Late-Stage Diversification by Selectivity Switch in meta-C–H Activation: Evidence for Singlet Stabilization

The full control of site selectivity in C–H activation
is paramount for the programmed late-stage functionalization of structurally
complex structures. During the past decade, directing groups have
revolutionized molecular synthesis in terms of ortho-selective C–H activation. In sharp contrast, a selectivity
switch that guides the typical ortho- to remote meta-C–H activation has thus far proven elusive.
Herein, we describe the realization of such a concept for a robust
selectivity control in ruthenium catalysis. The distal C–H
transformation was guided by key mechanistic insights into the mild,
synergistic action of carboxylates and phosphines in ruthenium­(II)
catalysis. Our findings allowed remote selectivity in broadly effective
late-stage diversification of structurally complex drugs and natural
product molecules, tolerating sensitive fluorescent dyes, drugs, lipids,
peptides, nucleosides, and carbohydrates.

在C-H激活过程中对位点选择性的全面控制对于结构复杂化合物的预定后期功能化至关重要。在过去十年中，导向基团在邻位选择性C-H激活方面革新了分子合成。与此形成鲜明对比的是，一种引导典型邻位至远程对位C-H激活的选择性转换至今尚未实现。本研究中，我们描述了实现这一概念以在钌催化中实现稳健选择性控制的方法。远程C-H转化是通过关键机理洞察，即羧酸盐和膦在钌(II)催化中温和协同作用的过程得以实现的。我们的研究进展使得在结构复杂药物和天然产物分子的广泛有效后期多样化中实现远程选择性成为可能，且对敏感荧光染料、药物、脂质、肽、核苷和碳水化合物具有良好的耐受性。