New Frontiers in the Streamlined Synthesis of N-Unprotected Chiral Heterocycles and Amines via Organo- and Transition Metal Catalysis

About This Grant

Project Summary Amines and their derivatives are indispensable to pharmaceuticals, agrochemicals, materials science, and natural products. On average, the top 200 best-selling small molecule drugs contain 2.8 nitrogen atoms, with 80% featuring at least one N-heterocyclic fragment, and 45% including chiral amine moieties. This underscores the urgent need for new synthetic methods that enable the rapid and efficient incorporation of nitrogen into simple and complex molecules alike. Current limitations in C–N bond-forming strategies restrict the ability to explore new nitrogen-rich chemical spaces, which are crucial for developing next-generation drugs and biologically active compounds. Addressing these challenges requires groundbreaking approaches to nitrogen transfer that are mechanistically novel, operationally simple, and broadly applicable across diverse substrates. This proposal outlines a bold and innovative five-year research program aimed at transforming the synthesis of nitrogen-containing compounds by developing pioneering amination strategies. Our efforts will focus on mechanistically distinct processes that address unmet needs in synthetic organic and medicinal chemistry. Specifically, we propose to: (1) Develop Catalyst-Free Olefin Difunctionalization Methods: Harnessing the unique reactivity of N-acyl-N-halo-O-sulfonyl hydroxylamines, we will achieve the direct halo-hydroxylamination of feedstock olefins, enabling the one-pot synthesis of structurally complex multifunctional hydroxylamine derivatives; (2) Pioneer Photochemical and Chiral Acid-Catalyzed Aziridination: Expand the scope of NH- and N-alkyl aziridination of isolated and conjugated olefins by leveraging photochemically generated nitrenoids and chiral acid catalysis, introducing new avenues for stereoselective and regioselective nitrogen transfer; (3) Explore Non-Catalytic and Catalytic Complexity-Building Transformations: Utilize structurally diverse cyclic and acyclic O-activated hydroxylamines and oximes as electrophilic aminating agents to achieve complexity- building transformations under mild, catalyst-free, and metal-catalyzed conditions; (4) Establish Scaffold- and Functional Group-Hopping Reactions: Design external-oxidant-free nitrogen insertions into heteroarenes, enamines, and enol ethers, enabling the creation of new chemical scaffolds with broad utility in drug discovery. Each proposed method represents a significant departure from traditional approaches, offering innovative solutions to longstanding challenges in nitrogen-transfer chemistry. By uncovering the mechanistic foundations of these regio-, stereo-, and chemoselective processes, we will define new paradigms in C–N bond formation. The operational simplicity and scalability of these transformations will accelerate their adoption by synthetic and medicinal chemistry communities, ensuring lasting impact. This research will advance both the fundamental understanding and practical application of amination chemistry, bridging the gap between academic discovery and industrial innovation. These efforts will provide transformative tools to explore uncharted nitrogenous chemical spaces, catalyzing progress in organic synthesis, chemical biology, and drug development.