Reactivity of Anomalous Aziridines for Versatile Access to High Fsp³ Amine Chemical Space

ConspectusThe manipulation of strained rings is a powerful strategy for accessing the valuable chemical frameworks present in natural products and active pharmaceutical ingredients. Aziridines, the smallest N-containing heterocycles, have long served as building blocks for constructing more complex amine-containing scaffolds. Traditionally, the reactivity of typical aziridines has been focused on ring-opening by nucleophiles or the formation of 1,3-dipoles. However, over the past decade, our group has pioneered highly chemo-, site-, and stereoselective Ag- and Rh-catalyzed nitrene transfer (NT) reactions of allenes and alkenes to furnish unusual, or "anomalous", aziridines. The unique features of these aziridines, coupled with our ability to control the fate of strained intermediates resulting from diverse reactions of these precursors, allow for their transformation to densely substituted, stereochemically complex N-heterocyclic structures that would otherwise be difficult to access using conventional strategies. Our research is driven by a keen interest in versatile synthetic approaches that explore high Fsp³ (the fraction of sp³ carbons relative to the total number of carbons in a molecule) amine chemical space, which holds promise for uncovering novel bioactivity toward challenging protein targets. We begin by outlining the design and synthesis of selected anomalous aziridines and highlighting the key features that are pertinent to their versatility as synthetic intermediates. We detail chemo-, site-, and stereoselective Rh-catalyzed NT of homoallenic sulfamates leading to the key (<i>E</i>)-methyleneaziridines (MAs) and the development of new Ag catalysts to achieve chemo- and enantioselective aziridinations of homoallenic and homoallylic carbamates/carbamimidates to yield bicyclic (methylene)aziridines. The chemoselective Ag-catalyzed NT of carbamimidates to accomplish intramolecular aza-Büchner reactions via polycyclic aziridine intermediates is also highlighted. Next, we focus on unlocking several modes of reactivity of our anomalous aziridines. These include regioselective ring-opening with nucleophiles and subsequent functionalization to afford amine stereotriads, the stereocontrolled formation and reaction of 2-amidoallyl cations, and alkene oxidation of endo- and exocyclic MAs. Additionally, due to the unusual molecular geometry of bicyclic (methylene)aziridines, the nitrogen lone pair can react with carbenes to generate aziridinium ylides that can be diverted along multiple pathways. From only a handful of anomalous aziridines, our chemistry is capable of delivering amine stereotriads, azetidines, azetidinones, piperidines, aminated cyclopentanes and cycloheptanes, azepines, and azepanes. Finally, we discuss our efforts to leverage this chemistry to explore the complex amine chemical space relevant to the natural products jogyamycin and methyl detoxinine. Ultimately, our goal is to use these methods to generate DNA-encoded libraries of high Fsp³ compounds with potential activity against difficult-to-target proteins.