Transannular C–H functionalization of cycloalkane carboxylic acids

Cyclic organic molecules are common among natural products and pharmaceuticals1,2. In fact, the overwhelming majority of small-molecule pharmaceuticals contain at least one ring system, as they provide control over molecular shape, often increasing oral bioavailability while providing enhanced control over the activity, specificity and physical properties of drug candidates3–5. Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable. In principle, molecular editing by C–H activation offers an ideal route to these compounds. However, the site-selective C–H functionalization of cycloalkanes remains challenging because of the strain encountered in transannular C–H palladation. Here we report that two classes of ligands—quinuclidine-pyridones (L1, L2) and sulfonamide-pyridones (L3)—enable transannular γ-methylene C–H arylation of small- to medium-sized cycloalkane carboxylic acids, with ring sizes ranging from cyclobutane to cyclooctane. Excellent γ-regioselectivity was observed in the presence of multiple β-C–H bonds. This advance marks a major step towards achieving molecular editing of saturated carbocycles: a class of scaffolds that are important in synthetic and medicinal chemistry3–5. The utility of this protocol is demonstrated by two-step formal syntheses of a series of patented biologically active small molecules, prior syntheses of which required up to 11 steps6.