Enantioselective Synthesis of β-Fluoro Amines via β-Amino α-Fluoro Nitroalkanes and a Traceless Activating Group Strategy.

Preparation of a range of enantioenriched β-fluoro amines (α,β-disubstituted) is described in which the nitrogen and fluorine atoms are attached to sp-hybridized carbons. The key finding is a chiral bifunctional Brønsted acid/base catalyst that can deliver β-amino-α-fluoro nitroalkanes with high enantio- and diastereoselection. A denitration step renders the nitro group "traceless" and delivers secondary, tertiary, or vinyl alkyl fluorides embedded within a vicinal fluoro amine functional group. A synthesis of each possible stereoisomer of a β-fluoro lanicemine illustrates the potential ease with which fluorinated small molecules relevant to neuroscience drug development can be prepared in a stereochemically comprehensive manner.