One-Pot Preparation of Enantiopure Fluorinated β-Amino Acid Precursors

Chiral beta-fluoro amines and beta,beta-difluoro amines are common substructures in medicinal compounds. Industrial syntheses typically use enantiopure starting materials, chiral auxiliaries, or the resolution of enantiomeric or diastereomeric mixtures to install these functionalities in enantiopure form. With the goal of improving access to these substructures, we recently developed the first catalytic enantioselective olefin aminohalogenation reaction, which produced chiral beta-fluoro amines in a single flask from achiral enal starting materials. This paper describes the extension of this method to the preparation of beta-amino-alpha, alpha-difluoro carbonyl compounds. Specifically, carbon-nitrogen and carbon-fluorine bond-forming reactions were combined in an organocascade reaction to produce beta-amino-alpha, alpha-difluoro carbonyl compounds containing alkyl substituents at the beta-position. As such, this method is mechanistically distinct from, and complementary to, existing one-pot catalytic enantioselective methods for the preparation of fluorinated beta-amino acid precursors.