Amides are prevalent functional groups that serve as the key building blocks of proteins. Whereas Nature can masterfully cleave amides through the action of enzymes such as proteases, the ability to break the C?N bond of amides using synthetic chemistry remains a challenge. The modest synthetic utility of amides as electrophiles can be traced to their low reactivity, which in turn is derived from the well-known resonance stability of amides. This proposal targets a new strategy to harness amide functional groups as synthons, which relies on the unprecedented nickel-catalyzed activation of amide C?N bonds. Preliminary results demonstrate the feasibility and mildness of this unique approach for the construction of C?heteroatom and C?C bonds. Our studies aim to establish the scope and limitations of this new methodology for the construction of important linkages, including sp2?sp3 C?C bonds with stereodefined quaternary centers. These efforts provide new opportunities in the area of strong bond activation by nickel catalysis, along with new tools for the manipulation of amides via C?N bond cleavage.
Contrary to Nature's ability to strategically manipulate amides by controlled carbon? nitrogen bond-breaking processes, the corresponding synthetic chemistry of amide bond cleavage has remained relatively underdeveloped. The unifying objective of this proposal is to develop a new catalytic platform to harness amide functional groups as synthons for the construction of carbon?heteroatom and carbon-carbon bonds, which are the building blocks of countless biologically important small molecules.
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