Base-Labile Safety-Catch Linker: Synthesis and Applications in Solid-Phase Peptide Synthesis

The safety-catch concept involves a protecting group that remains stable under a range of chemical conditions and subsequently becomes labile under one of those conditions upon a chemical modification of the protecting group. The safety-catch approach introduces flexibility into the scheme, enabling the use of the same reagent in two distinct steps of the chemical process. For example, it facilitates α-amino deprotection and final cleavage in a solid-phase peptide synthesis scheme. Herein, we developed a safety-catch linker based on sulfinyl designed to enable peptide elongation via fluorenylmethoxycarbonyl (Fmoc) chemistry. Subsequently, upon chemical modification (oxidation of the sulfinyl group into the corresponding sulfone), the peptide is released using a secondary amine via a β-elimination reaction, which also serves to remove the Fmoc group in each step. The optimization of both key reactions, oxidation of the linker, and peptide release were achieved using a multi-detachable system, which allows specific control of both reactions. The use of this linker opens the possibility of cleaving peptides from the solid support without trifluoroacetic acid.