Rhodium(III)‐Catalyzed C‐H/O₂ Dual Activation and Macrocyclization: Synthesis and Evaluation of Pyrido[2,1‐a]isoindole Grafted Macrocyclic Inhibitors for Influenza H1N1

Abstract The development of environment‐friendly, step economic couplings to generate structurally diverse macrocyclic compounds is highly desirable but poses a marked challenge. Inspired by the C−H oxidation mechanism of cytochromes P450, an unprecedented and practical Rh III ‐catalyzed acylmethylation macrocyclization via C−H/O 2 dual activation has been developed by us. The process of macrocyclization is facilitated by a synergic coordination from pyridine and ester group. Interestingly, the reaction mode derives from a three‐component coupling which differs from established olefination and alkylation paths. Density functional theory (DFT) calculations and control experiments revealed the mechanism of this unique C−H/O 2 dual activation. The newly achieved acylmethylation macrocyclic products and their derivatives showed a potent anti‐H1N1 bioactivity, which may provide an opportunity for the discovery of novel anti‐H1N1 macrocyclic leading compounds.