Copper-Catalyzed Late-Stage C(sp3)–H Amination of N-Terminal Glycine Peptides with Secondary Alkylamines

Abstract The pursuit of general C(sp3)–H amination methods using alkylamines, the most accessible and desirable nitrogen sources, represents a long-standing challenge in synthetic chemistry. This challenge is particularly acute in the context of late-stage peptide modification, where the incorporation of pharmaceutically privileged alkylamines such as piperidines and morpholines remains promising but largely underdeveloped. Herein, we report a copper-catalyzed, picolinamide (PA)-directed C(sp3)–H amination protocol that enables the direct, site-selective installation of abundant secondary alkylamines onto the α-position of N-terminal glycine residues in peptides. This method operates under mild, robust, operationally simple conditions and exhibits broad substrate scope (>50 peptide examples), with its synthetic utility highlighted by the direct construction of linker-free peptide-drug conjugates (PDCs) as well as seamless integration with solid-phase peptide synthesis (SPPS). Detailed mechanistic insights from spectroscopic studies and density functional theory (DFT) calculations support a pathway involving N-centered radical formation and a key N-acylimine intermediate. Notably, the secondary alkylamine serves as both radical precursor and nucleophile, facilitating access to high-valent Cu(III) intermediates and nucleophile addition steps in the catalytic cycle, respectively. Furthermore, this method allows modulation of peptide pharmacokinetic properties and exhibits promising anticancer activity in select PDCs, underscoring its potential for peptide-based medicinal chemistry.