Il est connu que les 4,5-méthano-L-prolines ont des conformations et des caractéristiques différentes que la L-proline. L’aplatissement du cycle pyrrolidine dans la proline joue un rôle important dans sa stabilité et la conformation spatiale des analogues 4,5-méthano- de la L-proline. Ainsi, des études approfondies ont été menées pour analyser les différences de structure et les modèles de pliage des cis- et trans-4,5-méthano-L-prolines et leurs oligomères en corrélation avec la délocalisation électronique n→π∗ entre les carbonyles adjacents. Dans cette thèse, la stabilisation n→π∗ entre les groupes carbonyl d’une amide et un ester a été analysée, divulguant des propriétés structurelles supplémentaires des 4,5-méthano-L-prolines. Les études spectroscopiques en RMN ont révélé les caractéristiques spatiales des cis- and trans-4,5-méthano-L-prolines corrélant avec l’équilibre d’isomérisation de l’amide trans : cis dans des environnements différents. En outre, le mécanisme de la cyclisation intramoléculaire des dimères cis-cis, trans-trans, et du mélange trans,cis-4,5-méthano-L-proline dans la formation des dicétopipérazines a révélé l'importance de la stabilisation n→π∗ sur les caractéristiques conformationnelles et de pliage. Des études de modélisation DFT ont également été menées afin de compléter nos résultats et de fournir des explications soutenant nos résultats expérimentale. / It is well known that 4,5-methano-L-prolines have different conformational properties and characteristics than proline. The flattening of the pyrrolidine ring plays a role in the stability and conformation of L-proline methanologs. Thus, extensive studies have been conducted to analyze the structural differences and folding patterns of cis- and trans-4,5-methano-L-prolines and their oligomers in correlation with the n→π∗ electron delocalization between the adjacent carbonyls of amide and ester groups. In this thesis, the n→π∗ stabilization of each derivative is analyzed, disclosing additional structural properties of 4,5-methano-L-prolines. NMR spectroscopic studies revealed the spatial characteristics of cis- and trans-4,5-methano-L-prolines in correlation to the amide trans : cis isomerization equilibrium in different solvents. In addition, the tendency of diketopiperazine formation from the cis-cis, trans-trans, and mixed trans,cis-4,5-methano-L-proline dimers reflected the importance of the n→π∗ stabilization on the conformation and folding characteristics.

Les cyclodipeptides et leurs dérivés, les dicétopipérazines (DKP), constituent une large classe de métabolites secondaires aux activités biologiques remarquables qui sont essentiellement synthétisés par des microorganismes. Les voies de biosynthèse de certaines DKP contiennent des synthases de cyclodipeptides (CDPS), une famille d’enzymes récemment identifiée. Les CDPS ont la particularité de détourner les ARNt aminoacylés de leur rôle essentiel dans la synthèse protéique ribosomale pour les utiliser comme substrats et ainsi catalyser la formation des deux liaisons peptidiques de différents cyclodipeptides. Le travail de thèse présenté dans ce manuscrit a pour objectif de caractériser la nouvelle famille des CDPS. Dans un premier temps, la caractérisation tant structurale que mécanistique de la première CDPS identifiée, AlbC de Streptomyces noursei, est présentée. Puis, les résultats obtenus avec trois autres CDPS, chacune de ces enzymes ayant des caractéristiques adéquates pour approfondir l’étude de la famille des CDPS, sont décrits. Ainsi, la CDPS Ndas_1148 de Nocardiopsis dassonvillei a permis d’étendre nos connaissances sur les bases moléculaires de la spécificité des CDPS. La CDPS AlbC-IMI de S. sp. IMI 351155 est un bon modèle pour analyser l’interaction de chacun des deux substrats nécessaires à la formation d’un cyclodipeptide. Enfin, la caractérisation de la CDPS Nvec-CDPS2 chez l’animal Nematostella vectensis a permis de fournir le premier exemple d’enzyme d’origine animale impliquée dans la synthèse peptidique non ribosomale. / Cyclodipeptides and their derivatives, the diketopiperazines (DKPs), constitute a large class of secondary metabolites with noteworthy biological activities that are mainly synthesized by microorganisms. The biosynthetic pathways of some DKPs contain cyclodipeptide synthases (CDPSs), a newly defined family of enzymes. CDPSs hijack aminoacyl-tRNAs from their essential role in ribosomal protein synthesis to catalyze the formation of the two peptide bonds of various cyclodipeptides. The aim of the work presented in this thesis manuscript is to characterize the CDPS family. At first, the structural and mechanistic characterization of the first identified CDPS, AlbC of Streptomyces noursei, is presented. Then, the results obtained with three other CDPSs, each of which having suitable properties to increase our understanding of the CDPS family, are described. The CDPS Ndas_1148 of Nocardiopsis dassonvillei extends our knowledge of the molecular bases of the CDPS specificity. The CDPS AlbC-IMI of S. sp. IMI 351155 is a good model to analyze the interaction of each of the two substrates required for the formation of a cyclodipeptide. Finally, the characterization of the CDPS Nvec-CDPS2 from Nematostella vectensis provides the first example of enzymes of animal origin involved in nonribosomal peptide synthesis.

Cyclodipeptides and their derivatives, the diketopiperazines (DKPs), constitute a large class of secondary metabolites with noteworthy biological activities that are mainly synthesized by microorganisms. The biosynthetic pathways of some DKPs contain cyclodipeptide synthases (CDPSs), a newly defined family of enzymes. CDPSs hijack aminoacyl-tRNAs from their essential role in ribosomal protein synthesis to catalyze the formation of the two peptide bonds of various cyclodipeptides. The aim of the work presented in this thesis manuscript is to characterize the CDPS family. At first, the structural and mechanistic characterization of the first identified CDPS, AlbC of Streptomyces noursei, is presented. Then, the results obtained with three other CDPSs, each of which having suitable properties to increase our understanding of the CDPS family, are described. The CDPS Ndas_1148 of Nocardiopsis dassonvillei extends our knowledge of the molecular bases of the CDPS specificity. The CDPS AlbC-IMI of S. sp. IMI 351155 is a good model to analyze the interaction of each of the two substrates required for the formation of a cyclodipeptide. Finally, the characterization of the CDPS Nvec-CDPS2 from Nematostella vectensis provides the first example of enzymes of animal origin involved in nonribosomal peptide synthesis.

SCH-64874 (5) is a fungal metabolite that inhibits the epidermal growth factor receptor (EGFR), a high-profile oncology target, with an IC50 of 1.0µg/mL. It is of particular interest because it is unlikely to inhibit the protein’s intramolecular kinase domain (as typical chemical EGFR inhibitors do), and may act instead by obstructing the receptor’s ligand binding and/or dimerisation processes. / In this work, the epipolythiodiketopiperazine family of natural products is reviewed, leading to a discussion of the probable biosynthetic pathways by which these complex molecules are produced in nature. A laboratory synthesis based on this proposed biosynthesis was subsequently proposed and undertaken. / The oxidation of aromatic systems was investigated, which led to the synthesis, for the first time, of complex functionalised arene oxides such as 178. The regioselective epoxidation of 178 was accessed by derivatisation as the Diels-Alder adduct 180. Subsequent epoxidation and manipulation led to the amino alcohol 195b, possessing the exo-epoxide endo-alcohol stereochemistry shown. / This stereochemical assignment was based on detailed NMR analysis of the product, and also on AM1 semi-empirical molecular modelling and Ab initio molecular orbital calculations, which were used to evaluate the relative stabilities of the cyclisation products.