Titolo della tesi: Synthesis of fused polycyclic heterocycles of biological interest via palladium and copper catalysis
Heterocyclic scaffolds are fundamental to medicinal chemistry due to their prevalence in bioactive natural products and pharmaceuticals. Their structural and electronic properties enable selective interactions with biological targets, motivating ongoing efforts to develop efficient methods for their synthesis and post-modification. In this context, palladium catalysis provides powerful platforms for C–C and C–heteroatom bond formation, notably through Tsuji–Trost allylations and C–H activation processes, while copper catalysis—exemplified by the Cu-catalyzed azide–alkyne cycloaddition (CuAAC)—offers complementary strategies for rapid heterocycle diversification under mild and operationally simple conditions. Building on this foundation, this doctoral research was directed toward the synthesis of fused polycyclic derivatives, achieved through a systematic investigation of the reactivity of (1H-indol-2-yl)methyl and (1H-indol-3-yl)methyl acetates toward an expanded set of soft nucleophiles—including phenols, arylsulfinates, α-amino acids, and β-dicarbonyl compounds. These transformations proceed either through palladium-mediated pathways, involving η³-π-indolyl–palladium intermediates, or via the in situ generation of highly electrophilic 2-alkylideneindolenines. In parallel, a complementary copper-assisted platform combining propargylation, CuAAC, and intramolecular C–H activation was developed to access complex 1,2,3-triazole-fused heterocycles, including triazoloquinolines and triazoloazepines. Additionally, a copper-mediated domino cyclization/oxidation protocol enabled one-pot synthesis of furanyl-substituted 1,2-diketones from diynyl diols. All of these studies were enabled by the careful optimization of reaction conditions for each transformation and, when required, by mechanistic investigations to elucidate the underlying reaction pathway. Lastly, a six-month research period at KU Leuven focused on synthesizing SF₅-containing analogues for potential biological applications. Overall, this research demonstrates how the synergistic application of palladium- and copper-based catalysis enable the efficient synthesis of architecturally complex and pharmacologically relevant molecular frameworks.