Toward solid-phase peptide fragment ligation by a traceless-Ugi multicomponent reaction approach

Area of Science:

• Organic Chemistry
• Peptide Chemistry
• Synthetic Chemistry

Background:

• Solid-phase peptide synthesis is crucial for creating peptides.
• Current ligation methods can be complex and require multiple steps.
• Efficient fragment coupling is essential for synthesizing longer peptides.

Purpose of the Study:

• To develop a new, efficient method for coupling peptide fragments on solid support.
• To utilize a traceless isocyanide-based multicomponent reaction for peptide ligation.
• To achieve a straightforward synthesis of fully deprotected oligopeptides.

Main Methods:

• Employing a microwave-assisted on-resin Ugi four-component reaction.
• Coupling a carboxyl-free peptide to a supported peptide with a free N-terminal amine.
• Utilizing an N-protected amide bond formation at the ligation site.
• Performing microwave-assisted acidolysis with trifluoroacetic acid for deprotection.

Main Results:

• Successfully attached peptide fragments on solid support.
• Efficiently removed the backbone amide protecting group.
• Produced fully deprotected peptides.
• Demonstrated the method's versatility with various fragment lengths, yielding diverse oligopeptides.

Conclusions:

• The described Ugi reaction/deprotection strategy provides a straightforward and efficient method for peptide fragment coupling on solid support.
• This approach simplifies the synthesis of oligopeptides, offering a valuable tool for peptide chemistry.
• Microwave assistance enhances reaction speed and efficiency in both the coupling and deprotection steps.