Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2009. / Includes bibliographical references (p. 170-191).

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Pharmaceuticals and personal care products (PPCPs) include a wide range of chemicals such as prescription and over-the-counter drugs, fragrances, diagnostic agents, and a litany of other compounds commonly added to household products such as sunscreens, soaps, toothpastes, and deodorants. If present in natural waters, PPCPs can come into contact with disinfectants during drinking water treatment processes. PPCPs are already known to form a variety of disinfection byproducts (DBPs) when oxidized by free chlorine, including trihalomethanes (THMs) and haloacetic acids (HAAs), many of which are known carcinogens. Salts, such as iodide, are also often present in natural water systems. Iodide is known to form a much more reactive oxidant, free iodine, when it reacts with free chlorine. Free iodine can react with organic compounds in waters to form iodinated byproducts, many of which have been shown to form in higher yields and to be more toxic than their chlorinated analogues. For this reason, it is necessary to more fully understand the fate of PPCPs during drinking water processes. The overall goals of this study are to 1) elucidate reaction mechanisms and product formation potentials for PPCP oxidation by free chlorine in the presence of iodide and 2) develop a computer model that can act as a predictive tool to aid in the assessment of potential risks resulting from PPCPs in source waters. Through the course of this research, a model was developed that could fit reaction rate parameters and accurately predict solution reactivity for a range of substituted phenols as well as PPCPs including bisphenol-A and triclosan. Past studies utilizing pseudo-first-order rate constants to determine a reaction rate over-simplified the analysis of halogen substitution reactions. Free chlorine reaction rate constant values were updated from the literature since the mechanism for electrophilic substitution was found to be different than stated in currently published literature. The involvement of H₂OCl⁺ was found to be negligible. The mechanism for the electrophilic substitution of phenolic compounds by free iodide was also different from current literature findings. We found that I₂, rather than H₂OI⁺, was an extremely important species for free iodine reactions and must be considered when analyzing the reaction kinetics. Finally, we found that small amounts of iodide can significantly affect product formation pathways thereby causing preferential formation of iodinated products and a potential increase in the total product formation. In general, the reaction kinetics were highly dependent upon the pH, iodide to free chlorine ratio, and the reactivity of the phenolic compound, and our model was able to successfully address changes in each of these variables. An LFER was developed that showed a linear relationship between reaction rates and the pK_a of a phenolic compound. It is believed that the model developed can be used as a predictive tool to estimate reactivity of natural waters for a range of phenolic PPCPs simply by using the compounds pK_a. / Ph. D.

Determination of the three-dimensional structure of enzymes at atomic resolution is a key prerequisite for elucidation of molecular mechanisms of catalysis and catalysis mechanism prediction. X-ray protein crystallography is the most widely used method today for determining protein structures. In this thesis we describe the expression, purification, crystallization and structure solution of two new enzymes: PyrH and PrnB. PyrH is a member of the new emerging family of FADH dependent tryptophan halogenases. It catalyzes the regioselective halogenation of tryptophan at the C-5 position of the indole ring. Elucidation of its structure (Chapter 2) and comparison with PrnA, aregioselective 7th tryptophan halogenase whose structure has already been solved confirmed the proposed mechanism of action for this class of enzymes. PrnB is the only enzyme known to perform exquisite and peculiar ring rearrangement chemistry: it converts 7-Cl-tryptophan and tryptophan into respectively monodechloroaminopyrrolnitrin and aminophenylpyrrole. We developed a method for expression and purification of milligrams of pure and homogeneous recombinant PrnB (Chapter 3). We identified suitable crystallization conditions and determined PrnB structure (Chapter 4). Analysis of the PrnB structure helped us to propose a reaction mechanism for this unique enzyme.

No presente trabalho, foi desenvolvida uma metodologia one-pot para obtenção de produtos 4-cloro-1-hidroxinaftaleno-2-oxazolinas (Cl-HNO) 4, utilizando um excesso de SOCl2 a partir da amida 3a. Para a formação do produto de interesse 4 foi desenvolvida uma proposta mecanística para a simultânea ciclização do anel 2- oxazolina e halogenção na porção do anel naftóico através de espectrometria de massas de alta resolução, difração de raios-x e cálculos teóricos. Em seguida, a hidrólise de 4 levou ao produto 5 com nova inversão de configuração no C4. Para funcionalização do ácido 5, foram reagidos grupos aminas e álcoois, conduzindo a uma pequena biblioteca de compostos inéditos com propriedades fluorescentes (6a-e, 7a-e) com Φf 0.8%-1.6%. Testes biológicos contra cepas de fungos foram realizadas. Em uma segunda etapa do trabalho, foi realizada a aplicação do anel 2-oxazolínico como ligantes em reações de acoplamento cruzado do tipo Suzuki-Miyaura. A síntese dos ligantes foi realizada em apenas dois passos reacionais, partindo das amidas 3a-c reagidas com Deoxo-Flúor® levando a três diferentes ligantes 8a-c. Os mesmos foram testados, e o ligante 8a levou aos produtos de acoplamento 9a-m com os melhores rendimentos de 59% a 95%. / In this work, we developed a new one-pot method for synthesizing 4-chlorinated 1- hydroxynaphthaleno-2-oxazoline (2-HNO) 4 by subjecting amide 3a to excess SOCl2. A mechanism for the formation of 4 is proposed, which involves simultaneous cyclization to form the 2-oxazoline ring and halogenation of the 2-hyrdoxynaphthalene ring. We present supporting evidence for this mechanism in the form of high resolution mass spectrometry, x-ray crystallography and theoretical calculations. Hydrolysis of 4 led to product 5 with inversion of configuration at C-4, confirmed by NMR spectra. To functionalize the acid 5, amines and alcohols were reacted with acid 5, leading to a small library of novel compounds having fluorescent properties (6a-e, 7a-e) with Φf 0.8%-1.6%. Furthermore, the library of compounds were used in biological testing against various strains of fungi. In the second stage of this work, we explored the application of the 2-oxazoline ring, through its use as a ligand in Suzuki-Miyaura cross-coupling reactions. The preparation of the ligands were obtained in only two reaction steps, starting from amides 3a-c were reacted with Deoxo-Fluor®, leading to three different ligands 8a-c, respectively. The same were tested, and the ligand 8a provided coupling products 9a-m in good yields of 59% to 95%.

No presente trabalho, foi desenvolvida uma metodologia one-pot para obtenção de produtos 4-cloro-1-hidroxinaftaleno-2-oxazolinas (Cl-HNO) 4, utilizando um excesso de SOCl2 a partir da amida 3a. Para a formação do produto de interesse 4 foi desenvolvida uma proposta mecanística para a simultânea ciclização do anel 2- oxazolina e halogenção na porção do anel naftóico através de espectrometria de massas de alta resolução, difração de raios-x e cálculos teóricos. Em seguida, a hidrólise de 4 levou ao produto 5 com nova inversão de configuração no C4. Para funcionalização do ácido 5, foram reagidos grupos aminas e álcoois, conduzindo a uma pequena biblioteca de compostos inéditos com propriedades fluorescentes (6a-e, 7a-e) com Φf 0.8%-1.6%. Testes biológicos contra cepas de fungos foram realizadas. Em uma segunda etapa do trabalho, foi realizada a aplicação do anel 2-oxazolínico como ligantes em reações de acoplamento cruzado do tipo Suzuki-Miyaura. A síntese dos ligantes foi realizada em apenas dois passos reacionais, partindo das amidas 3a-c reagidas com Deoxo-Flúor® levando a três diferentes ligantes 8a-c. Os mesmos foram testados, e o ligante 8a levou aos produtos de acoplamento 9a-m com os melhores rendimentos de 59% a 95%. / In this work, we developed a new one-pot method for synthesizing 4-chlorinated 1- hydroxynaphthaleno-2-oxazoline (2-HNO) 4 by subjecting amide 3a to excess SOCl2. A mechanism for the formation of 4 is proposed, which involves simultaneous cyclization to form the 2-oxazoline ring and halogenation of the 2-hyrdoxynaphthalene ring. We present supporting evidence for this mechanism in the form of high resolution mass spectrometry, x-ray crystallography and theoretical calculations. Hydrolysis of 4 led to product 5 with inversion of configuration at C-4, confirmed by NMR spectra. To functionalize the acid 5, amines and alcohols were reacted with acid 5, leading to a small library of novel compounds having fluorescent properties (6a-e, 7a-e) with Φf 0.8%-1.6%. Furthermore, the library of compounds were used in biological testing against various strains of fungi. In the second stage of this work, we explored the application of the 2-oxazoline ring, through its use as a ligand in Suzuki-Miyaura cross-coupling reactions. The preparation of the ligands were obtained in only two reaction steps, starting from amides 3a-c were reacted with Deoxo-Fluor®, leading to three different ligands 8a-c, respectively. The same were tested, and the ligand 8a provided coupling products 9a-m in good yields of 59% to 95%.

Ce travail s'articule autour de deux grandes parties : i- la synthèse de nouveaux tripodes tris-A,C,E-alpha-cyclodextrine, et l'étude de leurs complexes de coordination avec les métaux. La fonctionnalisation des bis-hétérocycles est une étape importante dans la préparation de ces tripodes moléculaires. En conséquence, la mise au point d'une nouvelle famille de réactifs, les tétrahalogeno-diarylglycoluriles, a permis une halogénation radicalaire sélective des systèmes hétéro-aromatiques pi-déficients non réactifs et impliqués dans la construction des podants cyclodextriniques. La sélectivité et le mécanisme de la réaction ont pu être expliqués en partie par la formation d'un complexe supramoléculaire [réactif /substrat] et l'existence d'interactions halogène-halogène dans le solide; ii- la mise en évidence d'une haute spéciation des tripodes cyclodextrines vis-à-vis d'un certain nombre de métaux et la formation d'hélices métallo-supramoléculaires chirales induite par l'implantation en position 6,6' des unités hétérocycliques. La configuration absolue des hélicates formés est résolue dans quelques cas / This work is structured around two main parts: i- the synthesis of new tris-A,C,E-alpha-cyclodextrin tripods, and studies of their complexes with transition metals. The functionalization of bis-heterocycles is an important step in the preparation of tripods. Therefore, the development of a new family of reagents tetrahalo-diarylglycolurils allowed a selective radical halogenation of heteroaromatic pi-deficient systems, non-reactive and involved in the construction of podants cyclodextrinics. The selectivity and the mechanism of the reaction could be partially explained by the formation of a supramolecular complex [reagent / substrate] and the existence of halogen-halogen interactions in solid state; ii- the highlight of a high speciation tripods cyclodextrins towards a number of metals and formation of supramolecular chiral metallo-helices induced by anchoring in position 6,6' of heterocyclic units. The absolute configuration of helicates formed in some cases is resolved

Syringolin A, a plant elicitor, was isolated in 1998 and has been identified as a potential anti-cancer compound based on its activity against proteasome. The unique structure of this natural product consists of a 12-membered diamide ring, formed by two non-proteinogenic amino acids 3,4-dehydrolysine and 5-methyl-4-amino-2-hexenoic acid, and a bis(valinyl)urea side chain which is connected to the macrocycle by a peptide bond. The construction of this challenging macrocylic core was achieved by a macrolactamization reaction using peptide coupling reagents BOP/HOAt, while the two (E)-configured double bonds in the ring were introduced by a Johnson-Claisen rearrangement and Wittig olefination respectively. Ru(bpy)3Cl2 which is an excellent visible light photoredox catalyst, has been extensively applied to organic syntheses in recent years. Although much research has focused on the study of the reductive quenching pathway, the oxidative quenching pathway has rarely been explored. Using persulfate as the electron acceptor, we have successfully developed a protocol for the oxidative functionalization of dialkylamides under mild reaction conditions. Further application has demonstrated a Friedel-Crafts amidoalkylation methodology applying various nucleophilic alcohols and arenes. The reaction can also be conducted under thermolysis condition without the photocatalyst, but requires elevated temperature. Both of the reactions generate N-acyliminium ion in situ as the key intermediate. The first example of photocatalytic halogenation has been achieved at room temperature using Ru(bpy)3Cl2 and polyhalomethanes (CBr4 and CHI3) as the electron acceptors. Excellent yields and high functional group tolerance have been established. Mechanistic studies indicate a single electron transfer (SET) pathway and the transformation is via a Vilsmeier-Haack type intermediate. Further expansion of this methodology to anhydride formation was achieved, providing a mild avenue for the synthesis of symmetric anhydrides. Furthermore, the use of a continuous flow reactor enabled the efficient large scale synthesis of anhydrides.