Catalytic Radical Processes for Stereoselective Chemical Synthesis
openNIGMS - National Institute of General Medical Sciences
PROJECT SUMMARY/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.
Up to $620K
health research