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Theses

CHIMIE DES NITRONES :
APPLICATIONS EN SYNTHESE ORGANIQUE ET A LA SYNTHESE DE COMPOSES BIO-ACTIFS

Abstract : The chemistry of nitrones is a powerful tool for organic chemists to prepare amino or N-hydroxyamino compounds. By virtue of their inherent electrophilic nature, they undergo a range of nucleophilic additions to afford N-hydroxylamines. Reactions of α amino N benzylnitrones with indolic cores gives indolic N-hydroxylamines in good yields. These are key intermediates in the synthesis of indolic alkaloids containing the 1 (indol 3' yl) 1,2 diaminoethane moiety such as discodermindole, topsentins, nortopsentins and hamacanthins. We have developed synthetic strategies to obtain these alkaloids from indolic N-hydroxylamines.

However, the difficulty of deprotection of the benzyl group in the presence of other chemical functionalities prone for cleavage under similar conditions, led us to prepare a new class of tert butylcarbamate protected nitrones. These N-Boc protected nitrones undergo a wide range of nucleophilic additions with organometallic reagents affording N-Boc-N-hydroxylamines, whose N-Boc group is easily removed. This method provided a variety of different organic synthons, which we have demonstrated to be powerful in organic synthesis. We engaged them in the synthesis of zileuton, a 5-lipoxygenase inhibitor, and to the synthesis of indolic 1,2-diamines including the 1-(indol-3'-yl)-1,2-diaminoethane moiety, key-intermediate in the syntheses of the targeted alkaloids.

We then tried to prepare N-sulfinyl nitrones, whose chiral electron withdrawing protecting group would easily be removed in acidic media and could induce diastereoselectivity during nucleophilic additions.

Finally, the results of several biological assays are presented. We evaluated their cytotoxicity, their inhibitory activity on the kinase CK2, the antibiotic activity on Staphylococcus aureus and the inhibitory activity on the efflux pump NorA.
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Submitted on : Wednesday, March 26, 2008 - 1:54:13 PM
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Xavier Guinchard. CHIMIE DES NITRONES :
APPLICATIONS EN SYNTHESE ORGANIQUE ET A LA SYNTHESE DE COMPOSES BIO-ACTIFS. Chimie. Université Joseph-Fourier - Grenoble I, 2006. Français. ⟨tel-00267072⟩

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