美国斯克里普斯研究所Yu Jin-Quan团队报道了环烷烃羧酸的跨环C–H官能化。相关研究成果发表在2023年5月31日出版的国际学术期刊《自然》。

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。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活化进行分子编辑为这些化合物提供了一条理想的途径。然而，环烷烃的位点选择性C–H官能化仍然具有挑战性，因为在跨环的C–H钯化中遇到了应变。

该文中，研究人员报道了两类配体奎宁环吡啶酮（L1，L2）和磺酰胺吡啶酮（L3）-能够实现中小型环烷烃羧酸的跨环γ-亚甲基C–H芳基化，环尺寸从环丁烷到环辛烷。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的分子编辑迈出了重要一步，而饱和碳环是一类在合成和药物化学中很重要的支架。研究人员通过一系列获得专利的生物活性小分子的两步正式合成证明了该方案的实用性，其先前的合成需要多达11个步骤。

附：英文原文

Title: Transannular C–H functionalization of cycloalkane carboxylic acids

Author: Kang, Guowei, Strassfeld, Daniel A., Sheng, Tao, Chen, Chia-Yu, Yu, Jin-Quan

Issue&Volume: 2023-05-31

Abstract: 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 candidates3,4,5. 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 chemistry3,4,5. 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.

DOI: 10.1038/s41586-023-06000-z

Source: https://www.nature.com/articles/s41586-023-06000-z