The Streptomyces metabolite 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC), the antheminones and the carvotacetone derivatives are all bioactive natural products, whose structure is based on the α oxymethyl-a,β-cyclohexenone moiety. Both COTC and antheminone A have been shown to exhibit cytotoxic and cancerostatic activity with low toxicity. The potent biological activity of these natural products has instigated numerous investigations into the synthesis of novel analogues in an attempt to determine the key structural features necessary for optimum bioactivity. The synthesis of a small library of novel anti-tumour agents which are structurally related to the natural products COTC and antheminone A is described, using the chiral pool material (-)-quinic acid as a starting material. At the outset, the aim of this project was to develop and optimise copper-mediated conjugate addition reactions and rhodium catalysed conjugate addition reactions of organoboron reagents to functionalised cyclic enones and subsequently, to apply the methodologies to the synthesis of the novel analogues. A range of novel mono-hydroxylated analogues bearing aryl side chains were prepared and their antiproliferative activity was assessed towards the A549 non-small cell cancer cell line. The biological assays revealed important structure-activity relationships and the most bioactive compound of this series had an IC50 value of 1.2 µM. In addition, the design and synthesis of a new class of GSH-activated prodrugs is described. These novel compounds are activated by GSH leading to intracellular release of an NQO1 inhibitor. The most potent compound of this new class of compounds had an IC50 value of 710 nm.

No description available.

Nosso objetivo principal é aproveitar a bem conhecida diastereosseletividade π-facial das (SS)-2-tolilsulfinil-1,4-benzoquinonas, em reações de Diels-Alder, para obter, via metátese olefínica fototérmica, precursores enantiopuros do capneleno e da icarugamicina. Devido à formação de uma inseparável mistura de produtos na reação da (SS)-2-tolilsulfinil-1,4-benzoquinona com 1-metilciclopentadieno comercial, esta rota se tornou inviável para obtenção do capneleno. Visando-se a síntese do precursor da icarugamicina, foram preparadas as 5 e 6-metil-2-tolilsulfinil-1,4-benzoquinonas mas, apesar dos bons resultados de seletividade π-facial que estas apresentaram com o 1,3-cicloexadieno, a eliminação espontânea de ácido sulfênico nos adutos de Diels-Alder formados impediu o uso destes últimos. Numa tentativa de sobrepujar este inconveniente, uma nova quinona clorada foi preparada mas esta se mostrou um oxidante frente ao 1,3-cicloexadieno. / Our main objective is to take advantage of the well known π-facial diastereoselectivity of (SS)-2-tolylsulfinyl-1,4-benzoquinones, in the Diels-Alder reactions, to obtain, via photo-thermal olefin metathesis, enantiopure precursors of capnellene and ikarugamycin. The formation of an inseparable mixture of products in the reaction of commercially available methylcyclopentadiene and (SS)-2-tolylsulfinyl-1,4-benzoquinone made this route unsuitable for obtaining capnellene. For the synthesis of ikarugamycin, the 5 and 6-methyl-2-(SS)-tolylsulfinyl-1,4-benzoquinones were prepared but, in spite of the good π-diastereoselectivity they exhibited, in the reaction with 1,3-cyclohexadiene, spontaneous elimination of sulfenic acid from the formed adducts precluded their use. In an attempt to overcome this very easy elimination, a chlorinated quinone was synthesized but it showed oxidizing properties in the presence of 1,3-cyclohexadiene.

Nosso objetivo principal é aproveitar a bem conhecida diastereosseletividade π-facial das (SS)-2-tolilsulfinil-1,4-benzoquinonas, em reações de Diels-Alder, para obter, via metátese olefínica fototérmica, precursores enantiopuros do capneleno e da icarugamicina. Devido à formação de uma inseparável mistura de produtos na reação da (SS)-2-tolilsulfinil-1,4-benzoquinona com 1-metilciclopentadieno comercial, esta rota se tornou inviável para obtenção do capneleno. Visando-se a síntese do precursor da icarugamicina, foram preparadas as 5 e 6-metil-2-tolilsulfinil-1,4-benzoquinonas mas, apesar dos bons resultados de seletividade π-facial que estas apresentaram com o 1,3-cicloexadieno, a eliminação espontânea de ácido sulfênico nos adutos de Diels-Alder formados impediu o uso destes últimos. Numa tentativa de sobrepujar este inconveniente, uma nova quinona clorada foi preparada mas esta se mostrou um oxidante frente ao 1,3-cicloexadieno. / Our main objective is to take advantage of the well known π-facial diastereoselectivity of (SS)-2-tolylsulfinyl-1,4-benzoquinones, in the Diels-Alder reactions, to obtain, via photo-thermal olefin metathesis, enantiopure precursors of capnellene and ikarugamycin. The formation of an inseparable mixture of products in the reaction of commercially available methylcyclopentadiene and (SS)-2-tolylsulfinyl-1,4-benzoquinone made this route unsuitable for obtaining capnellene. For the synthesis of ikarugamycin, the 5 and 6-methyl-2-(SS)-tolylsulfinyl-1,4-benzoquinones were prepared but, in spite of the good π-diastereoselectivity they exhibited, in the reaction with 1,3-cyclohexadiene, spontaneous elimination of sulfenic acid from the formed adducts precluded their use. In an attempt to overcome this very easy elimination, a chlorinated quinone was synthesized but it showed oxidizing properties in the presence of 1,3-cyclohexadiene.

The natural product 2 crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxy-cyclohex-2-enone (COTC) was isolated from the microorganism Streptomyces griseosporeus in 1975. It was shown to exhibit 'cytotoxic and cancerostatic activity'. The simplified synthetic analogue 2-crotonyl-oxymethyl-cyclohex-2-enone (COMC) has been shown to exhibit potent anti tumour activity against murine and human tumours in cell culture. For several years, the Whitehead research group at the University of Manchester have focused on the synthesis of COTC and COMC analogues in an attempt to produce compounds with enhanced cytotoxicity. In this thesis, the syntheses of several polyfunctionalised cyclohexenones are described. These compounds are analogues of COTC and COMC which also bear structural resemblance to the antheminone and carvotacetone natural products. Initially, the syntheses of six novel compounds from the chiral pool starting material (-)-quinic acid are described. The first four synthetic steps of each sequence were carried out by slight modification of procedures previously reported by the Whitehead research group. As part of the synthetic strategy, the diastereoselective conjugate addition of carbon nucleophiles to several polyfunctionalised cyclohexenones was investigated. The cytotoxicity of four of the synthetic analogues towards A549 non small cell lung cancer cells was investigated by use of an MTT assay. Two of the analogues were found to be more cytotoxic then COMC. The most effective synthetic analogue had an IC50 value of 2.2 μM. This analogue was more cytotoxic than similar molecules that had previously been synthesised by members of the Whitehead research group. Based on the results of the MTT assay, another two analogues were designed and their synthesis from (-)-quinic acid is described. The cytotoxicity of these analogues has yet to be assessed. In summary, the general synthetic strategies developed in this thesis will provide easy access to new analogues of the natural products, enabling the development of new cytotoxic compounds.

No description available.

Dans le contexte de la synthèse éco-compatible, la réactivité et le transfert de chiralité de sulfoximines dans quelques réactions domino ou consécutives diastéréosélectives ont été étudiés pour la synthèse de carbocycles et d’hétérocycles d’intérêt. L’emploi de béta-cétosulfoximines comme pronucléophiles dans des additions de Michael diastéréosélectives a aussi été étudié. Dans la plupart de ces cas, l’induction asymétrique de l’atome de soufre chiral s’est révélée faible. Dans un second temps, nous avons étudié l’addition de Michael énantiosélective des cyclobutanones activées sur les nitroalcènes par une approche organocatalytique. En utilisant un catalyseur bifonctionnel, les produits attendus présentant deux centres stéréogènes contigus dont un quaternaire, ont pu être obtenus avec de très bons rendements et d’excellentes diastéréo- et énantiosélectivités. Le potentiel synthétique de ces dérivés cyclobutaniques a pu être démontré, en particulier pour la synthèse de gamma-lactones optiquement actives. / In the context of eco-compatible synthesis, reactivity and chirality transfer of sulfoximines in some domino or consecutive diastereoselective reactions have been studied for the synthesis of carbocycles and heterocycles of interest. The use of béta-ketosulfoximines as pronucleophiles in diastereoselective Michael additions has also been studied. In most of these cases, the asymmetric induction of chiral sulfur atom was low. Then, we investigated the enantioselective Michael addition of activated cyclobutanones onto nitroalkenes by an organocatalytic approach. The resulting adducts exhibit two contiguous chiral carbon atoms including an all-carbon quaternary stereocenter. They were obtained with very good yields and excellent diastereo-and enantioselectivities by using a bifunctional catalyst. The synthetic potential of these cyclobutane derivatives could be shown, especially for the synthesis of optically active gamma-lactones.

Les transferts de nitrène représentent un outil synthétique très intéressant pour former simplement une liaison C-N à partir d’une liaison C-H. Notre laboratoire a développé des précurseurs de nitrène chiraux : les sulfonimidamides. Leur utilisation a abouti, en présence de catalyseurs de cuivre et de rhodium, à des réactions d’aziridination d’oléfine et d’amination C-H hautement diastéréosélectives. Ce projet de thèse s’inscrit dans la continuité de ces travaux. Les sulfonimidamides ont pu être combinés avec des complexes scorpionate de cuivre et d’argent, au cours d’une collaboration COST avec le groupe de Pedro Pérez à Huelva, avec de bons résultats pour l’aziridination d’oléfines et l’amination C-H. De même, des nouveaux complexes de cuivre développés dans l’équipe de Didier Bourissou à Toulouse, ont pu être testés avec succès pour l’aziridination de différentes oléfines, dans le cadre d’une collaboration ANR. D’autre part, le champ d’application de la réaction d’amination C-H catalysée par le rhodium a été étendu avec d’excellents résultats à des substrats complexes comme les terpènes et différents éthers d’énol, ainsi qu’à des substrats peu réactifs comme les alcanes. Enfin, des études mécanistiques ont été menées pour tenter d’élucider la nature du transfert de nitrène. Les résultats obtenus sont en faveur d’un mécanisme concerté asynchrone, mais ils ne permettent pas d’exclure définitivement un transfert radicalaire. L’isolement d’un complexe métal-carbène étant supposé plus aisé qu’un complexe métal-nitrène, nous nous sommes tournés vers le développement de carbènes de sulfoximines, analogues carbonés des sulfonimidamides, sans résultat satisfaisant pour le moment. / Catalytic nitrene transfers are useful tools in organic synthesis, to perform the transformation of a C-H bond into a C-N bond. Our group has previously demonstrated that sulfonimidamieds are efficient chiral nitrène precursors. Combined with copper or rhodium complexes, they have allowed to uncover olefin aziridination and C-H amination that occur with high level of stereoselectivity. These PhD studies stand within the framework of this topic. Sulfonimidamides have first been combined with scorpionate copper and silver complexes developed by Pedro Perez in Huelva, to afford either aziridines or C-H amination products in very good yields. In the same way, new copper catalysts developed in the group of Didier Bourissou in Toulouse were evaluated with good results in olefin aziridination. On the other hand, rhodium catalyzed C-H amination has been applied to more complex substrates such as terpenes and enol ethers, as well as to less reactives substrates like alkanes, with excellent results in terms of regio-, chemo-, and stereoselectivity. Mechanistic studies have also been conducted. These point to an asynchronous concerted nitrene transfer, but the involvement of radicals cannot be ruled out. We have finally turned our attention to the formation of carbenes from sulfoximines, which are the carbo-analogs of sulfonimidamides, but without success so far.

No description available.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-05-13T18:09:13Z No. of bitstreams: 1 fabiodesouzafernandes.pdf: 24065820 bytes, checksum: da2a7ed64d78294c49d6e226495eda40 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-06-27T21:20:25Z (GMT) No. of bitstreams: 1 fabiodesouzafernandes.pdf: 24065820 bytes, checksum: da2a7ed64d78294c49d6e226495eda40 (MD5) / Made available in DSpace on 2016-06-27T21:20:25Z (GMT). No. of bitstreams: 1 fabiodesouzafernandes.pdf: 24065820 bytes, checksum: da2a7ed64d78294c49d6e226495eda40 (MD5) Previous issue date: 2016-02-29 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Na Química Medicinal, dentre as várias técnicas de planejamento racional para a síntese de novas moléculas bioativas, a hibridação é umas das mais usadas. A união de dois ou mais compostos biologicamente ativos, no intuito de se criar um novo fármaco que conserve as propriedades biológicas das moléculas base e/ou crie uma nova atividade biológica para o composto híbrido, faz desta técnica um caminho rápido, eficaz e oportuno no descobrimento de novos candidatos a fármacos. Sinteticamente, dentre os vários métodos de junção de duas ou mais moléculas a Reação de Mannich está entre as metodologias aplicadas para isto. Este primeiro capítulo trata da síntese N-bases de Mannich derivadas da pirazinamida, que resultou na obtenção de dezenove compostos inéditos. Em um primeiro momento, foi realizada a tentativa de síntese de N-bases de Mannich derivadas da pirazinamida, utilizando três diferentes aminoálcoois Nalquilados. O desenvolvimento da metodologia mostrou que a reação era dependente do pH, tendo este que ser básico. No entanto, a baixa conversão da reação, juntamente com a difícil purificação do produto, uma vez que o mesmo apresentava o mesmo fator de retenção da pirazinamida e alta instabilidade impedindo qualquer funcionalização in situ inviabilizou qualquer possibilidade de continuação desta síntese. Desta forma, foi feita a substituição dos aminoálcoois N-aquilados por piperazinas N-substituídas, contendo cadeias lipofílicas, uma porção D-galactose, amidas lipofílicas, aminoalcoóis aromáticos e heteroaromáticos, sendo sintetizados 5 derivados inéditos da piperazina. A partir da reação de Mannich das piperazinas Nsubstituídas com a pirazinamida foram obtidas quatorze N-Bases de Mannich inéditas. Tanto as piperazinas N-substituídas como as N-bases de Mannich sintetizadas, foram submetidas à avaliação de suas atividades antibacterianas, antibiofilme e antituberculose, sendo que os resultados para atividade antibiofilme apresentaram bastante promissores. As lactamas são amidas cíclicas presentes em vários produtos naturais e em compostos sintéticos com atividade biológica. Devido a esta importância dentro da química medicinal, várias são as estratégias desenvolvidas para a síntese destes anéis heterocíclicos, com o objetivo de se conseguir uma síntese rápida, eficiente, estereoseletiva e utilizando a química verde para destes compostos. Dentre as várias metodologias sintéticas que permitem a obtenção estereoseletiva de Lactamas está à reação de Mannich-Acilação, inicialmente desenvolvida por Castagnoli em 1969 e aperfeiçoada recentemente pelo grupo de pesquisa do Professor Dr. Jared Shaw. Sendo assim, o segundo capítulo aborda desenvolvimento de uma metodologia a paritr da reação de Mannich-Acilação para a síntese de δ-lactamas como suporte para um estudo computacional sobre o mecanismo e estereoseletividade da reação. Para isso, a síntese do anidrido altamente reativo α-ciano glutárico, bem como, dos anidridos α- ciano glutárico substituídos com grupos metila ou fenila nas posições β ou γ foram realizadas. O escopo e as limitações da reação imina-anidrido com uma ampla variedade de iminas também foi investigada. As reações contendo aminas substituídas por grupos alquil volumosos e aromáticos foram mais diastereoseletivas. Já as reações envolvendo o uso dos anidridos α-ciano glutáricos não substituídos e contendo os grupos metila e fenila na posição β mostraram-se altamente diastereoseletivas, enquanto que para as reações envolvendo o anidrido α-ciano glutárico substituídos na posição γ houve uma perda da seletividade. Os estudos computacionais mostraram que a origem do estereocontrole da reação se dá na etapa de acilação, onde efeitos estéreos e trans anulares para o estado de transição na forma eclipsada justificam a formação do produto majoritário tendo uma relação syn entre os grupos carboxilato e fenil. Neste capítulo também foram exploradas algumas aplicações, no que diz respeito à utilização das δ-lactamas como possíveis inibidores da proteína FtsZ, em um estudo onde as δ-lactamas serviram como substratos na reação clássica de descarboxilação alilativa e na síntese dos produtos naturais Gelsidilam e Gelgamina B tendo a reação de Mannich-Acilação desenvolvida neste capítulo como uma das etapas chave. / In the Medicinal Chemistry, there are many techniques for development of new bioactive molecules. One way to do a rational planning of new drugs is using the molecular hybridization technique. In the molecular hybridization, the combination of two or more biologically active compounds in order to create a new pro-drug that preserves the biological properties or improve efficacy when compared to the parent drugs, makes this technique a quick way, effective and timely in the discovery of new drug candidates. Mannich reaction can be applicable to combine two or more fragments of drugs with biological activity. The first chapter will show the synthesis of new N-Mannich bases derived from pyrazinamide, which resulted in the synthesis of nineteen novel compounds. First of all, we tried to make the synthesis of new N-Mannich bases from of reaction between pyrazinamide, formaldehyde and N-alkylated amino alcohols. The development of this methodology showed that the reaction was pH dependent and it had to be basic. So we tried to control the pH of reaction using some bases, but the lower conversion of reaction together with the difficult purification of the product and the high instability led to an unsuccessful planning to get the products desired. Because of this, was made replacing of N-alkylated amino alcohols by N-substituted piperazines having lipophilic chain, D-galactose moiety, lipophilic amides, aromatic and heteroaromatic amino alcohols. With these new components we ran the Mannich reactions and was possible to synthesize fourteen novel N-Mannich bases. The N-substituted piperazines and N-Mannich bases synthesized were evaluated by antibacterial, antibiofilm and antituberculosis activities. The results of antibiofilm and antibacterial activity for some hybrids were very promising. In the second chapter, was developed a methodology to the synthesis of δ- lactams from cycloaddition between imines and cyano glutaric anhydrides like a support to mechanism and diastereoselectivity study of reaction. For this was made the synthesis of β, γ-substituted and unsubstituted cyano anhydrides. The scope of reaction was studied using differents amines and aldehydes. The reactions that were ran with bulky alkyl-substituted amines or aromatic amines were more selective than methylamine. The reactions involving the use of α-cyano-glutaric anhydrides unsubstituted or containing methyl groups and phenyl in the β position showed high diastereoselectivity. Reactions using the γ substituted anhydrides had a poor diastereoselectivity. Computational studies showed that acylation step is a determinant factor to diastereoselectivity, where the eclipsed transition state to anti product has steric and trans anular effects. Some applications of -lactams were made in other studies involving Tethering technique, decarboxylative allylation and total synthesis of Gelsedilam and Gelegamine B.