Kinetically Controlled Chemoselective Cyclization Simplifies the Access to Cyclic and Branched Peptides

Area of Science:

• Biochemistry
• Organic Chemistry
• Peptide Chemistry

Background:

• Chemoselective reactions are crucial for efficient peptide synthesis.
• Controlling reactivity based on peptide position is a key challenge.
• Bis(2-sulfanylethyl)amido groups offer potential for targeted modifications.

Purpose of the Study:

• To investigate the reactivity of a bis(2-sulfanylethyl)amido group at different peptide locations.
• To develop a kinetically controlled chemoselective peptide cyclization method.
• To achieve straightforward synthesis of cyclic and branched peptides.

Main Methods:

• Installation of a bis(2-sulfanylethyl)amido group at the C-terminus and on Asp/Glu side-chains.
• Kinetic analysis of the reaction rates at different positions.
• Development of a one-pot peptide cyclization protocol.

Main Results:

• The bis(2-sulfanylethyl)amido group reacts significantly faster when installed on the C-terminal end compared to Asp and Glu side-chains.
• This reactivity difference was exploited to design a kinetically controlled chemoselective cyclization.
• The method provides straightforward access to cyclic and branched peptides in a single reaction vessel.

Conclusions:

• Peptide C-terminal installation of the bis(2-sulfanylethyl)amido group offers enhanced reactivity.
• A novel, kinetically controlled chemoselective peptide cyclization has been developed.
• This approach simplifies the synthesis of complex cyclic and branched peptide structures.