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Oxyhomologation diastéréosélective de la sérine : développement de la méthodologie MAC

Abstract : MAC methodology is a synthetic technique which employs an umpolung reagent to formally insert a carbonyl function between an electrophile and a nucleophile. This thesis is devoted to the diastereoselective oxyhomologation of L-serine thanks to a significant development of 3-component one pot MAC methodology, providing a synthesis of orthogonally-protected derivatives of α, γ-dihydroxy-β-aminobutyric acid. This latter is a highly functionalized, acyclic, 4-carbon molecular building block which is a constituent part of various biologically active molecules.The synthesis of silylated MAC reagents from malononitrile was first studied. H-MAC-TBS’s synthesis was optimized and two new silylated MAC reagents, H-MAC-TES and H-MACTBDPS,were prepared.In a first study, the oxyhomologation of N-Boc-O-Bn-L-serinal was examined using H-MACTBS and a panel of alcohols in mild conditions.Methyl esters of orthogonally-protected α, γ-dihydroxy-β-aminobutanoic acid were prepared in good yields and with a diastereoisomeric ratio syn/anti = 80/20. The use of H-MAC-TBDPS improved the diastereoselectivity of the MAC reaction to syn/anti = 90/10.Subsequently, different cyclization modes of methyl α, γ-dihydroxy-β-aminobutanoate were investigated, leading to the selective synthesis of functionalized 3-, 5- and 6-membered ring heterocycles, including new highly functionalized oxazolidinones et oxazolines. In contrast, despite considerable efforts, we were unable to induce cyclisation to forma a 4-membered ring heterocycle, due to the surprising lack of nucleophilicity of the free alcohol function in the acyclic precursors.In a second study, we examined the oxyhomologation of Garners aldehyde, a cyclicN,O-protected derivative of L-serinal, using a selection of nucleophiles via one-pot MAC methodology. These reactions furnished protected ester and amide derivatives of α, γ-dihydroxy-β-aminobutyric acid in good yields with an anti diastereoselectivity with a ratio as high as syn/anti = 10/90 when H-MAC-TBDPS was used as the MAC reagent. These are the first known examples of MAC reactions which proceed with anti diastereoselectivity.Functionalized 3- and 5-membered ring heterocycles were prepared from these adducts,and via selective oxidation at the γ-position,orthogonally-protected derivatives of erythro-β-hydroxyaspartic acid and erythro-β-hydroxyasparagine were prepared.
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Mathieu Esgulian. Oxyhomologation diastéréosélective de la sérine : développement de la méthodologie MAC. Chimie organique. Université Paris-Saclay, 2017. Français. ⟨NNT : 2017SACLS392⟩. ⟨tel-01925860⟩



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