Late-Stage Diversification by Selectivity Switch in <i>meta</i>-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.在碳氢键活化（C–H activation）反应中实现位点选择性的完全调控，对于结构复杂分子的程序化后期官能团化而言至关重要。在过去十年间，导向基团极大地推动了邻位选择性碳氢键活化领域的分子合成发展。与之形成鲜明对比的是，能够实现从经典邻位到远程间位碳氢键活化的选择性调控开关，迄今为止仍难以达成。 在此，我们报道了在钌催化体系中实现此类选择性调控策略的研究成果，达成了鲁棒性优异的位点选择性控制。该远端碳氢键转化反应的实现，依托于我们对二价钌（ruthenium(II)）催化体系中羧酸盐与膦配体温和协同作用的关键机理认知。 我们的研究成果可实现结构复杂药物与天然产物分子的普适性后期衍生化，且兼容各类敏感底物，包括荧光染料、药物分子、脂质、多肽、核苷及碳水化合物。