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Nouvelle méthodologie de synthèse de γ-butyrolactones par une réaction domino métallo-catalysée entre dérivés halogénés, composés carbonylés, et accepteurs de Michael

Abstract : The γ-butyrolactone scaffold is a widespread naturally occurring motif, present in numerous compounds possessing biological activities. In this context, paraconic acids (bearing a carboxylic acid function at the position β to the carbonyl), constitute an important group of γ-butyrolactones that both display antitumor and antibiotic activities, but also represent relevant building blocks for the synthesis of diverse pharmacologically active compounds. However, the multicomponent synthesis of γ-butyrolactones has been only scarcely reported so far. Considering the selective reactivity of organozinc reagents, it was assumed that a range of 2,3-polysubstituted paraconic acids should be synthesized from an organozinc reagent, a carbonyl compound and a Michael acceptor through a metallo-catalyzed domino reaction involving the formation of three single bonds. This reaction allowed for the access to a wide range of 2,3-polysubstituted paraconic acids characterized by an unprecedented functionalized benzyl side chain in position β of the carbonyl. A study devoted to the elucidation of the mechanism of this reaction was carried out. The in vitro antitumor activity of a representative set of these compounds has been evaluated against various cancer cell lines (KB, HCT116, MCF7, HL60). These tests permitted to highlight a lead molecule, which was submitted to additional tests (PC3, SK-OV3, MCF7R, HL60R, MRC5, EPC, mechanism of action). IC50 between 0.6 and 6 µM have been measured for this compound. An extension of the reaction to ortho-bisubstituted compounds allowed for the domino diastereoselective synthesis of a range of ortho-condensed tricyclic lactones with good yields. Those compounds exhibit the tricyclic ABC pattern of strigolactones, hormones playing a fundamental role in the germination process of plants
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https://tel.archives-ouvertes.fr/tel-00674386
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Submitted on : Monday, February 27, 2012 - 11:31:38 AM
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Camille Le Floch. Nouvelle méthodologie de synthèse de γ-butyrolactones par une réaction domino métallo-catalysée entre dérivés halogénés, composés carbonylés, et accepteurs de Michael. Autre. Université Paris-Est, 2011. Français. ⟨NNT : 2011PEST1098⟩. ⟨tel-00674386⟩

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