In semi-arid environments, dry-land farming often exposes crops to drought stress. Although some plant species are well adapted to drought, most crops are not. Drought can reduce plant populations and limit growth and development in ways that have serious yield consequences. Planting at the beginning of the wet season, when rainfalls are often sporadic and unreliable, can expose young maize seedlings to severe drought. Through the use of plant growth regulators (PGR), maize seedlings can perhaps be altered to elicit responses that mimic drought adaptation mechanisms. A series of studies conducted in the laboratory and greenhouse looked at the response of maize seedlings (two hybrids that differed in their reported drought sensitivity) to severe drought and to PGR applications with or without drought. Results showed that drought stress altered plant morphology and key physiological parameters. Applications of three triazoles (paclobutrazol, uniconazole and tetraconazole) altered morphology and physiology in ways that might impart drought resistance. Paclobutrazol and uniconazole increased root:shoot ratio in laboratory studies and in the greenhouse. When compared to non-triazole-treated controls, uniconazole and paclobutrazol treatments caused water conservation in earlier stages of drought stress, and therefore afforded increased transpiration (and presumably less stress) at later stages. Uniconazole and tetraconazole increased photosynthesis of well-watered plants. Proline content was increased to a greater degree by these same two triazoles under drought stress conditions. It is hoped that knowledge obtained from these studies can be extended to drought-prone areas where maize dry-land farming is practiced. / Master of Science

本論文報道了 (a) 基於1,4-二取代 1,2,3-三唑的短肽類似物的合成及表徵，和 (b)這些類肽化合物在溶液相中的自組裝及凝膠化特性研究。 / 本論文第一章簡單地介紹及槪括基於三唑的寡聚物的構象和超分子的屬性。 / 本論文第二章報告1,4-二取代 1,2,3-三唑在類肽化合物中作為聯繫單元和作為構象控制的多功能性。 / 本論文第三章敍述了一類新的包含1,2,3-三唑在分子骨幹中的類肽化合物的合成及表徵。以炔丙胺/炔丁胺和 α-疊氮酸作為雙官能團前體，不同氨基酸成分和不同C-端基的系列類肽化合物由反覆的合成過程製備而來。用炔丙醇代替炔丙胺, 相應的酯類似物也被製備用作比較研究。 / 本論文第四章敍述了這些類肽化合物的自組裝及凝膠化特性。根據一維¹H 核磁共振，二維核磁共振 (2D)，氫/氘交換核磁共振 (H/D)， 蒸汽壓力均分子量 (VPO), 圓二色譜 (CD) 和紅外光譜分析研究，基於三唑類的短肽化合物Boc-aa¹aa²***aa[superscript n]-X 被發現以頭接尾的方式自我二聚 (K[subscript dsubscript isubscript m] ~10-680 M⁻¹)。二聚常數 (K[subscript dsubscript isubscript m])隨著氨基酸單位數目的增加而增大。在相同的寡聚系列中，K[subscript dsubscript isubscript m]值受到C-端基的大小的強烈影響。三肽類似物Boc-aa¹aa²aa³-X 還是許多芳烴類溶劑的優秀有機凝膠因子。掃描電子顯微技術(SEM)形態研究顯示三維網路形成於凝膠過程中。另一方面，結果顯示，類肽化合物的連結器長度在二級結構的形成和自組裝特性上發揮重要作用。 / 爲了進一步發展頭尾二聚的概念，本論文第五章敍述頭接尾的β-髮夾類似結構可通過適當的連結器偶聯兩個基於三唑的三肽類似物來獲得，如4-羥基脯氨酸的衍生物。一維¹H 核磁共振，二維核磁共振 (2D)，氫/氘交換核磁共振 (H/D)和紅外光譜等分析方法被用來研究其自組裝特性。 / 這篇論文展示了用三唑類體系結構設計類肽分子的可行性。產品結構表徵及性質探索的結果為這些新的類肽化合物的進一步調查和應用奠定了基礎。 / This thesis reported (a) the synthesis and characterization of 1,4-disubstituted 1,2,3-triazole-based oligopeptides, and (b) the study on self assembling and gelation properties of the peptidomimetic compounds. / Chapter one gave a brief introduction and review on the click triazole-based oligomers, including their conformational and supramolecular properties. / Chapter two reviewed the versatility of 1,4-disubstituted 1,2,3-triazole unit as a linker and as a conformational controlling unit in peptidomimetics. / Chapter three disclosed the synthesis and characterization of a new class of linear peptidomimetics incorporating 1,2,3-triazoles in the backbone. Several series of click peptidomimetics, containing up to four amino acid residues and of different amino acid compositions and different C-terminal groups, were prepared by an iterative synthetic procedure, in which propargyl amine/homopropargyl amine and α-azido acids were used as bifunctional precursors. Using propargyl alcohol instead of propargyl amine, the corresponding ester analogs were also prepared for comparison studies. / In chapter four, the self-assembly and gelation properties of these peptidomimetics were illustrated. Click triazole-based oligopeptides Boc-aa¹aa²***aa[superscript n]-X (n = 2, 3 or 4) were found to self-dimerize (K[subscript dsubscript isubscript m] ~ 10-1020 M⁻¹) in a head-to-tail fashion according to ¹H NMR, two-dimensional NMR (2D), hydrogen/deuterium (H/D) exchange NMR, vapor pressure osmometry (VPO), circular dichroism (CD) and FT-IR studies. The dimerization constant (K[subscript dsubscript isubscript m]) was found to increase with increasing number of the amino acid units. Within the same oligomeric series, the K[subscript dsubscript isubscript m] value was strongly affected by the size of the C-terminal end group. The tripeptides Boc-aa¹aa²aa³-X were also excellent organogelators of many aromatic solvents. Morphological study indicated thata three-dimensional network was formed during the gelation process. On the other hand, the corresponding triester analog 98 and elongated analogs l-Boc-aa¹aa²aa³-Prg did not exhibit any self assembling properties. This revealed that the linker length and the amide units inside the click peptidomimetics played an important role in both the formation of secondary structures and the self-assembly properties. / To further develop the idea of head-to-tail dimerization, chapter five described the head-to-tail β-hairpin like structures could be obtained by conjugating two click triazole-based tripeptides through an appropriate linker such as derivatives of 4-hydroxyproline. Analytical methods, such as ¹H NMR, two-dimensional NMR, H/D exchange NMR spectroscopy, and FT-IR studies, were used to determine their self assembling properties. / This thesis has demonstrated the feasibility of designing peptidomimetic molecules with the triazole architecture. The results of the product characterization and property exploration have laid down the groundwork for further investigation and application of this new of peptidomimetic compounds. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Ke, Zhihai. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 156-162). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Table of Contents --- p.i / Acknowledgements --- p.iv / Abbreviations --- p.v / Abstract --- p.vi / Publications related to this thesis --- p.x / Chapter Chapter One --- Click ChemistryA Powerful Tool to Create Supramolecular Chimeras / Chapter 1.1 --- Introduction to Click Chemistry --- p.1 / Chapter 1.2 --- General Synthetic Strategies of Acyclic Oligotriazoles --- p.6 / Chapter 1.3 --- Conformational Properties --- p.9 / Chapter 1.3.1 --- Helical Structures from Oligotriazoles --- p.9 / Chapter 1.3.2 --- Double Helical Structure from Oligotriazoles --- p.12 / Chapter 1.3.3 --- β-Strands and β-sheets derived from Oligotriazoles --- p.13 / Chapter 1.4 --- Supramolecular Properties --- p.14 / Chapter 1.4.1 --- Host-guest Binding --- p.14 / Chapter 1.4.2 --- Self Assembling Properties --- p.17 / Chapter 1.4.3 --- Chemosensing Properties --- p.19 / Chapter Chapter Two --- Click PeptidomimeticsTricks with Clicks / Chapter 2.1 --- Click ChemistryA New Ligation Tool for Peptidomimetics Synthesis --- p.20 / Chapter 2.2 --- Click Peptidomimetics --- p.22 / Chapter 2.2.1 --- Peptidepeptide --- p.23 / Chapter 2.2.2 --- Polymerpeptide --- p.25 / Chapter 2.2.3 --- Dendrimerpeptide --- p.26 / Chapter 2.2.4 --- Small moleculepeptide --- p.27 / Chapter 2.3 --- The triazole linkage as conformational control --- p.29 / Chapter 2.3.1 --- Triazole-based β-turn mimetics --- p.29 / Chapter 2.3.2 --- Cyclic turn mimetics --- p.31 / Chapter 2.3.3 --- Cis/trans-prolyl mimic --- p.33 / Chapter 2.3.4 --- Triazoles in helix bundles --- p.34 / Chapter 2.4 --- Oligotriazole peptides --- p.35 / Chapter 2.5 --- Summary and Aim of the Project --- p.36 / Chapter Chapter Three --- Design, Synthesis and Characterization of Oligotriazole-based Peptidomimetics / Chapter 3.1 --- Synthetic Design --- p.38 / Chapter 3.2 --- Choice of Reaction Conditions --- p.40 / Chapter 3.3 --- Synthesis of Linear Click Triazole-based Peptidomimetics --- p.41 / Chapter 3.3.1 --- Preparation of Click Triazole-based Peptidomimetics with Shorter Linkers --- p.42 / Chapter 3.3.2 --- Preparation of Click Triazole-based Peptidomimetics l-Boc-aa¹aa²**aa[superscript n]-X with a Longer Spacer --- p.47 / Chapter 3.3.3 --- Preparation of ester analogs and other model compounds --- p.49 / Chapter 3.4 --- Characterization of Linear Click Triazole-based Peptidomimetics --- p.51 / Chapter 3.4.1 --- Nuclear Magnetic Resonance (NMR) Spectroscopy --- p.52 / Chapter 3.4.1.1 --- ¹H NMR Spectroscopy --- p.52 / Chapter 3.4.1.2 --- ¹³C NMR Spectroscopy --- p.57 / Chapter 3.4.2 --- Mass Spectrometry Analysis --- p.59 / Chapter 3.4.3 --- High-performance Liquid Chromatography Analysis --- p.61 / Chapter 3.5 --- Conclusions --- p.62 / Chapter Chapter Four --- Self-Assembling Properties of Click Triazole-based Peptidomimetics / Chapter 4.1 --- Introduction --- p.63 / Chapter 4.2 --- Results and Discussion --- p.65 / Chapter 4.2.1 --- Nuclear Magnetic Resonance (NMR) Spectroscopy --- p.65 / Chapter 4.2.1.1 --- Variable Concentration ¹H NMR --- p.65 / Chapter 4.2.1.2 --- Two-dimensional ¹H NMR --- p.71 / Chapter 4.2.1.3 --- Hydrogen/deuterium (H/D) exchange --- p.74 / Chapter 4.2.2 --- Vapor Pressure Osmometry (VPO) --- p.77 / Chapter 4.2.3 --- Infra-red (IR) Spectroscopy --- p.78 / Chapter 4.2.4 --- Theoretical Calculation --- p.80 / Chapter 4.2.5 --- Circular Dichroism (CD) --- p.81 / Chapter 4.2.6 --- Gelation Behaviors --- p.83 / Chapter 4.2.6.1 --- General Gelation Properties --- p.83 / Chapter 4.2.6.2 --- Morphology Studies --- p.87 / Chapter 4.3 --- Conclusions --- p.90 / Chapter Chapter Five --- β-Hairpin Structure from Click Triazole-based Peptidomimetics / Chapter 5.1 --- Introduction and Design of β-hairpin --- p.91 / Chapter 5.2 --- β-Hairpin Like Click Triazole-based Peptidomimetics Based on a Bifunctional Aromatic Linker 105 --- p.92 / Chapter 5.3 --- β-Hairpin Like Click Peptidomimetics Based on a Proline Linker 113 --- p.97 / Chapter 5.4 --- Conclusions --- p.107 / Chapter Chapter Six --- Conclusion and Outlook --- p.109 / Chapter Chapter Seven --- Experimental Procedures / Chapter 7.1 --- General Information --- p.112 / Chapter 7.2 --- Experimental Procedures --- p.113 / Chapter 7.3 --- Other Experimental --- p.152 / References --- p.156 / Chapter Appendix 1 --- (Nuclear Magnetic Resonance Spectra) --- p.A1 / Appendix 2 --- p.A111

Além do controle de fungos fitopatogênicos, muitos fungicidas produzem efeitos fisiológicos positivos na planta, contribuindo para a melhoria da produtividade da cultura mesmo na ausência de doenças. O objetivo deste trabalho foi verificar se o fungicida Fluxapiroxade, aplicado de forma isolada e e em mistura com a Piraclostrobina, exerce algum efeito fisiológico na cultura de soja. Para tal, foram conduzidos dois experimentos (I - em campo e II - em câmara de crescimento), em blocos ao acaso, comparando seis tratamentos: [1] Testemunha, [2] Ciproconazol (100 g.ha-1 i.a), [3] Piraclostrobina (100 g.ha-1 i.a.), [4] Fluxapiroxade (50 g.ha-1 i.a.), [5] Fluxapiroxade (50 g.ha-1 i.a.) + Piraclostrobina (100 g.ha-1 i.a.) e [6] Piraclostrobina (75 g.ha-1 i.a). No experimento I, os tratamentos foram aplicados em R1 e R5.1, sendo avaliadas(os): a atividade das enzimas antioxidantes (superóxido dismutase, guaiacol peroxidase e catalase) no primeiro, quarto e sétimo dia após cada aplicação; o índice de área foliar aos 20 dias após cada aplicação; a massa de matéria seca de folha, haste e órgãos reprodutivos aos 20 dias após cada aplicação; o número de vagens por planta em R6, a produtividade e a massa de 1000 grãos. No experimento II, os tratamentos foram aplicados em V7 e foram avaliadas: a fotossíntese líquida, a respiração, a condutância estomática, a transpiração e a temperatura foliar das plantas, um dia após a aplicação, por meio de um analisador infra-vermelho de gás (IRGA). Não foram observadas alterações no índice de área foliar, massa de matéria seca, respiração, transpiração, condutância estomática, temperatura foliar, número de vagens e massa de 1000 grãos para o tratamento Fluxapiroxade, tanto isolado como em mistura com a Piraclostrobina. Porém, a aplicação do Fluxapiroxade isolado reduziu a atividade das enzimas antioxidantes e também a produtividade, embora tenha elevado a taxa fotossintética líquida. Em mistura com a Piraclostrobina, houve uma redução da atividade das enzimas antioxidantes, o que refletiu em uma tendência de prejuízo à produtividade. Por outro lado, o fungicida Piraclostrobina (75 g.ha-1) apresentou maiores massa de matéria seca de flor, atividade das enzimas antioxidantes, taxa fotossintética líquida e produtividade, o que sugere uma atuação benéfica desse fungicida no metabolismo fotossintético e antioxidante da planta. Na dose de 100 g.ha-1, entretanto, a Piraclostrobina reduziu a atividade das enzimas antioxidantes e a produtividade, parecendo exercer efeito contrário àquele observado para a dose de 75 g.ha-1, embora não tenha apresentado qualquer sintoma de fitotoxicidade. / Beyond the control of plant pathogenic fungi, many fungicides produce positive physiological effects on plants, contributing to crop yield even in the absence of disease. The objective of this research is to verify if the fungicide Fluxapyroxad, alone and mixed with Pyraclostrobin, has a physiological effect on soybean. Two experiments were carried out (I - field and II - growth chamber), in a randomized block, comparing six treatments: [1] Control, [2] Ciproconazol (100 g.ha-1 a.i.), [3] Pyraclostrobin (100 g.ha-1 a.i.), [4] Fluxapyroxad (50 g.ha-1 a.i.), [5] Fluxapyroxad (50 g.ha-1 a.i.) + Pyraclostrobin (100 g.ha-1 a.i.) and [6] Pyraclostrobin (75 g.ha-1 a.i.). Experiment I was conducted with five replications and treatments were sprayed on the leaves, at stages R1 and R5.1. The activity of antioxidant enzymes (superoxide dismutase, catalase and guaiacol peroxidase) was measured on the first, fourth and seventh day after each application. The leaf area index and the leaf, stem and flower/pod dry matter were measured 20 days after each application. The number of pods per plant, yield and weight of 1000 seeds were also measured. Experiment II was conducted with four replications and treatments were sprayed only at V7, due to limitation of space in the growth chamber. Net photosynthesis, respiration, stomatal conductance, transpiration and leaf temperature were measured one day after the application, by a \"Infra-Red Gas analyser\" (IRGA). No changes in leaf area index, dry matter, respiration, transpiration, stomatal conductance, leaf temperature, number of pods or weight of 1000 seeds were observed for the treatment Fluxapyroxad, neither alone nor in combination with Pyraclostrobin. The application of Fluxapyroxad alone reduced both the activity of antioxidant enzymes and yield, although net photosynthesis was increased. Fluxapyroxad + Pyraclostrobin reduced the activity of antioxidant enzymes and showed a tendency to reduce yield. Moreover, the treatment with Pyraclostrobin (75 g.ha-1) was superior in terms of flower dry matter, antioxidant enzyme activity, net photosynthetic rate and yield, suggesting that this fungicide may have a positive effect on photosynthetic and antioxidative metabolism of the soybean plant. Pyraclostrobin (100 g.ha-1), however, reduced antioxidant enzyme activity and yield, which suggests that an elevation in the Pyraclostrobin dose promotes the opposite effect of that observed for the recommended dose, although no phytotoxicity symptoms have appeared.

Além do controle de fungos fitopatogênicos, muitos fungicidas produzem efeitos fisiológicos positivos na planta, contribuindo para a melhoria da produtividade da cultura mesmo na ausência de doenças. O objetivo deste trabalho foi verificar se o fungicida Fluxapiroxade, aplicado de forma isolada e e em mistura com a Piraclostrobina, exerce algum efeito fisiológico na cultura de soja. Para tal, foram conduzidos dois experimentos (I - em campo e II - em câmara de crescimento), em blocos ao acaso, comparando seis tratamentos: [1] Testemunha, [2] Ciproconazol (100 g.ha-1 i.a), [3] Piraclostrobina (100 g.ha-1 i.a.), [4] Fluxapiroxade (50 g.ha-1 i.a.), [5] Fluxapiroxade (50 g.ha-1 i.a.) + Piraclostrobina (100 g.ha-1 i.a.) e [6] Piraclostrobina (75 g.ha-1 i.a). No experimento I, os tratamentos foram aplicados em R1 e R5.1, sendo avaliadas(os): a atividade das enzimas antioxidantes (superóxido dismutase, guaiacol peroxidase e catalase) no primeiro, quarto e sétimo dia após cada aplicação; o índice de área foliar aos 20 dias após cada aplicação; a massa de matéria seca de folha, haste e órgãos reprodutivos aos 20 dias após cada aplicação; o número de vagens por planta em R6, a produtividade e a massa de 1000 grãos. No experimento II, os tratamentos foram aplicados em V7 e foram avaliadas: a fotossíntese líquida, a respiração, a condutância estomática, a transpiração e a temperatura foliar das plantas, um dia após a aplicação, por meio de um analisador infra-vermelho de gás (IRGA). Não foram observadas alterações no índice de área foliar, massa de matéria seca, respiração, transpiração, condutância estomática, temperatura foliar, número de vagens e massa de 1000 grãos para o tratamento Fluxapiroxade, tanto isolado como em mistura com a Piraclostrobina. Porém, a aplicação do Fluxapiroxade isolado reduziu a atividade das enzimas antioxidantes e também a produtividade, embora tenha elevado a taxa fotossintética líquida. Em mistura com a Piraclostrobina, houve uma redução da atividade das enzimas antioxidantes, o que refletiu em uma tendência de prejuízo à produtividade. Por outro lado, o fungicida Piraclostrobina (75 g.ha-1) apresentou maiores massa de matéria seca de flor, atividade das enzimas antioxidantes, taxa fotossintética líquida e produtividade, o que sugere uma atuação benéfica desse fungicida no metabolismo fotossintético e antioxidante da planta. Na dose de 100 g.ha-1, entretanto, a Piraclostrobina reduziu a atividade das enzimas antioxidantes e a produtividade, parecendo exercer efeito contrário àquele observado para a dose de 75 g.ha-1, embora não tenha apresentado qualquer sintoma de fitotoxicidade. / Beyond the control of plant pathogenic fungi, many fungicides produce positive physiological effects on plants, contributing to crop yield even in the absence of disease. The objective of this research is to verify if the fungicide Fluxapyroxad, alone and mixed with Pyraclostrobin, has a physiological effect on soybean. Two experiments were carried out (I - field and II - growth chamber), in a randomized block, comparing six treatments: [1] Control, [2] Ciproconazol (100 g.ha-1 a.i.), [3] Pyraclostrobin (100 g.ha-1 a.i.), [4] Fluxapyroxad (50 g.ha-1 a.i.), [5] Fluxapyroxad (50 g.ha-1 a.i.) + Pyraclostrobin (100 g.ha-1 a.i.) and [6] Pyraclostrobin (75 g.ha-1 a.i.). Experiment I was conducted with five replications and treatments were sprayed on the leaves, at stages R1 and R5.1. The activity of antioxidant enzymes (superoxide dismutase, catalase and guaiacol peroxidase) was measured on the first, fourth and seventh day after each application. The leaf area index and the leaf, stem and flower/pod dry matter were measured 20 days after each application. The number of pods per plant, yield and weight of 1000 seeds were also measured. Experiment II was conducted with four replications and treatments were sprayed only at V7, due to limitation of space in the growth chamber. Net photosynthesis, respiration, stomatal conductance, transpiration and leaf temperature were measured one day after the application, by a \"Infra-Red Gas analyser\" (IRGA). No changes in leaf area index, dry matter, respiration, transpiration, stomatal conductance, leaf temperature, number of pods or weight of 1000 seeds were observed for the treatment Fluxapyroxad, neither alone nor in combination with Pyraclostrobin. The application of Fluxapyroxad alone reduced both the activity of antioxidant enzymes and yield, although net photosynthesis was increased. Fluxapyroxad + Pyraclostrobin reduced the activity of antioxidant enzymes and showed a tendency to reduce yield. Moreover, the treatment with Pyraclostrobin (75 g.ha-1) was superior in terms of flower dry matter, antioxidant enzyme activity, net photosynthetic rate and yield, suggesting that this fungicide may have a positive effect on photosynthetic and antioxidative metabolism of the soybean plant. Pyraclostrobin (100 g.ha-1), however, reduced antioxidant enzyme activity and yield, which suggests that an elevation in the Pyraclostrobin dose promotes the opposite effect of that observed for the recommended dose, although no phytotoxicity symptoms have appeared.

Memoria para optar al título de Químico / Se describe un sencillo método de aminación reductiva, basado en la reacción de Leuckart. Este método permite no sólo la reducción del óxido de grafito, sino que también da lugar a grafeno funcionalizado con grupos amina, donde el grado de aminación es de 3.2% en peso, según análisis mediante XPS. El grupo funcional nitrogenado dominante es la amina primaria, pero también se observaron grupos tipo pirrólico y lactama. Se encontró que el grafeno funcionalizado con amina es un material semimetálico debido a la carencia de brecha de bandas, a diferencia del óxido de grafito que presenta una brecha de banda de 2.16 eV. Es sabido que los compuestos grafíticos mejoran las propiedades eléctricas y mecánicas de nanocompósitos con respecto a la matriz polimérica en su estado puro. En este estudio se utiliza el óxido de grafeno reducido y aminado químicamente como refuerzo en nanocompósitos a base de caucho natural, donde se obtienen nanocompósitos de NR/rGO-Am con conductividades eléctricas de hasta 1.5 S/m, muy superior al NR (10-11 S/m) / A very simple method of reductive amination, based on the Leuckart reaction, is reported. This method enables not only the reduction of graphite oxide, but also results in functionalized graphene with amine groups, where the amination degree is 3.2 at.% As determined by XPS. The dominant nitrogen functional group was primary amine, but pyrrolic and lactam-type groups were also observed. It was found that the amine-functionalized graphene is a semimetallic material because of the lack of band gap, unlike the graphite oxide that presented a band gap of 2.16 eV. It is known that the using of graphitic materials improves the electrical and mechanical properties of nanocomposites respect to the polymer matrix in its pure state. In this study, reduced and aminated graphene oxide by chemical reaction is used as reinforcement in natural rubber based nanocomposites, where NR / rGO-Am nanocomposites are obtained with electrical conductivities of up to 1.5 S / m, much higher than NR (10-11 S / m) / FONDECYT 1131139

No description available.

Hemisynthèse stéréosélective d’acides aminés hétérosubstitués sur la chaîne latérale.Applications au radio-fluoromarquage pour l’imagerie de peptides.Ce travail de thèse, qui a été réalisé à l’Institut de Chimie Moléculaire de l’Université de Bourgogne et en collaboration avec l’Institut de Neuroscience Cognitives et Intégrative d’Aquitaine, porte sur la mise au point de nouvelles méthodes de synthèse d’acides aminés hétérosubstitués sur la chaine latérale par des groupements phosphorés ou silylés, ainsi que sur leurs applications. Dans une première partie, la synthèse d’acides aminés silylés sur la chaine latérale est réalisée sans racémisation par réaction de Wittig entre un sel de phosphonium, dérivé d’acide L-aspartique, avec un aldéhyde aromatique porteur du groupement silylé. Ces acides aminés ont été utilisés en synthèse peptidique pour donner des di- et tripeptides silylés par réaction avec des dérivés d’alanine et de phénylalanine. Il a été montré que les acides aminés et peptides silylés pouvaient être fluorés par réaction avec des fluorures, et que dans le cas de dérivés di-t-butylsilylés, les composés fluorés obtenus se révèlent d’une très grande stabilité à pH physiologique. L’étude de la fluoration des peptides di-t-butylsilylés par K18F/K222 a permis d’obtenir les dérivés radiomarqués avec des rendements radiochimiques et des activités molaires atteignant respectivement 39% et 410 GBq.mmol-1. Dans la seconde partie, la synthèse d’acides aminés et peptides hétérosubstitués ou fonctionnalisés sur la chaine latérale, a été mise au point. Le principe de cette synthèse repose sur une cycloaddition [3+2] entre un acide aminé porteur d’un groupement azido avec un alcyne disubstitué. Alors que la réaction par catalyse avec un sel de cuivre ou un complexe de ruthénium ne conduit pas aux produits recherchés, la cycloaddition a été mise au point sous microondes en utilisant le glycérol comme solvant. Dans ces conditions, 13 nouveaux acides aminés porteurs d’un noyau triazole en position γ, et des substituants silylés, phosphorés, amines, amides …ont été préparés sans racémisation et ce avec des rendements atteignant 89%. Les méthodologies mises au point dans ce travail de thèse offrent de nouvelles voies pour la synthèse de dérivés acides aminés silylés ou phosphorés utiles pour la chimie de coordination, la catalyse asymétrique et pour le radiomarquage par les ions fluorure 18F-.Mots clés : Phosphoniums, acides aminés, silanes ; [18F]-radiofluoration, triazoles. / Stereoselective hemisynthesis of lateral chain heterosubstituted aminoacids.Applications on radiofluorolabeling for peptide imaging.This thesis work, which was carried out at the Institute of Molecular Chemistry of the University of Burgundy and in collaboration with the Institute of Cognitive and Integrative Neurosciences of Aquitaine, focuses on the development of new methods for the synthesis of side chain heterosubstituted amino acids including phosphine containing or silyl groups, as well as on their applications. In a first part, the synthesis of side chain silylated amino acids is achieved without racemization using a key Wittig reaction between a phosphonium salt, derived from L-aspartic acid, and an aromatic aldehyde bearing the silyl group. These aminoacids have been used in peptide synthesis to give silylated di- and tripeptides by reaction with alanine and phenylalanine derivatives. It has been shown that the silylated aminoacids and peptides can be fluorinated by reaction with fluorides, and that in the case of di-t-butylsilyl derivatives, the fluorinated compounds obtained are found to be very stable at physiological pH. The study of the fluorination of di-t-butylsilyl peptides by K18F / K222 allowed to obtain radiolabelled derivatives with radiochemical yields and molar activities reaching 39% and 410 GBq.mol-1, respectively. In the second part, the synthesis of aminoacids and peptides heterosubstituted or functionalized on the side chain, was developed. The principle of this synthesis is based on a [3 + 2] cycloaddition between an aminoacid bearing an azido group with disubstituted alkyne. While the reaction catalyzed using a copper salt or a ruthenium complex does not lead to the desired products, the cycloaddition was developed under microwave irradiation using glycerol as a solvent. Under these conditions, 13 new amino acids carrying a triazole ring at the γ position, and bearing silyles, phosphines, amines, amides.. substituents were prepared without racemization and with yields up to 89%. The methodologies developed in this thesis offer new efficient ways for the synthesis of silyl or phosphorus amino acid derivatives, useful for coordination chemistry, asymmetric catalysis and radiolabeling by the fluoride ion18F-.Key words: Phosphoniums, aminoacids, silanes, [18F]-radiofluorination, triazoles

Depuis une trentaine d'année, l'obtention de composés chiraux énantiopurs tient un rôle prépondérant dans la synthèse de molécules biologiquement actives, tout particulièrement dans les domaines de la pharmacie de l'agrochimie et de la parfumerie. Cet engouement pour la synthèse énantiosélective a conduit à la mise au point de multiples ligands chiraux et notamment les diphosphines chirales par atropoisomérie initiées par les travaux de Noyori et Takaya. Nous nous sommes intéressés à la synthèse de nouveaux ligands hétérocycliques bidents et chiraux par atropoisomérie par des voies de synthèse originale où une double construction des hétérocycles sera mise en œuvre dans l'étape clé. En parallèle, nous avons aussi développé une approche de synthèse permettant l'obtention de mono et bis phosphonates atropochiraux utilisant des allènes comme précurseurs de la synthèse. / Atropisomeric diphosphine ligands play a crucial role in the synthesis of enantiopur molecules, particularly in pharmaceutical, agrochemical and flavors industries. Growing demand in asymmetric synthesis, impose to develop news ligands by rapid, economic and effective strategies of synthesis. This optically pure ligand was combined with multiples transition metal to form catalyst what will have used wide variety of entioselective reaction type.Over the past few years, a new family of ligands has emerged, possessing biheterocyclic skeleton and thus allowing the introduction of different steric and electronic interactions. We will report a efficient syntheses of the new atropisomeric five-membered heterocyclic diphosphines with original strategy of synthesis whose the main stages consist in a double heterocyclic construction. In the second part, we will develop an approach permitting to obtain atropochiral phosphonates with a similar strategy of synthesis from allenylphosphine oxides or allenylphosphonates as precursors.

L'intérêt croissant de la communauté scientifique pour le noyau 1,2,4-triazole nous a amené à développer une nouvelle synthèse de cet hétérocycle substitué sur les positions 3, 4 et 5 par des acides aminés. L'étape clé de la synthèse est une étape de couplage-cyclisation utilisant du benzoate d'argent. Nous avons prouvé qu'il est possible d'utiliser des α-aminoacides comme produit de départ.L'étude cette réaction a montré qu'elle n'induit pas d'épimérisation sur les atomes de carbones en α des positions 3, 4 et 5 du noyau triazole et que le traitement optimisé permet d'éliminer les sels métalliques jusqu'à des concentrations très basses. L'optimisation du traitement nous a également permis d'améliorer les rendements et d'effectuer une monté en échelle de la synthèse. Nous avons alors utilisé cette plateforme hétérocyclique pour étudier l'affinité d'analogues rigidifiés de deux neuropeptides envers leurs cibles respectives : le récepteur cholécystokinine 2 et le récepteur µ-opioïde. Ce travail nous a permis d'obtenir plusieurs ligands ayant une activité submicromolaire pour ces récepteurs. Nous pensons qu'une optimisation des propriétés de ces composés peut être d'un grand intérêt clinique et que l'approche suivie pour leur mise au point peut s'appliquer à d'autres RCPGs. / The growing interest of the scientific community for the 1,2,4-triazole heterocycle led us to develop a new synthesis of this ring trisubstituted in positions 3, 4, and 5 by amino acids. The key step is a coupling-cyclisation step using silver benzoate for which we proved that α-aminoacid can be used as starting material.The study of this reaction showed that it does not induce epimerization on carbon atom in α of the position 3, 4 or 5 on the triazole ring. The optimized work up has been shown to limit metal residual traces at a very low concentration. This optimization allowed us to increase yields and to scale-up reaction. We used this scaffold to study affinity of neuropeptides rigidified analogs to their respective targets: cholecystokinin 2 and µ opioid receptors. This work led us to submicromolar affinity compounds for these receptors. We think that an optimization of these compounds can be of great clinical interest and that our strategy for the discovery of new ligands can be applied to several other GPCRs.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.