A facile and stereocontrolled synthesis of γ-substituted γ-fluoroglutamates by conjugate addition: conflicting effect between fluorinated enaminoester and hinderered Michael acceptor.

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 (19)F and (1)H 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.