Catalytic radical processes for… (R35GM156311) – Project Grant to Trustees Of Boston College

Abstract: Catalytic radical processes for stereoselective chemical synthesis homolytic one-electron radical chemistry, complementing heterolytic two-electron ionic chemistry in terms of reactivity and selectivity, has recently garnered significant traction in organic synthesis. IT encompasses fundamental reactions like radical addition, radical substitution, atom abstraction, and radical scission, while offering appealing attributes. These include fast reaction rates under mild, neutral conditions across a variety of solvents, including water, and a reduced sensitivity to the electronic and steric properties of substrates, allowing for tolerance of common functional groups. Additionally, neutral radical species naturally engage in homolytic cascade reactions, enabling the rapid assembly of complex molecular structures in a single operation. However, the full synthetic potential of radical reactions has been constrained by the longstanding challenges in controlling reactivity and selectivity, largely due to their diverse and often indiscriminate nature, which frequently leads to a complex mixture of products. Particularly, achieving enantioselectivity in radical reactions has been exceptionally difficult, owing to the easy inversion at prochiral faces of the trivalent radical intermediates. To address these inherent challenges and fully harness the potential of radical chemistry in organic synthesis, our laboratory's research has been focused on establishing metalloradical catalysis (MRC) as a comprehensive framework to guide the development of general approaches for controlling the reactivity and stereoselectivity of homolytic radical reactions. MRC harnesses metal-centered radicals in open-shell metal complexes as one-electron catalysts for the homolytic activation of substrates. This activation process generates metal-supported organic radicals as pivotal intermediates, directing both the reaction pathway and the stereochemical outcome of subsequent catalytic radical processes. In contrast to the traditional metal catalysis, MRC operates via one-electron chemistry, employing stepwise radical mechanisms. Over the next five years, guided by MRC principles, our research program aims to develop innovative metalloradical systems for catalytic radical processes with applications in stereoselective chemical synthesis. We plan to leverage D2-symmetric chiral amidoporphyrins, characterized by their tunable electronic, steric, and chiral properties. The focus will be on utilizing cobalt(II) complexes of these porphyrin ligands as chiral metalloradical catalysts. These catalysts will be pivotal in advancing enantioselective c-h alkylation and amination reactions, as well as in addressing challenging issues in various radical cyclization reactions. Our studies are expected to lead to development of CO(II)-based catalytic radical processes for stereoselective alkene cyclization and c-h functionalization. These processes are anticipated to be broadly applicable to practical synthesis of biologically significant natural products and pharmaceutically relevant small molecules.

Action	Obligated	Date
Amendment	$620,000	Jul 14, 2026
Original award	$620,000	Aug 12, 2025

Catalytic radical processes for stereoselective chemical synthesis

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