LEVERAGING SULFUR SYNERGY WITH CARBENES/NITRENES FOR SITE-SELECTIVE TRANSFORMATIONS - Leveraging Sulfur Synergy with Carbenes/Nitrenes for Site-Selective Transformations Modified Project Summary/Abstract Section: The pace of drug discovery has notably decelerated, with current expenditures for developing a single pharmaceutical agent surpassing $4 billion. This slowdown is primarily due to the limited chemical diversity in existing discovery libraries, which limits our ability to identify novel bioactive compounds and renders numerous targets undruggable. Expanding chemical space through scaffold hopping, transforming established drug frameworks into new structures, provides an efficient route to novel therapeutics. Nonetheless, the selective modification of complex molecules remains a significant synthetic challenge due to the presence of multiple reactive sites. This research endeavors to address these challenges by leveraging the unique synergy between sulfur and isoelectronic reactive intermediates, such as carbenes and nitrenes. The metallomimetic nature of sulfur stabilizes these reactive species and influences their selectivity, enabling precise, chemoselective transformations under mild, metal-free conditions. Our primary hypothesis posits that sulfur can direct highly chemo-, regio-, and stereoselective reactions, thereby facilitating late-stage skeletal editing of complex molecules while minimizing environmental impacts associated with metal-based transformations. Aim 1 focuses on developing and applying sulfenylcarbenes as innovative reagents for scaffold hopping, transforming common aromatic heterocycles into medicinally relevant N-heterocycles and facilitating metal-free peptide stapling. These one-carbon insertion reagents, bearing diverse functional groups such as alkyne, cyano, or sulfonamide, will serve as handles for late-stage diversification under aqueous conditions. Aim 2 investigates sulfenylnitrenes for single nitrogen-atom transfer, enabling late-stage nitrogen incorporation into heterocycles and complex small molecules under metal- and additive-free aqueous conditions. Furthermore, the study will explore sulfinylnitrenes derived from bench-top-stable precursors. Aim 3 extends this sulfur-enabled carbene/nitrene chemistry to DNA-encoded libraries (DELs), incorporating single carbon or nitrogen atoms to enhance DEL diversity. Site-selective cyclopropanation will generate covalent warheads for protein targeting. Mechanistic investigations, combining experimental and computational approaches, will elucidate the fundamental reactivity of sulfur-based carbenes and nitrenes. Collectively, these studies aim to develop innovative, metal-free, environmentally sustainable techniques for late-stage molecular diversification, skeletal editing, and site-specific modification of peptides and proteins. By enabling access to previously inaccessible chemical space, this research endeavors to provide transformative tools for drug discovery and the development of next-generation therapeutics.
