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Synthèse d'analogues de l'acide nonactique
Formation d'un macrotétrolide original

Abstract : Several natural products contain the subunit nonactic acid, such as pamamycines, fegrisolide C and nactines. The latest are a familly of macrotetrolides which display antibacterial, insecticidal, antitumor activities. Nonactin is the lowest homologue of the nactines and has received considerable attention from synthetic chemists. However, to the best of our knowledge, only one synthesis of non-natural nonactin analogue has been reported.
This work is dedicaded to the preparation of nonactic acid analogues and their cyclisation to form the corresponding macrotetrolides.
The strategy is based on three diastereoselective steps : an alkylation / reduction of ester, construction of a tetrahydrofuran unit by eletrophilic cyclisation and finally reduction of halogenated compound under radical conditions.
b-ketoesters were reduced into racemic and enantioselective way to b-hydroxyesters, then benzylated. The alkylation / reduction key step was then performed under various conditions. Firstly, a one pot reaction led to g,d‑unsaturated alcohols with moderate yield (47%) and selectivity (~ 6:4). Then, we realized this transformation in two steps : alkylation of ester followed by reduction of ketone intermediate or reduction of ester to aldehyde followed by alkylation. In theses two cases, g,d‑unsaturated alcohols were obtained with higher efficiency (65%) and good diastereoselectivity (85:15). Finally, we tried an allylation of the aldehyde to give the homoallylic alcohol with a diastereoselectivity up to 98:2. Homologation of the double bond and protection of the hydroxy group resulted in g,d‑unsaturated ethers which were cyclized stereoselectively into cis‑2,5‑disubstituted tetrahydrofurans, in the presence of bromine or iodine monobromide. The last key step of reduction under radical conditions lead to the formation of the expected nonactic acid analogue with both good yield and selectivity. To conclude, we have developped a versatile and highly efficient route for the synthesis of nonactic acid analogues, with 39% overall yield in 9 steps only.
The corresponding macrotetrolide have been synthesized in a classical way, with an overall yield of 15%.
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Submitted on : Wednesday, March 5, 2008 - 2:39:36 PM
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  • HAL Id : tel-00260647, version 2

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Ludovic Coutable. Synthèse d'analogues de l'acide nonactique
Formation d'un macrotétrolide original. Autre. Université du Maine, 2007. Français. ⟨tel-00260647v2⟩

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