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Orientador: Paulo Cesar Muniz de Lacerda Miranda Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química Resumo: A elipticina, isolada pela primeira vez em 1959 a partir da Ochrosia elliptica Labill, possui propriedades antineoplásicas devido, principalmente, a sua habilidade intercalante entre a estrutura do DNA e a inibição da topoisomerase II, enzima responsável pelo desemaranhamento da hélice dupla. Uma nova abordagem para sua síntese foi proposta, fundamentada na utilização do N-óxido da isoquinolino-5,8-diona como intermediário versátil, capaz de influenciar a regioquímica na adição nucleofílica. A entrada de nucleófilos em isoquinolinodionas se dá preferencialmente na posição 7, já que o nitrogênio do heterociclo reduz a densidade eletrônica do anel aromático, tornando a posição 7 mais eletrofílica. Apesar da introdução do N-óxido ter favorecido a formação de produtos 6-substituídos em uma relação de até 7:1, a velocidade da reação aumentou significativamente, o que nos chamou atenção. Cálculos teóricos DFT foram realizados para simular as coordenadas de reação e foi observado que o N-óxido promoveu uma assistência inesperada durante processos de tautomerismos em cascata, após a adição do nucleófilo, sendo cruciais para direcionar o ataque na posição 6 e acelerar o processo. A elipticina foi obtida em 6 etapas a partir da 5,8-dimetoxisoquinolina com 19,4% de rendimento global, sendo esta síntese uma das rotas mais curtas e de maior rendimento já relatadas. O acesso à funcionalização da posição 6 na isoquinolinodiona também nos permitiu a criação de uma nova classe de compostos de origem não natural, as isocaulibugulonas Abstract: Ellipticine, isolated for the first time in 1959 from Ochrosia elliptica Labill, has antineoplastic properties, mainly due to its intercalating ability between the DNA structure and the inhibition of topoisomerase II, the enzyme responsible for unraveling the double helix. A new approach for its synthesis was proposed, based on the use of isoquinoline-5,8-dione N-oxide as a versatile intermediate, capable of conducting the regiochemistry in the nucleophilic addition. The entry of nucleophiles into isoquinolinediones occurs preferentially in position 7 since the nitrogen of the heterocycle reduces the electronic density of the aromatic ring, making position 7 more electrophilic. Although the introduction of N-oxide has favored the formation of 6-substituted products in a ratio of up to 7:1, an unexpected outcome was the increased kinetics of the reaction, which caught our attention. Theoretical DFT calculations were performed to simulate the reaction coordinates, and it was observed that the N-oxide promoted unexpected assistance during cascade tautomerism processes after the addition of the nucleophile, being crucial to direct the attack at position 6 and accelerate the process. Ellipticine was obtained in 6 steps from 5,8-dimethoxyisoquinoline with 19,4% overall yield, this synthesis being one of the shortest routes and highest yield ever reported. The functionalization of the 6-position of the isoquinolinedione also allowed us to create a new class of compounds of non-natural origin, the isocaulibugulones Doutorado Química Orgânica Doutor em Ciências CAPES 001 FAPESP 2014/25770--6

The following manuscript encompasses all efforts in the development of a methodology that aims for the direct functionalization of the benzenoid and dicarbonyl ring of 1,4-naphthoquinones, referred to as A-ring and B-ring, respectively, via rhodium catalysed C-H activation-functionalization, and all other reactions that have been discovered during the research process. In a first approach, optimization studies were carried out to define the best reactional conditions for C5 and C2-halogenation, followed by the appliance of the optimized methodology in different naphthoquinoidal substrates. In a second part, the recently discovered C-2 halogenation/phenyl selenylation protocol was explored and the new methodology applied to a wild range of 1,4-benzoquinones. The C5-halogenation process opened way for new modifications in the A-ring, such as palladium cross-coupling and copper-catalysed organoyl-thiolation reactions. Finally, all new compounds were evaluated against Trypanosoma cruzi trypomastigote forms, with the majority of them presenting remarkable bioactivity.

This review aims at to the presentation and discussion of the principal aspects of the C-H activation by transition metals. Representative examples were selected from the recent literature to illustrate these principles beginning with somewhat simple examples and moving up to more complex ones. The synthetic potential of the C-H activation, as well as the potential advantages and disadvantages of the methodology are highlighted with relevant recent examples, along with brief insights on the mechanism aspects of these reactions.