Catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines using asymmetric protonation: A method development and mechanistic study

A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C-F stereocenter in high enantioselectivity, and is also amenable to stereogenic C-CF 3 bonds. Extensive DFT calculations provide evidence for a stereocontrolled proton transfer from the catalyst to substrate as the rate determining step, and show the importance of steric interactions from the catalyst alkyl groups in enforcing high enantioselectivity. Crystal structure data shows the dominance of non-covalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and protein data bank mining has indicated benzylic fluorination using this approach has potential for improved potency in several marketed drugs.