The research on phosphorus-chalcogen compounds enjoys a long tradition in the field of inorganic chemistry, which has led to applications such as strike-anywhere matches, precursors for metal chalcogenide thin films and versatile reagents in organic synthesis. Whereas a wide range of phosphorus-sulfur and -selenium systems is known, the literature lacks information about compounds incorporating phosphorus-tellurium bonds. This thesis describes fundamental studies that develop the basic understanding of the synthesis of phosphorus-tellurium systems and the structural characteristics of these species. The focus will be on cyclic structural motifs as these offer novel bonding modes and often an interesting reactivity. In addition, the novel compounds are compared with the properties of the sulfur and selenium analogues. Three different approaches were developed to stabilise and study compounds incorporating phosphorus-tellurium bonds: a) Stabilisation of binary organophosphorus-tellurium heterocycles by bulky substituents, b) the utilisation of P₂N₂ rings based on the dianions [{EP(NtBu)(μ-NtBu)}₂]²⁻ (E = S, Se, Te) and c) the peri-substitution of phosphorus and tellurium atoms on an acenaphthene backbone. The use of sterically demanding substituents led to the isolation of the first series of structurally characterised organophosphorus(III)-tellurium heterocycles of the type (RP)[sub]nTe[sub]m including three- to six-membered ring systems. The mild oxidation of [{EP(NtBu)(μ-NtBu)}₂]²⁻ (E = S, Se, Te) with iodine yielded macrocyclic (S, Se) or oligomeric systems (Te). Furthermore, a collection of novel P₂N₂-supported phosphorus-chalcogen heterocycles incorporating main group elements was synthesised employing [{EP(NtBu)(μ-NtBu)}₂]²⁻ (E = S, Se, Te) in metathetical reactions with main group element halides. Extension of this approach to transition metal halides generated some unusual metallocycles, as well as macrocycles and ladders incorporating coinage metals. The first peri-substituted phosphorus-tellurium species were studied regarding their interatomic and intermolecular forces. Systems of the general formula RTe–Acenap–P(iPr)₂ were shown to exhibit extensive through-space spin-spin coupling. In addition, the influence of oxidation and complexation on these interactions was investigated and the formation of peri-substituted phosphorus-tellurium cations exhibiting P–Te bonds was observed.

Peptidomimetics are synthetic oligomers that resemble the activities of peptides. Their advantages over peptides include high stability towards proteolysis and enormous chemical diversity. Over the past two decades, there have been extensive efforts to develop peptide mimics, such as beta-peptides, peptoids, D-peptides, etc. The research on peptidomimetics have led to many important applications in both medicinal and material science. In order to explore new functions, the discovery of peptidomimetics with novel frameworks is essential. We reported the synthesis and evaluation of a new class of peptidomimetics, termed as gamma-AApeptides. Previous studies of gamma-AApeptides have revealed that gamma-AApeptides are highly resistant to proteolysis, and are highly amendable to chemical diversification. However, new biological activities and folding properties of gamma-AApeptides still need to be explored. In order to expand the potential of gamma-AApeptides in chemical biology and medicinal chemistry, I have been focusing on the development of new methods to synthesize linear and cyclic gamma-AApeptides, development of one-bead-one-compound (OBOC) gamma-AApeptide libraries for the discovery of inhibitors against beta-amyloid aggregation, exploring new helical foldamers for the rational design of protein-protein interaction (PPI) inhibitors, and studying cyclic gamma-AApeptides for antimicrobial development.

Summary of the thesis This works aims at reporting a novel strategy that combines controlled ring-opening polymerization of lactones initiated by a cyclic tin(IV) dialkoxide and intramolecular cyclization by photo-cross-linking of pendant unsaturations next to the propagating sites. No linear species is ever involved in the polymerization, which allows higher molecular weight macrocycles to be prepared with high efficiency. Moreover, the synthetic route is very flexible to the point where macrocyclic polyesters with more complex although well-defined architectures, such as tadpole-shaped and sun-shaped copolyesters, can be tailored. Synthesis of well-defined star- and eight-shaped polyesters and twin tadpole-shaped amphiphilic copolymers has also been explored by using a spirocyclic tin(IV) alkoxide as initiator.

Cyclic peptides possess desirable characteristics as potential pharmaceutical scaffolds. The cyanobactin family of cyclic peptide natural products boast diverse structures and bioactivity. Exemplars are the patellamides, which have attracted attention due to their ability to reverse the effects of multi-drug resistance in human leukemia cells. In addition to their macrocyclic architecture patellamides contain azol(in)e heterocycles and d-amino acids. This structural complexity makes them challenging targets for chemical synthesis. Understanding their biosynthesis will enable the development of a biotechnological ‘toolkit' for the synthesis of new pharmaceutical compounds. Patellamides are ribosomally-synthesised and post-translationally modified peptides (RiPPs) and much of their biosynthesis has been elucidated, however there are still elements of their biosynthesis that are not yet fully understood. PatA and PatG contain C-terminal domains of unknown function (DUFs). The crystal structure of PatG-DUF has been solved and subsequent to biochemical and biophysical investigation PatG-DUF was found not to constitute an essential part of the biotechnological ‘toolkit' and can be excluded from in vitro enzyme-based synthesis of cyanobactin-like cyclic peptides. The cyanobactin heterocyclases are able to introduce heterocycles into a peptide backbone, seemingly irrespective of the neighbouring residues; however a molecular rational governing substrate recognition is unknown. Additionally the mechanism of heterocyclisaton is disputed. Analysis of crystal structures of LynD in complex with cofactor and substrate (solved by Dr Jesko Koehnke) enabled the active site and substrate recognition site to be located. A new mechanism for heterocyclisation has been proposed. Guided by the substrate recognition observed in complex structures a constituently active heterocyclase (AcLynD) has been engineered, which is able to process short, leaderless peptide substrates. Epimerisation in cyanobactin biosynthesis is believed to be spontaneous, but its precise timing is uncertain. NMR analysis of selectively labelled peptide substrates processed by the modifying enzymes, identified epimerisation to be spontaneous on the macrocycle, regardless of whether the neighbouring heterocycles have been oxidised. A one-pot in vitro synthesis of cyanobactins has been developed, and employed to create a number of patellamide D analogues to ascertain structural-activity relationships.

xx, 290 p. : ill. (some col.) / Macrocyclic phosphine compounds have long been sought as ligands for transition metal complexes because of their strong binding properties. Despite considerable effort in this field, no general methods for synthesizing phosphine macrocycles or their complexes have been developed. This dissertation describes attempts to synthesize an iron complex with a water-soluble macrocyclic tetraphosphine ligand for use in separating nitrogen from natural gas. Chapter I reviews previous syntheses of macrocyclic phosphine ligands and their complexes, focusing on ligand synthesis, coordination chemistry, and demetallation of the complexes. Chapter II reports on the synthesis of water-soluble secondary bidentate phosphine ligands, their coordination chemistry with iron(II), and attempts to use these complexes as templates for forming a macrocyclic iron-phosphine complex by reactions with carbon electrophiles. Over the course of treating these iron complexes with various carbon electrophiles, an interesting reaction between bromomaleic anhydride and proton sponge was discovered. Chapter III explores the product, 4-maleicanhydrido-1,8-bis-(dimethylamino)naphthalene (MAPS). Due to its conjugated donor-acceptor network, which is disrupted upon protonation, MAPS acts as a colorimetric version of a proton sponge. The attachment of MAPS to amine-functionalized solid supports, forming solid-supported proton sponge reagents, is also described. Chapter IV discusses the synthesis of an iron(II) complex of the water-soluble phosphine 1,2-bis(di(hydroxymethyl)phosphino)ethane (DHMPE). Although unbound hydroxymethylphosphines commonly react with NH-functional amines via the phosphorus Mannich reaction, this and other complexes of DHMPE do not undergo this reaction. Further investigation with hydroxymethylphosphine-boranes suggests that the currently-accepted mechanism of the phosphorus Mannich reaction is incorrect, and an alternate mechanism is proposed. Chapter V discusses the synthesis and functionalization of copper(I) complexes of water-soluble phosphines. Unlike the complexes described in Chapter I, these complexes readily react with α,ω-dihalides or di(acyl chloride)s, forming complexes whose mass spectra correspond to those with macrocyclic phosphine ligands. Unlike most macrocyclic tetraphosphine complexes, these complexes can be demetallated by treatment with sulfide. Finally, a new synthesis of water-soluble macrocycles, based on lessons learned during the course of these investigations, is proposed. This dissertation includes previously published and unpublished co-authored material. / Committee in charge: Dr. Michael M. Haley, Chairperson; Dr. David R. Tyler, Advisor; Dr. Darren W. Johnson, Member; Dr. Shih-Yuan Liu, Member; Dr. Mark H. Reed, Outside Member

La thérapie photodynamique (PDT) est une technique thérapeutique qui permet un traitement localisé par irradiation lumineuse d’un photosensibilisateur (PS) grâce à la génération d’une espèce cytotoxique, généralement de l’oxygène singulet. Cependant, de nombreux PS sont également luminescents et les deux processus sont compétitifs. L’emploi de métaux de transition est connu pour améliorer le processus de PDT mais l’impact des ions lanthanides(III) en PDT est encore peu connu. Par ailleurs, l’utilisation de l’absorption biphotonique a de nombreux avantages parmi lesquels la possibilité d’exciter le PS dans la fenêtre de transparence biologique pour des applications en milieux biologiques.Les travaux de cette thèse visent à étudier quel est l’influence de la complexation d’un atome de lanthanide(III) à un PS sur la photophysique de désexcitation de ce dernier. Les complexes synthétisés et ceux étudiés ont montré que l’effet dépend du lanthanide(III). Il est ainsi possible, avec un choix judicieux du métal, de favoriser une voie de désexcitation par rapport à une autre. En particulier, l’ion Gd(III) se révèle avoir un effet bénéfique important pour la génération d’oxygène singulet et cet effet s’ajoute à celui que des atomes lourds comme le brome peuvent avoir. L’ion Yb(III) en revanche, favorise de manière générale le transfert d’énergie par effet d’antenne et la luminescence du lanthanide est alors le processus majoritaire. Enfin, l’emploi de Gd(III) complexé à un PS excitable à deux photons ouvre la voie à des agents théranostiques moléculaires combinant l’IRM en tant que fonction d’imagerie et la PDT pour la thérapie. / Photodynamic Therapy (PDT) is a therapeutic technique which consists in generating a highly reactive species, generally singlet oxygen, by shining light on a photosensitizer (PS). However, many PS are also luminescent and both processes are competitive. The use of transition metals is well known to enhance the PDT effect, but little is known about the effect of lanthanide(III) metals.On the other hand biphotonic absorption has numerous advantages, among them the possibility to excite the PS in the so-called biological transparency window for biological applications.The aim of this PhD is to get a better comprehension of the effect of complexation of a lanthanide(III) atom with a PS on the photophysics and deactivation pathways of the latter. The synthesis and conducted studies of lanthanide complexes showed that the effect is dependent on which lanthanide(III) metal is used. Thus by choosing carefully the lanthanide metal, one can favor one deactivation pathway over another. In particular, the Gd(III) ion turns out to be very efficient in promoting singlet oxygen generation and its effect is additive to the already known positive effect of heavy atoms such as bromine. On the opposite, the Yb(III) ion mainly favors the energy transfer through the antenna effect and the complex preferentially emits light.Finally, using Gd(III) linked to a two-photon excited PS opens the path to molecular theranostic probes combining MRI as a imagery technique and PDT as a therapeutic one.

El diseño molecular fundamentado en la imitación de las complejas estructuras y procesos que se encuentran en la naturaleza se conoce como Química bioinspirada o Química biomimética. Una de las aproximaciones utilizadas en esta disciplina es la preparación de compuestos seudopeptídicos macrocíclicos a partir de aminoácidos naturales y componentes abióticos. En la naturaleza existen proteínas con propiedades muy específicas y diversas. El uso de la información codificada en las cadenas laterales de los aminoácidos es un factor clave que, a su vez, puede utilizarse con ventaja para el diseño de seudopéptidos con propiedades específicas bien definidas. Por tanto, una selección apropiada de los componentes estructurales, naturales y no naturales, permite el diseño estructural adecuado para obtener la funcionalidad deseada. / The molecular design based on the imitation of the complex structures and processes found in nature is known as bioinspired Chemistry or biomimetic Chemistry. An approach used in this discipline is the preparation of macrocyclic pseudopeptidic compounds from natural amino acids and abiotic components. Proteins exist in nature with very specific properties encoded by the diverse structural and conformational information of the amino acids side chains. The use of this information is a key factor in the design of pseudopeptides with well-defined properties. Therefore, a suitable structural design to obtain the desired functionality relies on the appropriate choice of structural components, natural and abiotic.

The major aim of research reported on this thesis uses X-ray crystallography to investigate the structural features of a series of pentafluorosulfuranyl (SF₅) containing aromatic compounds, chalcogen amides, 2,4-diaryl-1,3-selenazoles and 2,4-diaryl-1,3-chalcogen azoles bearing SF₅ group and organo phosphorus-chalcogen macrocycles incorporationg double OP(S)SC[sub]n or OP(Se)SeC[sub]n scaffolds. The basic theory of crystallography is introduced in Chapter 1, followed by a general discussion on pentafluorosulfuranyl (SF₅) containing heteroatom compounds and sulfur/selenium heterocycles in Chapter 2. Ten pentafluorosulfuranyl (SF₅)-containing aromatic compounds have been studied crystallographically in Chapter 3. All S-F bond lengths in these compounds are very similar [1.571(3) to 1.618(3) Å and 178.5(3) to 180.0° for the C-S-F(ax) bond] and the angles of two adjacent F(eq) is approximate to 90°. The intramolecular C[sub](aryl)-H···F(eq) and intermolecular C[sub](aryl)-H···O/N/F/Cl interactions, and π-stacking interactions are observed in the packing frameworks. X-ray crystal structure analysis reveals that in the structures of 2,4-diaryl-1,3-selenazoles in Chapter 4, the five-membered N-C-Se-C-C rings have either planar or near-planar conformations, and exhibit a series of the intramolecular and intermolecular C-H∙∙∙O/N/Se/Br/Cl) interactions and π-stacking interactions. The crystal structures of 2,4-diaryl-1,3-chalcogen azoles with both a pentafluorosulfuranyl (SF₅) group and a five-membered N-C-Se-C-C ring have been investigated in Chapter 5. A diverse picture of molecular configuration and intramolecular/intermolecular C-H∙∙∙N/Se/S and π-stacking interactions information are disclosed in selenamide, thiamides, 1,3-selenazoles and 1,3-thiazoles. Nine organo phosphorus-chalcogen macrocycles with nine- to fifteen-membered ring incorporating double OP(S)SC[sub]n or OP(Se)SeC[sub]n scaffolds have been discussed crystallographically in Chapter 6. The similar intramolecular and intermolecular C-H∙∙∙O, C-H∙∙∙S or C-H∙∙∙Se interactions are observed to lead to the similar packing networks.

Les macrocycles représentent une catégorie chimique unique en chimie organique et ils possèdent des applications dans les industries pharmaceutique et agrochimique, en parfumerie, et dans les matériaux. Une propriété importante des macrocycles est la possibilité de démontrer de la chiralité planaire menant à des atropoisomères distincts aux propriétés uniques. Très peu de techniques générales existent pour le contrôle de l’atropoisomérisme au sein des macrocycles, rendant leur synthèse un véritable défi. Nous avons accompli le premier exemple d’une synthèse biocatalytique énantio- et atroposélective de p-cyclophanes planaires chiraux. En utilisant une lipase immobilisée commercialement disponible (CALB) et des matériaux de départ pro-chiraux simples, nous avons été en mesure de générer 23 différentes structures avec des rendements entre 11 et 88 %. Des analyses SFC ont permis l’évaluation de l’énantioenrichissement des différents macrocycles, étant compris entre 96 et >99 % ee. Surtout, les macrocycles planaires chiraux ayant des substituants de type halogène ou borylé peuvent subir de la diversification moléculaire au-delà des limites tolérées par l’enzyme. Notre découverte ouvre la porte à l’utilisation de biocatalyseurs pour le contrôle de l’atropoisomérisme lors de la formation de structures macrocycliques. / Macrocycles represent a unique chemotype in organic chemistry, with applications ranging from pharmaceuticals, agrochemicals, aromachemicals and material science. An important property of macrocycles is the possibility of displaying planar chirality yielding distinct atropisomeric structures with unique properties. Very few generalized techniques capable of controlling atropisomerism in macrocycles exist, rendering their synthesis extremely challenging. We have achieved the first example of enantio- and atroposelective biocatalytic synthesis of planar chiral p-cyclophanes. Employing a commercially available immobilized lipase (CALB) and simple pro-chiral starting materials, we were able to generate 23 different structures with yields ranging from 11 to 88 %. SFC analysis permitted evaluation of the enantioenrichment of the different macrocycles, which ranged from 96 to >99 % ee. Importantly, planar chiral macrocycles having halogen or borylated substituents are capable of molecular diversification outside the boundaries of what may be tolerated by the enzyme. Our discovery paves the way for the use of biocatalysts in the control of atropisomerism during macrocycle formation.

No description available.