Synthesis of Non-Coded Amino Acids with a Salicylaldehyde Tag for Reversible-Covalent Peptides

Inserting electrophilic species into small molecule ligands or peptides is a well-established method for enhancing binding affinity to target proteins. The salicylaldehyde (SA) tag forms stable imine bonds with the ϵ-amino group of lysine, a common protein residue (10.1002/cbic.202300743). This study outlines the optimized synthesis of two new non-coded α-amino acids featuring the SA tag. These building blocks enable the flexible insertion of the SA tag into peptide sequences, facilitating the design of lysine-engaging ligands (10.1002/ejoc.202400229).