No description available.

Ces travaux de thèse s'inscrivent dans un projet à long terme visant à développer de nouveaux outils nécessaires à l'élucidation de mécanismes biologiques impliquant des interactions de type protéine-protéine mettant en jeu des structures secondaires protéiques de type polyproline II (PPII). En particulier, nous nous sommes intéressés à la conception, synthèse et valorisation de spirolactames originaux capables de mimer une hélice PPII, point de départ dans la recherche de nouvelles molécules d'intérêts thérapeutiques. Cette structure secondaire unique, caractéristique des ligands SH3, joue un rôle essentiel dans certaines activités biologiques telles que les phénomènes de reconnaissance, la transduction de signal, la transcription, la mobilité cellulaire, les réponses immunitaires et se trouve aussi impliquée dans des pathologies majeures telles que le SIDA, la Maladie d'Alzheimer et plusieurs tumeurs cancéreuses. Face à l'importance des structures secondaires PPII dans des cibles d'intérêt thérapeutique, dans les phénomènes de reconnaissance protéine-protéine, et face à l'absence dans la littérature de mimes PPII pertinents, ces travaux se sont attachés à l'élaboration et la valorisation d'outils PPII contraints, stables vis-à-vis de la dégradation protéasique. Ils nous ont tout d'abord permis de développer un accès stéréocontrôlé à une plateforme spiro [4,4] inédite, en nous appuyant sur une réaction de contraction de cycle développée récemment dans notre groupe, le réarrangement transannulaire de lactames activés (TRAL). Les études de dynamique moléculaire, et de dichroïsme circulaire nous ont permis de démontrer que certains des composés spiro synthétisés adoptent une structure "PPII-like", d'autres semblent au contraire se structurer en coude bêta. / This work is part of a long term project with the aim to develop new tools for the elucidation of biological mechanisms involving protein-protein interactions with the participation of the protein secondary structure named polyproline type II (PPII). In particular, we are interested in the design, the synthesis and the development of original spirolactams as first mimics of PPII helix, the starting point in the discovery of new compounds of therapeutic interest. This unique secondary structure, characteristic of SH3 ligands, plays a critical role in various biological activities such as the phenomena of recognition, signal transduction, transcription, cell motility, immune responses and is also involved in major diseases such as AIDS, Alzheimer's disease and several carcinogenic tumors. Regarding the importance of the PPII secondary structures in targets of therapeutic interest and in the phenomena of protein-protein recognition, and observing the absence in the literature relevant PPII mimics, this thesis have focused on the development of constrained PPII tools, stable versus protease degradation. This work first allowed us to develop an stereocontroled access to a novel spiro [4.4] scaffold, relying on a new ring contraction reaction recently developed in our group, namely transannular rearrangement of activated lactams (TRAL) . Studies of molecular dynamics, and circular dichroism have demonstrated that some of the synthesized spiro compounds adopt a "PPII-like" structure, others seems to be structured in beta-turn.

This thesis deals with an enantioselective synthesis of cyclic compounds by using a combination of organocatalysis and transition metal catalysis. The thesis deals mainly with usage of aminocatalyst for activation of aldehydes and copper catalyst for activation of terminal triple bond. The first part is focused on the preparation of starting compounds for cyclizations (α-oxoesters, α- substituted nitroalkanes and α-substituted aldehydes). The second part concerns carbocyclization itself and optimization of reaction conditions to achieve highly stereoselective reaction. Powered by TCPDF (www.tcpdf.org)

This thesis describes the total synthesis of the polyketide derived marine natural product (-)-maurenone (14) and synthetic studies of a model system for the marine polyketides, the spiculoic acids (20, 22-24). A biomimetic approach involving cyclisation of linear polyketide precursors to install the complex chemical frameworks was employed. Maurenone is a polypropionate derived metabolite isolated from pulmonate molluscs collected off the coast of Costa Rica. While structural assignment following isolation revealed a relatively uncommon tetra-substituted dihydropyrone moiety the only stereochemical information deduced was the trans-relative relationship between the C8 and C9 protons. The total synthesis of a series of eight stereoisomeric putative structures was achieved in order to assign the stereochemistry of (-)-maurenone (14), as that depicted above. A time and cost efficient strategy was developed utilising common intermediates providing access to the eight stereoisomeric structures in a convergent manner. Six key fragments, four aldehydes (109) and two ketones (110), were synthesised using highly diastereoselective syn- and anti-boron aldol reactions and were coupled using a lithium-mediated aldol reaction. Trifluoroacetic acid-promoted cyclisation/dehydration enabled installation the ƒ×-dihydropyrone ring. All eight isomers of one enantiomeric series were synthesised by coupling two ketones with each of four aldehydes. By comparison of the NMR data for the eight isomers with that reported for the natural product, the relative stereochemistry was established as shown. The (-)-enantiomer of maurenone was synthesised in nine linear steps (13 % overall yield) from (R)-2-benzylpentan-3-one ((R)-40) and (R)-2-benzoyloxypentan-3-one ((R)-39). The spiculoic acid family of polyketide derived natural products, isolated from plakortis sponges, possess a unique [4.3.0]-bicyclic core which is proposed to be formed via an enzyme catalysed Intramolecular Diels-Alder (IMDA) cycloaddition reaction of linear polyene precursors 25. Model linear precursors (114), possessing various olefin geometries at C2 and both stereochemical orientations of the C5 stereocentre, were synthesised in order to examine stereoselectivity of the thermally induced IMDA cycloaddition reaction. The two alternative C4-C6 stereotriads of the linear precursors 114 were achieved by employing highly diastereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the facial preference of (R)-2-benzoyloxypentan-3-one ((R)-39), and a syn-titanium aldol reaction, under the control of chiral N-acylthiazolidinethione ((R)-43a). The diene and dienophile moieties were installed using either standard Wittig, H.W.E. or ¡§modified¡¨ Julia olefination reactions. A thorough stereochemical assignment of the cycloadducts of the thermally induced IMDA reaction of each linear precursor was accomplished employing 2D NMR techniques. Comparison of the stereochemistry of each of the cycloadducts with the spiculoic acids revealed that the linear precursor (2E,5S)-114 produced a cycloadduct 232 with stereochemistry analogous to the natural products in 94 % diastereoselectivity. Thus, a synthetic approach to the spiculoic acids via synthesis of a linear precursor 285 possessing a TBS ether at C5 in the S configuration was proposed. Unfortunately, problems encountered in the synthesis of the proposed linear precursors to the spiculoic acids ultimately prevented the total synthesis from being achieved.

143 f. / Submitted by Ana Hilda Fonseca (anahilda@ufba.br) on 2013-09-24T14:26:15Z No. of bitstreams: 1 Dissertação Maria Candeia Kuliakita.pdf: 4339184 bytes, checksum: 54063fe95edeaa2662c649acf009c9ae (MD5) / Approved for entry into archive by Ana Hilda Fonseca(anahilda@ufba.br) on 2013-09-24T14:27:50Z (GMT) No. of bitstreams: 1 Dissertação Maria Candeia Kuliakita.pdf: 4339184 bytes, checksum: 54063fe95edeaa2662c649acf009c9ae (MD5) / Made available in DSpace on 2013-09-24T14:27:50Z (GMT). No. of bitstreams: 1 Dissertação Maria Candeia Kuliakita.pdf: 4339184 bytes, checksum: 54063fe95edeaa2662c649acf009c9ae (MD5) Previous issue date: 2012 / CNPq / Desenvolveram-se neste trabalho atividades experimentais empregando as reações de Mannich, utilizando-se o dímero di-hidróxi-acetona, um derivado da glicerina. A glicerina obtém-se como co- produto da produção de biodiesel. Sem êxitos nas tentativas feitas para a reação de Mannich, partiu-se então para reações aldólicas organocatalisadas. Nesta rota preparou-se a di-hidroxi-acetona sililada (97% de rendimento), que foi empregada como reagente na reação aldólica com o 4-nitrobenzaldeído. O aldol foi obtido como mistura enantiomérica enriquecida, na proporção diastereoisomérica de 5:1 (syn/anti). Posterior acetilação em 90% de rendimento permitiu avaliar, através de HPLC com coluna quiral, o excesso enantiomérico em cerca de 90%. O aldol acetilado teve seu grupo TBS primário removido (96-100 % de rendimento). No entanto, as tentativas de oxidação e preparação do ácido não foram exitosas. Como alternativa, reações de redução para a obtenção de dióis foram feitas obtendo-se dióis com estreoquímica relativa 1,3-anti em rendimento de 80%. Reações de redução por aminação também foram realizadas, mas sem resultados satisfatórios. Em paralelo a estas reações foram preparados derivados de ácidos triterpênicos (ácidos betulínico e ursólico), triterpenos (lupeol) e esteroides (estigmasterol e β-sitosterol) com ácidos oleico e hexanoico, preparando-se compostos com potencial atividade anticâncer e anti-AIDS. / Salvador

This diploma thesis deals with the stereoselective addition reaction of benzothiophenone derivatives to ketimines derived from isatin using bifunctional organocatalysis. The stereoselective addition reaction was optimized to provide the appropriate reaction conditions which were subsequently used to study the scope of the reaction. Keywords Organocatalysis, stereoselective synthesis, bifunctional organocatalysts, ketimines, sulphur heterocykles.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第21049号 / 薬科博第92号 / 新制||薬科||10(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 大野 浩章, 教授 竹本 佳司, 教授 高須 清誠 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Ces travaux de thèse s'inscrivent dans un projet à long terme concernant le développement de nouvelles réactions de contraction de cycle originales afin d'accéder à des édifices moléculaires organisés à activités biologiques potentielles. Généralement découvertes de manière fortuite, les réactions de contraction de cycle sont des réarrangements offrant l'avantage de modifier rapidement le squelette des molécules et permettant donc un accès facile à des analogues structurels, une propriété intéressante et utile aussi bien en chimie de synthèse qu'en chimie médicinale. Dans cette optique, trois réactions de contraction de cycle différentes ainsi que leurs applications seront rapportées dans ce manuscrit. La première décrit la réactivité particulière des bis-Boc 2,5-dicétopipérazines (DKPs) en milieu basique et leur conversion en hydantoïnes, deux squelettes hétérocycliques d'intérêt pharmacologique. Ce nouveau réarrangement a été appliqué à différentes DKPs avec des rendements satisfaisants et de bons excès énantio- ou diastéréoiso-mériques. L'intérêt des bis-Boc DKPs en tant que plateforme de départ dans la construction de structures complexes a ensuite été démontré lors de l'obtention de spirolactames grâce à l'utilisation de la réaction de réarrangement transannulaire de lactames activés (TRAL) et la mise au point d'une stratégie de cyclisation rapide et efficace. Après dimérisation de ces bicycles, les études par dichroïsme circulaire, RMN et modélisation moléculaire ont mis en évidence un comportement similaire à celui d'hélices de polyproline II (PPII), des structures peptidiques secondaires largement impliquées dans les interactions protéine-protéine et dans des processus pathogènes. Afin de valider le potentiel de mimes de nos dimères, une fonctionnalisation de ces substrats s'est avérée nécessaire, qui a été en partie réalisée grâce à la découverte d'une nouvelle réaction de contraction de cycle. Effectuée à chaud dans plusieurs solvants et en présence d'un catalyseur de type triflate, ce réarrangement permet la conversion de quelques bicycles accolés en spirocycles avec de bons rendements. L'intérêt de ces travaux réside ainsi sur l'utilisation de 2,5-dicétopipérazines activées comme substrat de départ et démontre la gamme d'applications multiples des réactions de contraction de cycle. / This work is part of a long-term project aiming to develop new and original ring contraction reactions to access organised molecular edifices with potential biological activities. Ring contraction reactions are usually discovered in a fortuitous manner and present the advantage of rapid and efficient modifications of the molecular skeletons, allowing thus an easy access to structural analogues, a useful and interesting property both in terms of synthetic and medicinal chemistry. With this aim in mind, three different ring contraction reactions, as well as their uses, are reported in this manuscript. The first one describes the particular reactivity of bis-Boc 2,5-diketopiperazines (DKPs) in a basic medium and their conversion into hydantoins, two heterocyclic skeletons with pharmacological interest. This new rearrangement has been applied to several DKPs with acceptable yields and good enantio- or -diasteroiso-meric excesses. The interest of bis-Boc DKPs as starting platforms for the construction of complex structures has later been demonstrated with the obtaining of spirolactams thanks to the use of the transannular rearrangement of activated lactams (TRAL) reaction followed by a fast and efficient ring-synthesis strategy. The studies by circular dichroism, NMR and molecular modelling performed after the dimerisation of those bicycles showed a similar behaviour to the one of polyproline II (PPII) helix, a secondary peptidic structure involved in protein-protein interactions and in pathogenic processes. A functionalization of our dimer then turned out to be necessary in order to validate the mimic potential of our dimers, which was done in part thanks to the discovery a new ring contraction reaction. In the presence of a triflate catalyst in various solvents under high temperatures this rearrangement allows a clean conversion of some fused bicycles into spirocycles with good yields. The interest of this work thus lies in the use of activated 2,5-diketopiperazines as starting materials and demonstrates the wide range of applications of ring contraction reactions.

This thesis describes the synthetic preparation of somecompounds, which can serve as chemical signals for use in thedevelopment of control methods for pest insects. The compoundssynthesised are of the isoprenoid type and of two kinds:carvone derivatives and germacranes. The derivatives of carvoneare based on modifications of this compound, by reactions ofeither its endocyclic or its exocyclic double bond. One type ofmodifications was accomplished by chemoselective additions ofthiophenol. The latter ones imply additions to the exocyclicdouble bond and seem to constitute general, previously rarelystudied reactions. In other modifications of its exocyclic side chain, carvoneafforded some sesqui- and diterpeniod natural products. Thefollowing compounds were synthesised in an enantioselectiveway: (-)-epi-delobanone, (-)-delobanone,(-)-7-hydroxy-3,10-prenylbisaboladien- 2-one (an insecticidalconstituent of Croton linearis) as well as its diastereomer andsome other compounds with similar structures. All of thesecompounds weretested for their antifeedant/feeding deterrentcapability against gnawing of the pine weevil, Hylobiusabietis. The germacranes prepared by means of enantioselective totalsyntheses are: (–)- 1(10),5-germacradien-4-ol and(–)-germacrene D. The former is a constituent of thedefence secretion (an allomone) from the larvae of the pinesawfly, and the needles of Scots pine. (–)-Germacrene D isa ubiquitous compound in nature. For example, it occurs in thepeels of apples and acts as one component of a lure (akairomone) to the apples, which attracts the codling moth,Cydia pomonella. The main problem in the total syntheses of the germacraneswas the formation of the unsaturated monocyclic 10-memberedring. This was achieved by intramolecular alkylation with asuitably functionalised/protected cyanohydrin derivative,which, after further elaboration, afforded a monocyclic10-membered enone, that was used in the syntheses of the twogermacranes mentioned above. In the initial steps in thesynthetic sequence the stereochemistry was established byalkylation of an amide enolate attached to a chiral auxiliary.This approach could most likely also readily furnish the(+)-enantiomers of these germacrenes (of the germacraneterpenoid class) using the opposite enantiomer of the chiralauxiliary in the initial steps. <b>Keywords</b>: isoprenoids, natural product synthesis,allelochemicals, kairomones, allomones, bisabolane terpenoids,Hylobius abietis, germacrane terpenoids, Neodiprion sertifer,stereoselective synthesis.