Hayden J. Bell and Lara R. Malins
Org. Biomol. Chem., 2022,20, 6250-6256
DOI:
10.1039/D2OB00782G,
Paper
A two-component reductive amination approach to the synthesis of peptide macrocycles is reported which leverages the inherent reactivity of proteinogenic amine nucleophiles. Unprotected peptides bearing α-amine and side chain amine motifs undergo two-fold reductive amination reactions with 2,6-pyridinedialdehyde linkers in aqueous media to afford macrocyclic peptide products with backbone embedded pyridine motifs. Dialdehyde staples bearing valuable azide and alkyne handles also enable the post-cyclisation modification of peptides using copper-catalysed azide–alkyne cycloaddition (CuAAC) chemistry.