Asymmetric Synthesis of 3,4-Disubstituted 2‑(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2‑(2,2,2-Trifluoro-1-hydroxyethyl)azetidines

Enantiopure
4-formyl-β-lactams were deployed as synthons
for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)­azetidines
via trifluoromethylation through aldehyde modification followed by
reductive removal of the β-lactam carbonyl moiety. Subsequent
treatment of the (in situ) activated 2-trifluoroethylated azetidines
with a variety of nitrogen, oxygen, sulfur, and fluorine nucleophiles
afforded chiral 3,4-disubstituted 2-(trifluoromethyl)­pyrrolidines
in good to excellent yields (45–99%) and high diastereoselectivities
(dr >99/1, 1H NMR) via interception of bicyclic aziridinium
intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated
in a selective way and used for further synthetic elaboration to produce,
for example, a CF3-substituted 2-oxa-4,7-diazabicyclo[3.3.0]­octan-3-one
system.