtained, as a 1:1 mixture of atropisomers. Efforts to separate the atropisomers formed failed and even the use of chiral HPLC failed to resolve the material. To complete the Chapter, two analogues of ancistrotanzanine A were prepared – the tetrahydroisoquinoline and the methoxy ether. Chapter 4 summarises the above results and discusses the future potential of this research. / Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2010

This thesis describes the development of a synthetic route that encodes a library of compounds containing medium-sized ring systems, with particular emphasis on the use of oxidative fragmentation and rearrangement strategies. Chapter 1 introduces diversity oriented synthesis (DOS) with particular emphasis on medium-sized ring synthesis and fragmentation/rearrangement protocols to achieve diversity. A more detailed discussion of oxidative fragmentation and rearrangement methods is also presented. Chapter 2 describes strategies for the synthesis of a collection of heterocyclic compounds known as diazabenz[e]aceanthrylenes. The scope of the reaction was explored as a function of a range of substituents and of the ring size of the N-aryl lactam that was used. Spectroscopic observations associated with this set of compounds are also discussed. Chapter 3 describes the development of an m-CPBA-mediated oxidative fragmentation of the diazabenz[e]aceanthrylenes. Analysis of the products from these reactions revealed the presence of atropisomerism due to restricted rotation about the N sp²-C(aryl) sp² bond. Chapter 4 focuses on a related example of oxidative fragmentation from the literature. A previously overlooked stereogenic axis is explored in this system using X-ray crystallographic analysis and variable temperature ¹H NMR spectroscopy. Reinterpretation of the reported mechanism-probing experiment led to the isolation of an alternative isomeric product and an improved interpretation for the reaction outcome is presented. Variable temperature ¹H NMR spectroscopic experiments revealed the energy barrier to racemisation in the medium-sized ring-containing analogues and based on this data the mode of ring inversion is discussed. Chapter 5 describes three rearrangements of the medium-sized ring system created in Chapter 3 including the formation of an azepinoindole ring structure, a Favorskii reaction and spiro-oxindole synthesis. A rationalisation for these reaction outcomes is included along with experimental support of mechanistic proposals. The generality and scope of the reactions are demonstrated including a nucleophile screen. Chapter 6 describes the synthesis of a library of 69 compounds consisting of examples of the core structures described in Chapters 2, 3 and 5. A discussion of the selection process and adaption of the protocol to parallel synthesis is presented. This chapter concludes with preliminary screening of the library against a variety of strains of yeasts and bacteria.

Une échelle de taille contenant 20 substituants usuels en chimie a été construite à partir des barrières de rotations de N-aryl-thiazoline-2-thiones. L’énergie d’activation ΔG≠rot qui est mesurée reflète l’encombrement stérique du substituant en ortho du cycle benzénique. Les perturbations électroniques, et les facteurs externes tels que la température ou le solvant sont négligeables. La grande sensibilité du modèle proposé conduit au classement suivant Me > Cl et CN > OMe > OH. Ces classements divergents décrits dans la littérature seront discutés. Une limitation du modèle proposé concerne les substituants très volumineux comme le CF3 et l’iPr qui apparaissent plus petit qu’ils ne le sont en réalité à cause d’un encombrement stérique dans l’état fondamental qui abaissent la valeur de la barrière de rotation. / A steric scale of 20 recurrent groups was established from comparison of rotational barriers on N-(o-substituted-aryl)-thiazoline-2-thione atropisomers. The resulting energy of activation ΔG≠rot reflects the spatial requirement of the ortho substituent borne by the aryl moiety, electronic aspects and external parameters (temperature and solvent) generating negligible contributions. Concerning divergent rankings reported in literature, the great sensitivity of this model allowed to show unambiguously that a methyl appears bigger than a chlorine, and gave the following order in size: CN > OMe > OH. For the very bulky CF3 and iPr groups, constraints in the ground state decreased the expected ΔG≠rot values resulting in a minimization of their apparent sizes.

Cette thèse décrit une méthodologie innovante d’extraction et d’hémisynthèse simultanée, dénommée SECheM (Simultaneous Extraction and Chemical Modification) sur une plante mauritanienne le Cienfuegosia digitata Cav. Cette méthodologie présente plusieurs avantages : (a) elle permet d’éviter les étapes critiques au niveau de la séparation et de la purification du gossypol, un polyphénol instable isolé de la plante ciblée (b) elle permet de stabiliser le gossypol thermiquement en le transformant en base de Schiff beaucoup plus stable. (c) elle présente un avantage en termes de réduction du nombre d’étapes et de temps. La même méthodologie a été utilisée pour accéder à des analogues bases de Schiff énantiomériquement pures du gossypol seulement en 2 étapes. Ces dernières transformées efficacement en complexes métalliques énantiomériquement purs se sont montrés être intéressants d’un point de vue catalytique. / This PhD work describes an innovative methodology for simultaneous extraction and semisynthesis, named SECheM (Simultaneous Extraction and Chemical Modification) on a Mauritanian plant: Cienfuegosia digitata Cav. This methodology offers many advantages: (a) It is a perfect solution to circumvent critical steps in the extraction, separation and purification processes of gossypol that is unstable polyphenol isolated from the targeted plant (b) It allows an in-situ preparation of more stable gossypol Schiff base derivatives (c) It shows an important reduction of step number and also the time needed for the process. The same SECheM methodology was used to access enantiomerically pure Schiff base derivatives of gossypol in only two steps. The latters were efficiently transformed into enantiomerically pure metallic complexes that appear to be very interesting in a catalytic reaction.

There are 209 PCB congeners, 136 of which have been found in technical PCB mixtures and hence may be found in the environment as a result of either intentional or unintentional release. The identification and quantification of the congeners are difficult due to analytical bias from coeluting PCBs and other persistent organic pollutants. Among the 209 possible PCB congeners, 19 tri- and tetra-ortho chlorinated congeners exist in stable atropisomeric conformations. The racemization barrier were determined for twelve of the nineteen atropisomers and was found to be between 176-185 kJ × mol-1 and ca. 250 kJ × mol-1 for tri- and tetra-ortho PCB, respectively. Further, a buttressing effect of 6.4 kJ × mol-1 was observed for congeners with vicinal ortho-meta chlorines. Comprehensive two-dimensional gas chromatography (GC×GC) was used to analyze the atropisomers and other PCBs. A Longitudinally Modulated Cryogenic System (LMCS) was used with liquid CO2 as cryogen. The LMCS was optimized for semi-volatile organic substances, primarily PCBs. The trap temperature was shown to be an important factor for the trapping and desorption efficiency, as was the thermal mass of the column used in the modulator region. A number of column sets were tested and the separation efficiency, congener resolution and analysis time was evaluated. Good separation of non- and mono-ortho PCBs and “bulk” PCBs (in a technical PCB) was obtained within 8 min using a smectic liquid crystal column (LC50) as the first and a nonpolar column as the second dimension column. Using a second column, an efficient nonpolar (DB-XLB) column, which separates many PCB congeners, were combined with a polar (cyanopropyl) or shape selective (LC50) second dimension column. As a maximum, 181 of the 209 congeners and 126 of the 136 Aroclor PCBs were resolved. The seven frequently measured PCBs (PCBs 28, 52, 101, 118, 138, 153 and 180) and all WHO-PCBs were separated from all other Aroclor PCBs. Chiral PCBs are released into the environment as racemic mixtures. However, organisms have been shown to enantiomerically enrich many of the atropisomers, suggesting that enantioselective biotransformations occur. Non-racemic PCB enrichment has also been seen in mammalians including humans, which is of particular concern because of the potential health risk. An analytical procedure were therefore developed and used to determine the levels of atropisomeric PCBs, planar-PCBs (WHO-PCBs) and total PCBs in seals with different health status. GC×GC was used to separate the target PCBs from other PCBs and potential interferences. A chiral column (permethylated â-cyclodextrin) was used in combination with a polar or shape selective column and enantiomeric fractions (EFs) were determined for five atropisomeric PCBs, i.e. CBs 91, 95, 132, 149 and 174. Some atropisomers had EF that deviated largely from racemic. The deviation was larger in liver than blubber, indicating enantioselective metabolism. However, there was no selective passage of the studied atropisomeric PCBs across placenta and no selective blood-brain barrier. Similarly, no correlation between EFs and health status was observed, although there was a correlation between total PCBs and health status.

Ces travaux de thèse ont porté sur le développement d’une méthodologie de conversion de chiralité centrale vers axiale pour la formation de 4-arylpyridines atropoisomères, et de son application en synthèse totale. En premier lieu, une méthodologie de synthèse organocatalysée a été optimisée pour la préparation de 1,4-dihydropyridines énantioenrichies et hautement encombrées. Le défi a été, ici, de réussir à trouver le bon compromis entre sélectivité et réactivité afin de générer suffisamment d’encombrement sur la position C4 de la 1,4-dihydropyridine énantioenrichie, et de pouvoir accéder, après conversion du centre stéréogène (C4) en axe de chiralité, à un atropoisomère 4-arylpyridine stable. Une optimisation des conditions opératoires pour l’oxydation de ces 1,4-dihydropyridines énantioenrichies en 4-arylpyridines correspondantes a ensuite été menée et a permis d’atteindre des conversions de chiralité modérées à totales. Sur la base de cette stratégie, la synthèse énantiosélective de la (+)-streptonigrine, produit naturel présentant un motif 4-arylpyridine, a été envisagée selon deux stratégies principales s’appuyant sur des processus organocatalysés. / This work focused on the development of central-to-axial chirality conversion methodology for the synthesis of 4-arylpyridine atropisomers, and its application in total synthesis. In the first place, synthetic methodology was optimised for the synthesis of enantioenriched and hindered 1,4-dihydropyridines. At this point, the challenge was to find the right compromise between selectivity and reactivity to get enantioenriched dihydropyridines with sufficient bulkiness around the C4 position, for formation of stable 4-arylpyridine atropisomers after conversion of the chiral center (C4) to a chiral axis. A detailed screen was performed to find the optimal oxidation conditions leading to moderate to full chirality conversion. Based on this strategy, the total synthesis of (+)-streptonigrin, a natural product containing a 4-arylpyridine framework, was planned following two main pathways using organocatalytic transformations as key steps.

Ce travail décrit de nouveaux composés thérapeutiques anticancéreux traçables par imagerie optique appelés théranostiques optiques.Après un premier chapitre bibliographique décrivant le contexte de l’imagerie et la thérapie des cancers, un deuxième chapitre présente une première série de théranostiques BODIPY-phosphine-or dont la synthèse a été optimisée (diminution du nombre d’étapes, baisse du temps de réaction, compatibilité avec une augmentation d’échelle). Leur conjugaison à des biomolécules (glucose, peptide) a été réalisée par une méthode simple et efficace par couplage entre l’atome d’or de la sonde et la fonction thiol de la biomolécule (modifiée ou non), conduisant à une liaison or-soufre. Elle permet une biovectorisation pour rendre les composés plus sélectifs des cellules tumorales vis à vis des cellules saines. Les études photophysiques et biologiques réalisées ont démontré tout le potentiel de ces théranostiques dans le cadre d’un suivi de composé in vitro et l’impact que pouvait avoir le vecteur choisi.Le troisième chapitre présente deux autres séries de théranostiques et précurseurs visant deux objectifs distincts pour rendre la sonde plus compatible avec une imagerie optique in vivo. La modification structurale de la plateforme BODIPY par introduction de groupements augmentant la conjugaison permet d’obtenir des BODIPYs absorbant et émettant dans la « fenêtre thérapeutique » (650 900 nm, proche infrarouge). Des études préliminaires in vivo ainsi que des tests en imagerie photoacoustique ont donné des résultats prometteurs. Une deuxième modification structurale par introduction de groupements encombrants sur chaque face du BODIPY vise à empêcher l’agrégation des BODIPYs en milieu biologique (phénomène connu pour affecter leurs propriétés optiques). Cette approche « Picket-Fence » des porphyrines transposée en série BODIPY a permis d’appliquer pour la première fois en série BODIPY le concept d’atropoisomérie et d’atropoisomères interconvertibles. / This work describes new anticancer agents that could be detected by optical imaging, namely optical theranostics.After a first chapter describing the context of cancer imaging and therapy, a second chapter describes a first series of BODIPY-phosphine-gold theranostics, the synthesis of which has been optimized (less steps, shortening the reaction time, scale up). Their conjugation with biomolecules (glucose, peptide) has been achieved by developing a simple and efficient method that leads to the coupling between the gold atom of the probe and the thiol of the biomolecule (modified or not), leading to a gold sulfur bound. Hence, it makes the biovectorization of the probes possible in order to get selectivity against tumor cells compared with healthy cells. Subsequent photophysical and biological studies demonstrated the potential of such theranostics, such as in vitro monitoring, and the impact of a chosen biomolecule (vector).A third chapter presents two additional series of theranostics and precursors with two distinct objectives aimed at making the probe more suitable for in vivo optical imaging. A first structural modification of the BODIPY platform was achieved upon introducing chemical groups allowing an extention of the π conjugation. It leads to BODIPYs that absorb and emit in the « therapeutic window » (650 900 nm, NIR). Preliminary in vivo studies and preliminary photoacoustic imaging studies with such compounds led to promising results. A second structural modification upon introducing bulky groups on each face of the probe was aimed at preventing stacking of BODIPYs platforms in biological media (a phenomenon known to affect their optical properties). Hence, a porphyrin « Picket Fence » approach was successfully transposed to BODIPY together with the concept of atropisomery and atropisomer interconversion.