Synthesis and Application of Bioactive N-Functionalized Aziridines

Aziridines-three-membered nitrogen heterocycles that engage in strain-accelerated ring opening chemistry-are not common functional groups in bioactive natural products. As such, the discovery and optimization of predictable and general methods for the construction of aziridines is critical to the development, evaluation, and optimization of small molecules that contain aziridines. In this review, we discuss modern synthetic strategies for the construction of aziridines. Synthetic methods are categorized based on the synthetic logic used to assemble the aziridine ring: 1) Addition of nitrene equivalents to olefins, 2) addition of carbene equivalents to imines, and 3) intramolecular cyclization chemistry. Special emphasis is given to methods that allow modular control over the identity of the exocyclic nitrogen valence, which directly impacts the electrophilicity, and thus biological activity, of the resulting aziridines. After describing the state of the art in aziridine synthesis, we discuss established and emerging biological applications of aziridine-containing small molecules, including application as proteomics probes that enable liganding of nonstandard amino acid residues and application in lipidomics. Finally, extant synthetic challenges that must be addressed to realize the full potential of aziridine-based small molecules are described.