Stereoselective construction of β-, γ- and δ-lactam rings via enzymatic C–H amidation

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C–H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ- and δ-lactams via the haemoprotein-catalysed intramolecular C–H amidation of readily accessible dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation, yielding the desired lactam products in high yields with high enantioselectivity and on a preparative scale. Mechanistic and computational studies were conducted to elucidate the nature of the C–H amidation and enantiodetermining steps and provide insights into the protein-mediated control of the regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in fewer steps (7–8 versus 11–12) than previously reported, further demonstrating the power of biosynthetic strategies for the preparation of complex bioactive molecules.