Late-stage Modification Of Peptides Via Palladium-catalyzed C-H Activation

Peptides are important life building materials.Due to the unique structure,peptides have excellent biological activities in clinical treatment,such as antibacterial,antiviral,antitumor and immunosuppressive activities.Exploring the structural diversity have great potential for drug discovery,so the structural modification of peptides has attracted great interest from many organic chemists and pharmaceutical scientists.Over the past several decades,transition-metal catalyzed carbon-hydrogen bond activation has been rapidly developed as an important branch of organic synthetic chemistry.With this new strategy,peptide derivatives can be selectively functionalized to directly construct carbon-carbon bonds and carbon-heteroatom bonds,such as arylation,alkylation,fluorination,hydroxylation and diazotization,etc.Azetidine is an important class of alkaloids.The strategy of structural modification in peptide derivatives to synthesize the alkaloids not only increases the molecular structure of the peptides,but also have great significance for medicinal chemistry.We have developed a strategy that using an intramolecular palladium-catalyzed amination of unactivated?-C?sp³?-H with available straight-chain or cycloalkyl dipeptide substrates to construct complex polycyclic nitrogen-containing heterocycles with pyridinecarboxamide as a directing group.The method exhibits high functional-group tolerance and enables the synthesis of azabicyclic scaffolds,including various dipeptide molecules.We have also explored the palladium-catalyzes the dual activation of both C?sp²?-H and C?sp³?-H bonds through screening the reaction conditions and studying the regulation of ligands,catalysts and oxidants.Lastly,our group reported the reaction of a cobalt-mediated aminoquinoline-directed C?sp²?-H bond activation to construct C-S bond.The diarylsulfide compounds are synthesized by using a readily available quinolinamide substrate as starting material,Co?OAc?₂?4H₂O as a metal reagent,S₈ as an oxdiant.The further investigation of this project was conducted by adding free radical trapping agents and speculative synthesis of reaction intermediates with an aim of exploring its reaction mechanism.The reaction mechanism was believed to lay a foundation for the further study of cobalt-involved construction of C-S bonds.