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.