Late-Stage Amination of Peptides on the Solid Phase

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Peptide Chemistry

Background:

• Late-stage peptide modification enables rapid generation of peptide mimetic libraries.
• Methods for late-stage amine introduction into peptides are limited but hold significant therapeutic potential.

Purpose of the Study:

• To present a novel protocol for late-stage peptide amination via an on-resin iodination-substitution approach.
• To demonstrate the compatibility and versatility of the method with various amine nucleophiles.

Main Methods:

• On-resin iodination followed by nucleophilic substitution with diverse amines.
• Application of the method to introduce pharmacologically relevant amines and metal-binding ligands.

Main Results:

• The protocol is compatible with primary and secondary amines, anilines, and heteroaromatic N-nucleophiles.
• Good to excellent yields were achieved for most amine introductions.
• Introduction of tris(2-aminoethyl)amine (tren) into a tryptophan zipper scaffold demonstrated metal-induced stabilization (>30 K).

Conclusions:

• The developed late-stage amination protocol is a valuable tool for peptide modification.
• This method facilitates the incorporation of functional amines for drug discovery, catalysis, and exploring metal-peptide interactions.