No description available.

The alkoxytriphenylphosphonium ion intermediate of the Mitsunobu reaction for the esterification and inversion of configuration of an alcohol can be generated using the Hendrickson reagent, triphenylphosphonium anhydride trifluoromethanesulfonate, 27. While 27 was used in place of the Mitsunobu reagents (triphenylphosphine and a dialkyl azodicarboxylate) for the esterification of primary alcohols, the reaction failed with secondary alcohols such as (-)-menthol giving predominately elimination rather than the desired SN2 displacement. The difference between the two reactions was shown to be related to the more 'ionic' conditions generated when the Hendrickson reagent 27 was employed. An extreme sensitivity of the Mitsunobu reaction to the presence of salts was discussed and may indicate a mechanism involving ion pair clustering. Five-, six- and seven-membered cyclic analogues of the Hendrickson reagent 90-92 were prepared. A kinetic comparison of the cyclic analogues 90-92 revealed that a considerable increase in the rate of esterification could be achieved when the five-membered ring analogue 90 was used in a non-polar solvent such as toluene. Selected acyclic analogues of the Hendrickson reagent 27 possessing tributyl 118, tricyclohexyl 130 and diphenyl-2-pyridyl 137 functionalities were synthesised. However when 118, 130 and 137 were used for the attempted esterification of (-)-menthol, elimination was the major reaction pathway. Diphenyl-2-pyridylphosphonium anhydride triflate 137 was found to be a useful reagent for the synthesis of acyclic dialkyl ethers from primary alcohols. A polymeric version of the five-membered ring analogue 56, prepared by reaction of the polymer-supported 1,2-bis(diphenylphosphinyl)ethane 57 with triflic anhydride, was used for the preparation of simple esters and amides. A new dehydrating agent, polymer-supported triphenylphosphine ditriflate 157, was readily prepared from the oxidised form of commercially available polymer-supported triphenylphosphine and triflic anhydride. A wide range of dehydration-type reactions, such as ester, amide, anhydride, peptide, ether and nitrile formation, were performed in high yield using polymer-supported triphenylphosphine ditriflate 157. The reagent 157 was easily recovered and re-used several times without loss of efficiency. The use of 4-dimethylaminopyridine allowed the esterification of secondary alcohols with 157 to proceed without elimination and gave esters in high yield but with retention of configuration. Both reagents 56 and 157 provide an alternative to the Mitsunobu reaction, where the use of azodicarboxylates and chromatography to remove the phosphine oxide by-product can be avoided. However, the Mitsunobu reaction retains its supremacy for the inversion of configuration of a secondary alcohol. Preliminary investigations on the phosphityation of alcohols via the Hendrickson reagent 27, 1,3-benzodioxole formation using the Mitsunobu reaction and azodicarboxylate alternatives in the Mitsunobu reaction are described.

No description available.

Ce travail décrit la synthèse, l’oligomérisation et l’étude structurale de [alpha-N-amino]mères. En extrapolant une stratégie de synthèse originale d’alpha-hydrazinoacides optiquement purs développée au LCPM nous avons pu obtenir de manière satisfaisante les N-aminodipeptides, précurseurs indispensables à la suite du projet. Nous avons pu montrer que l’activation du partenaire acide impliqué dans la réaction clé de Mitsunobu, habituellement obtenue par l’utilisation du groupement phtalimide, pouvait être avantageusement réalisée par l’introduction d’une fonction hydrazone à caractère fortement électroattracteur. Une extension de cette méthode de synthèse sur résine est un résultat qui constitue une mise en œuvre efficace de la réaction de Mitsunobu en SPS. Les N-aminodipeptides obtenus ont ensuite été engagés dans des réactions d’oligomérisation. Une étude préliminaire en phase liquide a permis de démontrer la faisabilité d’un couplage peptidique classique entre deux unités pseudopeptidiques déprotégées. La suite de l’étude a été effectuée sur phase solide et nous a permis d’obtenir les tous premiers oligomères à squelette alpha-N-aminopeptidique jamais synthétisés à ce jour. Enfin, dans le troisième chapitre, ces oligomères ont été étudiés par modélisation moléculaire et par différentes méthodes spectroscopiques (RMN, IR) qui ont permis de mettre en évidence un repliement par l’établissement de liaisons hydrogène intramoléculaires / This work describes the synthesis, the oligomerization and the structural study of N-aminopeptides. By extrapolating an original strategy of hydrazinoacids synthesis developed in the LCPM we were able to obtain N-aminodipeptides in high optical purity in a satisfactory way. These compounds were the indispensable precursors in order to continue the project. We were able to show that the activation of the acidic partner involved in the key reaction of Mitsunobu usually obtained by the use of the phtalimide group, could be advantageously realized by the introduction of a hydrazone moiety with strong electron-withdrawing character. An extension of this method on solid support is a result which constitutes an effective application of a Mitsunobu protocol in Solid Phase Organic Chemistry. The N­aminodipeptides thus obtained were studied in reactions of oligomérisation. A preliminary study in liquid phase allowed to demonstrate that a classic peptidic coupling reaction could occur between two pseudopeptidic units. The continuation of the study was made on solid phase and allowed us to obtain the first [alpha-N-amino]peptides never synthesized to this day. Finally, in the third chapter, these oligomers were studied by molecular modelling and various spectroscopic methods (NMR, IR) who allowed to suggest a folding by the establishment of intramolecular hydrogen bonds

Dans une première partie, la protection des phénols et des pyridinols a été étudiée. Une nouvelle méthode de tetrahydropyranylation a été développée via la réaction de Mitsunobu. Les pyridinols et des phénols ont ainsi été protégés sous forme d'acétal. Cette méthode est sélective d'un phénol vis-à-vis d'un alcool ou d'une amine. La métallation régiosélective des pyridinols 3- et 4- OTHP a été ensuite réalisée. La fonctionnalisation de ces composés, via des réactions successives de métallation et une hydrolyse acide, a permis la synthèse de pyridinols difonctionnalisés "one-pot". Dans le but d'étudier le pouvoir ortho-directeur du groupe O-THP lors de la réaction de métallation, des essais de déprotonations compétitives ont été réalisés avec un pyridinol protégé par un OMe ou une carbamate. Dans une seconde partie, nous avons étudié une synthèse courte et efficace de la (-)-lentiginosine et de ses épimères à partir de la 2-bromopyridine avec de bons rendements. Nous avons synthétisé la (-)-lentiginosine et deux de ses épimères avec de bons rendements. Au cours de cette synthèse, nous avons développé une nouvelle méthodologie de quaternarisation de pyridine via la réaction de Mitsunobu. / We report that the tetrahydropyranylation of pyridinols and phenols, exhibiting especially very low nucleophilicities, can be achieved by means of Mitsunobu reaction with 2-hydroxy-tetrahydropyran. We studied the regioselective deprotonation of 3- an 4-(tetrahdropyran-2-yloxy)pyridines with n-butyllithium. Trapping the lithiated species with various electrophiles afforded functionalized pyridines in good yields. A one-pot procedure also allowed the double fuctionalization at C4 and C2 in the case of 3-O-THP-pyridine. The ortho-metallating ability of this group was examined in comparison with other well-known oxygen-based ortho-directing groups. A four-step synthesis of (-)-lentiginosine and its epimers is described starting from 2-bromopyridine. The key step consisted of a quaternarization of a fully unprotected pyridinium-polyol unit using Mitsunobu methodology. We have demonstrated that the Mitsunobu reaction is viable as a new methodology for the N-alkylation of pyridine and for the formation of bridgehead azabicyclic compounds from pyridine derivatives

Limiter la perte d'atomes, privilégier l'usage de catalyseurs, s'abstenir de l'utilisation de réactifs toxiques et éviter les étapes de purifications sont certains des challenges de la chimie moderne. De nombreuses recherches ont donc été consacrées au développement de réactions dites ''tandems''. La réaction d'isomérisation d'alcène permet dans certains cas de générer une toute nouvelle réactivité au sein d'une molécule, en déplaçant une double liaison. Cette réaction requiert souvent un catalyseur de type hydrure avec un métal de transition. Ce mémoire décrit la mise au point de nouvelles réactions ''tandems'' dont l'une des composantes mise en jeu est une réaction isomérisation d'oléfine. Une attention toute particulière a été adressée à la synthèse de vinylboronates notamment par métathèse croisée. Outre les nombreuses applications en synthèse organique qui sont présentées dans ce mémoire, ces intermédiaires peuvent être isomérisés en allylboronates. Ces derniers peuvent réagir avec un aldéhyde pour donner des alcools homoallyliques avec une complète diastéréosélectivité. Ces alcools ont, entre autres, été utilisés en synthèse totale de plusieurs molécules naturelles complexes présentant un motif 2,3-dihydrobenzofurane. / Some of the new challenges of modern synthetic chemistry are: atom economy, employment of catalytic processes, avoidance of toxic reactants and limitation of purification steps. A lot of work has been devoted to the development of tandem reactions. A new reactivity could be generated in a molecule thanks to an isomerisation (or migration) reaction of an alkene. This reaction often needs an hydride specie which comes from a transition metal catalyst. This PhD thesis is about the development of new tandem reactions in which at least one step is an isomerisation of an olefin. A great attention has been dedicated to the synthesis of vinylboronates especially with a cross-metathesis strategy. These intermediates are of great importance in organic chemistry and can be useful in a wide range of reactions. One of those reactions is the transformation of vinylboronates to allylboronates thanks to an isomerisation step. Allylboronates can then react with aldehydes to generate homoallylic alcohols with total diastereoselectivity. These new reactions have found applications in total synthesis of natural molecules with a 2,3-dihydrobenzofuran core.

Les vinylphosphonates fonctionnalisés représentent une classe importante de briques moléculaires utilisées en synthèse organique et suscitent un grand intérêt au niveau biologique. Ainsi, nous avons étudié différentes voies de synthèse pour accéder à ces composés. Il en ressort une méthode généralisable, faisant intervenir une réaction de substitution organocatalysée, à partir d’un substrat phosphoré original, et permettant d’obtenir de nombreux vinylphosphonates non décrits jusqu’ici. Par la suite, la synthèse de vinylphosphonates azahétérocycliques a été abordée en employant la réaction de métathèse cyclisante à partir de substrats adéquats, eux-mêmes obtenus par le biais de la méthodologie décrite précédemment.Nous avons enfin mis au point la première synthèse totale énantioselective de la molécule UPF 702 (vinylphosphonate cyclique comportant un motif acide aminé), connue pour ses propriétés biologiques notamment comme agoniste de récepteurs du glutamate et présentant ainsi un potentiel thérapeutique contre les maladies du système nerveux central. Deux voies de synthèses ont été imaginées, basées sur des réactions organocatalysées et de métathèse cyclisante. L’introduction de la chiralité a été réalisée via des réactions de désymétrisation ou de dédoublement enzymatiques et l’accès à l’amine par un réarrangement de Curtius. / Functionalized vinylphosphonates constitute an important class of building blocks used in organic synthesis and aroused great interest due to their various biological activities. Thus, we developed several synthetic methodologies to reach these compounds. The most general method entails an organocatalyzed substitution reaction using an original substrate, and allows the synthesis of numerous hitherto unknown vinylphosphonates.Then, the synthesis of azaheterocyclic vinylphosphonates was investigated using the ring closing metathesis from appropriate substrates which are obtained through the above methodology.Finally, we have set up the first enantioselective synthesis of UPF 702 (a cyclic vinylphosphonate including the amino acid moiety), known to exhibit agonist activity towards glutamate receptors, and thus potentially active against central nervous system diseases. Two synthetic approaches were devised, based on the organocatalyzed substitution followed by ring closing metathesis. The enantioselectivity was brought by enzymatic resolution or desymmetrisation, whereas the amino acid was prepared via a Curtius rearrangement.

Due to their outstanding properties, poly(arylene ethers) are useful as toughness modifiers in epoxy resins (EP). Furthermore, these polymers show rather low intrinsic fire risks. According to recent research it has been incorporated that poly(arylene ether phosphine oxides) [PAEPO’s] can further improve the fire behavior. Increasing phosphorous content of the PAEPO can influence the fire behavior too. Fire retardants containing phosphorus – regardless of whether an additive or reactive approach is used – show different mechanisms in the condensed and gas phase. In the present study PSU Control (BPA based polysulfone) with four different PAEPO’s and their corresponding blends with an EP were investigated. All poly(arylene ether phosphine oxides) were synthesized by nucleophilic aromatic polycondensation. The polymers obtained covered a wide range of weight average molar masses (6,000 – 150,000 g/mol) as determined by size exclusion chromatography with multi-angle light scattering detection (MALLS). FTIR, NMR spectroscopy and MALDI-TOF revealed formation of the desired polymer structure of the linear poly(arylene ethers). All polymers were easily soluble in common organic solvents, thus enabling processing from solution.The pyrolysis and the fire retardancy mechanisms of the polymers and blends with epoxy resin (EP) were tackled by means of a comprehensive thermal analysis (thermogravimetry (TG), TG-evolved gas analysis) and fire tests [PCFC, limiting oxygen index (LOI), UL-94, cone calorimeter]. The Mitsunobu reaction of Dimethyl-5-hydroxyisophthalate and a long chain semifluorinated alcohol requires triphenyl phosphine as a reactant. Identical, in some case higher yield was obtained in the usual conditions, with triphenyl phosphine and with trivalent phosphorus containing polymers, which was prepared in solvent free bulk (melt) polymerization technique from trivalent phosphorus monomer and a silylated diphenol in presence of CsF. Purification and the recovery of the final product which is always a big challenge in case of Mitsunobu reaction, was far more easier using polymer compared to triphenyl phosphine. During polymerization there was a possibility to have polymer having repeating unit containing both trivalent phosphorus and phosphine oxide. The trivalent phosphorus content of the polymer can be varied using different molar concentration of CsF.

<p>U radu je ostvarena enantiodivergentna totalna sinteza oba enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C polazeći iz D-glukoze. Ključne faze u sintezi 7-epi-(+)-goniofufurona bile su stereoselektivna adicija fenilmagnezijum bromida na aldehidnu grupu pogodno za&scaron;tićene dialdoze, i stereospecifično formiranje furano-laktonskog prstena ciklokondenzacijom odabranog hemiacetalnog derivata sa Meldrum-ovom kiselinom. Sinteza (+)-goniofufurona i (+)-krasalaktona C zahtevala je inverziju konfiguracije na C-5<br />u zajedničkom intermedijeru, koja je efikasno ostvarena u uslovima Mitsunobu-ove reakcije, ili alternativno oksidacijom benzilne hidroksilne grupe u prohiralni keton, uz naknadnu stereoselektivnu redukcijom sa borohidridom. Sličan pristup je zatim primenjen za sintezu neprirodnih (&minus;)-enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C, dva nova konformaciono ograničena analoga (+)- i (&minus;)-goniofufurona (oksetani 36 i ent-36), kao i odgovarajućih 7-deoksigenovanih derivata (31 i ent-31). Takodje je razvijena i prva totalna sinteza prirodnog (+)-krasalaktona B (3) i alternativna sinteza (+)-krasalaktona C (4) polazeći iz D-glukoze. Selektivni pristup molekulima 3, odnosno 4 omogućen je promenom uslova za TBDPS deprotekciju u finalnom intermedijeru 53. Osnovna karakteristika pomenutih pristupa je njihova generalnost i fleksibilnost. Na taj način je omogućena sinteza serije analoga i derivata (+)-goniofufurona, ili 7-epi-goniofufurona, uključujući i do sada nepoznate 7-epi-(+)-krasalaktone B (6) i C (7), 5,7-di-O-cinamoil derivate 8 i 9, 5,7-di-O-izopropilidenske derivate 5 i 10, kao i vi&scaron;e lipofilnih derivata (jedinjenja 26, 30, 33, 65, ent-30 i ent-33). Konačno, u drugom delu rada, ispitan je uticaj sintetizovanih stiril-laktona na rast odabranih tumorskih ćelijskih linija in vitro.</p> / <p> Enantiodivergent total syntheses of both (+)- and (&minus;)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from D-glucose. The key steps of the synthe-sis of 7-epi-(+)-goniofufurone were a stereo-selective addition of&nbsp;<br /> phenyl magnesium bromide to a protected dialdose, followed by a stereospecific furano-lactone ring formation by condensation of a partially protected lactole with Meldrum&rsquo;s acid. The synthesis of (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was applied to the synthesis of the unnatural enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C, two novel, conformationally constrained analogues of both (+)- and (&minus;)-goniofufurone (oxetanes 34 and ent-34). as well as the corresponding 7-deoxygenated derivatives (31 and ent-31). We have also developed the first total synthesis of (+)-crassalactone B (2) and an alternative synthesis of (+)-crassalactone C (3) starting from D-glucose. Finally, the synthesized styryl-lactones were evaluated for their antiproliferative activity against a panel of human tumor cell lines.</p>

Due to their outstanding properties, poly(arylene ethers) are useful as toughness modifiers in epoxy resins (EP). Furthermore, these polymers show rather low intrinsic fire risks. According to recent research it has been incorporated that poly(arylene ether phosphine oxides) [PAEPO’s] can further improve the fire behavior. Increasing phosphorous content of the PAEPO can influence the fire behavior too. Fire retardants containing phosphorus – regardless of whether an additive or reactive approach is used – show different mechanisms in the condensed and gas phase. In the present study PSU Control (BPA based polysulfone) with four different PAEPO’s and their corresponding blends with an EP were investigated. All poly(arylene ether phosphine oxides) were synthesized by nucleophilic aromatic polycondensation. The polymers obtained covered a wide range of weight average molar masses (6,000 – 150,000 g/mol) as determined by size exclusion chromatography with multi-angle light scattering detection (MALLS). FTIR, NMR spectroscopy and MALDI-TOF revealed formation of the desired polymer structure of the linear poly(arylene ethers). All polymers were easily soluble in common organic solvents, thus enabling processing from solution.The pyrolysis and the fire retardancy mechanisms of the polymers and blends with epoxy resin (EP) were tackled by means of a comprehensive thermal analysis (thermogravimetry (TG), TG-evolved gas analysis) and fire tests [PCFC, limiting oxygen index (LOI), UL-94, cone calorimeter]. The Mitsunobu reaction of Dimethyl-5-hydroxyisophthalate and a long chain semifluorinated alcohol requires triphenyl phosphine as a reactant. Identical, in some case higher yield was obtained in the usual conditions, with triphenyl phosphine and with trivalent phosphorus containing polymers, which was prepared in solvent free bulk (melt) polymerization technique from trivalent phosphorus monomer and a silylated diphenol in presence of CsF. Purification and the recovery of the final product which is always a big challenge in case of Mitsunobu reaction, was far more easier using polymer compared to triphenyl phosphine. During polymerization there was a possibility to have polymer having repeating unit containing both trivalent phosphorus and phosphine oxide. The trivalent phosphorus content of the polymer can be varied using different molar concentration of CsF.