New Selective Reactions of Carbocations

This MIRA renewal proposal builds on the foundational advances made in the previous funding period to further explore and expand the synthetic utility of carbocation chemistry, with an emphasis on catalytically generated, highly reactive vinyl carbocations. The overarching goal is to develop novel, selective synthetic methodologies that leverage the unique reactivity of these intermediates, enabling the construction of complex, enantioenriched molecular frameworks relevant to bioactive compound development. The proposed research encompasses three major thrusts: (1) expansion of enantioselective C–H insertion reactions of vinyl carbocations to access diverse cyclic and polycyclic systems, (2) development of innovative electrophilic reactions and cross-coupling methodologies involving vinyl carbocations, and (3) the creation of advanced (bio)catalysts, including chiral IDPi catalysts and engineered protein enzymes, to mediate selective transformations. In parallel, the program seeks to deepen the mechanistic understanding of carbocation chemistry through computational and experimental studies. Building on the applicant’s pioneering efforts in microcrystal electron diffraction (microED), the renewal also aims to advance the application of microED in structural studies of reactive intermediates and organic synthesis. The anticipated outcomes of this work include transformative synthetic methodologies and fundamental insights into carbocation reactivity and catalysis. These contributions will not only address longstanding challenges in organic synthesis but also support the mission of NIGMS by advancing basic science that underpins biomedical innovation. Project Number: 1R35GM162340-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Hosea Nelson | Institution: CALIFORNIA INSTITUTE OF TECHNOLOGY, PASADENA, CA | Award Amount: $446,219 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MBBC-J (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11269112