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.