Utilisation de la chimie ''click'' Diels-Alder pour la construction d'hétérocycles oxygénés bioactifs; synthèse d'anhydrides maléiques, de cadiolides, de furo[2,3-b]chromones et découverte inusitée du réarrangement des 3-acyl-2-alkoxyfuranes

Authors: Thibault, Charles
Advisor: Boukouvalas, John
Abstract: This work concerns the use of Diels-Alder ''click'' chemistry for the construction of biologically active oxygen containing heterocycles. First of all, aversatile pathway to substituted maleic anhydrides is illustrated by the synthesis of the nanomolar FTase inhibitor chaetomellic anhydride A(2.31a), a germination promoter(1.26), and a novel bis-anhydride (1.27) cross-linking reagent for cell or tissue fixation. Starting from commercial or easily prepared alkynes, these targets were assembled in two steps by click-unclick oxazole-alkyne cycloaddition-cycloreversion and furan oxyfunctionalization. Secondly, a concise, modular and efficient synthesis of cadiolides A, B, and Dis reported. Prominent steps include : (i) one-pot assembly of a key β-aryl--benzoylbutenolide building block by regiocontrolled "click-unclick"oxazole-ynone Diels-Alder cycloaddition-cycloreversion and ensuing 2-alkoxyfuran hydrolysis, and (ii) a protecting group-free vinylogous Knoevenagel condensation enabling rapid access to cadiolides A, B and D from a common precursor. Then, the unexpected discovery of the ring-degenerate rearrangement of 3-acyl-2-alkoxyfurans to 2-substituted 3-carboalkoxyfurans is described. This transformation, once optimized, enabled the rearrangement of 13 different substrates. The scaffolding power of this chemistry is demonstrated by the first synthesis of pumiloxide aldehyde, a rare labdane furfural isolated from Turreanthus africanus, a cameroonian medicinal treeused to treat intestinal worms. Finally, the synthesis of furo[2,3-b]chromones by a Diels-Alder retro Diels-Alder / oxa-Michael addition-elimination tandem is discussed. This new methodology gives access to 5 different 3-substituted furo[2,3-b]chromones. The remarkable service ability of this transformation is highlighted by the first synthesis of bothriofuran A, a natural product isolated from Bothriocline laxa. Even though many research groups demonstrateinterest in the synthesis of suchcompounds, our work represents the first exemple of a natural furo[2,3-b]chromone synthesis.
Document Type: Thèse de doctorat
Issue Date: 2018
Open Access Date: 25 June 2019
Permalink: http://hdl.handle.net/20.500.11794/35274
Grantor: Université Laval
Collection:Thèses et mémoires

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