A Versatile Strategy for Head-to-Tail Macrocyclization and Traceless Backbone Editing of Short Peptides

Area of Science:

• Chemical Biology
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Efficient synthesis of head-to-tail macrocyclic peptides is challenging, especially for homochiral sequences.
• Existing methods often struggle with peptides lacking turn-inducing residues.
• Need for novel strategies to improve macrocyclization efficiency and peptide diversity.

Purpose of the Study:

• To investigate thioimidates as a functional group to promote macrocyclization of peptides.
• To develop a mild method for converting thioimidates to native amides post-cyclization.
• To explore the utility of thioimidates for post-cyclization backbone modifications.

Main Methods:

• Incorporation of a single thioimidate into peptide sequences.
• Macrocyclization reactions under optimized conditions.
• Silver(I)-mediated conversion of thioimidates to amides and other derivatives.
• Solid-phase peptide synthesis (SPPS) compatibility assessment.

Main Results:

• Thioimidate incorporation significantly improved macrocyclization efficiency for challenging peptide sequences.
• High-yielding cyclizations were achieved for tetra- and pentapeptides.
• A mild Ag(I) protocol successfully converted thioimidates to native amides.
• Thioimidates served as versatile branch points for creating diverse peptide derivatives.

Conclusions:

• Thioimidates are effective in promoting peptide macrocyclization by inducing preorganization.
• The developed method provides access to previously inaccessible macrocyclic peptides.
• Thioimidates offer a powerful and versatile platform for expanding cyclic peptide diversity.