A Facile and Stereocontrolled Synthesis of γ-Substituted γ-Fluoroglutamates by Conjugate Addition: Conflicting Effect between Fluorinated Enaminoester and Hinderered Michael Acceptor

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• 作者：Emmanuelle Drge ; Anas Guillaume ; Nadjia Boukhedimi ; Jrme Marrot ; Claire Troufflard ; Marie-Elise Tran Huu-Dau ; Delphine Joseph ; Sandrine Delarue-Cochin
• 刊名：Journal of Organic Chemistry
• 出版年：2010
• 出版时间：November 19, 2010
• 年：2010
• 卷：75
• 期：22
• 页码：7596-7604
• 全文大小：996K
• 年卷期：v.75,no.22(November 19, 2010)
• ISSN：1520-6904

文摘

Asymmetric Michael addition of chiral 2-fluoroenaminoesters derived from (S)-1-phenylethylamine to α-substituted methyl acrylate leads to diastereomeric γ-substituted γ-fluoroglutamate precursors. The tertiary center bearing the amino acid function in its natural configuration is generated with a high level of stereocontrol in contrast to the quaternary carbon center. Diastereomeric γ-substituted γ-fluoroglutamates were efficiently separated and isolated as thioketal derivatives harboring very good enantioselectivity. The Michael addition diastereoselectivity was studied for the asymmetric conjugate addition of fluorinated chiral β-enaminoester to methyl α-acetamidoacrylate by ¹⁹F and ¹H NMR experiments as well as ab initio computations. An interfering conjunction between hindrance of the electrophile and a destabilizing effect of the fluorine atom borne by the nucleophile is revealed.