Depuis de nombreuses années, les phosphines chirales multifonctionnelles se sont révélées être des outils synthétiques puissants en organocatalyse asymétrique. Ces catalyseurs qui contiennent un site de base de Lewis et un site d'acide de Bronsted, ont reçu une attention particulière en raison de leur efficacité pour créer des liaisons C-C avec de très bonnes énantiosélectivités. A notre connaissance, la synthèse d'organocatalyseurs de type thiourée-phosphine dérivés de la (L)-proline n'a jamais été décrite dans la littérature. Ce sujet de thèse concerne la synthèse d'une nouvelle famille d'organocatalyseur chiral de type thiourée-phosphine dérivée de (L)-proline, un produit naturel, disponible et peu coûteux. Nous avons mis au point plusieurs méthodes de synthèse efficaces qui nous ont permis de préparer trois familles de phosphines-thiourées à partir de la (L)- proline. Ainsi, sept nouveaux composés énantiopurs ont été préparés au cours de ce travail. Ces composés ont été utilisés comme catalyseurs dans des réactions asymétriques catalysées par des phosphines. Ces réactions incluent la cyclisation [3+2], la réaction de Baylis-Hillman, la réaction de Friedel-Crafts, la réaction de substitution nucléophile. / For many years, multifunctional chiral phosphines have proven to be powerful synthetic tools in asymmetric organocatalysis. These catalysts, containing Lewis basic and Brnsted acidic sites, have received considerable attention owing to their highly efficiency to create C-C bond by asymmetric organocatalysis. To our knowledge, the synthesis of organocatalysts type thiourea-phosphine derivatives (L) -proline have never been described in the literature. In this work, we wish to report the synthesis of new family of bifunctional chiral thiourea-phosphine organocatalyst derived from L-proline, a natural available product. We developed efficient methods to prepare three families of phosphine thiourea derived from L-proline. Thus, Seven new enantiopure compounds were synthesized in this study. They were used as catalyst asymmetric reaction catalyzed by phosphines: [3+2] cyclisation, Baylis-Hillman reaction, Friedel-Crafts reaction and nucleophilic substitution.

The behavior and facial expressions performed by cats have been reported to be visibly affected by the perceived taste quality of a food item. The goal of the present study was to assess how cats react to pleasant and unpleasant tastes. The facial and behavioral reactions of 13 cats to different concentrations of L-Proline and quinine monohydrochloride as well as mixtures with different concentrations of the two substances were assessed using a two-bottle preference test. The cats were videotaped during the tests and the frequency and duration of 50 different behaviors was analyzed in Noldus the Observer XT. The cats responded to tastes regarded as pleasant by having their eyes less than 50 % open for significantly longer periods of time compared to a water control. Tongue protrusions were also observed significantly more frequently when the cats sampled from a solution with a preferred taste compared to a water control. When encountering solutions of quinine monohydrochloride or mixtures containing quinine monohydrochloride the cats were observed to perform tongue protrusion gapes much more frequently compared to a water or L-Proline control. Even though the cats did not significantly differ in the number of times they licked at spouts containing the 50 mM L-Proline and 500 mM quinine monohydrochloride mixture compared to a 50 mM L-Proline, no masking effect could be confirmed as there was no increase in the acceptance of the mixture was observed. The present study suggests that the knowledge about behavioral responses to pleasant or unpleasant taste can be utilized in future studies on how cats perceive different tastes.

In the Ward Group, stereoselective aldol reactions of thiopyran derived templates play an important role in polypropionate natural product syntheses. Central to this approach is the diastereo- and enantioselective synthesis of all possible aldol adducts 3 arising from tetrahydro-4H-thiopyran-4-one (1) and 1,4-dioxa-8-thiaspiro[4.5] decane-6- carboxaldehyde (2). There are four possible diastereomers of 3 indicated by the relative configurations at positions 3 and 1’ (syn or anti) and positions 1’ and 6’ (syn or anti). Up to date, the asymmetric aldol reaction of 1 with 2 catalyzed by L-proline or its tetrazole analogue 12 provides efficient access to 3,1’-anti-1’,6’-syn-3 (3-AS) without need for chromatography (>40 g scale; 75% yield, >98% ee) and 3,1’-syn-1’,6’-syn-3(3-SS) (via isomerization of 3-AS; >75% yield, 2 cycles); however, the preparation of enantiopure 3,1’-anti-1’,6’-anti-3 (3-AA) and 3,1’-anti-1’,6’-syn-3 (3-SA) still requires the use of enantiopure aldehyde 2 in a diastereoselective synthesis. Without a simple and scalable route, access to enantioenriched iterative aldol adducts and polypropionate natural products that are based on 3-AA and 3-SA skeletons are hindered. It was observed that conducting the asymmetric aldol synthesis of 3-AS on large scale gave enantioenriched 3-AA as a very minor product. This observation triggered the hypothesis of using L-proline to resolve racemic 3-AA via a retro-aldol reaction.In this thesis, the development, optimization, and application of an unprecedented L-proline catalyzed enantioselective retro-aldol reaction is described. Interesting mechanistic insights were uncovered. An unexpected isomerization process between 3-AA and 3-SA occurs in parallel with the retro-aldol process. The method was demonstrated to be a robust, flexible, and readily scalable process to access highly enantioenriched 3-AA (ee > 95%) and 3-SA (ee > 95%). To the best of our knowledge, this reaction represents the only reported enantioselective retro-aldol reaction catalyzed by L-proline.

Title page, table of contents and summary only. The complete thesis in print form is available from the University of Adelaide Library. / During early embryogenesis pluripotent cells of the inner cell mass (ICM) give rise to a second pluripotent cell population known as the primitive ectoderm an obligate developmental intermediate and the substrate for gastrulation. The ICM and primitive ectoderm are distinguished on the basis of morphology, gene expression and differentiation potential. However, the signals and mechanisms involved in the transition form ICM to primitive ectoderm are not understood. Culture of ES cells in the presence of a conditioned medium MEDII leads to a transition of ES cells to a population of pluripotent primitive ectoderm-like (EPL) cells that are the in vitro equivalent of the primitive ectoderm. In terms of EPL cell formation the bioactive component of MEDII was identified as L-proline. In this thesis the molecular mechanism by which L-proline induces EPL-cell formation was elucidated. As well as L-proline, short L-proline containing peptides were also shown to induce EPL-cell formation but different peptides displayed different abilities to induce the transition with some inducing the complete transition and others inducing morphology changes only. The mechanism of L-proline induced EPL-cell formation was shown to be independent of NK receptors. The mechanism of L-proline induced EPL-cell formation, as deduced from the results presented in this thesis, was suggested to involve the internalisation of L-proline via the SAT2 amino acid transporter into ES cells as competitive inhibitors of SAT2 prevented EPL-cell formation. MAPK signalling via the action of MEK1 was implicated in L-proline induced EPL-cell formation as inhibitors of MEK1 prevented EPL-cell morphology, gene expression and differentiation potential in the presence of Lproline. PI3K signalling was implicated in L-proline-induced EPL-cell morphology since PI3K inhibitor L Y294002 maintained domed colonies in the presence of L-proline but failed to maintain an ES-cell gene expression profile and differentiation potential. Both MAPK and PI3K signalling were suggested to lie down-stream of L-proline action since treatment of ES cells with L-proline induced the activation of ERK1/2 and Akt down-stream effectors of MAPK and PI3K signalling respectively. A gene potentially involved in the Pl3K-rnediated rnorphology change was Lefty2. Therefore, the mechanism of L-proline induced EPL-cell formation appears to involve internalisation of L-proline and at least two signalling pathways down-stream of L-proline, which regulate different components of the transition. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1281009 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

L'organocatalyse asymétrique est un domaine en plein développement. L'immobilisation de ce type de catalyseurs pourrait présenter de multiples avantages. Ces travaux de thèse s'intéressent à la préparation de silices hybrides organiques/inorganiques par voie sol-gel et aux applications de ces matériaux en organocatalyse asymétrique. La première partie du manuscrit est consacrée à une présentation bibliographique du sujet. Dans la deuxième partie, l'utilisation de la L-proline comme modèle est décrite. Des matériaux contenant un fragment L-proline ont été préparés et leurs performances catalytiques évaluées pour une réaction d'aldolisation asymétrique. Les processus à l'origine des propriétés catalytiques modérées de ces catalyseurs supportés sont discutés. La troisième partie porte sur le catalyseur de Takemoto, organocatalyseur bifonctionnel contenant un groupement donneur de liaisons hydrogène et une fonction amine tertiaire. Les différentes stratégies envisagées pour préparer des dérivés silylés de ce catalyseur sont exposées. Enfin, la nanostructuration de silsesquioxanes par le biais de liaisons hydrogène entre fonctions thiourée est présentée. / Asymmetric organocatalysis is a blossoming area of research. Immobilisation of this kind of catalysts could present numerous advantages. This thesis deals with the sol-gel synthesis of organic/inorganic hybrid silicas and their applications in asymmetric organocatalysis. The first part of this work is dedicated to a bibliographic presentation of this area of research. In the second part, the use of L-proline as a model is described. Hybrid materials containing a L-proline component were prepared and their catalytic performances were evaluated in an asymmetric aldolisation reaction. The processes accounting for the moderate performances of these materials are discussed. The third part relates the synthetic strategies used to prepare silylated derivatives of the Takemoto catalyst, a bifunctional catalyst containig a H-bond donnor and a tertiary amine. Finally the nanostructuring of bridged silsesquioxanes through H-bonding interactions between thiourea cross-linkers is presented.

Ce travail de thèse porte dans un premier temps sur la synthèse de nouveaux sels d’azolinium chiraux précurseurs de carbènes N-hétérocycliques. Deux nouvelles familles de sels ont été préparées à partir de la L-proline. Nous avons pu caractériser les NHC issus de ces sels, par la formation des dimères, des thiones et des complexes de rhodium correspondants. Dans un second temps, ces nouveaux sels d’azolinium ont été évalués dans la réaction d’addition conjuguée de réactifs de Grignard sur des cétones α,β insaturées. Les résultats ont montré de très bonnes activités catalytiques, et de très bonnes régiosélectivités. Les énantiosélectivités obtenues sont encourageantes. Ensuite, ces catalyseurs ont été engagés dans la réaction de substitution allylique. Une bonne activité catalytique a aussi été observée malgré des régiosélectivités et des énantiosélectivités modérées. Enfin, ces sels ont été employés comme précurseurs de NHC pour la réduction asymétrique de cétones aromatiques par transfert d’hydrogène. Les complexes formés se sont montrés actifs mais non énantiosélectifs. / This work deals with, at first, the synthesis of new chiral azolinium precursors to N-heterocyclic carbenes. Two families have been prepared from the L-proline. The structures of some NHC dimmers, thiones and [Rh-NHC] complexes were characterized and confirmed by different analysis methods.Secondly, these new salts were evaluated in the conjugate addition reaction of Grignard reagents to α,β-unsaturated ketones. The results obtained shown very good catalytic activity, excellent regioselectivity with moderate enantioselectivity. They were also involved in the allylic substitution reaction. Good catalytic activity was observed despite moderate regioselectivity and enantioselectivity. Finally, these azolinium salts were employed as NHC precursors for the asymmetric transfer hydrogenation of aromatic ketones. The complexes proved to be active, but non enantioselective.

Cette thèse porte sur la préparation de nouveaux catalyseurs chiraux à partir de composés naturels issus de la biomasse, et leurs applications en organocatalyse asymétrique. La première partie décrit la synthèse de thiourées énantiomériquement pures dérivées de l'isosorbide et l’isommanide. Ces thiourées ont été évaluées comme catalyseurs organiques dans des réactions asymétriques de Friedel-Crafts, d’alkylation, d’addition de type aza-Michael, d’hydroamination et de type Morita-Baylis-Hillman (MBH). Les meilleurs résultats en termes de réactivité et d’induction asymétrique, ont été obtenus dans le cas de la réaction de Friedel-Crafts. La deuxième partie est consacrée à la conception et la synthèse de thiourée-phosphines chirales à partir de la L-proline. Ces thiourée-phosphines sont capables de promouvoir la formation de liaisons C-N et C-S, selon un processus de substitution allylique énantiosélectif d’adduits modifiés de MBH. De très bons rendements (jusqu’à 98%) et énantiosélectivités (jusqu'à 93%) ont été obtenus. Dans la troisième partie, nous avons développé le premier exemple de cyclisation [4 + 2] entre un allénoate et un alcène tétrasubstitué, catalysée par une amine tertiaire. Nous avons montré que des composés de type 4H-pyranniques peuvent être sélectivement obtenus, avec d’excellents rendements, en utilisant le DABCO comme catalyseur. Dans le cas de catalyseur organique de type alcaloïde, le β-ICD conduit sélectivement aux composés 2H-pyranniques avec des excès énantiomériques jusqu’à 71 % ee. / The thesis focused on the preparation of new chiral catalysts derived from biomass and their applications in asymmetric organocatalysis. The first part described the synthesis of chiral thioureas derived from isosorbide and isomanide, naturally renewable resource, in moderate to good overall yields. These thioureas were evaluated in asymmetric reactions such as Friedel-Crafts alkylation, aza-Michael addition, hydroamination, Morita-Baylis-Hillman reaction. Good yields and enantioselectivities were obtained. The second part of our work went on the design and synthesis of chiral thiourea-phosphines from L-Proline. These thiourea-phosphines promoted C-N and C-S bond formation via the asymmetric allylic substitution of tert-butoxycarbonyloxy adducts. Good yields (up to 98 %) and enantioselectivities (up to 93 %) were observed. In the third part, we have developed the first example [4+2] annulation of allenoate and all-carbon tetrasubstituted alkenes catalyzed by an amine. In the case of DABCO catalyst, 4H-pyrans were isolated exclusively in good to excellent yield under mild reaction conditions. While employing β-ICD as catalyst, the enantioenriched 2H-pyran derivatives were obtained with enantiomeric excess up to 71 % ee.

Alguns organismos podem biossintetizar L-prolina (L-Pro) principalmente via L-glutamato (L-Glu). A Δ1-pirrolina-5-carboxilato (P5C) sintase (P5CS) converte o L-Glu ao intermediário da via, o P5C que uma vez formado é reduzido a L-Pro via P5C redutase (P5CR). Nesse trabalho, verificou-se a possível ocorrência dessa via em Tritryps. Em Trypanosoma cruzi toda a via é operativa, em Trypanosoma brucei está ausente, enquanto que em Leishmania amazonensis acontece parcialmente. A biossíntese de L-Pro em T. cruzi é abordada com mais detalhes. Ambas as enzimas da via foram expressas e tiveram sua localização determinada no citosol, compartimento distinto das enzimas do catabolismo de L-Pro. Ainda realizou-se a caracterização bioquímica da TcP5CR, que curiosamente sofre inibição incompetitiva pelo NADPH, e por isso é candidata a regular esse metabolismo. Por fim, evidenciou-se a saída do P5C da mitocôndria, possibilitando a existência de um mecanismo de transidrogenação via a interconversão de L-Pro em P5C e vice versa. / Some organisms biosynthesize L-proline (L-Pro) mainly from L-glutamate (L-Glu). The Δ1-pyrroline-5-carboxylate (P5C) synthase (P5CS) converts L-Glu into the intermediate P5C, which in turn, is reduced to L-Pro by a P5C reductase (P5CR). In this study, we verified the possible occurrence of this pathway in Tritryps. In Trypanosoma cruzi the entire route is operative. In Trypanosoma brucei, is absent, while Leishmania amazonensis this pathway is partially operative. In T. cruzi, both enzymes were expressed and had their location determined in the cytosol, differently from those of the catabolism of L-Pro. In addition, the biochemical characterization of TcP5CR showed an uncompetitive inhibition by NADPH, and therefore it is a candidate to be a regulation point of the pathway. Finally, it was observed the exit of PC5 from the mitochondria, a condition for the existence of a transhydrogenation mechanism via the interconversion between Pro and P5C.

Yes / Studies on the substrate selectivity of recombinant ferrous-iron- and 2-oxoglutarate-dependent proline hydroxylases (PHs) reveal that they can catalyse the production of dihydroxylated 5-, 6-, and 7-membered ring products, and can accept bicyclic substrates. Ring-substituted substrate analogues (such hydroxylated and fluorinated prolines) are accepted in some cases. The results highlight the considerable, as yet largely untapped, potential for amino acid hydroxylases and other 2OG oxygenases in biocatalysis.

Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) derivatives possess cancerostatic and anti-infective properties thus making them candidates of possible antibacterial agents. ²-lactam antibiotics are vital weapons for the treatment of bacterial infections, but their existence and effectiveness has been faced with resistance from ²-lactamases. Therefore, the need for new effective antimicrobial drugs is very crucial. In this work, we synthesized in high yields, PBD analogs 1−3, 5 and 7−9 in three to four synthetic steps from commercially available L-proline and isatoic anhydride. MTT Assay was employed to test the in vitro cytotoxicity of PBD analogs 1, 2, 5 and 7 on cancer cell lines including MCF-7, SKBR-3, SKMEL-2, CaCo 2 and Mia Paca. These compounds decreased the cell viability of MCF-7 by roughly 20% however, 1 and 5 had no effect on the SKMEL-2 cell lines. The inhibitory efficacy of these PBDs were also tested against TEM-1 and P99 Serine class A and C ²-lactamases.