Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Nature. 2023 Jun;618(7965):519-525. doi: 10.1038/s41586-023-06000-z. Epub 2023 May 31.
Cyclic organic molecules are common among natural products and pharmaceuticals. 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. 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. 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 steps.
环状有机分子在天然产物和药物中很常见。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的形状，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。因此，直接、立体选择性地合成功能化碳环的新方法是非常需要的。原则上，通过 C-H 活化进行分子编辑为这些化合物提供了理想的途径。然而，由于在反环 C-H 钯化过程中遇到的应变，环烷烃的位点选择性 C-H 功能化仍然具有挑战性。在这里，我们报告了两类配体——喹诺啶-吡啶酮（L1、L2）和磺酰胺-吡啶酮（L3）——能够对从小到中等大小的环烷酸羧酸进行反式γ-亚甲基 C-H 芳基化，环大小从环丁烷到环辛烷不等。在存在多个β-C-H 键的情况下，观察到了极好的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：这一类支架在合成和药物化学中都很重要。该方案的实用性通过两步法对一系列专利生物活性小分子进行了正式合成，而这些小分子的先前合成需要多达 11 步。
