Late-Stage, Stereoretentive, and Site-Selective Modification of Synthetic Peptides by Using Photoredox Catalysis

Area of Science:

• Chemical synthesis
• Organic chemistry
• Peptide chemistry

Background:

• Late-stage functionalization is key for creating diverse peptide analogs.
• Cysteine residues offer a versatile handle for chemical modification.
• Developing site-selective methods is crucial for complex peptide synthesis.

Purpose of the Study:

• To develop a photoredox-catalyzed late-stage functionalization strategy for peptides.
• To enable the introduction of non-natural aliphatic, hydrophobic residues.
• To achieve site-selective modification in the presence of other reactive groups.

Main Methods:

• Activation of cysteine residues as C-rich-type thioethers.
• Incorporation of modified cysteine into peptide synthesis (solid-phase or solution-phase).
• Photoredox catalysis to generate stereoretentive and site-selective alanyl radical intermediates.
• Reaction of the radical intermediate with non-activated alkenes.
• Development of a method to prevent amine residue alkylation.

Main Results:

• Successful activation of cysteine residues as thioethers.
• Generation of alanyl radical intermediates via photoredox catalysis.
• Stereoretentive and site-selective radical formation, even with free cysteines.
• Formation of non-natural residues by reacting radicals with alkenes.
• Demonstrated applicability to both linear and cyclic synthetic peptides, including protection against amine alkylation.

Conclusions:

• A novel photoredox-catalyzed late-stage functionalization of peptides has been established.
• This method allows for the precise introduction of diverse non-natural residues.
• The strategy is robust, site-selective, and applicable to complex peptide structures.