Rozprawy doktorskie na temat „Mitsunobu reaction”

A 31P NMR based study of the Mitsunobu esterification reaction has been undertaken. Three intermediates have been identified: an alkoxytriphenyiphosphonium carboxylate, a dialkoxytriphenyiphosphorane and an (acyloxy)alkoxytriphenylphosphorane. These three species are in equilibrium with each other, the position of the various equilibria depending on the polarity of the solvent, pKa of the acid and structure of the alcohol. Given the choice between a primary and secondary alcohol, only the phosphorane and oxyphosphonium salt corresponding to the primary alcohol are observed. The implications of these findings for the regioselectivity and stereoselectivity of the Mitsunobu reaction are discussed. Formation of the phosphonium salt is facilitated in more polar solvents or with acids of low pKa. The chemical shift of the alkoxyphosphonium carboxylate was found to be extraordinarily sensitive to the presence of proton sources and solvent, varying over a range of more than 100 ppm. The peripatetic nature of this species has been interpreted in terms of a rapid equilibrium between the alkoxytriphenylphosphonium carboxylate and the corresponding (acyloxy)alkoxytriphenylphosphorane. Substitution of triphenylphosphine by tributylphosphine using otherwise standard Mitsunobu protocol revealed clean formation of a single intermediate, the alkoxyphosphonium carboxylate. In the absence of acid, at least two species were observed, a dialkoxyphosphorane and an alkoxyphosphonium alkoxide salt. Replacement of iriphenylphosphine by 9-phenyl-9-phosphafluorene confirmed that betaine formation was irreversible and proceeded via a nucleophiic addition, not a cheleotropic mechanism. Modification of triphenylphosphine by incorporation of an alcoholic or acidic moiety into the structure allowed detection of a possible O,Nphosphorane, an intermediate previously postulated in the Mitsunobu reaction. The synthesis of a series of bulky phosphines showed that steric congestion about the phosphonis atom retarded the rate of betaine (and particularly) phosphorane formation. An EPR based study has revealed for the first time that radicals are formed during the reaction of phosphines with azodicarboxylates. Evidence is presented to suggest that the betaine arising from this reaction may be formed via a single electron transfer pathway. The reaction of diphenylphosphine and of diphenylphosphine oxide with azodicarboxylates is examined. Diphenylphosphine reacts surprisingly sluggishly, whereas diphenyiphosphine oxide reacts rapidly to give the expected addition product. An 'abnormal' Mitsunobu-like reaction involving catalytic amounts of triphenylphosphine in the presence of diisopropyl azodicarboxylate and a,co-dithiols to afford disulfides has been studied. The mechanism is discused in terms of expulsion of triphenyiphosphine from either an S,S-dithiophosphorane or thiophosphonium thiolate salt. The substitution of a,w-dithiols by a,w-mercaptoalcohols was also briefly examined. Finally, diphenyl(2-pyridyl)phosphine was used in place of triphenylphosphine for those Mitsunobu reactions where removal of wiphenylphosphine oxide is difficult or troublesome.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Division of Science and Technology
Science, Environment, Engineering and Technology
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A novel manifold has been developed, catalytic in phosphorus (V), that promotes the dehydration reaction of an alcohol to give the symmetrical ether product. This has been achieved through the development of a novel dioxyphosphorane catalyst that, in conjunction with a triflic acid cocatalyst, conducts the coupling reaction without the need for any additional stoichiometric reagents. This has allowed the omission of the explosive diazo-compounds that are required in the widely-accepted Mitsunobu conditions, and has reduced the amount of inconvenient and difficult-to-remove phosphorus waste that is usually associated with phosphorus-mediated reactions. This work constitutes the first example of a phosphorus (V)-catalysed Mitsunobu-type etherification reaction.

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

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.

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.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Science
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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.

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

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 zaštićene 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-5u 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 (−)-enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C, dva nova konformaciono ograničena analoga (+)- i (−)-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 više 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.
Enantiodivergent total syntheses of both (+)- and (−)-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  phenyl magnesium bromide to a protected dialdose, followed by a stereospecific furano-lactone ring formation by condensation of a partially protected lactole with Meldrum’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 (−)-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.

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.

碩士
中國醫藥大學
藥物化學研究所碩士班
99
Herein we report C-arylglycosylation and O-glycosylation of exo-glycals, in which two products are generated in association with Suzuki-Miyaura reaction and Mitsunobu reaction C-arylglycosides were synthesized in moderate to good yields by reaction of exo-glycals and arylboronic acids in the presence of 0.5 equiv. Pd(OAc)2. The C-arylglycosylation reaction of a aryl-Pd complex to exo-glycals double bond followed by syn elimination of HPd(OAc) to provide a carbon-Ferrier type product. Mitsunobu reagent mediated O-glycosylation of exo-glycals have been carried out in moderate yields, in which a mixture of two products are often obtained resulting from Ferrier rearrangement and substraction. The exo-glycals reacte with various phenol derivates to afford glycoside with highly α- Stereosrlective.

The research work delineates a flexible and novel route for the diastereoselective construction of diversely substituted N-heterocyclic variants as valuable scaffolds for natural products and pharmaceuticals, starting from an easily accessible prochiral α-phenyl-β-enamino ester. By taking advantage of the Cp2TiCl-mediated reductive epoxide opening-cyclization, an expedient and unified approach has been accomplished to gain access to a handful of iridoid monoterpenes in an enantiomerically divergent manner starting from (+)-β-citronellene. Also, a radical approach to build oxa-quaternary centers, structural feature of various natural-products-inspired synthons have been undertaken via Cp2TiCl-mediated reductive epoxide opening-cyclization protocol. Furthermore, the feasibility of Cp2TiCl-promoted radical cyclization has also been explored onto N-tethered epoxy indoles which provide an efficient route for the construction of pyrrolo/piperidino[1,2-a]indole derivatives.

碩士
高雄醫學大學
醫藥暨應用化學系碩士班
92
Part Ⅰ As part of an ongoing study of the chemistry of benzoheterocyclic compounds, a series of 10-membered macrocyclic ethers annulated with substituted benzene is described. O-allylbenzylalcohols and O-allyl- phenols, derived from isovanillin, were coupled by the Mitsunobu reaction to construct the intramolecular dienes as precursor for ring- closing metathesis (RCM). Finally, by the treatment of Grubbs’ catalyst the intramolecular dienes were cyclized to give the desired compounds, 10-membered macrocyclic ethers, respectively. Part Ⅱ Two new methods for the conversion of alcohols into alkyl chloride are established. Method 1, alcohols were reacted with DIAD, TPP and 2-thiothiazoline to undergo Mitsunobu reaction to produce 2-alkylthio- thiazolines which were subsequently treated with ethyl chloroformate to produce alkyl chlorides in good yields. Mothod 2, alcohols were reacted with triphenylphosphine (TPP), diisopropyl azodicarboxylate (DIAD) in THF, followed by treating with ethyl chloroformate to afford alkyl chlorides in one pot in moderate yields.

Thesis titled, “Design, Synthesis and Conformational Analysis of Hydrogen Bond Surrogate (HBS) Stabilized Helices in Natural Sequences. Helically Constrained Peptides for Potential DNA-Binding”, describes the development of a novel covalent hydrogen bond surrogate (HBS) model and its incorporation in short (4-8 residues) unstructured peptide sequences with coded amino acids, through a facile solution phase synthetic method (SPSM), to constrain them into α- helical conformations with highest known stabilities and helicities. The synthetic protocol was developed for mass scale combinatorial synthesis of helical peptidomimetics. NMR, FT-IR, CD spectra and molecular dynamics simulations of variants of the HBS-constrained helical peptidomimetics were analyzed to determine the optimum number of sp2 atoms and the residue preferences that yield both the α-helical and the 310-helical folds with high structural integrity in the shortest sequences. The HBS-constrained helical peptidomimetics were used to derive experimental evidence that the 2-state Helix-Coil Transition occurs at each residue during helix folding and that this process is entropically driven. Further, the role of temperature on the denaturation of secondary structures was investigated using these HBS-constrained helical models. Helical peptidomimetics of the DNA-binding domain in the zinc-finger human TTK protein have been synthesized, which have proven to be promising mimics for DNA-binding and subsequent transcription regulation.
CSIR

Les accouchements prématurés restent un défi pour la médecine moderne. Malgré les efforts de préventions déployés, les taux de naissances prématurés sont en constante augmentation dans les pays industrialisés. Le récepteur interleukine-1 (IL-1R) a été étudié dans le but de développer des agents thérapeutiques pouvant prolonger la gestation et mener à des prognostiques néonataux. Dans cette optique, il y a été démontré que le peptide 101.10 possède a démontré une capacité à moduler le récepteur IL-1R, retarder les accouchements prématurés et réduire l’incidence de la rétinopathie prématurée par un mécanisme allostérique impliquant une signalisation biaisée. Dans le but d’étudier la conformation active du peptide 101.10 et d’en améliorer l’activité, nous avons développé une méthode pour introduire des α-amino γ-lactames β-substituées dans des séquences peptidiques. Appliquer cette stratégie au peptide 101.10 a permis d’améliorer la compréhension de la relation structure-activité pour la modulation allostérique du récepteur IL-1R. Les composés peptidomimétiques ont le potentiel de mimer la conformation et l’activité des peptides bioactifs. Ils offrent le potentiel d’améliorer la reconnaissance moléculaire, d’optimiser le transport à travers des différentes membranes biologiques et d’augmenter la résistance métabolique. Parmi les différentes classes de composés peptidomimétiques, les α-amino γ-lactames (Agl) permet de rigidifier par des liens covalents la chaine peptidique principale favorisant les structures secondaires de type tour β. Les analogues Agl β-substituées mimer et rigidifier la chaine latérale des acides aminés. Cette thèse introduit des méthodes efficaces pour la synthèse stéréocontrolée des résidus α-amino γ-lactames β-substituées possédant diverses fonctionnalités. L’introduction de ces résidus dans différents peptides bioactifs a été effectuée pour étudier leur relation structure-activité. En utilisant le peptide modulateur du récepteur IL-1R 101.10 comme peptide représentatif, la présente recherche a permis d’identifier de nouveaux agents tocolytiques qui peuvent prolonger la gestation et améliorer le pronostique néonatal. Dans le chapitre 2, des stéréo-isomères de (Agl) et β-hydroxy-α-amino-γ-lactam (Hgl) ont été utilisés pour étudier l’influence de la configuration du groupement hydroxyle sur la conformation et l’activité du peptide 101.10. L’orientation de ce groupement dans les peptides Agl et Hgl s’est avéré avoir une influence conformationnelle et sur l’activité. La spectroscopie par dichroïsme circulaire (CD) a illustré la propension de certains analogues, comme le [(3R,4S)-Hgl3]-101.10, à adopter des tours β. Les analogues Agl et Hgl ont été examinés dans une série d’essais in vitro et in vivo modélisant les accouchements prématurés. Dépendant de leur structure et configuration, les analogues lactames ont démontré une sélectivité fonctionnelle différente dans diverse processus biologiques, démontrant les particularités de divers phénotypes. Par exemple, l’inhibition des JNK et ROCK kinases s’est avérée importante respectivement dans leurs effets tocolytiques et dans la diminution de la vaso-oblitération. Notamment, parmi les douze analogues testés, [(3R,4S)-Hgl3]-101.10 s’est avéré démontrer la même activité in vitro et in vitro que le peptide parent. Dans le chapitre 3, des méthodes de déplacement du groupement hydroxyle des résidus Hgl ont permis l’introduction stéréosélective de substituent en position β des résidus Agl. Une combinaison de réaction de Mitsunobu sur les résidus trans Hgl et une ouverture nucléophile les sulfamidates cycliques dérivés des lactames cis, ont mené à l’obtention de mime rigidifiés de résidus Ser, Thr, Cys, Dap, Dab, His et Met. Dans le chapitre 4, différentes lactames β-substitués ont été introduits dans la séquence du peptide 101.10 par une combinaison de chimie en solution et sur support solide pour étudier d’avantage les éléments structurels nécessaire pour réguler l’activité et la signalisation de cette cytokine clef dans la médiation de l’inflammation. Considérant l’activité de l’analogue [(3R,4S)-Hgl3]-101.10, plusieurs analogues β-substitués possédant une orientation similaire pour la chaine principale et latérale ont été synthétisés. Certains analogues ont démontré une activité biologique prometteuse dans des modèles de rétinopathie et seront étudiés dans le futur. En conclusion, des méthodes de synthèse d’α-amino-γ-lactames et de leur contrepartie β-substitués et leur introduction dans des peptides d’intérêt pour étudier leur relation structure-activité ont été développés. En utilisant ces méthodologies sur le modulateur allostérique du récepteur IL-1R 101.10, le conformère actif in vivo responsable de l’activité tocolytique et protectrice contre la rétinopathie associée aux accouchements prématures ont été identifiés. Considérant l’utilité de la synthèse de lactames pour le développement d’agents susceptibles de prolonger la gestation et d’améliorer le prognostique associé aux accouchements prématurés, cette thèse a permis la conception de prototypes de médicaments pour traiter les accouchements prématurés ainsi que l’évaluation des contraintes structurelles pertinentes pour la biologie des peptides.
Preterm birth (PTB) is an unmet biomedical need. Despite efforts to counter the onset of preterm labor, the rate of premature birth has increased steadily in developed countries. The interleukin-1 receptor (IL-1R) has been pursued as a target for designing agents which can prolong labor and improve neonatal outcomes. Towards these goals, a lead peptide 101.10 had been shown to modulate the IL-1R, to delay PTB and to mitigate associated retinopathy of prematurity (ROP) by an allosteric mechanism featuring biased signaling. With the goals of understanding the active conformers and improving the activity of 101.10, methods were conceived for the synthesis and introduction of β-substituted α-amino γ-lactams into peptides. Applying such methods on 101.10 has provided insight into the structure-activity relationships required for allosteric modulation of the IL-1R. Peptidomimetics are promising structures that replicate peptide function and conformation. They offer the potential to improve molecular-recognition, to enhance transport across biological membranes, and to resist metabolism. Among peptidomimetic classes, α-amino γ-lactam (Agl) residues introduce covalent constraint to rigidify the peptide backbone and have been employed to favor turn secondary structures. β-Substituted Agl analogs offer additional potential to mimic and restrict peptide side-chain geometry. This thesis introduces effective methods for the stereo-controlled synthesis of β-substituted α-amino γ-lactams residues having various side chain functionality. Introduction of the parent Agl residue and β-substituted counterparts into biologically active peptides has been explored to study structure-activity relationships. Employing the IL-1R modulator 101.10 as a representative peptide, the described research has furnished novel labor delaying agents that can improve neonatal outcomes. In chapter 2, α-amino-γ-lactam (Agl) and β-hydroxy-α-amino-γ-lactam (Hgl) stereoisomers were employed to study the influence of configuration and hydroxyl group side chain on conformation and activity of the interleukin-1 receptor modulator peptide 101.10. The configuration and hydroxyl group side chain influenced the conformation and biological activity of Agl and Hgl-101.10 analogs. Circular dichroism (CD) spectroscopy illustrated β-turn conformers for specific analogs, such as [(3R,4S)-Hgl3]-101.10. The Agl and Hgl analogs were examined in a series of in vitro assays and in vivo models of PTB. Contingent on their structure vi and configuration, the lactam analogs exhibited different functional selectivity in the various biological pathways, and indicated the requirement for specific phenotypes. For example, inhibition of the JNK and ROCK kinase pathways were respectively shown to be important for delaying labor and diminishing vaso-obliteration in the PTB and ROP models. Notably, among the twelve analogs, [(3R,4S)-Hgl3]-101.10 was found to exhibit identical in vitro and in vivo activity as the parent peptide. In chapter 3, methods were developed for displacement of the β-hydroxy-α-amino-γ-lactam (Hgl) residue alcohol to introduce stereo-selectively different β-substituents on Agl residues. A combination of Mitsunobu chemistry on the trans Hgl residue, and nucleophilic ring opening of the cyclic sulfamidate derived from the cis lactam counterpart provided constrained mimics of Ser, Thr, Cys, Dap, Dab, His and Met residues. In chapter 4, various β-substituted lactams were introduced into the sequence of 101.10 by combination of solution and solid phases chemistry to further study the structural requirements for regulating the activity and signaling of this key cytokine mediator of inflammasome activation. Considering the activity of [(3R,4S)-Hgl3]-101.10, the β-substituted Agl analogs were synthesized possessing similar backbone and side chain configurations. Certain analogs exhibited promising biological activity in the ROP model meriting further study. In sum, methods were conceived for the synthesis and application of α-amino-γ-lactams and their β-substituted analogs to study peptide structure-activity relationships. Employing this chemistry on the IL-1R allosteric modulator 101.10 has identified the active conformer and in vitro activity responsible for ability to delay labor and mitigate retinopathy of prematurity. Considering the utility of the lactam synthesis methods for the development of improved agents for delaying labor and improving neonatal outcomes, this thesis has conceived useful prototypes for drugs to treat PTB, as well as useful methods for dissecting the structural requirements for peptide chemical biology.