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

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Biochemistry

Background:

• The safety-catch concept utilizes protecting groups that are stable under specific conditions and become labile after chemical modification.
• This approach offers flexibility in chemical processes, allowing reagents to serve dual roles, such as in solid-phase peptide synthesis (SPPS).
• Current SPPS methods often rely on harsh reagents like trifluoroacetic acid for final peptide cleavage.

Purpose of the Study:

• To develop a novel safety-catch linker based on a sulfinyl group for fluorenylmethoxycarbonyl (Fmoc) based SPPS.
• To enable peptide elongation and subsequent cleavage from a solid support under mild conditions.
• To provide a method for cleaving peptides without the need for trifluoroacetic acid.

Main Methods:

• Design and synthesis of a sulfinyl-based safety-catch linker.
• Incorporation of the linker into Fmoc-based SPPS for peptide chain elongation.
• Chemical modification (oxidation) of the sulfinyl group to a sulfone to trigger cleavage.
• Utilized a multi-detachable system for optimizing oxidation and peptide release reactions.

Main Results:

• The developed sulfinyl linker successfully enabled peptide elongation using standard Fmoc chemistry.
• Oxidation of the sulfinyl group to a sulfone rendered the linker labile.
• Peptide release was achieved via a β-elimination reaction mediated by a secondary amine, which also removed the Fmoc group.
• Optimized conditions allowed for controlled oxidation and efficient peptide cleavage from the solid support.

Conclusions:

• A novel sulfinyl-based safety-catch linker was successfully developed for Fmoc-SPPS.
• This linker facilitates a mild and controlled method for peptide cleavage from solid supports, avoiding trifluoroacetic acid.
• The system offers enhanced flexibility and control in peptide synthesis, opening new possibilities for complex peptide preparation.