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Approche de synthèse du tricycle ABC du taxol.

Abstract : Taxol is a natural compound discovered in 1965 from an extract of yew tree (Taxus Brevifolia Nutt.). Due to its original mechanism, this molecule became a reference for anti-cancer treatments. Since then, researchers have been attracted by the great number of oxygen functionalities and chiral centres and also by the eight-membered ring which belongs to its tetracyclic core. Discovered in the 70s, ring-closing metathesis is a powerful synthetic tool allowing the preparation of rings of different sizes. This thesis aims at using this reaction in order to prepare the eight-membered ring of taxol. The first retrosynthesis uses the RCM to close the B cycle between C9 and C10. The first part is related to the preparation of the metathesis precursors. However, by using either Shapiro or Nozaki-Hiyama-Kishi reactions, those precursors could not be prepared. A new strategy has then been designed: the B ring can be closed between C10 and C11. The diene necessary for the RCM reaction is now prepared by a nucleophilic addition between C ring precursor and the linear precursor of A ring. These two molecules are both prepared using fast, simple and efficient methods, giving optically active products. Nucleophilic additions are then studied. Conditions are optimized in order to obtain with a good yield the desired compound as a 1:1 mixture of two diastereoisomers, separated during the next step. X-rays of both compounds allows the attribution of the relative configuration of all chiral centres. These compounds are then transformed into metathesis precursors. Degradation of the diastereomer with the wrong stereochemistry for the total synthesis of taxol is observed under metathesis conditions. However under the same conditions the right diastereomer gives way to the desired cis cyclooctene. Furthermore with Grubbs I catalyst a mixture of cis and trans cyclooctene could be observed. In the end, the introduction of the oxygen functionality on the C ring has been studied by using the Wieland-Miescher ketone as a starting material.
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Submitted on : Friday, July 30, 2010 - 3:11:39 PM
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  • HAL Id : pastel-00001803, version 1



Stéphanie Schiltz. Approche de synthèse du tricycle ABC du taxol.. Chimie. Ecole Polytechnique X, 2005. Français. ⟨pastel-00001803⟩



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