Peptide macrocyclisation via late-stage reductive amination

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Peptide macrocycles are important scaffolds in drug discovery and chemical biology.
• Existing methods for macrocyclization can be complex and require protecting groups.
• Developing efficient and versatile methods for peptide macrocycle synthesis is crucial.

Purpose of the Study:

• To develop a novel two-component reductive amination strategy for peptide macrocycle synthesis.
• To utilize readily available proteinogenic amine nucleophiles without protection.
• To introduce versatile handles for post-cyclization modifications.

Main Methods:

• A two-component reductive amination reaction between unprotected peptides and 2,6-pyridinedialdehyde linkers.
• Reactions performed in aqueous media, leveraging the reactivity of α-amine and side chain amine motifs.
• Post-cyclization modification using copper-catalyzed azide-alkyne cycloaddition (CuAAC) chemistry on dialdehyde staples.

Main Results:

• Successful synthesis of peptide macrocycles with backbone-embedded pyridine motifs.
• Demonstrated efficiency of the two-fold reductive amination in aqueous conditions.
• Incorporation of azide and alkyne handles for subsequent functionalization via CuAAC.

Conclusions:

• The reported method provides an efficient and versatile approach to peptide macrocycle synthesis.
• This strategy simplifies macrocyclization by avoiding peptide protection steps.
• The incorporated handles allow for facile diversification of the synthesized macrocycles.