Christopher Lamartina
New York University
Photoredox-Catalyzed Lysine C(sp3)–H Functionalization for Peptide Editing
The selective chemical modification of lysine residues beyond its epsilon-amino group remains a long-standing challenge in peptide synthesis due to the conformational flexibility of the residue, the nucleophilicity of the amine group, and the inert C(sp3)−H bonds of the aliphatic side chain. Herein we report a photoredox-catalyzed reaction for site-selective C(sp3)−H functionalization of lysine and related primary amine residues through alpha-amino radical intermediates generated from trifluoroacetamide protecting groups. This transformation proceeds under mild conditions and exhibits broad tolerance to residue identity and alkene coupling partners. The technology is compatible with standard Fmoc-solid phase peptide synthesis and direct on-resin modification. The method facilitates intermolecular alkylation, intramolecular macrocyclization, and polarity-reversed reactivity, providing access to a diverse array of unnatural amino acid motifs and peptide architectures. Collectively, this work establishes redox-active amide protecting groups as versatile handles for radical generation in complex molecular settings and expands the toolbox for late-stage peptide diversification.
Authors: Christopher Lamartina & Paramjit Arora
Institution: New York University
The selective chemical modification of lysine residues beyond its epsilon-amino group remains a long-standing challenge in peptide synthesis due to the conformational flexibility of the residue, the nucleophilicity of the amine group, and the inert C(sp3)−H bonds of the aliphatic side chain. Herein we report a photoredox-catalyzed reaction for site-selective C(sp3)−H functionalization of lysine and related primary amine residues through alpha-amino radical intermediates generated from trifluoroacetamide protecting groups. This transformation proceeds under mild conditions and exhibits broad tolerance to residue identity and alkene coupling partners. The technology is compatible with standard Fmoc-solid phase peptide synthesis and direct on-resin modification. The method facilitates intermolecular alkylation, intramolecular macrocyclization, and polarity-reversed reactivity, providing access to a diverse array of unnatural amino acid motifs and peptide architectures. Collectively, this work establishes redox-active amide protecting groups as versatile handles for radical generation in complex molecular settings and expands the toolbox for late-stage peptide diversification.
Authors: Christopher Lamartina & Paramjit Arora
Institution: New York University
