Cyclic organic molecules are common among natural products and pharmaceuticals^1,2. 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 candidates^3,4,5. 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 chemistry^3,4,5. 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.

环状有机分子在天然产物和药物中很常见^1,2。事实上，绝大多数小分子药物都至少含有一个环系统，因为它们可以控制分子形状，通常可以提高口服生物利用度，同时增强对候选药物的活性、特异性和物理性质的控制^3,4,5。因此，非常需要用于官能化碳环的直接位点和非对映选择性合成的新方法。原则上，通过 C-H 激活进行分子编辑为这些化合物提供了理想的途径。然而，由于跨环 C-H 钯化中遇到的应变，环烷烃的位点选择性 C-H 官能化仍然具有挑战性。在这里，我们报道了两类配体——奎宁环吡啶酮（L1，L2）和磺酰胺吡啶酮（L3）)—能够对中小型环烷羧酸进行跨环 γ-亚甲基 C-H 芳基化，环尺寸范围从环丁烷到环辛烷。在存在多个 β-C-H 键的情况下观察到优异的 γ-区域选择性。这一进展标志着实现饱和碳环分子编辑的重要一步：饱和碳环是一类在合成和药物化学中非常重要的支架^3,4,5。该协议的实用性通过一系列专利生物活性小分子的两步正式合成得到证明，之前的合成需要多达 11 个步骤⁶。