Carbon-heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments, because carboxylic acids, amines, and alcohols are ubiquitous in bioactive molecules and the reactions are highly functional group compatible. However, C–N and C–O bonds can be a metabolic liability, as they are prone to hydrolysis and these bonds can alter binding properties in an unpredictable way, potentially decreasing drug efficacy. While C(sp2)–C(sp3) linkages are a desirable alternative in many cases, methods to make these bonds require different starting materials or are less functional group compatible, limiting the accessible chemical space. Accessing these C–C bonds from the same starting materials used for amide and ester bond formation would be a useful addition to the chemical biology synthetic toolbox. We have recently developed a nickel-catalyzed decarbonylative cross-electrophile approach that couples activated carboxylic acids (via O-2-pyridyl esters) with alkyl radical sources derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). The key to this process is a remarkably fast, reversible oxidative addition/decarbonylation sequence facilitated by pyridone and bipyridine ligands that, under conditions that purge CO(g) from the reaction, lead to selective formation of desired C–C bonds. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug development, and this is demonstrated in the coupling of a typical PROTAC anchor with common linkers via C–C linkages.

Decarbonylative cross-electrophile coupling: Synthesis of C–C bonds from carboxylic acids and amines

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