The synthesis of monodentate biphenyl-amido proligands is reported as well as a series of complexes of lithium with these ligand systems. The solid-state molecular structure of these lithium amides are described as well as their use as synthons in the preparation of amido-arene aluminum complexes. Structural and spectroscopic data suggest that these species exhibit weak arene to metal donation. Attempts to generate aluminum cations from these species are detailed. A new synthetic route to titanium “constrained geometry” precatalysts was utilized to prepare a series of titanium complexes with similar pendant arene groups. The homopolymerization activity of these catalyst systems with ethylene and styrene is detailed. Combination of a sterically encumbered phosphine and large, electrophilic borane was used to effect heterolytic cleavage of disulfides to afford novel thiophosphoniumthioborate salts. A series of exchange reactions demonstrated the facile reversal of this reaction. Similar phosphine-borane systems are found to exhibit divergent reactivity with terminal alkynes, affording either phosphonium-alkynylborate salts from deprotonation or phosphonium-vinyl-borate zwitterions from addition. The scope of Lewis acid, Lewis base and alkyne combinations used to effect similar reactivity is detailed. It was found that the reaction of pyrroles, boranes, and alkynes formed similar addition products that were found to undergo further reactivity to afford C-vinyl pyrroles and nitrogen-boron bicyclic compounds. The synthesis of N-alkyl-bis(pentafluorophenyl)boryl amidinates is presented. The reactivity of these compounds with a variety of small molecules is reported. Reaction with CO2, CO, di-iso-propylcarbodiimide, tert-butyl isocyanide, and benzaldehyde as well as thermally-induced intramolecular rearrangement of these compounds affords a variety of novel nitrogen-boron heterocycles.

The synthesis of monodentate biphenyl-amido proligands is reported as well as a series of complexes of lithium with these ligand systems. The solid-state molecular structure of these lithium amides are described as well as their use as synthons in the preparation of amido-arene aluminum complexes. Structural and spectroscopic data suggest that these species exhibit weak arene to metal donation. Attempts to generate aluminum cations from these species are detailed. A new synthetic route to titanium “constrained geometry” precatalysts was utilized to prepare a series of titanium complexes with similar pendant arene groups. The homopolymerization activity of these catalyst systems with ethylene and styrene is detailed. Combination of a sterically encumbered phosphine and large, electrophilic borane was used to effect heterolytic cleavage of disulfides to afford novel thiophosphoniumthioborate salts. A series of exchange reactions demonstrated the facile reversal of this reaction. Similar phosphine-borane systems are found to exhibit divergent reactivity with terminal alkynes, affording either phosphonium-alkynylborate salts from deprotonation or phosphonium-vinyl-borate zwitterions from addition. The scope of Lewis acid, Lewis base and alkyne combinations used to effect similar reactivity is detailed. It was found that the reaction of pyrroles, boranes, and alkynes formed similar addition products that were found to undergo further reactivity to afford C-vinyl pyrroles and nitrogen-boron bicyclic compounds. The synthesis of N-alkyl-bis(pentafluorophenyl)boryl amidinates is presented. The reactivity of these compounds with a variety of small molecules is reported. Reaction with CO2, CO, di-iso-propylcarbodiimide, tert-butyl isocyanide, and benzaldehyde as well as thermally-induced intramolecular rearrangement of these compounds affords a variety of novel nitrogen-boron heterocycles.

Unspecific peroxygenase (EC 1.11.2.1) represents a group of secreted hemethiolate proteins that are capable of catalyzing the selective mono-oxygenation of diverse organic compounds using only H2O2 as a cosubstrate. In this study, the peroxygenase from Agrocybe aegerita (AaeUPO) was found to catalyze the hydroxylation of various linear (e.g n-hexane), branched (e.g. 2,3-dimethylbutane) and cyclic alkanes (e.g. cyclohexane). The size of n-alkane substrates converted by AaeUPO ranged from gaseous propane (C3) to n-hexadecane (C16). They were mono-hydroxylated mainly at the C2 and C3 position, rather than at the terminal carbon, and the corresponding ketones were formed as a result of overoxidation. In addition, a number of alkenes were epoxidized by AaeUPO, including linear terminal (e.g. 1-heptene), branched (2-methyl-2-butene) and cyclic alkenes (e.g. cyclopentene), as well as linear and cyclic dienes (buta-1,3-diene, cyclohexa-1,4-diene). Furthermore, the conversion of terminal alkynes (e.g. 1- octyne) gave the corresponding 1-alkyn-3-ol in low yield. Some of the reactions proceeded with complete regioselectivity and - in the case of linear alkanes, terminal linear alkenes and alkynes - with moderate to high stereoselectivity. The conversion of n-octane gave (R)-3-octanol with 99% enantiomeric excess (ee) and the preponderance of the (S)-enantiomer reached up to 72% ee of the epoxide product for the conversion of 1-heptene. Catalytic efficiencies (kcat/ Km) determined for the hydroxylation and respectively epoxidation of the model compounds cyclohexane and 2-methyl-2-butene were 2.0 × 103 M-1 s-1 and 2.5 × 105 M−1 s−1. The results obtained in the deuterium isotope effect experiment with semideuterated n-hexane and the radical clock experiment with norcarane clearly demonstrated that the hydroxylation of alkanes proceeds via hydrogen abstraction, the formation of a substrate radical and a subsequent oxygen rebound mechanism. Moreover, stopped-flow experiments and substrate kinetics proved the involvement of a porphyrin radical cation species (compound I; AaeUPO-I) as reactive intermediate in the catalytic cycle of AaeUPO, similar to other hemethiolate enzymes (e.g. cytochrome P450 monooxygenases, P450s). / Die Gruppe der Unspezifischen Peroxygenasen (EC 1.11.2.1) umfasst extrazelluläre Häm-Thiolat-Enzyme, die mittels H2O2 als Cosubstrat die selektive Monooxygenierung unterschiedlicher organischer Verbindungen katalysieren. In der vorliegenden Arbeit konnte gezeigt werden, dass die von Agrocybe aegerita sekretierte Peroxygenase (AaeUPO) verschiedene lineare (z. B. n-Hexan), verzweigte (z. B. 2,3-Dimethylbutan) und zyklische Alkane (z. B. Cyclohexan) hydroxyliert. Die Größe der von der AaeUPO umgesetzten Substrate reichte vom gasförmigen Propan (C3) bis hin zu n-Hexadekan (C16). Die Alkane wurden bevorzugt am zweiten und dritten Kohlenstoffatom (C2 und C3) hydroxyliert; eine Hydroxylierung am terminalen Kohlenstoff konnte nur vereinzelt und in geringem Umfang beobachtet werden. Die Überoxidationen der primär gebildeten, sekundären Alkohole führte außerdem zur Entstehung der entsprechenden Ketonderivate. Darüber hinaus wurde eine Vielzahl linearer terminaler (z. B. 1-Hepten), verzweigter (z. B. 2-Methyl-2-Buten) und zyklischer Alkene (z. B. Cyclopenten) sowie linearer und zyklischer Diene (1,3-Butadien, 1,4-Cyclohexadien) durch die AaeUPO epoxidiert. Die Umsetzung terminaler Alkine (z. B. 1-Octin) führte zur Entstehung der jeweiligen 1-Alkin-3-ole. Manche dieser Reaktionen verliefen ausgeprägt regioselektiv und, im Falle der linearen Alkane sowie der linearen terminalen Alkene und Alkine, mit mittlerer bis hoher Stereoselektivität. So ergab beispielsweise die Umsetzung von n-Octan einen Enantiomerenüberschuss größer 99% für (R)-3-Octanol; die Epoxidierung von 1-Hepten lieferte einen Enatiomeerenüberschuss (ee) von bis zu 72% für das (S)-Enantiomer. Die katalytischen Effizienzen, die für die Hydroxylierung bzw. Epoxidierung der Modellverbindungen Cyclohexan und 2-Methyl-2-Buten ermittelt wurden, betragen 2.0 × 103 M-1 s-1 und 2.5 × 105 M−1 s−1. Der ausgeprägte Deuterium-Isotopen-Effekt, der im Zuge der Umsetzung von semideuteriertem n-Hexan beobachtet wurde sowie die Ergebnisse des Radical-Clock-Experiments mit Norcarane als Substrat bestätigten, dass die Hydroxylierung von Alkanen über Wasserstoffabstraktion, die Bildung eines Substratradikals und anschließende direkte Sauerstoffrückbindung verläuft. Die Stopped-Flow-Experimente belegen zudem das Auftreten eines Porphyrin-Kationradikal-Intermediates (Compound I; AaeUPO-I) im katalytischen Zyklus der AaeUPO (vergleichbar mit dem reaktiven Intermediat der P450-Monooxygenasen).

The syntheses of novel poly(paraphenyleneethynylene)s, PPEs, and poly(aryleneeethynylene)s, PAEs, as well as hybrid poly(paraphenyleneethynylene)- poly(paraphenylenevinylene)s, PPE-PPVs, are presented. Fluorescent PPEs decorated with biologically relevant ligands are utilized in model biosensing schemes. PPE-PPV hybrids, as well as their highly emissive oligomeric, cruciform model compounds are studied in an effort to modify the bandgap of the parent PPE backbone. Improved hole and electron injection capabilities are demonstrated with these hybrid conjugated materials. Structural variation and morphological effects of PPEs, PPE-PPVs and model compounds are studied to elucidate the effects upon the photophysical properties of the emissive materials.

Thesis (Ph. D.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Ce mémoire présente une nouvelle méthode pour la synthèse de 1,3-énynes par dimérisation d’alcynes terminaux. La méthode de synthèse utilisée est la métallaphotorédox, une technologie qui s’est largement développée au cours des dernières années. Celle-ci nécessite l’utilisation de la lumière visible comme source d’énergie, un photocatalyseur qui peut absorber la lumière ainsi qu’un catalyseur métallique qui peut interagir avec le photocatalyseur. La dimérisation d’alcyne peut être achevée en soumettant un alcyne terminal face à de la lumière bleue en présence du photocatalyseur 4CzIPN, du catalyseur Co(BF4)2·6H2O, du ligand DPPP et de la base DIPEA qui fait office d’anode sacrificielle, dans l’acétonitrile. Les réactions d’homo-dimérisation (un alcyne avec un autre alcyne identique) fournissent des rendements de 48 à 90 % avec un rapport E:Z de >99:1 pour l’ényne formé. Des réactions d’hétéro-dimérisation (un alcyne avec un alcyne différent) peuvent également être effectuées entre un alcyne aliphatique ou aromatique et un alcyne de silyle (TMS ou TIPS) et les rendements varient de 47 à 99 % avec un rapport E:Z de >99:1 pour l’ényne formé. Cette méthodologie a ensuite été appliquée pour des réactions de macrocyclisation. Trois macrocycles à 17, 18 et 19 chaînons ont pu être synthétisés de cette manière avec des rendements respectifs de 25, 91 et 37 %. / This thesis presents a new methodology for the synthesis of 1,3-enynes by dimerization of terminal alkynes. The synthetic method used is based on metallaphotoredox, a technology that was largely developed during the last few years. The latter uses visible light as an energy source, a photocatalyst that can absorb the light and a metal-based catalyst that interacts with the photocatalyst. The dimerization of alkyne can be achieved by submitting a terminal alkyne under blue light irradiation in the presence of the photocatalyst 4CzIPN, the catalyst Co(BF4)2·6H2O, the ligand DPPP and the base DIPEA which is used as a sacrificial anode, in acetonitrile. The reactions of homo-dimerization (one alkyne with an identical alkyne) provides yields ranging from 48 to 90 % and a E:Z ratio of >99:1 for the resulting enyne. Reactions of hetero-dimerization (one alkyne with a different alkyne) can also be achieve with an aliphatic or aromatic alkyne and a silyl alkyne (TMS or TIPS) with yields ranging from 47 to 99 % and a E:Z ratio of >99:1 for the resulting enyne. This methodology was then applied for macrocyclization reactions. Macrocycles with 17-, 18- and 19- members ring were synthesized that way, with yield of 25, 91 and 37 % respectively.

A central quest in biology is to understand the structure-function relationship of complex biological systems. The brain represents the ultimate complexity of a biological system: (1) the vertebrate brain contains 107-1011 neurons interconnected with glial cells; (2) over tens of diverse cell types are organized in a hierarchical way over an intricate landscape; (3) coordinated electrical and chemical activities of neuronal ensembles generate emergent properties and functions; and (4) each neuron can extend over large volumes with its spatial scales spanning 6 orders of magnitude. As a result, compared to other organ systems, our understanding of the brain remains primitive and obscure in terms of both its structures and its functions. Accordingly, many grand challenges endure in brain sciences, including comprehensively mapping neuronal wiring of the brain, an exhaustive taxonomy of cell types in the brain, and robust diagnostic and therapeutic strategies for brain diseases. These challenges are difficult to tackle with existing microscopy methods, because general trade-offs prevail between number of colors, imaging depth, spatial resolution, imaging throughput, sensitivity, and specificity. Therefore, the quest to understand the brain calls for advances and innovations on novel microscopy methods.The evolution of modern Raman microscopy is fundamentally driven by the development of novel spectroscopy methods. The advancement of molecular spectroscopy in turn pushes forward and benefits from, the progress in vibrational probes, labeling chemistry, and sample processing and transformation. In particular, stimulated Raman scattering (SRS) microscopy offers high sensitivity and fast acquisition for biomedical imaging, by harnessing accelerated vibrational transition from stimulated emission. Bio-orthogonal chemical imaging provides chemical specificity and minimal perturbation for visualizing metabolic dynamics of small molecules, by using tiny vibrational probes such as deuterium and alkyne. Electronic pre-resonance SRS (epr-SRS) microscopy further enhances the sensitivity to the nanomolar level for imaging specific proteins, by exploiting electronic pre-resonance of specially designed Raman dyes. Despite these notable innovations, the imaging depth of these Raman microscopy methods is limited to superficial layers of biological tissues (~100 μm) due to light scattering. This dissertation contributes to the development of advanced Raman microscopy methods for volumetric imaging with extended imaging depth in scattering tissues. For this purpose, we develop a set of tissue clearing strategies tailored to specific Raman imaging modalities. In addition, we develop image analysis methods to extract systems information from volumetric high-dimensional imaging datasets. Equipped with our volumetric imaging and analysis methods, we elucidate intricate structures and functions of the brain at both physiological and pathological conditions, providing implications for brain tumor metabolism and cerebellum development. Chapter 1 introduces an overview of Raman microscopy with particular emphasis on SRS and epr-SRS microscopies. Chapter 2 discusses the principles of tissue clearing with special focus on the basis of light scattering, the working mechanisms of different categories of tissue clearing methods, and the rationale underlying the development and evolution of these tissue clearing methods. Chapter 3 describes the development of volumetric chemical imaging, which brings label-free SRS microscopy, bio-orthogonal chemical imaging, and metabolic imaging to the realm of volumetric imaging with greater than 10-fold depth extension. Chapter 4 depicts the development of volumetric multiplex imaging, which generalizes epr-SRS microscopy to the territory of volumetric imaging. With this method we achieve one-shot imaging of more than 10 colors over millimeter-thick brain tissues, extending the imaging depth of multiplex protein imaging by 10~100 folds. Chapter 5 is a manuscript of an ongoing project on imaging nanocarriers for drug delivery across the blood-brain barrier (BBB). We develop a method of correlative multispectral SRS and fluorescence microscopy to image nanoparticles by SRS with multispectral information and particle counting capability and to image tissue context (especially cerebral vasculature) by fluorescence with high specificity. Using this method, we achieve direct imaging of nanocarriers that cross the BBB with definitive spectral evidence and single particle sensitivity. The preliminary results quantifying the proportion of nanoparticles that cross the BBB provide implications that challenge the current understanding of drug delivery to the brain.

Le noyau pipéridine est un des motifs les plus courant dans les produits naturels et pharmaceutiques ce qui explique que la synthèse énantiosélective de piperidines polyfonctionnalisées soit un domaine particulièrement dynamique. De par sa capacité à associer une fonction amine à un groupement carbonylé, la réaction de Mannich est un outil efficace pour former une liaison C-C de manière énantiosélective tandis que la réaction d’hydroamination intramoléculaire d’alcynes est pratique pour construire des hétérocycles azotés par formation de liaisons C-N. Dans cette thèse, nous avons combiné ces deux stratégies pour former de manière concise et énantiosélective des pipéridines polysusbstituées. Un couplage énantiosélectif de Mannich anti-sélectif fut employé pour préparer des amines chirales contenant une fonction alcyne connectée à un noyau aromatique riche en électrons. En présence d’acide de Brønsted, une réaction d’hydroamination cyclisante eut lieu démontrant une réactivité arylogue d’ynolethers et d’ynamines, la régiosélectivité de la cyclisation dépendant fortement de la densité électronique de l’alcyne. Ainsi lorsque la densité électronique est insuffisante, des pyrrolidines à cinq chainons furent obtenus tandis que lorsque la densité électronique est élevée des piperidines furent isolées, illustrant la passage d’une activation de triple liaison par liaison hydrogène à sa protonation. A partir des tetrahydropyridines et piperidines, une étude fut lancée dans le but d’achever la première synthèse totale énantiosélective du produit naturel koumine, un alcaloïde de type Gelsemium. / Piperidine ring is one of the most common heterocycles in natural products and the motif is especially well represented in pharmaceuticals. Consequently, enantioselective synthesis of multi-substituted piperidines is an important topic of investigation. For the synthesis of nitrogen-containing compounds, asymmetric Mannich coupling is a useful strategy while intramolecular hydroamination of alkynes is a practical route to construct N-heterocyclic products. In this thesis, the two strategies were combined. anti-Selective enantioselective Mannich reactions were thus employed to prepare chiral arylalkynyl amines. Connected to various aromatics, the reactivity of the triple bond was then studied in the framework of the intramolecular hydroamination reaction promoted with Brønsted acid. It was shown that depending on the electronic density of the alkyne, these adducts were converted into 5- or 6-membered rings, highlighting the balance between H-bonding and protonation. Tetrahydropyridines and piperidines were thus obtained with high regio-, diastereo-, and enantioselectivity and further functionalizations were also investigated in view of the first enantioselective total synthesis of Gelsemium alkaloid koumine.

No description available.

Higher carbon chain sugars have gained increased interest recently; they are important building blocks of natural and unnatural products with biological properties. The synthesis of these higher sugar skeletons is commonly known to be achieved with the Wittig methodology which exploits phosphorus ylide chemistry. This method has been successfully used for the synthesis of the higher carbon sugars. The aim of this project was to synthesise ß,ß'-dioxo sugar-derived phosphorus ylides, a new class of ylides, as versatile intermediates to valuable higher carbon sugar derivatives and carbohydrate mimics. Model reactions were initially conducted; tetrahydro-2-furoic acid and tetrahydro-2H-pyran-4-carboxylic acid, compounds which are structurally similar to the precursor sugars, were identified as suitable model compounds. These compounds were converted to acyl chlorides and then converted to ß,ß'-dioxo phosphorus ylides precursors by acylation. The methodology proved successful and 8 examples were isolated. However, low yields were obtained due to the inevitable formation of triphenylphosphine oxide. The method was then extended to sugar derivatives, prepared using standard protecting group chemistry. It was found that acylation could be achieved using the simple acyl chloride route or peptide coupling methodology for sugar derivatives which were acid sensitive. ß,ß'-dioxo sugar-derived phosphorus ylides (16 examples) were successfully isolated in low yields. The oxidation and thermal reactivity of the ß,ß'-dioxo ylides were studied. Oxidation resulted in the successful synthesis of vicinal tricarbonyls, isolated as a mixture with the gem-diols (hydrates). The thermal decomposition of the ylides gave alkynes in moderate yields.