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 sp3-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.