A reductive acidolysis final deprotection strategy in solid phase peptide synthesis based on safety-catch protection

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Solid-phase peptide synthesis (SPPS) is a crucial technique for creating peptide-based therapeutics and research tools.
• Conventional deprotection methods can be harsh, potentially damaging sensitive peptide sequences or leading to side reactions.
• There is a continuous need for milder and more efficient deprotection strategies in SPPS.

Purpose of the Study:

• To develop a novel reductive acidolysis final deprotection strategy for SPPS.
• To introduce new safety-catch type semi-permanent protecting groups and linkers.
• To enable the synthesis of peptides with improved efficiency and reduced side-product formation.

Main Methods:

• Development of novel protecting groups and linkers based on 4-methylsulfinylbenzyl (MBS) protection.
• Implementation of a two-dimensional protection scheme utilizing acid-labile temporary groups and acid-stable, reductive acidolysis-cleavable semi-permanent groups.
• Synthesis of four model peptides, including two with C-terminal amide functionalities, to validate the strategy.

Main Results:

• Successful development and application of a reductive acidolysis deprotection strategy.
• Demonstrated the utility of new MBS-derived protecting groups and linkers.
• Achieved efficient synthesis of model peptides, confirming the strategy's effectiveness for C-terminal amide peptides.

Conclusions:

• The novel reductive acidolysis strategy offers a mild and effective final deprotection method for SPPS.
• The developed protecting groups and linkers provide orthogonal cleavage conditions, enhancing synthetic control.
• This approach is suitable for synthesizing complex peptides, including those with C-terminal amides, advancing peptide chemistry.