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

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.

Automated summary

Inspired by the C-H oxidation mechanism of cytochromes P450, a practical Rh-III-catalyzed acylmethylation macrocyclization via C-H/O-2 dual activation has been developed. The macrocyclization process is facilitated by a synergic coordination from pyridine and ester group. This unique reaction mode differs from established olefination and alkylation paths, and its mechanism has been revealed through density functional theory (DFT) calculations and control experiments. The newly achieved acylmethylation macrocyclic products and their derivatives exhibit potent anti-H1N1 bioactivity, which may lead to the discovery of novel anti-H1N1 macrocyclic leading compounds.