This thesis describes stereospecific fluorination reactions, and addresses the synthesis of fluorosugars. In Chapter 1, the influence of fluorine on the physical properties of organic molecules, as well as its stereoelectronic effects, are introduced. Furthermore, an overview of nucleophilic and electrophilic fluorination reactions is given. Chapter 2 describes the dehydroxyfluorination of allylic alcohol diastereoisomers 155a and 155b, which can proceed either by direct or allylic fluorination. The regio- and stereo- selectivities were also assessed. Chapter 3 outlines the synthesis of the novel trifluoro D-glucose analogue 193 and trifluoro D-altrose analogue 216. The transport of these hexose analogues across the red blood cell membranes was then explored, to investigate the influence of polarity versus hydrogen bonding ability in carbohydrate-protein interactions. Chapter 4 describes the development and optimisation of Bio’s methodology, to promote stereospecific dehydroxyfluorination of benzylic alcohols (R)-213 and (R)-227 by addition of TMS-amine additives 226 and 229. And finally Chapter 5 reports the experimental procedures as well as the characterisation and the crystallographic data of the molecules prepared in this thesis.

Dans cette thèse les résultats dans le domaine de la synthèse des dérivée des TADDOL et leur capacité d’induction chirale sont présentés. Une librairie des TADDOLs a été synthétisée et une analyse conformationnelle par VCD a été faite. Ces composés enantiopurs ont été testés dans la réaction de cyanosilylation enantioselective en donnant des résultats moyens. En partant de TADDOL nous avons synthétisé des dérivée phosphorés, des amines et des (thio)urées. Les dérivés de P(III) ont été utilisés comme ligands pour le palladium dans l’alkylation allylique asymétrique et les amines dans le réarrangement des époxydes meso. Les (thio)urées ont été testées pour leur capacité de complexation des anions carboxylates. / In this thesis are presented the results in the field of synthesis of TADDOL derivatives and their chiral induction capacity. A family of TADDOLs was synthesized and a conformational analysis was performed by VCD. These enantipure compounds were tested in enantioselective cyanosilylation reactions obtaining moderate results. Starting from TADDOL we obtained phosphorus derivatives, amines and (thio)ureas. The P(III) derivatives were tested as ligands for palladium in asymmetric allylic alkylation and the amines in the rearrangement of meso-epoxides. The (thio)ureas were screened for complexation capacity for carboxylate anions.

6 Title: Sythesis and catalytic properties of ferrocenophane phosphines Author: Karel Škoch Institution: Faculty of Science, Charles University in Prague, Department of Inorganic Chemistry Supervisor: prof. RNDr. Petr Štěpnička, Ph.D. Keywords: ferrocene, ferrocenophane, phosphine ligands, palladium, asymetric catalysis, aza- Morita-Baylis-Hillman reaction, asymetric allylic alkylation Abstract: This Thesis describes the preparation of five sterically and electronically different ferrocene phosphines, (R)-1,1'-[1-(diarylphosphino)propan-1,3-diyl]ferrocenes (R)-1a-e, and a study into their coordination and catalytic properties. The key precursor of the phosphine synthesis, chiral alcohol (R)-2, was prepared according to the procedure described in the literature. Alcohol (R)-2 was converted with retention of configuration to diarylphosphines (R)-1a-e in one-step reaction with trimethylsilylchloride and sodium iodide and then with the corresponding diarylphosphine. Phosphines 1a-e were characterized by NMR and MS methods. For the basic representative 1a the following palladium(II) complexes were prepared: [PdCl(LNC )(1a)] (10, LNC = 2-[(dimethylamino)methyl]phenyl-C1 ,N) and trans- [PdCl2(1a)2] (9a). In addition, the isomeric complex cis-[PdCl2(1a)2] (9b) was isolated from the reaction mixture after catalytic...

A series of chiral phosphinoferrocene amides was prepared by the condensation either of 1'- (diphenylphosphino)ferrocene-1-carboxylic acid (Hdpf) or its planar-chiral 1,2-isomers and amino acid methyl esters in the presence of peptide coupling agents. The resulting phosphinoamides were tested as ligands in Cu-catalyzed asymmetric conjugate additions of diethylzinc to chalcones and in Pd-mediated asymmetric allylic substitution reactions of 1,3- diphenylallyl acetate with the respective nucleophile (alkylation, amination and etherification). The catalytic tests were focused on an optimization of the reaction parameters (solvent, temperature, base, metal/ligand ratio) and on survey of various substrates. Compounds based on Hdpf proved to be better ligands in both catalytic reactions than their planar chiral analogues. In order to rationalize the influence of the ligand structure on the reaction course and also to interpret the catalytic results, several model complexes were prepared and structurally characterized. Other three series of non-chiral complexes were prepared from the corresponding (η6 - arene)ruthenium(II) precursor and Hdpf-glycine conjugates; the neutral complexes of the type [(arene)RuCl2(Hdpf-Gly(R)-κP)] (arene = benzene, p-cymene, hexamethyl-benzene; R = OMe, NH2, OH) as well as two...

Le mycothiazole-4,19-diol, découvert en 2006, est une molécule naturelle isolée de l’éponge marine cacospongia mycofijiensis, dont il n’existe à ce jour aucune synthèse. La structure originale, combinée à la faible abondance naturelle et à une activité biologique potentielle du mycothiazole-4,19-diol font de cette molécule une cible synthétique attractive pour le chimiste organicien et constitue l’objectif de ces travaux de thèse. Le principal enjeu de cette synthèse est la construction du motif diol-1,2 allylique. Au total, quatre déconnections ont été étudiées. Pour chacune d’entre elles, plusieurs approches ont été effectuées afin de construire de manière efficace et élégante le mycothiazole-4,19-diol. Une étude sur l’utilisation du palladium en synthèse organique a également été effectuée au cours cette thèse. Parmi les nombreux systèmes catalytiques dans lesquels ce métal intervient, nous nous sommes intéressés à l’oxydation aérobique des alcools en leurs dérivés carbonylés. Nous avons élaboré un nouveau système permettant l’oxydation sélective des alcools allyliques. Les résultats obtenus sur la haute chimiosélectivité intramoléculaire font de cette méthode un outil puissant et efficace et a été mis à profit dans le cadre des approches du mycothiazole-4,19-diol. Une étude supplémentaire réalisée sur l’utilisation du palladium en réactions séquentielles a également été menée avec l’élaboration d’un processus oxydation aérobique-formation de liaison C-C par couplage de Heck. L’originalité de la méthodologie développée est que le catalyseur intervient dans deux réactions totalement différentes permettant ainsi la synthèse rapide de molécules relativement complexes à partir de substrats simples. / Mycothiazole-4,19-diol is a natural compound isolated in 2006 from a marine sponge cacospongia mycofijiensis which has never been synthesized. Its unique structure, its weak abundance and its potential biological activity make mycothiazole-4,19-diol an attractive target in organic chemistry. The challenge is the building of allylic diol-1,2 moiety. In order to make a concise and elegant synthesis of this molecule, four disconnections and many approaches have been studied. A study about the use of palladium in organic synthesis has also been done. Among all the catalytic systems in which this metal is involved, we were first interested in the aerobic oxidation of alcohols into their corresponding carbonyl compounds. We have elaborated a new catalytic system which enables the selective oxidation of allylic alcohols. This methodology has been applied in the different synthetic approaches towards the mycothiazole-4,19-diol. A second study has been done about the use of palladium in sequential processes. We have elaborated a new catalyzed process with two sequential different steps: allylic alcohol oxidation-Heck reaction. The originality of this system is that the catalyst is involved in both reactions which makes an easy access to functionalized α,β-unsaturated ketones from allylic alcohols.

The topic of this thesis is the design and synthesis of biaryl-based self adaptableligands for asymmetric metal catalysis. The results discussed in papers I-III are covered, together with some unpublished results concerning substrate-adaptable catalysts. A general survey of self-adaptable catalysts is presented first. The second chapter of this thesis starts with a survey of inversion barriers in biphenyl-based ligands and catalysts. Thereafter, the determination of barriers to conformational adaptation in dibenzoazepines and dibenzophosphepines is described. Palladium complexes with a diphosphine ligand or a diamine ligand, as well as the free diamine ligand, were studied. Entropies and enthalpies of activation were determined with variable temperature NMR spectroscopy. The mechanism of conformational change in the metal complexes was elucidated. The third chapter describes the synthesis of semiflexible and rigid phosphinite ligands, as well as their application in rhodium-catalysed asymmetric hydrogenation. Modest enantioselectivities (up to 63% ee) were obtained. The semiflexible ligand was found to behave like the most active rigid diastereomer. The fourth chapter describes the behaviour of amine and phosphoramidite ligands in model complexes relevant to the palladium-catalysed asymmetricallylic alkylation of benchmark substrates. Diphosphoramidite and aminephosphoramiditeligands were designed and synthesised. Pd(olefin) complexesof diamine and diphosphoramidite ligands were studied, and their symmetry determined. It was found that both types of ligands are able to adapt their conformation to the substrate. / QC20100630

This thesis deals with the development and application of methods for asymmetric olefinations, in particular Horner-Wadsworth-Emmons (HWE) reactions, in the synthesis of certain natural products. Relying on asymmetric HWE reactions to access key building blocks, two natu-ral products, pyranicin and pyragonicin, were synthesized from common late intermediates. The utility of the HWE reactions is highlighted through a desymmetrization of a meso-dialdehyde as well as a stereoconvergent reaction sequence employing the sequential use of a HWE parallel kinetic resolution fol-lowed by a Pd-catalyzed allylic substitution to convergently transform a race-mate to a single stereoisomer of the product. Methodological extensions of these syntheses include a divergent synthesis of 2,3,6-substituted tetrahydropyran derivatives and application of Zn-mediated asymmetric alkynylations to install key stereocenters. Synthetic studies directed towards a more complex target, mucocin, employing a triply convergent strategy, have also been performed. Expedient and reliable routes to three key fragments were developed, as well as methodology to access to all nine stereocenters. The fragment coupling to assemble the oligonuclear core still remains a challenge, however. Key features of the synthesis include the formation of two fragments from a common precursor derived from an asymmetric HWE desymmetrization, Zn-mediatedated asymmetric alkynylations, a stereoselective oxa-Michael cyclization dependent on a simultaneous protective group migration and a one-pot procedure for the synthesis of a TBS protected iodohydrin from a terminal epoxide. An investigation of the possibilities for developing a transition metal catalyzed asymmetric olefination using a chiral Re-complex is outlined. An enantioen-riched BINAP-Re complex was synthesized and characterized by X-ray. An efficient protocol for the olefination of functionalized aldehydes employing this catalyst was developed, but gave racemic products in two attempted kinetic resolutions of racemic substrates, most likely due to a reaction pathway proceeding via a non-metal associated phosphonium ylide. / QC 20100921

This thesis deals with the design and synthesis of ligands for asymmetric catalysis: palladium catalyzed allylic alkylations, and rho-dium and iridium catalyzed hydrogenations of olefins. Chirally flexible phosphepine ligands based on biphenyl were synthesized and their properties were studied. The rotation barrier for configurationally flexible phosphepines was determined by NMR spectroscopy. The ratio of the atropisomers was shown to depend on the group bound to phosphorus. Only complexes with two homochiral ligands bound to the metal center were observed upon complexation with Rh(I). It was shown that one diastereomer of the flexible ligand exhibits higher activity but lower selectivity than its diastereomer in the rhodium catalyzed hydrogenation of methyl alfa-acetamidocinnamate. These ligands were also tested in nickel catalyzed silabora-tions. Chiral P,N-ligands with pseudo-C2 and pseudo-CS symmetry based on pyrrolidines-phospholanes or azepines-phosphepines were synthesized and studied in palladium catalyzed allylic alkylations. Semi-flexible azepine-phosphepine based ligands were prepared and their ability to adopt pseudo-C2 or pseudo-CS symmetry depending on the substrate in allylic alkylations was studied. It was shown on model allyl systems with flexible N,N-ligands that the ligand prefers CS-symmetry in compexes with anti-anti as well as syn-syn allyl moieties, but that for the latter type of complexes, according to computations, the configuration of the ligand is R*,R* in the olefin complexes formed after addition of a nucleophile to the allylic group. A preliminary investigation of the possibilities to use a su-pramolecular approach for the preparation of P,N-ligands with pseudo-C2 and pseudo-S symmetry was made. An N,N-ligand with C2 symmetry was prepared and its activity in palladium catalyzed ally-lic alkylation was studied. Pyridine-based P,N-ligands were tested in iridium catalyzed hy-drogenations of unfunctionalized olefins with good activities and se-lectivities. In order to attempt to improve the selectivity, ligands with a chirally flexible phosphepine fragment were prepared and applied in catalysis with promising results. / QC 20100929

La mise au point de méthodologies de synthèse permettant d’obtenir des substances énantiopures présentant une diversité structurale importante est une préoccupation majeure de la chimie contemporaine. L’efficacité de ces approches doit être désormais évaluée au regard de critères tel que la pureté optique et l’analyse de l’impact écologique des processus mis en jeu. Au cours de ce travail nous avons développé de nouvelles méthodologies permettant d’accéder à des γ-lactones polyfonctionnelles chirales. La 5-hydroxyfuran-2(5H)-one, petite molécule bio-sourcée, a servi d’élément clé pour la construction du cycle γ-lactone. Dans une première approche, des γ-lactones chirales possédant une grande diversité structurale ont été obtenues par une séquence réactionnelle « one pot ». Une première étape de catalyse organique a permis d’activer le transfert énantiosélectif d’acides boroniques sur la 5-hydroxyfuran-2(5H)-one ; l’adduit chiral obtenu a ensuite été engagé dans une réaction de Passerini pour construire le cycle lactone. Dans une deuxième partie, nous avons mis au point des réactions d’alkylation de γ-lactones, catalytiques et énantiosélectives, pour la formation de γ-lactones possédant un centre quaternaire. L’utilisation de complexes du palladium et de l’iridium a permis d’effectuer des réactions d’Alkylation Allylique Asymétrique avec un très bon contrôle de l’induction asymétrique. Le squelette carboné des lactones obtenues par AAA a permis d’effectuer une fonctionnalisation inédite d’hétérocycles aromatiques par des réactions sigmatropiques [3,3]. Enfin des réactions d’alkylations énantiosélectives induites par un catalyseur organique ont été évaluées. / The development of new synthetic pathway leading to enantiopure compounds with significant structural diversity is an ongoing challenge in many fields of chemistry. The efficiency of these processes has to be evaluated, not only in term of quantitative criteria, such as yields and/or optical purities of obtained compounds, but also by analyzing the environmental impact of the different processes involved. In this work, we sought to develop new methodologies for the synthesis of polyfunctional chiral γ-lactones. The 5-hydroxyfuran-2(5H)-one, a bio-based molecule, was used as a platform to the construction of the γ-lactone ring. In the first part of our work, a variety of chiral γ-lactone displaying a great structural diversity were obtained by a one-pot sequential reaction. First, a step of enantioselective organocatalysis allowed the activation for the transfer of boronic acids on the hydroxyfuran-2(5H)-one; then the chiral adduct formed was engaged in a Passerini reaction leading to the construction of the lactone ring. In a second part, our efforts focused then on the development of catalytic asymmetric alkylation reactions leading to the construction of γ-lactones bearing an all-carbon quaternary stereocenter. Asymmetric allylic reactions were carried out with a very good control of the selectivity of the reaction by the use of palladium and iridium complexes catalysts. Theses lactones bearing an [1,5]-diene scaffold were then engaged in a sigmatropic [3,3] reaction opening a path for a new approach to the functionalization of aromatic heterocycles. Finally, the use of organic enantioselective catalysis was envisioned for the creation of all-quaternary stereocenters.

Plusieurs ligands dérivés de la D-glucosamine, conçus pour différentes réactions catalytiques,ont été synthétisés. Les ligands pour la catalyse homogène basés sur 1,2-glucodiamine ontété préparés, et utilisés dans des réactions d'alkylation allylique, d'hydrogénation et d'additionde Michael.La D-glucosamine a utilisee pour la preparation de catalysateur type de SPAC (SupportedAqueous Phase Catalyst). Ce catalysateur hétérogène été utilisé avec de très bons résultatsdans les réactions de couplage croisé de Suzuki Miyaura. Le catalyseur a également étérecyclé. Des essais de préparation de ligands greffés sur une matrice de silice de type SBA-15ont été réalisés ainsi que des ligands à base de poly (éthylène) glycol. / Several ligands derived from D-glucosamine, designed for different catalytic reactions havebeen synthesized. The ligands for homogeneous catalysis based on 1,2-glucodiamine wereprepared, and used in reactions of allylic alkylation, hydrogenation and Michael addition.Supported Aqueous Phase Catalyst (SAPC) system was prepared from D-glucosamine anduse with very good results in Suzuki Miyaura cross coupling reactions. Catalyst was alsorecycled. Attempt to prepare ligands grafted on SBA-silica matrix were made as well asligands containing poly(ethylene) glycol moiety.