Helical foldamers offer variety and flexibility in the design of molecular systems, with different types of backbone geometry and side chains available to influence both structure and function. Such foldamers based on an aliphatic N,N'-linked oligourea backbone have been studied in recent years and have been shown to form very stable hydrogen-bonded 2.5(12/14) helices. This project investigated the creation of hydrogen-bonded oligourea helices to explore concepts of conformational control. Both an achiral helical system with a single chiral influence and meso oligourea helices were synthesised and analysed. The formation of a helical conformation was achieved in an achiral oligourea helix consisting of gem-dimethyl residues using a single terminal chiral controller unit based on cis-1,2-diaminocyclohexane (Dac). A preferred screw-sense was established in some oligomers, and the structural importance of the gem-dimethyl side chains and the terminal substituents was demonstrated. Urea-linked meso homo-oligomers of Dac were found to adopt a stable helical conformation, and values for their barriers of screw-sense inversion could be calculated. Conformational control of meso oligourea helices was explored through two main approaches: (i) intrinsic screw-sense preference through symmetry-breaking and (ii) the use of ligands to either induce or invert screw-sense preference. The synthetic precursors of meso oligoureas are chiral as they possess two different terminal substituents, which breaks the meso symmetry. Amplifying the difference in hydrogen-bonding capabilities of terminal substituents allowed control over the screw-sense preference of such oligomers. Binding of a chiral carboxylate ligand (Boc-D-Pro) to a meso oligourea led to a bias in screw-sense equilibrium; the binding affinity and a 1:1 ligand-foldamer complex stoichiometry were established. Finally, selective binding of achiral anions (AcO-, H2PO4-) to one terminus was used to achieve inversion of screw-sense preference of chiral oligourea helices. This research represents the first investigation of meso oligomers and uses conformational control through symmetry and symmetry-breaking as a novel concept.

The objective of this thesis is the study of the control of the shape of formamidine motifs and application to folding open-ended structures and more elaborate macrocycles. The multi-step synthesis of macrocycles M1 and M2, which are analogs of 18-crown ether-6, have been successfully achieved. Macrocycles M1 and M2 have been fully characterized. The study of the crystal structures of M1 and M2 gave interesting information about their packing and molecular recognition properties. Moreover, analysis of some by-products formed in macrocyclizations gave intriguing results. The existence of a four-pyridine-unit interlocked catenane which was isolated from the synthesis of M1 has been confirmed by MS-MS. A surprisingly large 54-membered macrocycle “Maxi-M2” was isolated from the synthetic crude product of M2 and confirmed by X-ray crystallography. Driven by the desire to understand the formation of catenane and “Maxi-M2”, a systematic study of the corresponding condensation reaction was performed. The E isomers derived from N-acyl-N’-substituted formamidoximes were, for the first time, reported and isolated. The protons can facilitate E to Z isomerization. The best conditions to selectively generate either the E or Z isomers have been fully studied and applied to the synthesis. The unexpected formation of the E isomers may promote polymerization and limit the yield improvement of macrocyclization. Therefore, a new synthetic method for the target macrocycle M2 was investigated, trying to avoid the formation of E isomers and thus cyclize more efficiently. / Thesis (Master, Chemistry) -- Queen's University, 2011-08-05 14:48:21.156

Chapter 1 outlines the development of a catalytic electrocyclic process and its exploitation in asymmetric synthesis. Since Woodward and Hoffmann delineated a rationale for the mechanism and stereochemistry of these reactions they have become powerful synthetic tools. The aim of this project was to investigate catalytic asymmetric 6π electrocyclizations that will enable the rapid synthesis of highly functionalized molecules. We have demonstrated that the transient hexatriene precursors for [1,6]-electrocyclization are difficult to synthesize. When possible the central cis-alkene prefers to exist in a trans-configured geometry, while the free ketone undergoes an essentially irreversible oxo-electrocyclization. However the precursors for [1,5]-electrocyclization could be assembled via the Suzuki or Stille reactions. We have established a methodology for [1,5]-electrocyclization using chiral phase-transfer catalysis. These reactions afford the electrocyclized products in excellent yield and diastereoselectivity with enantiomeric excess up to 68%. These transformations offer a glimpse of the potential of electrocyclic reactions. In chapter 2, the effects of cyclic backbones on the secondary structures of γ-peptides were evaluated. Two series of abiotic γ-peptides were synthesized with five and six-membered cyclic backbones. We have demonstrated that intra-residue nearest-neighbour hydrogen bonds may be favoured when the flexibility of the ring constraint can permit their formation. These cyclic backbone containing γ-peptides have been shown to populate a bend-ribbon conformation in the solution and solid phase by NMR and X-ray crystallography respectively.

Aromatic oligoamide foldamers possess a high potential for mimicking the secondary structures of biopolymers. These oligomers are efficiently designed, easy to synthesize, and allow one to reach a wide range of stable folded states.Thus far, we want to utilize stable states of these oligomers and a variety of groove binding agents combining together , and then study their influence on DNA.

Aromatic oligoamide foldamers has high potential to mimic the secondary structures of biopolymers. These oligomers by using intramolecular hydrogen bonds and £k-£k interaction of aromatic rings to form a stable foldamer. We use the helical form of these oligomers and combine to the groove binding agents, then study the influence on DNA .

La possibilité de reproduire une activité enzymatique de manière artificielle est l’un des objectifs de la chimie moderne mais reste un grand défi, même dans le cas de l’activation de petites molécules. Dans le cas du dihydrogène, certaines bactéries s’en servent comme vecteur d’énergie par l’intermédiaire d’enzymes appelées hydrogénases qui peuvent former ou consommer le dihydrogène grâce à des complexes à base de métaux non nobles. Le dihydrogène pouvant être également utilisé comme vecteur d’énergie dans nos sociétés, les hydrogénases font l’objet de nombreuses recherches. Jusqu’à présent, la plupart des complexes modèles d’hydrogénases se sont employés à modifier la première sphère de coordination pour reproduire au mieux ses propriétés électroniques. Néanmoins, l’étude de mutations ciblées des hydrogénases indique que plusieurs résidus d’acides aminés présents dans le site actif sont indispensables à la stabilité du complexe et à son efficacité catalytique, montrant ainsi comment le mime d’une deuxième sphère de coordination pourrait améliorer les propriétés des catalyseurs artificiels. Notre approche a consisté en l’utilisation de foldamères de type oligoamide aromatique, formant un cône autour d’un complexe modèle d’hydrogénase. La synthèse convergente du composé final, son étude structurale à l’état solide (diffraction des rayons X), en solution (RMN, IR) ainsi que sa dynamique ont été étudiées. La modification de la première sphère de coordination du complexe modèle en présence du foldamère est également décrite et montrant notamment leur interaction. / The ability to replicate enzymatic activity with a synthetic molecule is a highly sought after goal in modern chemistry. However, it remains a big challenge even in case of activation of small molecules. In the case of hydrogen, some bacteria can use it as energy carrier by means of enzymes called hydrogenases that can reversely make or break the bond of hydrogen molecules and are made of earth abundant metals. As hydrogen could be used for the same purpose of energy storage in our society, hydrogenases caught interest of scientific community. To date, most biomimetic hydrogenase models mainly focus on first coordination sphere modifications to fine-tune structure and physical properties. However, point mutation studies indicate that several of the amino acid residues surrounding the enzyme active site are required for structural stability or high turnover frequencies. It shows how mimicking second coordination sphere could improve the capabilities of synthetic catalysts. Our approach used aromatic oligoamide foldamers as helical scaffolds around an inspired 2Fe2S4cluster. Convergent synthesis of the final molecule and structural studies in the solid state (x-ray) and in solution (NMR, IR) as well as the dynamic behaviour are reported. Modifications of the first coordination sphere of the model complex in presence of the foldamer are also described, showing interactions between them.

In the study of structurally restricted cyclic β-amino acids and peptides, methanopyrrolidine-5-carboxylic acids (MetPyr-5-acids), or 5-syn-carboxy-2-azabicyclo[2.1.1] hexanes, and derivatives were investigated. MetPyr-5-acids are a series of highly conformationally constrained β-proline derivatives, which belong to a novel category of β-amino acids utilized as building blocks for the synthesis of β-peptides. These β-peptides lack the backbone hydrogen bonds necessary for folding in the usual manner. Substituents and functional groups in this ring system were envisioned to impact the folding properties and functionalities of the corresponding β-peptides. In the present study, the analogues of MetPyr-5-acids with C6- substitutions were prepared, and the folding properties of their peptides were explored. To introduce different functionalities at C6 in MetPyr-5-acids, 6-syn-hydroxymethyl substituted derivatives were synthesized and were used as key intermediates. In the synthesis of this core structure, the major steps in their preparation included the Michael addition of benzyloxymethyl allyl amine to 3-butynone, followed by UV light irradiation of the diene to afford 5-acetyl-6-benzyloxymethyl-2-azabicyclo[2.1.1]hexane. Haloform (Br2/NaOH) oxidation of the acetyl group leads to the 6-substituted MetPyr-5-acid. Resolution of the racemate was achieved either by resolving (±)-6-syn-benzyloxymethyl-MetPyr-5-acid via a classical crystallization resolution method using (S)-(-)-α-methylbenzylamine, or by chiral preparative HPLC separation of (±)-6-syn-benzyloxymethyl-MetPyr-5-acid methyl ester. The absolute stereochemistry was confirmed by X-ray crystallography of a derivative. Novel analogs with a range of functionalities incorporated at the C6 position in MetPyr-5-acid were synthesized from 6-syn-hydroxymethyl-MetPyr-5-acid methyl ester, and include hydrophilic groups such as hydroxyl, amino, methyl ether, and hydrophobic groups, such as substituted phenyl groups and triazole. From the protected C6-substituted analogs of MetPyr-5-acids, peptide oligomers of C6-benzyloxymethyl-2,4-methanopyrrolidine-b-amino acid were prepared up to the length of octomer in high yields. This series of oligomers were characterized by circular dichroism (CD) and indicated enhanced order of folding uniformity for the tetramer and up, with increasing ordered folding for longer oligomers. The octomer exhibited minimal solvent effects, and was stable with increasing temperature up to 80 °C. Analysis by NMR of the iso-butyric amide capped monomer indicated a mixture of cis/trans conformation favoring the cis conformation. This was slightly different from the C6 unsubstituted iso-butyric amide derivative, which favored the trans conformation. For the dipeptide, the C6-benzyloxymethyl substitution increased the percentage of cis conformation of the dipeptide amide bond, but the major peptide had the trans conformation. This demonstrated that C6 substitutions could shift the cis/trans equilibrium towards the cis conformation. Longer oligomers showed ordered secondary folding structure as demonstrated by the increase in ellipticity per amino acid unit, but was too complicated to be determined by NMR analysis. Both the CD patterns and molecular model calculation predicted that the longer oligomers (tetramer and above) favor the trans conformation. This preference was driven by the backbone dipole effect. II. SYNTHESIS OF 2,2-DISUBSTITUTED PYRROLIDINE-3-CARBOXYLIC ACIDS Due to the perceived steric influence of 2,2-disubstitution in the pyrrolidine-3-carboxylic acid, it is believed that the adjacent amide/peptide bonds should result in a trans amide bond conformation. Because of the difficulty in introducing disubstitution at the hindered C2 position, the synthesis of such derivatives has not been successful. For this reason a new method was introduced to prepare novel derivatives, at the N- and C- termini of protected 2,2-dimethyl pyrrolidine-3-carboxylic acid, i.e., benzyloxycarbonyl protected 2,2-dimethylpyrrolidine-3-carboxylate. This procedure included the Michael addition of 2-nitropropane to dimethyl fumarate, followed by ring closure of the amino ester derived from reduction of the nitro ester providing the pyrrolidinone. Reduction of the pyrrolidinone to the pyrrolidine with borane finished 2,2-dimethylpyrrolidine-3-carboxylate in moderate overall yield. A preliminary set of two amides, iso-butyric amide and 3,5-dichlorobenzamide of this 2,2-dimethylpyrrolidine-3-carboxylate, were also prepared. NMR analysis of this pyrrolidine derivative suggested the amide bonds adopted the trans conformation. It was concluded that steric bulk of the 2,2-disubstitution favorably influenced the trans amide conformation. This demonstrated that trans amide conformation control of a β-proline amide was possible. / Chemistry

La chimie des foldamères est un domaine de recherche en pleine expansion où les chimistes explorent la construction d’architectures artificielles variées mimant les structures repliées des biopolymères naturels. Les foldamères d’oligoamides quinoline, constituent une branche importante des foldamères montrant de nombreuses caractéristiques attractives, incluant la stabilité et la prédictibilité de leurs conformations repliées, qui en font de bons candidats pour des applications biologiques. Jusqu’à présent, la plupart des études sur les foldamères d’oligoamides quinolines ont été menées dans des solvants organiques. Cette thèse a pour objectif d’étendre leur portée au milieu aqueux et présente plusieurs méthodologies pour parvenir à leur solubilité, leur repliement, la variation de leurs chaines latérales, leur agrégation et leur capacité à former des cristaux dans l’eau.Tout d’abord, une méthode de synthèse en phase solide a été développée permettant l’accès rapide aux foldamères hybrides α-amino acide/quinoline (X/Q). Leur étude dans l’eau montre que contrairement aux foldamères hybrides de type (XQ)n, ceux de type (XQ2)n sont capables d’adopter une conformation hélicoïdale présentant un alignement des chaines α-amino acides dans l’espace. Ensuite, plusieurs chaines latérales courtes ont été identifiées pour doter les foldamères aromatiques d’une solubilité et d’une capacité à cristalliser dans l’eau. Six oligoamides quinoline ont ainsi été synthétisés pour une étude modèle. Des cristaux ont été obtenus pour toutes les séquences sauf une, présentant une excessive solubilité dans l’eau. Enfin, des efforts ont été faits pour construire des faisceaux d’hélices auto-assemblés dans l’eau à base d’effets hydrophobes et d’interactions électrostatiques. Les études RMN et cristallographiques ont indiqué que les effets hydrophobes étaient plus faibles qu’attendu et ne provoquaient pas d’agrégation forte. / Foldamer chemistry is a rapidly expanding research field where chemists explore the construction of various artificial architectures that mimic the folded structures of biopolymers found in nature. Quinoline oligoamide foldamers, as an important branch of foldamers, have been shown to possess many desirable features, including stability and predictability of their folded conformations, and are promising candidates to achieve biological applications. Up to now, most investigations of quinoline oligoamide foldamers have been carried out in organic solvents. This thesis is aimed to expand their scope in aqueous medium and presents several methodologies to achieve solubility, folding, side-chain variation, aggregation and crystal growth ability in water.First, a solid phase synthesis method was developed to enable the fast access to α-amino acid/quinoline (X/Q) hybrid oligoamide foldamers. The study of these hybrid foldamers in water showed that contrary to (XQ)n-type foldamers the (XQ2)n-type foldamers could adopt aromatic helical conformations with α-amino acid side chains aligned in space. Then, several short side chains were identified to endow aromatic foldamers with both solubility in, and crystal growth ability from water. Six quinoline oligoamides displaying these side chains were synthesized as a case study. Crystals were obtained from aqueous medium in all cases but one, exceedingly soluble in water. At last, efforts were made to construct self-assembled aromatic helix bundles in water based on hydrophobic effects and electrostatic interactions. NMR and crystallographic studies indicated that hydrophobic effects are weaker than expected and not strongly conducive of aggregation.

L’élaboration de nouveaux oligomères capables de mimer les propriétés des protéines naturelles est devenue un domaine de recherche très important, non seulement du point de vue structural mais aussi médicinal. Les peptides comportant des acides β-aminés ont été extensivement étudiés tandis que les recherches dans le domaine des γ-peptides sont plus récentes. Néanmoins, ces derniers montrent déjà des propriétés structurales uniques ainsi que des activités biologiques prometteuses.Dans notre laboratoire nous nous intéressons au développement d’une synthèse générale de nouveaux acides β,γ-diaminés à partir d’acides ∝-aminés naturels, notamment à la 3-déoxyaminostatine, et à leur utilisation dans la synthèse peptidique pour obtenir des peptides non-naturels afin d’étudier leurs propriétés conformationnelles. La stratégie de synthèse élaborée dans notre laboratoire et améliorée au cours de ces travaux a permis d’élargir la gamme des acides β,γ-diaminés. Deux diastéréomères cis et trans issus de la L-leucine, de la L- et D-phénylalanine ont été obtenus et engagés dans la synthèse de nouveaux peptides hybrides α/γ. Deux séries de peptides hybrides α/γ ont été étudiées. Les analyses structurales de la série comportant des acides ∝-aminés de configuration L montrent une capacité à adopter des structures secondaires bien définies, stabilisées par des liaisons hydrogènes intramoléculaires, impliquant notamment l’azote situé en β. De plus, une voie de synthèse vers un analogue d’un antibiotique naturel, le gramicidine S, a été proposée. Dans cet analogue, le motif D-Phe-L-Pro est remplacé par l’acide β,γ-diaminé issu de la D-phénylalanine. / The design of a new oligopeptides, capable to mimic the properties of natural proteins, is an important field not only for structural studies but also in the developpement of new efficient drugs. The peptides featuring β-amino acids have been extensively explored, whereas the research in γ-peptides is more recent. The studies of γ-peptides show their ability to adopt stable secondary structures and also to have a promising biological activity. Our laboratory is interested in the synthesis of new β,γ-diaminoacids.The aim of this work is a developpement of new synthetic route starting from different natural α -amino acids and to use obtained β,γ-diaminoacids to access novel unnatural peptides having specific conformational properties.The synthetic strategy, developed and optimized in our laboratory during this work, gives access to diastereomers cis and trans from L-leucine, L- and D-phenylalanine which were used in the synthesis of a new hybrid α/γ-peptides. The structural studies were performed on two series of hybrid α/γ-peptides consisting of β,γ-aminoacid from L-leucine and L- or D-α-amino acids. In the first case, the peptides are able to adopt stable secondary structures stabilized by intramolecular hydrogen bonds involving the nitrogen on the β-position. In addition, we present the synthesis of an analogue of gramicidine S, a naturally occuring antibiotic cyclic peptide. The dipeptide pattern D-Phe-L-Pro has been replaced with the β,γ-diaminoacid synthesized from D-phenylalanine.

Avec 8,8 millions de décès dénombrés en 2015, le cancer est l’une des plus grandes causes de mortalité dans le monde. De nouvelles stratégies thérapeutiques ont émergé et l’identification de nouvelles cibles biologiques comme notamment la protéine Asf1, un chaperon d’histone H3-H4 surexprimée dans les cellules cancéreuses et en particulier le cancer du sein. Cette protéine possède différentes fonctions dans la cellule et agit à plusieurs endroits par des interactions protéine-protéines. Au cours de cette thèse de doctorat, nous avons développé une stratégie originale de design d’inhibiteurs d’interactions protéine-protéine avec des foldamères peptidomimes à base d’urées. Ces foldamères ont 1) la capacité de se replier en hélice 2,5, rappelant les hélices α des peptides et 2) d’être hautement tolérés et initiateurs d’hélicité lorsqu’ils sont conjugués à des fragments peptidiques. Nous avons développé des oligomères mixtes comprenant une alternance de segment(s) peptidique(s) et multi-urée, appelées chimères, ayant l’avantage de combiner la reconnaissance naturelle de peptides et la forte propension des oligourées à former des hélices stables. Après une étude structurale montrant qu’avec l’insertion d’un court segment à base d’urées dans un peptide hydrosoluble adoptant une conformation en hélice  la conformation hélicoïdale pour une majorité des chimères est conservée, des composés mimant la partie hélicoïdale C-terminale de l’histone H3 ont été élaborés. Une interaction de l’ordre du micromolaire avec Asf1 a été observée en solution puis validée à l’état solide par cristallographie aux rayons X. En vue d’optimiser la reconnaissance de ces chimères avec la surface d’Asf1 et leur sélectivité, un panel de modifications a été réalisée (i.e. séquence primaire, longueur du segment urée). Nous avons ainsi conçu des chimères α/urée possédant des affinités de liaison pour Asf1 comprises entre le nano- et micromolaire. Le composé le plus prometteur a été internalisé avec succès dans des cellules cancéreuses après conjugaison bioreductible avec un peptide vecteur et pourrait conduire à la mort cellulaire de la lignée tumorale étudiée. / In 2015, 8.8 million of death were due to cancer making it an important cause of death in the world. The necessity to develop new anticancer treatments led to the search and discovery of new biological targets, such as Asf1, a histone chaperone protein of H3-H4 which is overexpressed in cancer cells, in particular in breast cancer. This protein plays a role in different biological processes in cells through protein-protein interactions (PPIs). During this thesis, we developed an original strategy to design inhibitors of PPIs with urea-based peptidomimetics. These foldamers are able to fold into stable 2.5-helix reminiscent to the natural α-helix. Designed urea-based foldamers have been synthesized as hybrid oligomers consisting of α-peptide and oligourea segments. With a combination of the two backbones, these compounds named “chimeras” presents advantages of both species with the natural recognition of α-peptides and the innate helical stability of oligourea. First, a model study was performed to evaluate the impact of the introduction of short urea segments into a long water-soluble peptide. Circular dichroism experiments confirmed that the helical conformation was conserved. New series of compounds that mimic a helical part of H3 were synthesized and their interaction with Asf1 was studied in solution and in solid state using a range of biophysical methods. Several modifications into the sequence were performed (side chain substitution, size of the urea segment or compound) in order to improve the recognition of Asf1 surface as well as their selectivity. We conceived oligourea-peptide chimeras with affinity for Asf1 in the micromolar range. Our best compound linked to a cell penetrating peptide was shown to enter into cells and to induce cell death.