The origin of the first RNA polymers is central to most current theories regarding the origin of life. However, difficulties associated with the prebiotic formation of RNA have lead many researchers to conclude that simpler polymers, or proto-RNAs, preceded RNA. These earlier polymers would have been replaced by RNA over the course of evolution. A remaining difficulty for this theory is that the de novo synthesis of a feasible proto-RNA has not yet been demonstrated by plausible prebiotic reactions. This thesis focuses on two problems associated with prebiotic proto-RNA synthesis: The formation of nucleosides and the necessity of reversible backbone linkages for error correction in nucleic acid polymers. "The Nucleoside Problem", or the lack of success in forming pyrimidine nucleosides by plausible prebiotic reactions, represents a significant stumbling block to the RNA world hypothesis. Nearly four decades ago Orgel and coworkers demonstrated that the purine nucleosides adenosine and inosine are synthesized by heating and drying their respective bases and ribose in the presence of magnesium, but these reaction conditions do not yield the pyrimidine nucleosides uridine or cytidine from their respective bases. In this thesis a potential solution to The Nucleoside Problem is hypothesized based upon a proposed chemical mechanism for nucleoside formation. This hypothesis is supported by the successful synthesis of 2-pyrimidinone nucleosides by a plausible prebiotic reaction in good yield, demonstrating that pyrimidine nucleosides could have been available in the prebiotic chemical inventory, but that uridine and cytidine were likely not abundant. Reversible backbone linkages are necessary to provide a mechanism for error correction in non-enzymatic template-directed syntheses of proto-RNAs. In this thesis, acetals are explored as low-energy, reversible linkage groups for nucleosides in polymers. The synthesis of glyoxylate-acetal nucleic acids (gaNAs) through simple heating-drying reactions from neutral aqueous solutions is demonstrated, and these linkages are shown to be hydrolytically stable under a considerable range of solution conditions. Computational models demonstrate that the glyoxylate linkage is an excellent electronic and isosteric replacement for phosphate. Molecular dynamics simulations also indicate that a gaNA duplex would have structural properties that closely match a phosphate-linked RNA helix, suggesting the possibility for cross-pairing between gaNAs and RNAs, allowing for sequence transfer and genetic continuity through the evolution from proto-RNAs to RNA. The principles illustrated in this thesis by 2-pyrimidinone nucleoside and gaNA synthesis can be extended to other prebiotic condensation reactions. Factors affecting condensation yield, such as thermodynamics, kinetics, reactant solubility, and salt effects, are summarized herein.

This thesis describes the synthesis of novel ligands that include enantiomerically pure acetal and oxazoline moieties. These ligands are utilised in a number of metalmediated asymmetric syntheses. All asymmetric acetals and pyridine based acetals are synthesised in good yield in a single step from their corresponding enantiomerically pure diols. C2 symmetric bisacetals are investigated as ligands in the organolithium and Grignard additions to benzaldehyde with promising results. C2 symmetric bisacetals and pyridine based acetals are tested for their ability to induce asymmetry in copper(l) catalysed cyclopropanation of styrene using ethyl diazoacetate and the lanthanide(lII) catalysed Diels-Alder cycloaddition involving Danishefsky's diene with little success. Enantiomerically pure phosphinooxazoline ligands are available in good yield in two steps from their corresponding enantiomerically pure aminoalcohols. Enantiomerically pure acetal substituted pyridines and phosphinooxazoline ligands are considered in the rhodium (I) catalysed hydrosilylation of ketones. Reaction conditions for the more successful phosphinooxazoline ligands are optimised. Using these ligands a range of enantiomerically enriched alcohols is presented in good yield and enantiomeric excess. Novel phosphinooxazoline ligands are applied to the palladium(O) catalysed allylic substitution reaction with excellent enantioselectivities of the substitution product.

Cette thèse porte sur les réactions abiotiques catalysées par un acide dans les systèmes biologiques. Elles sont définis comme des systèmes réactionnels composés d'un substrat xénobiotique - un acétal cyclique dans ce travail - stable dans des conditions biologiques et clivable à un pH bas et d'un catalyseur acide hétérogène correspondant biocompatible. Le défi de cette approche est de maintenir le catalyseur actif dans un milieu biologique tamponné et toujours capable d'hydrolyser le substrat xénobiotique d'acétal et de maintenir le pH tamponné du système vivant dans son état d'origine. Dans la première partie de ce travail, nous nous concentrons sur le réglage précis des acétals cycliques. Nous identifions 4 structures acétales et montrons que les changements structurels conduisent à une réactivité différente dans différentes gammes de pH, chacune correspondant à des applications possibles in vivo, notamment des lieurs stables pour les conjugués anticorps-médicaments et des lieurs clivables dans des conditions physiologiques pour la bioconjugaison.La deuxième partie est axée sur le catalyseur biocompatible. Ici, nous identifions deux catalyseurs biocompatibles solides, ayant différents degrés d'hydrophobie et de propriétés d’adsorption : le copolymère Nafion NR-50 et le copolymère PEG-AASA. Nous démontrons qu’avec un traitement approprié, ils peuvent maintenir un pH interne inférieur à 4, hydrolyser le substrat et ne pas affecter le biofluide hautement tamponné utilisé comme solvant. / This thesis object is acid-catalysed abiotic reactions in biological systems. They are defined as reaction systems composed by a xenobiotic substrate – a cyclic acetal in this work - stable in biological conditions and cleavable at low pH and a corresponding biocompatible heterogeneous acid catalyst. The challenge of this approach is to keep the catalyst active in a buffered biological media and still capable of hydrolysing the xenobiotic acetal substrate and to maintain the buffered pH of the living system in its original state. In the first part of this work we focus on the fine-tuning of cyclic acetals. We identify 4 acetal structures and we show that structural changes lead to a different reactivity in different pH ranges, each corresponding to possible applications in vivo, including stable linkers for antibody drug conjugates and linkers cleavable in physiological conditions for bioconjugation.The second part is focused on the biocompatible catalyst. Herein we identify two solid biocompatible catalysts, with different degree of hydrophobicity and adsorbance properties: Nafion NR-50 and PEG-AASA co-polymer. We demonstrate that, upon proper treatment, they can maintain an inner pH < 4, hydrolyse the substrate and do not affect the highly buffered biofluid used as solvent.

La fonctionnalisation C(sp3)-H catalysée par des métaux de transitions, ouvre de nombreuses perspectives en synthèse organique, permettant des voies d'accès plus économes en atomes, et en étapes à des molécules à forte valeur ajoutée. Dans cette optique, une méthode efficace permettant l'arylation des liaisons C(sp3)-H en position α d'un groupement attracteur, plus communément appelée α -arylation a récemment fait l'objet d'une attention toute particulière de la part de la communauté scientifique. Le travail détaillé dans ce manuscrit décrit les dernières avancées de cette méthodologie, ainsi qu'une variante «β-arylation » développée au laboratoire qui constitue une évolution significative dans le domaine de l'arylation regiosélective des liaisons C(sp3)-H non activées. Dans le cadre de ce projet de thèse nous nous sommes efforcés de développer cette nouvelle réaction que nous avons pu optimiser pour l'étendre à une famille plus étendue de substrats de type amino-esters. Dans la continuité de ce travail nous avons réalisé la première réaction d'arylation migratoire sélective d'amino-esters pouvant aller jusqu'à la position η d'une chaîne alkyle linéaire. Enfin, dans le but d'accéder à de nouvelles molécules à plus haute valeur ajoutée, nous avons pu appliquer notre méthodologie aux acetals de cétènes silylés permettant de dépasser certaines limitations du système existant. Dans ce cas précis, des conditions plus douces (sans base forte) ont permis l'arylation de substrats dits sensibles et par extension la synthèse de lactones fonctionnalisées / The transition metal catalysed functionalization of C(sp3)-H bonds unlocks numerous perspectives within organic synthesis in terms of atom economical access routes to otherwise difficult to synthesise molecules. One efficient method to exact such transformations involves the exploitation of an activated C-H bond situated adjacent to an activating electron withdrawing group, allowing facile insertion of a transition metal catalyst species and subsequent functionalization with a new species (normally an aryl group). This strategy is generally termed ‘α-functionalization’. The work detailed within this manuscript describes a diversion from the classic, and well documented α-functionalization reaction, in which rearrangement steps within the catalytic cycle give rise to β- and more remote substrate functionalization. The first new methodology to be described involves a fundamental extension to the in-house developed β-arylation reaction, in which, through careful substrate and ligand choice, this methodology could be applied to achieve the functionalization of simple ester enolates in remote γ- to η - positions. The developed strategy allowed the synthesis of a small range of interesting homophenylalanine analogues, and higher homologues. The second methodology to be described involves a necessary modified protocol for the β-arylation reaction, in which silyl ketene acetals were exploited as mild metal-enolate surrogates, allowing the coupling of base-sensitive substrates. The previously described reaction scope has been extended in terms of both the electrophile and nucleophile coupling partners through the development of mild reaction conditions, which subsequently allowed application of several products towards the synthesis of lactones

<p>This study addresses the issue of how to convert peptides into drug-like non- peptides with retained biological activities at peptide receptors. Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Ang II) was used as a model peptide. </p><p>Knowledge of the bioactive conformations of endogenous peptides is invaluable for the conversion of peptides into less peptidic analogues. Effectively constrained cyclic analogues, with retained pharmacological activities, may provide valuable information about the bioactive conformations of the peptide in question. </p><p>This thesis describes the development of synthesis for a number of protected, aldehyde-functionalized building blocks for standard solid phase peptide synthesis, and their use for the preparation of cyclic peptide analogues. The effect of variations in the side-chain lengths of the building blocks, on the outcome of the cyclizations was studied. Incorporation of a building block derived from L-aspartic acid afforded bicyclization towards the C-terininal end of the peptide, while for the corresponding L-glutamic acid derived building block, N-terminal directed bicyclization was achieved. A building block derived from L-2-aminoadipic acid was exploited for monocyclization furnishing <i>cis-</i> and <i>trans-</i> vinyl sulfide bridged peptide analogues. </p><p>The described cyclization methods have been applied to the synthesis of a number of conformationally constrained Ang II analogues, for which the pharmacological properties have been evaluated. Two of the Ang II analogues synthesized displayed high affinities and full agonist activities at the AT₁ angiotensin receptor, and have proven to be useful tools in the search for the bioactive conformation of Ang II.</p>

This study addresses the issue of how to convert peptides into drug-like non- peptides with retained biological activities at peptide receptors. Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Ang II) was used as a model peptide. Knowledge of the bioactive conformations of endogenous peptides is invaluable for the conversion of peptides into less peptidic analogues. Effectively constrained cyclic analogues, with retained pharmacological activities, may provide valuable information about the bioactive conformations of the peptide in question. This thesis describes the development of synthesis for a number of protected, aldehyde-functionalized building blocks for standard solid phase peptide synthesis, and their use for the preparation of cyclic peptide analogues. The effect of variations in the side-chain lengths of the building blocks, on the outcome of the cyclizations was studied. Incorporation of a building block derived from L-aspartic acid afforded bicyclization towards the C-terininal end of the peptide, while for the corresponding L-glutamic acid derived building block, N-terminal directed bicyclization was achieved. A building block derived from L-2-aminoadipic acid was exploited for monocyclization furnishing cis- and trans- vinyl sulfide bridged peptide analogues. The described cyclization methods have been applied to the synthesis of a number of conformationally constrained Ang II analogues, for which the pharmacological properties have been evaluated. Two of the Ang II analogues synthesized displayed high affinities and full agonist activities at the AT1 angiotensin receptor, and have proven to be useful tools in the search for the bioactive conformation of Ang II.

Η Ecteinascidin 743 είναι ένα σπουδαίο αντικαρκινικό φάρμακο, που καταστρέφει μέσω αλκυλίωσης τα καρκινικά κυττάρα και είναι εμπορικά διαθέσιμο με το όνομα Yondelis. Χρησιμοποιείται στην Ευρώπη, τη Ρωσία και τη Νότια Κορέα για τη θεραπεία του σαρκώματος του μαλακού ιστού, δηλαδή καρκίνου των ιστών που υποστηρίζουν το σώμα, όπως οι μύες, τα αιμοφόρα αγγεία και άλλα είδη ιστών που υποστηρίζουν και προστατεύουν τα όργανα του σώματος. Η Ecteinascidin 743 βρίσκεται υπό κλινικές δοκιμές για τη θεραπεία και άλλων μορφών καρκίνου, όπως του καρκίνου του μαστού, του προστάτη, των ωοθηκών, των νεφρών, των πνευμόνων και του μελανώματος. Απομονώθηκε από το μικρό θαλάσσιο οργανισμό, Ecteinascidia turbinate, που ζει στις θάλασσες της Καραϊβικής και ανακαλύφθηκε ότι έχει αντικαρκινική δράση το 1969. Αυτό το φυσικό προϊόν αποτέλεσε πηγή έμπνευσης για την παρούσα ερευνητική εργασία, όπου στην ρετροσυνθετική του πορεία (Εικόνα 3) περιλαμβάνεται η σύνθεση ενός μορίου πιπεραζίνης, καθώς και ενός β-λακταμικού δακτυλίου. Οι β-λακτάμες χρησιμοποιούνται σήμερα ως βακτηριοκτόνα, αντιβιοτικά, αναστολείς των πρωτεασών σερίνης και αναστολείς της ακυλομεταφεράσης της χοληστερολης (acyl-CoA: cholesterol acyltransferase, ACAT), η οποία είναι υπεύθυνη κυρίως για την αθηροσκληρωτική στεφανιαία καρδιακή νόσο. Η ασθένεια αυτή αποτελεί ήδη την πιο κοινή μορφή ασθένειας που προσβάλλει την καρδιά και μία σημαντική αιτία πρόωρου θανάτου στην Ευρώπη, σε κράτη της Βαλτικής, τη Ρωσία, τη Βόρεια και Νότια Αμερική, την Αυστραλία και τη Νέα Ζηλανδία. Η αθηροσκλήρωση σχετίζεται με την στεφανιαία καρδιακή νόσο, η οποία αποδίδεται στην ανικανότητα της στεφανιαίας κυκλοφορίας να τροφοδοτεί με επαρκές αίμα το μυ της καρδιάς και τους περιβάλλοντες ιστούς. Οι παράγοντες που οδηγούν στην αθηροσκλήρωση είναι τα υψηλά επίπεδα χοληστερόλης, η υπέρταση, ο διαβήτης, το κάπνισμα, οι κακές διατροφικές συνήθειες, η παχυσαρκία και η έλλειψη σωματικής άσκησης. Οι παραπάνω δράσεις των β-λακταμών έχουν καταστήσει πολύ ενδιαφέρουσα τη στερεοεκλεκτική και εναντιοεκλεκτική σύνθεση αυτών. Ένας β-λακταμικός δακτύλιος είναι μία λακτάμη με δομή ετεροατομικού τετραμελούς δακτυλίου, που αποτελείται από τρία άτομα άνθρακα και ένα άτομο αζώτου. Ο β-λακταμικός δακτύλιος είναι μέρος της δομής μερικών κατηγοριών β- λακταμικών αντιβιοτικών, όπως οι πενικιλίνες, οι κεφαλοσπορίνες, οι κεφαμυκίνες, οι καρβαπενέμες, οι μονοβακτάμες, και οι τρινέμες. Οι ενώσεις των β-λακταμών παρασκευάστηκαν σύμφωνα με την Mannich αντίδραση μέσω σουλφινιμινών. Οι πιπεραζίνες χρησιμοποιούνται σήμερα ως μυκητοκτόνα, αγχολυτικά, αντιικά, και ανταγωνιστές του υποδοχέα της σεροτονίνης (5-HT). Η τελευταία θεραπευτική ικανότητα των πιπεραζινών είναι πλέον ένα θέμα εκτενούς επιστημονικής έρευνας και περιλαμβάνει υποδοχείς-στόχους που ανήκουν στην κατηγορία των υποδοχέων συζευγμένων με G-πρωτεΐνη (G-ptotein-coupled receptors, GPCRs). Η εκλεκτικότητα των πιπεραζινών για τις GPCRs εμφανίζεται εξαιτίας της βασικότητας. Αυξάνοντας το μέγεθος του όρθο υποκαταστάτη σε Ν-άρυλο πιπεραζίνες, αυξάνεται η ικανότητα πρόσδεσής τους και η λειτουργική τους δραστικότητα. Οι πιπεραζίνες είναι οργανικές ενώσεις, που αποτελούνται από έναν εξαμελή δακτύλιο, ο οποίος περιέχει δύο άτομα αζώτου, που βρίσκονται στις θέσεις 1 και 4 του δακτυλίου. Οι ενώσεις των πιπεραζινών παρασκευάστηκαν σύμφωνα με την Diels-Alder αντίδραση μέσω σουλφινιμινών. Οι σουλφινιμίνες αποτέλεσαν το μόριο-κλειδί για την σύνθεση όλων των τελικών επιθυμητών προϊόντων και είναι γνωστές ως πολύ καλοί πρόδρομοι αμινών, όταν αντιδράσουν με οργανομεταλλικές ενώσεις [RLi, RMgX (αντιδραστήρια οργανολιθίου, αντιδραστήρια Grignard)]. Οι οπτικώς καθαρές σουλφινιμίνες είναι σημαντικές δομικές μονάδες (building blocks) στην ασύμμετρη σύνθεση άμινο παραγώγων, και παρασκευάζονται σε πολύ καλές αποδόσεις μέσω ενός σταδίου από αρωματικές, ετεροαρωματικές και αλιφατικές αλδεΰδες. Στην παρούσα ερευνητική μελέτη συντέθηκαν νέες β-λακταμικές ενώσεις και υποκατεστημένες ενώσεις πιπεραζίνης, συμπληρώνοντας έτσι και ενισχύοντας τα ήδη υπάρχοντα δεδομένα για τις συγκεκριμένες κατηγορίες ενώσεων αφενός και, αφετέρου, παρέχοντας νέα δεδομένα για την ολική σύνθεση του φυσικού προϊόντος, Ecteinascidin 743 (σύνθεση των εξαμελών αζόξυ προϊόντων 18, 19 και 20). Η ρετροσυνθετική ανάλυση της Ecteinascidin 743, που περιγράφηκε αρχικά, δύναται να εφαρμοστεί, σύμφωνα με τα αποτελέσματα της παρούσας ερευνητικής εργασίας. / Ecteinascidin 743 is an important antitumor drug that can service a novel way of killing cancer cells, and it is sold under the brand name Yondelis. It has been approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma, cancers of the supporting tissues of the body, such as muscles, fat, blood vessels or in any other tissues that support, surround and protect the organs of the body. Ecteinascidin 743 is undergoing clinical trials for the treatment of breast, prostate, ovarian, renal, lung, and melanoma cancers. It is isolated from the Caribbean tunicate Ecteinascidia turbinate, and was found to have anticancer activity in 1969. We were inpired by this natural product and as we can observe from its retrosynthetic analysis (Scheme 3), the synthesis of a piperazine molecule and a β-lactam ring are involved. The extreme importance of β-lactams serving not only as bactericidal and as key structural units of several important antibiotics, but also as mechanism-based inhibitors of serine proteases and as inhibitors of acyl-CoA cholesterol acyltransferase (ACAT), which is mainly responsible for atherosclerotic coronary heart disease. Coronary heart disease is already the most common form of disease affecting the heart and is an important cause of premature death in Europe, the Baltic states, Russia, North and South America, Australia and New Zealand. Atherosclerosis is most commonly equated with atherosclerotic coronary artery disease, which is rendered in the failure of the artery circulation to supply with sufficient blood the heart muscle and the surrounding tissues. Risk factors for the coronary heart disease include high levels of cholesterol, hypertension, diabetes, smoking, bad diet habbits, obesity, and lack of excercise. The above activities of β-lactams have propelled strong resurgent interest toward their stereoselective and enantioselective synthesis. A β-lactam ring is a lactam with a heteroatomic four-membered ring structure, consisting of three carbon atoms and one nitrogen atom. Penicillins, cephalosporins, cephamycins, carbapenems, monobactams, and trinems are classified as b-lactam antibiotics. β-Lactams were prepared by the Mannich reaction using sulfinimines. Piperazines are used now-a-days as antifungals,antidepressants, antiviral, and serotonin receptor antagonists (5-HT). The latter therapeutic area of piperazines has been the subject of intense research and includes targets belonging to the G-Protein- Coupled Receptor (GPCR) superfamily. The selectivity of piperazines towards GPCRs has deen attributed to their basicity. Increasing the size of the ortho substituent in N-aryl piperazines resulted in an increase in binding affinity and functional potency. Piperazines are organic compounds that consists of a six-membered ring containing two opposing nitrogen atoms, at the 1 and 4 positions of the ring. Piperazines were prepared by the Diels-Alder reaction using sulfinimines. Sulfinimines are the key-compounds for the synthesis of the final desirable products described herein and excellent precursors of amines, when they react with organometallic compounds [RLi, RMgX (organolithium reagents, Grignard reagents)]. Enantiomerically pure sulfinimines representing, important building blocks in the asymmetric synthesis of amine derivatives, are prepared in high yields in one step from aromatic, heteroaromatic, and aliphatic aldehydes. In this project, novel β-lactam compounds and substituted piperazine compounds were synthesized, in order to complete and highlight the already existing data for these specific compounds classes and provide new data about the total synthesis of the natural product, Ecteinascidin 743 (synthesis of six-membered azoxy products 18, 19 and 20). The retrosynthetic analysis of Ecteinascidin 743 could be viable given the result described in Scheme 44.

L’alcool polyvinylique a été fonctionnalisé avec des aldéhydes et des acides boroniques dans le but d’obtenir des polymères pouvant apporter de la brillance tout en étant solubles dans les formulations de rouges à lèvres ou de vernis à ongles. De bons taux de fonctionnalisation ont été obtenus permettant d’avoir une bibliothèque de poly(vinyl acétals) et de poly(vinyl esters boroniques) d’une cinquantaine de polymères. Une multi-fonctionnalisation du PVA a été effectuée pour obtenir des polymères alliant ces deux propriétés. Cinq poly(vinyl acétals) ont ainsi permis d’apporter une forte brillance à des rouges à lèvres. La E-poly-L-lysine a également été fonctionnalisée avec diverses cétones afin d’obtenir de nouvelles poly-4-imidazolidinones. Ces polymères sont prometteurs pour des applications dans des produits cosmétiques tels que des soins. Ils ont également été utilisés en catalyse organique asymétrique. / Poly(vinyl alcohol) has been functionalized with aldehydes and boronic acids to obtain polymers with high shining and being soluble in cosmetic formulations as lipsticks or nail polishes. Good grafting rates have been obtained permitting to have a library of about fifty poly(vinyl acetals) and poly(vinyl boronic esters). Multi-functionalization has been developped to obtain polymers having these both properties. Five polymers gave strong shining to lipsticks. E-poly-L-lysine was also functionalized with several ketones to obtain new poly-4-imidazolidinones. These polymers are promising for cosmetic applications as skincare products. They were also used for organocatalysis.

La Polymérisation Radicalaire par Ouverture de Cycle (R-ROP) est une méthode de synthèse de polymères contenant des fonctions chimiques de choix dans le squelette carboné grâce à un mécanisme d'addition-fragmentation. L'utilisation de monomères spécifiques, les Acétals Cétènes Cycliques (CKA), permet dans certaines conditions l'obtention de polyesters aliphatiques dont la propriété de (bio)dégradation présente de nombreuses applications. Cette méthode relativement peu étudiée depuis les années 1980 présente un fort potentiel mais également de nombreuses limites. Ce travail de thèse a consisté à comprendre l'origine de ces limites pour tenter d'y apporter des solutions, grâce à une approche combinée expérience-théorie.Nous avons montré que l'obtention exclusive de polyesters découle d'une compétition cinétique et que le comportement des différents monomères s'explique par des interactions orbitalaires dépendant de la géométrie, la flexibilité et la substitution des cycles. D'autre part, nous avons mis en évidence l'extrême difficulté de propagation des monomères propageant via des radicaux stabilisés par des cycles aromatiques. Cette faible réactivité inhérente à la double liaison riche en électrons des CKA est également la cause de l'incorporation restreinte des monomères cycliques en copolymérisation avec des monomères vinyliques usuels. La rationalisation de la copolymérisation a été mise à profit pour réaliser des copolymérisations de type statistique et alternée. Enfin, l'étude du contrôle de la R-ROP par les nitroxydes a montré la présence de réactions secondaires propres à ce système et permettant actuellement un contrôle partiel de la polymérisation. / The Radical Ring-Opening Polymerization (R-ROP) is a synthetic pathway to introduce chemical functions into a polymer backbone due to an addition-fragmentation mechanism. Using specific monomers like Cyclic Ketene Acetals (CKA) in the right conditions allows preparing aliphatic polyesters which have numerous applications thanks to their (bio)degradability. This method has been quite faintly investigated since the 1980s and even if it has a great potential, it suffers of numerous limitations. This PhD work consisted in the understanding of those limitations to try bringing solutions to them, with a combined approach of experiments and theory.We first demonstrated that the exclusive preparation of polyesters comes from a kinetic competition. The behavior of the distinct monomers is explained by orbital interactions depending on the geometry, flexibility and substitution of the cycles. Then, we highlighted the extremely difficult propagation of the monomers propagating with stabilized aromatic radicals. This low reactivity inherent to the electron-rich double link of the CKAs is also the cause of low polyester introduction during the copolymerization with usual vinyl monomers. We took advantage of the CKA copolymerization rationalization to realize statistical and alternate copolymerizations. At last, the study of the nitroxide mediated R-ROP demonstrated the occurrence of side reactions characteristic of this system that allow at present a partial control of the polymerization.

Les symbioses bactérie-légumineuse (nodulation) et champignon-plante (mycorhization) présentent un intérêt agrobiologique et écologique majeur ; elles permettent aux plantes de croître naturellement sur un sol aride et peu fertile. Il a été démontré très récemment que les signaux impliqués dans la mise en place de la symbiose endomycorhizienne à arbuscule (facteurs "Myc") sont très proches de ceux de la nodulation. Il s'agit de molécules appartenant à la famille des lipo-chitooligosaccharides. Afin de réaliser la synthèse de ces molécules, deux nouvelles méthodologies ont été développées. L'ouverture oxydante d'acétals de 4,6-O-benzylidène de plusieurs glycopyranosides (en série gluco, galacto et manno) par le diméthyldioxirane (DMDO) a été étudiée. Le contrôle de la régiosélectivité a été effectué grâce au groupement protecteur introduit sur la fonction alcool de la position 3. La formation directe de β-glycosides de la N-acétyl-D-glucosamine par catalyse au triflate de fer (III) a été étudiée. La réaction a été menée sous irradiation micro-ondes ou en flux continu (système minifluidique Vapourtec®). Une nouvelle stratégie pour la synthèse du facteur [Myc-IV (C16:0, S)] a ensuite été établie. Nous avons utilisé un réactif peu toxique et non odorant pour introduire le motif thio nécessaire à la formation de deux liaisons glycosidiques. Le disaccharide précurseur de l'unité réductrice a été obtenu grâce à la première méthodologie développée au cours de cette thèse. / Arbuscular mycorrhiza (AM) is a root endosymbiosis between plants and fungi. It has an agrobiological interest and a crucial ecological importance because it allows plants to grow on aride and infertile soil. Recently, the structure of the symbiotic signal "Myc factor" was identified as a mixture of lipochitooligosaccharides (LCOs). In order to propose a new synthesis of LCOs, we developed two green methodologies in glycochemistry. We performed the oxidative cleavage of 4,6-O-benzylidene acetals of various glycopyranosides (gluco, manno and galacto series) with dimethyldioxirane (DMDO) and its regioselective control with a suitable protecting group at position 3. We investigated the formation of β-glycoside of N-acetyl-D-glucosamine using catalytic iron (III) triflate. The reaction can be performed using microwave irradiation or, for scale-up synthesis, flow chemistry using Vapourtec® minifluidic system. We establish a new strategy for the total synthesis of the most abundant Myc factor [Myc-IV (C16:0, S)]. We used odorless and few toxic MbpSH reagent to introduce the activated thio residue involved in two glycosylation reactions. The disaccharide acceptor precursor of the reducing end was obtained after oxidative cleavage of the 4,6-O-benzylidene moiety by DMDO.