Synthesis of Noncoded Amino Acids Bearing a Salicylaldehyde Tag for the Design of Reversible‐Covalent Peptides

Insertion of electrophilic species on the structure of small molecule ligands or peptides is a well‐known strategy to increase their binding affinity for the target protein of interest. Among these reactive units, the salicylaldehyde (SA) tag can form remarkably stable imine bonds with the ϵ‐amino group of lysine, a highly frequent residue in proteins. In this work, we describe the optimized synthesis of two new noncoded α‐amino acids, starting from l‐homoserine and featuring the SA tag on the side chain. One of these final compounds was successfully inserted into a model tripeptide through in‐solution synthesis. These building blocks will allow the versatile insertion of the SA tag at suitable position of peptide sequences, opening to a tailored design of Lys‐engaging peptide ligands. We present the design and synthesis of two novel noncoded α‐amino acids, incorporating a lysine‐engaging salicylaldehyde tag on the side chain. These key building blocks open to the versatile positioning of the electrophile tag within peptide sequences, enabling tailored design of reversible‐covalent peptide binders for clinically‐relevant proteins.