Exploring the Role of Ketene Precursors and Acid Activators in β‐Lactam Synthesis: A Comprehensive Review

ABSTRACT β‐Lactams are the class of important small‐sized heterocycles known for their unique structure and significant antibiotic potential. In recent years, the scope of β‐lactams has expanded beyond antibiotics to include properties, such as anticancer activity, cholesterol absorption inhibition, enzyme inhibition, antifungal effects, and so forth. This has prompted extensive research into β‐lactam derivatives, exploring their potential applications in medicinal, pharmaceutical, and organic chemistry. Numerous synthetic strategies for β‐lactam synthesis have been developed over the years, with Staudinger's [2+2] ketene‐imine cycloaddition emerging as the most widely used approach. This method is favored due to its mild reaction conditions, the ease of substrate accessibility, and its efficiency. Consequently, ketenes have become critical intermediates in β‐lactam synthesis. A comprehensive review of different ketene precursors and acid activators are therefore valuable for researchers in this field. This review primarily focuses on the molecules and reagents used for the in situ generation of ketenes in the synthesis of β‐lactam heterocycles via Staudinger's [2+2] cycloaddition.