Stereodivergent Conjugate Addition between Iminium and α-Azaaryl α-Fluoroenolate Intermediates by Synergistic Amine and Lewis Acid Catalysis

Abstract

Despite advances in the field of asymmetric catalysis, the synthesis of complete sets of stereoisomers in multistereogenic molecules, particularly those incorporating a fluorine atom, remains a challenging task. We report, herein, a stereodivergent method for the synthesis of tertiary alkyl fluorides in vicinal stereogenic pairs through the conjugate addition of α-fluoro azaaryl acetamides to α,β-unsaturated aldehydes catalyzed by the combination of two chiral catalysts: a copper Lewis acid and an amine. This process occurs through a synergistic catalytic cycle in which the reaction between in situ-generated chiral iminium and α-azaaryl α-fluoroenolate intermediates constructs a stereogenic carbon–carbon bond, furnishing an array of 4-fluorinated 1,5-aldehyde amides with high stereocontrol. By simply varying the combinations of the catalyst enantiomers, all four stereoisomers of the addition products are selectively accessible. Moreover, the reaction products can be further derivatized into other enantioenriched fluorinated molecules, some of which contain two fluorinated stereocenters within three contiguous stereocenters.