Controlling a Difficult Radical Sequence Enables Asymmetric β-Lactam Synthesis

Radical reactions offer powerful opportunities in synthesis, but controlling their stereochemical course remains difficult, especially when productive bond formation must compete with fragmentation and other fast radical pathways. We report a catalyst-controlled radical strategy for the asymmetric synthesis of β-lactams from readily accessible α-diazoacetamides. A rationally designed cobalt metalloradical catalyst supported by an alkyne-bridged chiral amidoporphyrin ligand enables enantioselective 1,4-C–H alkylation through a stepwise mechanism involving 1,4-hydrogen atom abstraction followed by 4- exo-tet radical substitution, a combination of elementary radical steps that is typically disfavored. The reaction proceeds under mild conditions across a broad range of substrates, including complex derivatives of drugs and natural products, to furnish chiral β-lactams in high yields and enantioselectivities. Computational and experimental studies reveal that a confined chiral cavity and cooperative non-covalent interactions direct both radical reactivity and stereocontrol. The resulting chiral β-lactams undergo diverse stereospecific transformations and provide access to the cholesterol-lowering drug (–)-ezetimibe.