De nouveaux phosphinites énantiopurs à la structure hélicoïdale ont été synthétisés et utilisés en catalyse asymétrique. Les plateformes 2,15-dihydroxyhélicènes ciblées pour l’étude ont été synthétisées selon deux voies de synthèse, par photocyclisation oxydante et par cycloaddition [2+2+2] catalysée au cobalt et au rhodium. Les énantiomères ont été séparés par HPLC chirale préparative ou synthèse des diastéréoisomères puis séparation sur gel de silice. Les Hélixols énantiomères ont ainsi été obtenus avec des excès énantiomériques supérieurs à 99.5 %. Si les structures hélicoïdales cycliques désirées n’ont pu être obtenues en raison de la distance excessive entre les deux fonctions phénol, la double phosphorylation conduit à de nouveaux ligands bisphosphinites à chiralité hélicoïdale. Ces derniers ont été utilisés dans des réactions de cycloisomérisation énantiosélective d’énynes-1,6 catalysées à l’or ; et d’alkylation allylique asymétrique catalysée au palladium. / New [6]helicene-based bisphosphinites were synthetized and used in asymmetric catalysis. Desired 2,15-dimethoxy[6]helicenes were synthetized by two pathways: photochemical oxidative cyclization and CoI or RhI-catalyzed [2+2+2] cycloaddition. Both enantiomers of [6]Helixols were obtained by preparative chiral HPLC and/or using a chiral agent (up to 99.5 % ee). Even if desired helical cyclic scaffolds cannot be obtained due to the large distance between the two oxygen atoms. The synthesis of new [6]helicenes-based bisphosphinites were developed. Those last were used in gold-catalyzed enantioselective cycloisomerization of 1,6-enynes and Pd-catalyzed asymmetric allylic alkylation.

Ce manuscrit traite de la mise au point d’une méthode d’accès éco-compatible à des squelettes carbocycliques et hétérocycliques, présents dans de nombreux composés d’intérêt biologique. Cette méthode met en œuvre une réaction de cycloaddition [2+2+2] catalysée par un métal de transition. Dans un premier temps, une voie d’accès à des fluorénones hautement substituées, ainsi qu’à des analogues a été développée. Cette voie utilise une réaction de cycloaddition [2+2+2] de diynes-[alpha, omega] pontés par un groupe benzoyle, avec des alcynes, en présence de RuCl3·nH2O. Dans un deuxième temps, des dérivés 2-aminopyridines diversement fonctionnalisés ont été synthétisés via une catalyse au ruthénium neutre (RuCl3·nH2O) ou cationique (Cp*Ru(CH3CN)3PF6), et ce à partir de la cycloaddition [2+2+2] de diynes et de cyanamides. Dans le cas où Cp*Ru(CH3CN)3PF6 a été utilisé comme catalyseur, une excellente régiosélectivité a été observée, ce qui a permis d’isoler une grande variété de 2-aminopyridines, dont des halopyridines, des vinylpyridines, ou des amino-aza-fluorénones. Dans une dernière partie, la cycloaddition [2+2+2] énantiosélective de triynes prochiraux avec des mono alcynes a été examinée. Elle a été conduite en utilisant un catalyseur cationique au rhodium, le complexe [Rh(cod)2]BF4/(R)-BINAP, et a permis la préparation de dérivés de 1,3-dihydroisobenzofuranes énantiomériquement enrichis, contenant un carbone quaternaire stéréogène. / This manuscript focused on the development of eco-friendly and mild processes to access original carbocyclic and heterocyclic scaffolds of biological interest through transition-metal-catalyzed [2+2+2] cycloaddition reactions. Initially, an efficient and practical route for the preparation of highly substituted fluorenones and analogues via solventless RuCl3·nH2O-mediated [2+2+2] cycloaddition of benzoyl bridged [alpha, omega]-diynes and alkynes was developed. Secondly, various functionalized 2-aminopyridine derivatives were synthesized using both neutral RuCl3·nH2O and cationic Cp*Ru(CH3CN)3PF6 complexes to catalyze the [2+2+2] cycloaddition of diynes and cyanamides under solvent-free conditions. With Cp*Ru(CH3CN)3PF6 as catalyst, excellent regioselectivities were achieved to provide a wide range of 2-aminopyridines of high synthetic utility involving halopyridines, vinyl pyridines and amino-aza-fluorenones. Finally, the enantioselective rhodium-catalyzed [2+2+2] cycloaddition of prochiral triynes and monoalkynes was carried out in the presence of cationic [Rh(cod)2]BF4/(R)-BINAP complex to provide enantioenriched 1,3-dihydroisobenzofuran derivatives containing a quaternary carbon stereogenic center.

Esta tesis describe el estudio de la aplicación en síntesis de N-terc-butanosulfinil derivados de alquil, alquenil, homoalil y homopropargil aminas como intermedios para acceder a moléculas orgánicas de mayor complejidad. Por un lado, se ha estudiado la adición de compuestos organomagnesianos y organolíticos a N-terc-butanosulfinil iminas, y los distintos derivados de aminas que se obtienen como resultado se han usado como precursores de alcaloides pirrolodínicos y piperidínicos, así como para acceder a anillos tipo azepano. Por otro lado, también se presentan aplicaciones en síntesis de N-terc-butanosulfinil homoalil y homopropargil aminas, que pueden participar en reacciones de oxidación allílica y cicloadiciones [2+2+2], respectivamente, para dar lugar a compuestos polifuncionalizados, en el caso de los derivados de homoalil aminas, y derivados de 9-amino-9, 10-dihidrofenantrenos y 1,2,3,4-tetrahidroisoquinolinas, en el cado de los derivados de homopropargil aminas.

O objetivo deste trabalho foi investigar o uso de NbCl5 como ácido de Lewis em reações de cicloadição. Foram estudadas algumas reações de cicloadição [2 + 2], Reações de Diels-Alder entre enonas e ciclopentadieno e Reações da aza-Diels-Alder com bases de Schiff, avaliando o efeito da temperatura e da concentração molar do NbCl5. A comparação dos rendimentos, dos produtos formados e do tempo de reação com NbCl5, também foi um ponto fundamental da pesquisa. As reações de cicloadição [2 + 2] foram realizadas entre ésteres propiólicos e diferentes tipos de alcenos (éteres enólicos de silício e alcenos alifáticos). Nas reações com os éteres enólicos de silício não foi verificada a formação dos respectivos adutos de ciclobuteno, pois o NbCl5 promove a quebra da ligação oxigênio-silício, não levando à formação do produto desejado. Nas reações com os alcenos alifáticos foi possível obter o respectivo aduto, porém com rendimentos menores que com outros ácidos de Lewis. Quanto às reações de Diels-Alder, foram investigadas as reações entre diferentes ciclo-enonas (dienófilos de baixa reatividade) com ciclopentadieno (dieno) na presença de NbCl5. Os resultados obtidos indicam que o NbCl5 é um bom ácido de Lewis para ativar reações de Diels-Alder, apresentando tempos reacionais menores e alta diastereosseletividade a temperaturas mais baixas, quando comparado com outros ácidos de Lewis. A possibilidade de efetuar reações do Diels-Alder a -78 0C é um dos aspectos de destaque neste trabalho, pois, além de demonstrar a forte ativação do sistema enona exercido pelo NbCl5, possibilita obter produtos com alta seletividade. Paralelamente aos estudos de sistemática reacional foram realizados estudos de elucidação estrutural completa de alguns dos compostos sintetizados, utilizando-se diversas técnicas de RMN (uni e bidimensionais), e o auxílio de cálculos teóricos. Nas reações de aza-Diels-Alder entre bases de Schiff e di-hidropirano, o NbCl5 se mostrou um ótimo catalisador para a síntese de derivados de piranoquinolinas. Estes derivados formam uma importante classe de produtos naturais que apresentam ampla atividade biológica. As reações foram conduzidas com baixas concentrações de nióbio e em tempos relativamente curtos, obtendo-se rendimentos variando de 72 a 96 %. Outro fator a se destacar é a alta diastereosseletividade encontrada nestas reações. Também foram realizados estudos da atividade tripanocida dos derivados de piranoquinolinas preparados através das reações de aza-Diels-Alder catalisadas por NbCl5. / The aim of this work was to investigate the use of NbCl5 as Lewis acid in cycloadittion reactions. We have studied [2 + 2] cycloaddition reactions, Diels-Alder reactions between enonas and cyclopentadiene and aza-Diels-Alder reactions with Schiff bases. The effects of the temperature and of the molar concentration of NbCl5 were also evaluated. Comparasion of reaction yields, obtained products as well as reation time with NbCl5 were also a key point on this work. The [2 + 2] cycloaddition reactions were performed using propiolic ester and different types of alkenes (silyl enol ethers and aliphatic alkenes). In the reactions with silyl enol ethers, formation of the corresponding cyclobutene aductts was not verified, since the NbCl5 promotes the rupture of oxygen-silicon bonds, and the desired product is not obtained. In the reactions with aliphatic alkenes, it was possible to obtain the adduct, however, in lower yields as compared to those obtained with others Lewis acids. Regarding the Diels-Alder reactions, we have investigated reactions using different cycloenones (dienophiles of low reactivity) with cyclopentadiene (diene) with NbCl5. The obtained results indicate that NbCl5 is a good Lewis acid to activate these Diels-Alder reactions, resulting in shorter reaction times and higher diastereoselectivity at lower temperatures than other Lewis acids. The possibility of carrying out Diels-Alder reaction at -78 0C is another remarkable aspect of this work. Besides demonstrating the strong activation of the enone system by NbCl5, it opens the possibility of obtaining high stereoselectivity. We have also performed studies of complete structural elucidation of some compounds by using different NMR techniques (uni and bidimensional), with the help of theoretical calculations. In the aza-Diels-Alder reactions between Schiff bases and dihydropyran, the NbCl5 was an excellent catalyst for the synthesis of pyranoquinoline derivatives. These derivatives are an importante class of natural products that exhibit wide range of biological activity. The reactions were carried out at low concentration of niobium and in relatively short times, resulting in yields varying from 72 to 96 %. Another aspect that should be remarked is the high diastereoselectivity found in these reactions. We have also carried out studies of tripanocydal activity of pyranoquinoline derivatives prepared through aza-Diels-Alder reactions catalyzed by NbCl5.

The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA.

L’obtenció de lligands quirals eficients i de fàcil accés segueix essent un dels objectius principals en catàlisi. Les fosfines estereogèniques voluminoses han mostrat ser molt eficients en un ampli ventall de reaccions catalítiques. No obstant, la seva síntesis de forma enantiomèricament pura és molt sovint complicada. Podem considerar que els mètodes més efectius per a la construcció de fòsfor estereogènic són els desenvolupats per Jugé i Evans basats en l’obertura d’oxazafosfolidines enantiopures i la desprotonació enantioselectiva de fosfino-borans, respectivament. Aquests mètodes, tanmateix, presenten limitacions i desavantatges. Aquest fet confereix atractiu al desenvolupament de nous processos per a la síntesi de fòsfor estereogènic. En la present tesi doctoral, es va estudiar la condensació de fenil i tert-butilfosfines amb el (cis)-1-amino-2-indanol. Aquestes ens conduí a les corresponents oxazafosfolidines amb bon rendiment i diastereoselectivitats de fins a 18 : 1. La condensació amb aquest aminoalcohol ens proporcionà oxazafosfolidines amb funció NH lliure. Justament aquesta nova funcionalitat s’ha revelat clau en la química d’obertura d’anells d’oxazafosfolidines. Pel que fa l’obertura d’anell de la 2-feniloxazafosfolidina amb organolítics, aquestes transcorregueren amb inversió o retenció depenent de la substitució sobre l’àtom de nitrogen. Quan tenim un grup NH, l’obertura transcorre amb inversió mentre que quan el nitrogen està substituït amb un metil s’observa retenció tal i com havia descrit Jugé i col•laboradors. En la mateixa línia, l’obertura d’anell de la 2-tert-butiloxazafosfolidina amb el grup NH lliure amb organomagnesians té lloc de forma totalment estereoselectiva a temperatures elevades amb inversió. També s’ha desenvolupat una obertura reductiva de la 2-tert-butiloxazafosfolidina mitjançant l’ús combinat d’una font d’hidrur i un magnesià. Aquesta obertura també és totalment estereoselectiva i no té precedents en la literatura. Els productes d’obertura de la 2-feniloxazafosfolidina es van hidrolitzar segons la metòdica descrita per Jugé a les corresponents metoxifosfines amb bons rendiments i elevats ee. Els productes d’obertura de la 2-tert-butiloxazafosfolidina amb grups alquil es van poder trencar de l’auxiliar quiral amb Li/NH3(liq.) obtenint-se les aminofosfines amb ee>99%. Alternativament, es va desenvolupar una seqüència d’eliminació i posterior hidròlisis que permet alliberar les aril-tert-butilaminofosfines amb bons rendiments i ee>99%. Aquests es va derivatitzar la tert-butilaminofosfina en diferents compostos. Finalment també es va descriure una nova família de lligands basats en fosfinosulfonamides. Es van descriure nous complexos de Rh-fosfinosulfonamida els quals es van aplicar a la reacció de cicloaddició [2+2+2] intramolecular de manera exitosa. Aquests complexos ens van permetre superar amb escreix els resultats descrits prèviament. Finalment, es va dissenyar una nova família de lligands que hem anomenat ThaxPHOS. Es van emprar aquests en la reacció de Pauson-Khand intermolecular catalítica enantioselectiva. La desprotecció i complexació amb dicobalt dóna molt bon resultats i bones diastereoselectivitats gràcies a equilibracions tèrmiques. Inicialment, es va dissenyar una estratègia estequiomètrica enantioselectiva per a l’obtenció de l’adducte de Pauson-Khand amb acetilè lliure sense emprar l’acetilè en forma de gas. L’aplicació d’aquests complexos en la reacció catalítica han donat els millors resultats mai descrits en aquest camp. S’ha plantejat un nou mecanisme catalític per justificar els resultats obtinguts. / The synthesis of efficient and easily affordable chiral ligands are one of the main goals in catalysis. Bulky stereogenic phosphine have demonstrated to be excellent ligands in a broad range of catalytic reactions. Furthermore, their synthesis in an optically pure form is usually difficult. We can consider that the method developed independently by Jugé and Evans are the most effective in this field. Nevertheless, these methods have some drawbacks. These downsides need to be improved and new synthetic methodologies need to be developed to obtain stereogenic phosphorus compounds. In this doctoral thesis we studied the condensation of phenyl- and tert-butylphosphines with (cis)-1-amino-2-indanol. These allowed us to obtain the corresponding oxazaphospholidines with excellent yields and diastereoselectivities (up to 18 : 1). These condensations allowed us to get a free NH functionality. We saw as this secondary amine was the key for our ring-opening strategy. Taking advantage of this group, we performed the ring-opening reaction allowing us to obtain the corresponding ring-opened product with inversion of configuration on the phosphorus atom. This reaction was carried out with total diastereoselectivity, and the ring-opened products obtained from 2-phenyloxazaphospholidine were hydrolyzed following the Jugé procedure described in literature. We obtained the corresponding methoxyphosphine with excellent yields and high ee. The ring-opened products obtained from 2-tert-butyloxazaphospholidine with alkyl groups were reductively cleaved with Li/NH3(l) affording the corresponding aminophosphine with ee>99%. Alternatively, we developed a new strategy based on elimination-hydrolysis to free the corresponding aryl-tert-butylaminophosphines with excellent results and optically pure. Subsequently, we described a new ligand family based on phosphinosulfonamide. We described new complexes of Rh-phosphinosulfonamide and we tested them in the intramolecular cycloaddition [2+2+2] significantly improving on the previous results described. Finally, we designed a new family of PnP* ligands called ThaxPHOS. These ligands were used in the enantioselective catalytic intermolecular Pauson-Khand reaction. The deprotection and successive coordination gave excellent yields and diastereoselectivities due to thermal equilibration. We used ThaxPHOS ligands in this reaction and we described the best results ever obtained in this field and we described a new catalytic mechanism to explain our results.

O objetivo deste trabalho foi investigar o uso de NbCl5 como ácido de Lewis em reações de cicloadição. Foram estudadas algumas reações de cicloadição [2 + 2], Reações de Diels-Alder entre enonas e ciclopentadieno e Reações da aza-Diels-Alder com bases de Schiff, avaliando o efeito da temperatura e da concentração molar do NbCl5. A comparação dos rendimentos, dos produtos formados e do tempo de reação com NbCl5, também foi um ponto fundamental da pesquisa. As reações de cicloadição [2 + 2] foram realizadas entre ésteres propiólicos e diferentes tipos de alcenos (éteres enólicos de silício e alcenos alifáticos). Nas reações com os éteres enólicos de silício não foi verificada a formação dos respectivos adutos de ciclobuteno, pois o NbCl5 promove a quebra da ligação oxigênio-silício, não levando à formação do produto desejado. Nas reações com os alcenos alifáticos foi possível obter o respectivo aduto, porém com rendimentos menores que com outros ácidos de Lewis. Quanto às reações de Diels-Alder, foram investigadas as reações entre diferentes ciclo-enonas (dienófilos de baixa reatividade) com ciclopentadieno (dieno) na presença de NbCl5. Os resultados obtidos indicam que o NbCl5 é um bom ácido de Lewis para ativar reações de Diels-Alder, apresentando tempos reacionais menores e alta diastereosseletividade a temperaturas mais baixas, quando comparado com outros ácidos de Lewis. A possibilidade de efetuar reações do Diels-Alder a -78 0C é um dos aspectos de destaque neste trabalho, pois, além de demonstrar a forte ativação do sistema enona exercido pelo NbCl5, possibilita obter produtos com alta seletividade. Paralelamente aos estudos de sistemática reacional foram realizados estudos de elucidação estrutural completa de alguns dos compostos sintetizados, utilizando-se diversas técnicas de RMN (uni e bidimensionais), e o auxílio de cálculos teóricos. Nas reações de aza-Diels-Alder entre bases de Schiff e di-hidropirano, o NbCl5 se mostrou um ótimo catalisador para a síntese de derivados de piranoquinolinas. Estes derivados formam uma importante classe de produtos naturais que apresentam ampla atividade biológica. As reações foram conduzidas com baixas concentrações de nióbio e em tempos relativamente curtos, obtendo-se rendimentos variando de 72 a 96 %. Outro fator a se destacar é a alta diastereosseletividade encontrada nestas reações. Também foram realizados estudos da atividade tripanocida dos derivados de piranoquinolinas preparados através das reações de aza-Diels-Alder catalisadas por NbCl5. / The aim of this work was to investigate the use of NbCl5 as Lewis acid in cycloadittion reactions. We have studied [2 + 2] cycloaddition reactions, Diels-Alder reactions between enonas and cyclopentadiene and aza-Diels-Alder reactions with Schiff bases. The effects of the temperature and of the molar concentration of NbCl5 were also evaluated. Comparasion of reaction yields, obtained products as well as reation time with NbCl5 were also a key point on this work. The [2 + 2] cycloaddition reactions were performed using propiolic ester and different types of alkenes (silyl enol ethers and aliphatic alkenes). In the reactions with silyl enol ethers, formation of the corresponding cyclobutene aductts was not verified, since the NbCl5 promotes the rupture of oxygen-silicon bonds, and the desired product is not obtained. In the reactions with aliphatic alkenes, it was possible to obtain the adduct, however, in lower yields as compared to those obtained with others Lewis acids. Regarding the Diels-Alder reactions, we have investigated reactions using different cycloenones (dienophiles of low reactivity) with cyclopentadiene (diene) with NbCl5. The obtained results indicate that NbCl5 is a good Lewis acid to activate these Diels-Alder reactions, resulting in shorter reaction times and higher diastereoselectivity at lower temperatures than other Lewis acids. The possibility of carrying out Diels-Alder reaction at -78 0C is another remarkable aspect of this work. Besides demonstrating the strong activation of the enone system by NbCl5, it opens the possibility of obtaining high stereoselectivity. We have also performed studies of complete structural elucidation of some compounds by using different NMR techniques (uni and bidimensional), with the help of theoretical calculations. In the aza-Diels-Alder reactions between Schiff bases and dihydropyran, the NbCl5 was an excellent catalyst for the synthesis of pyranoquinoline derivatives. These derivatives are an importante class of natural products that exhibit wide range of biological activity. The reactions were carried out at low concentration of niobium and in relatively short times, resulting in yields varying from 72 to 96 %. Another aspect that should be remarked is the high diastereoselectivity found in these reactions. We have also carried out studies of tripanocydal activity of pyranoquinoline derivatives prepared through aza-Diels-Alder reactions catalyzed by NbCl5.

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-04-27T10:56:43Z No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-04-27T11:18:27Z (GMT) No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) / Made available in DSpace on 2018-04-27T11:18:27Z (GMT). No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) Previous issue date: 2018-02-20 / A obtenção de aminoácidos halogenados é de grande importância para síntese orgânica e para a área biológica, uma vez que estes são valiosos intermediários sintéticos e se apresentam como produtos biologicamente funcionais. Neste contexto, as azalactonas são precursores interessantes, uma vez que podem atuar como aminoácidos protegidos e serem utilizadas na síntese de derivados de aminoácidos e heterociclos complexos. Neste trabalho são descritas a abertura e halogenação das azalactonas de Erlenmeyer-Plöchl sob uma abordagem organocatalítica, utilizando ácido canforsulfônico (ACS) e N-bromosuccinimida (NBS) como agente halogenante. A condição otimizada para obtenção do produto halogenado consistiu na utilização de 30 mol% de ACS, 1.2 equivalente de NBS e 4 mL de metanol, a 65°C por 7 horas, obtendo-se uma imina halogenada com 83% de rendimento. Devido as dificuldades encontradas durante a avaliação do escopo de substratos, investigou-se a redução one-pot da imina halogenada, entretanto não foi possível obter um aumento da razão diastereoisomérica no produto desejado. Diante dos contratempos encontrados na metodologia proposta, investigou-se o uso da catálise foto redox irradiada por luz visível na tentativa de halogenação do heterociclo azalactônico. Entretanto, ao utilizar esta abordagem, observou-se a homodimerização das azalactonas de Erlenmeyer-Plöchl ao invés da halogenação da mesma, levando a um produto de cicloadição [2+2]. Em diclorometano, a utilização do fotocatalisador de rutênio favoreceu a formação de um sistema tricíclico do tipo espiro. Já em meio metanólico, o fotocatalisador metálico favoreceu a formação do produto de abertura dos dois anéis azalactônicos com 59% de rendimento, enquanto que o uso do corante orgânico Eosina Y levou à formação de um cicloaduto assimétrico, com a abertura de apenas um dos anéis azalactônicos (40% de rendimento). Avaliou-se o escopo de substratos utilizando Eosina Y como fotocatalisador e os rendimentos obtidos foram de moderados a bons (12 a 78%). Todos os produtos foram caracterizados por RMN de 1H, 13C, e IV. / Halogenated amino acids are of great importance for both organic synthesis and biological areas, once these are valuable synthetic intermediates and presented as biologically functional products. In this context, azlactones are interesting precursors that can act as protected amino acids and have been used in the synthesis of amino acid derivatives and complex heterocycles as well. This work describes Erlenmeyer-Plöchl’s azlactone ring opening following by halogenation under an organocatalytic approach, using camphorsulfonic acid (CSA) and N-bromosuccinimide (NBS) as halogenating agent. The optimized reaction conditions for the halogenated product consisted on the use of 30 mol% CSA, 1.2 equivalent of NBS and 4 mL of methanol, at 65°C for 7 hours, to afford a halogenated imine with 83% of yield. Due to the difficulties in the substrate scope (purification process), a one-pot reduction of the halogenated imine was investigated, however, it was not possible to obtain a good diastereoisomeric ratio of the desired product. In view of setbacks encountered in the proposed methodology, the use of visible light photoredox catalysis in attempt to halogenate the azlactone heterocycle was investigated. However, using this approach, homodimerization of Erlenmeyer-Plöchl’s azlactones was observed instead of halogenation, leading to a cycloaddition [2+2] derived product. In dichloromethane, the use of ruthenium photocatalyst favored the formation of a tricyclic spiro type system. Switching to methanol as solvent, the metallic photocatalyst led the formation of the opening product with two azlactone rings, in 59% yield, whereas the organic dye Eosin Y conducted the formation of an asymmetric cycloadduct, with the ring opening of only one of the azlactone (40% yield). The substrate scope was evaluated using Eosin Y as photocatalyst and the products were isolated in yields ranging from 12 to 78%. All products were characterized by 1H NMR, 13C and IR.

Les transformations photochimiques sont des outils puissants pour créer de la diversité moléculaires à partir de substrats facilement accessibles; elles requièrent le réactif le plus simple : un photon. Les réactions de cycloaddition [2+2] photochimiques de composés carbonylés ou carboxylés α,β-insaturés avec des oléfines sont les réactions photochimiques les plus largement utilisées en synthèse organique. Les photoadduits cyclobutaniques sont très appliqués en synthèse multi-étapes de produits naturels ou dérivés et sont également prisés comme intermédiaires de synthèse du fait de la grande réactivité intrinsèque liée à leur tension de cycle. Dans la première partie de cette thèse, nous nous sommes intéressés à une approche photochimique pour la synthèse de β-acides aminés cyclobutaniques substitués. Notre objectif était de mettre en place une synthèse robuste et efficace sur l’échelle du gramme des acides cis- et trans-2-aminocyclobutane-1-carboxyliques (cis- et trans-ACBC) diversement substitués en position 3 ou 4. La construction du cycle à quatre chaînons a été réalisée via une réaction de cycloaddition [2+2] photochimique entre le tert-butoxyéthène et le maléimide ou l’anhydride maléique. Les fonctions amine et acide carboxylique ont ensuite été générées par des processus consécutifs ou “one-pot” impliquant un réarrangement de Hofmann. Les mélanges racémiques des 3- et 4-cis-syn-hydroxy-ACBCs ont été dédoublés via l’utilisation d’une oxazolidinone chirale, donnant accès aux β-acides aminés énantiopures ciblés sur grande échelle, sous la forme déprotégée ou protégée orthogonalement. Le contrôle d’une procédure d’épimérisation cis-trans a permis l’accès aux composés trans-syn-3-hydroxy-ACBC à partir des substrats cis-syn-3-hydroxy-ACBC. Enfin, les composés ACBCs diversement substitués en position 3 et de configuration cis-anti ou trans-anti ont pu être préparés grâce à une réaction de Mitsunobu ou d’autres transformations de type SN2, à partir des réactifs cis-syn- ou trans-syn-3-hydroxy-ACBC correspondants. Dans la seconde partie de cette thèse, nous avons étudié des processus photochimiques tandem et cascade initiés par une réaction de cycloaddition [2+2] photochimique. En collaboration avec un chercheur post-doctorant, nous avons réalisé la synthèse contrôlée d’une librairie d’acétals cyclobuténiques et d’oxétanes polycycliques, via des photoréactions tandem et cascade entre des cyclopent-2-énones et des partenaires alcènes. Le processus tandem résulte d’une réaction de cycloaddition [2+2] photochimique suivie d’une fragmentation de type Norrish I et d’un transfert d’hydrogène en position γ, conduisant aux aldéhydes cyclobuténiques protégés in situ sous la forme de dérivés acétals stables. La triple cascade réactionnelle a permis l’accès à de nouveaux oxétanes tricycliques angulaires par le biais d’une réaction de Paternò-Büchi intramoléculaire à partir des aldéhydes cyclobuténiques précédemment cités. La généralisation de ces deux processus domino a été étudiée à partir d’un panel de cyclopent-2-énones et de trois partenaires alcènes représentatifs. La formation de certains des composés obtenus a pu être expliqué par à une réaction supplémentaire de type SN’. Une étude préliminaire de cette transformation non-attendue a été réalisée. / Photochemical transformations are powerful tools for the creation of molecular diversity from simple and readily available starting materials; they employ the simplest of reagents, a photon. Photochemical [2+2] cycloaddition reactions of α,β-unsaturated carbonyl or carboxyl compounds with olefins are one of the most widely applied photochemical reactions in organic synthesis. The cyclobutane photoadducts have been used ubiquitously in multi-step syntheses of a wide array of natural products or related derivatives, and they have also been used as intermediates in other synthetic procedures which exploit their strained molecular skeletons and their resulting intrinsic chemical reactivity.In the first part of this thesis, we focused on a photochemical approach for the synthesis of ring-substituted cyclobutane β-amino acids. Our objective was to establish a robust, large-scale and efficient synthesis of cis- and trans-2-aminocyclobutane-1-carboxylic acids (cis- and trans-ACBC) diversely substituted at the 3- or 4-positions. The cyclobutane ring was constructed using a photochemical [2+2] cycloaddition reaction between tert-butyl vinyl ether and either maleimide or maleic anhydride. The amine and carboxylic acid functions were subsequently installed through consecutive or one-pot protocols including a Hofmann rearrangement. The protected racemates of 3- and 4-cis-syn-hydroxy-ACBCs obtained in this way were resolved using a chiral oxazolidinone auxiliary to provide a large scale access to enantiomerically pure samples of the target β-amino acids in either free or orthogonally protected form. A controlled cis-to-trans epimerization procedure from cis-syn-3-hydroxy-ACBC substrates permitted facile access to target trans-syn-3-hydroxy-ACBCs. Finally, diversely substituted 3-ACBCs with cis-anti or trans-anti relative configurations were synthesized using Mitsunobu or other SN2-type reactions, starting from corresponding cis-syn- or trans-syn-3-hydroxy-ACBC derivatives.In the second part of the thesis, we investigated photochemical tandem and cascade processes which began with a photochemical [2+2] cycloaddition reaction. In collaboration with a post-doctoral researcher, we reacted cyclopent-2-enones and alkenes to afford libraries of cyclobutene acetals and polycyclic oxetanes, in a controlled manner, via tandem and triple cascade photoreactions. The tandem process consisted of a photochemical [2+2] cycloaddition followed by Norrish I/γ-H transfer which led to cyclobutene aldehydes; these reactive photoadducts were trapped in situ as stable acetal derivatives. The triple cascade process provided access to unprecedented angular tricyclic oxetanes via an intramolecular Paternò-Büchi reaction of the above-mentioned cyclobutane aldehydes. The scope of these two domino processes was investigated using panels of 2- and 4-substituted cyclopent-2-enones and three representative alkene partners. The formation of some of the compounds obtained during this study was attributed to an additional SN’ reaction. Preliminary investigations on this unexpected transformation were performed.

The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA. / Fundação Para a Ciência e a Tecnologia (FCT)