Catalytic Asymmetric Aza‐[2+2] Cyclization Reaction of Simple Ketoimine

Abstract Herein, we report the first catalytic enantioselective aza‐[2+2] cyclization of simple ketoimines, thereby addressing a persistent challenge in four‐membered aza‐ring construction. While the aza‐[2+2] cyclization represents the most straightforward approach to azetidine synthesis, previous methodologies have been strictly limited to ketoimines, all with an EWG at the central reactive carbon, and predominantly employing cyclic imine substrates. Through rational design of an in situ‐generated magnesium catalytic system and systematic investigation of imine electronic effects, we have successfully developed an asymmetric protocol for simple ketoimines. This breakthrough enables efficient access to enantioenriched monocyclic azetidines with excellent stereocontrol. Moreover, a streamlined one‐pot tandem oxidation readily converts these azetidines into valuable quaternary chiral β‐lactams—privileged scaffolds that are prominent in numerous pharmaceuticals and bioactive agents. A combination of comparative studies, the calculation results of the HOMO and LUMO energies of different imines, relative control experiments, and a series of detailed NLE analysis revealed the coordination difference and the catalytic cycle. The catalytic protocol was used for the synthesis of a series of β‐lactams containing aryl or alkyl groups, as well as for pharmaceutical active molecules’ β‐lactam‐modifications. Importantly, the preliminary attempt to take advantage of the significant ring strain of β‐lactam for peptide modifications was also achieved on tryptophan.