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Theses

Vers la synthèse énantiosélective du Dolabélide C.

Abstract : A new family of cytotoxic macrolactones, dolabelides, was isolated from the sea hare Dolabella auricularia. These 22 and 24-membered ring lactones discovered in the 90s exhibit interesting antitumoral properties. In this work, we explored the enantioselective synthesis of several fragments of Dolabelide C. We have first synthesized the C1-C15 fragment in a convergent manner in 17 steps for the longest linear sequence in 11% overall yield. The protected syn 1,3-diol functional group at C9 and C11 was installed by an intramolecular conjugate addition of a hemiacetal anion to a double bond; then a diastereoselective Mukaiyama aldol allowed the formation of the C6-C7 bond and established the C7 stereocenter. We have also investigated a new approach to obtain a precursor of the C16-C30 fragment of Dolabelide C. This synthon was synthesized in 6 steps from methyl acetoacetate in 11% overall yield. The C19 stereocenter was established by a Noyori asymmetric hydrogenation and a diastereoselective Paterson aldol was employed to form the C21-22 bond and establish the C21 and C22 stereocenters. Finally, we have investigated the hydrogenation of O-benzyl ether protective groups in the presence of diverse functional groups by catalytic hydrogenolysis with Raney Nickel in ethanol. Primary and even secondary benzyl ethers can be selectively deprotected in good yields in the presence of para-methoxybenzyl ethers and 4,6-disubstituted 1,3-benzylidene acetals.
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Submitted on : Wednesday, July 28, 2010 - 4:47:03 PM
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Aurélie Vincent. Vers la synthèse énantiosélective du Dolabélide C.. Génie chimique. Ecole Polytechnique X, 2006. Français. ⟨pastel-00002092⟩

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