Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C–H Amidation

Abstract Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Given their widespread presence in bioactive molecules, methods for the asymmetric synthesis of these molecules, in particular through the selective functionalization of ubiquitous yet unreactive aliphatic C–H bonds, are highly desirable. In this study, we report the development of a novel strategy for the asymmetric synthesis of 4-, 5-, and 6-membered lactams via an unprecedented hemoprotein-catalyzed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation producing an array of β-, γ-, and δ-lactam molecules in high yields, with high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C–H amination and enantiodetermining steps in these reactions and provide insights into protein-mediated control of regioselectivity and stereoselectivity. Using this system, it was possible to accomplish the chemoenzymatic total synthesis of an alkaloid natural product and a drug molecule in much fewer steps (7-8 vs. 11-12) than previously possible, which showcases the power of this biosynthetic strategy toward enabling the preparation of complex bioactive molecules.