Organocatalytic enantioselective [2 + 2] cycloadditions towards chiral fused α-trifluoromethyl azetidines

Access to relatively high-energy azetidines in enantioenriched form via a function- and diversity-oriented approach is highly desired in the field of drug discovery. Although the demands for α-trifluoromethyl azetidines with great biological potential still exist, effective strategies for the catalytic asymmetric synthesis of these chemical entities with structural diversity remain elusive. To conquer this frontier, we, herein, report the development of a building block protocol for the facile assembly of enantioenriched α-trifluoromethyl azetidines via peptide-mimic phosphonium salt-catalyzed asymmetric [2 + 2] cycloadditions of tethered trifluoromethyl ketimines and allenes. Of note, this methodology could allow for the enantioselective synthesis of a diverse set of six-membered ring-fused α-trifluoromethyl azetidines bearing two densely functionalized carbon stereocenters in high yields with excellent diastereo- and enantioselectivities. Besides the fundamental appeal of this strategy, scale-up experiments and representative transformations could enable its prompt application in synthetic chemistry.