Synthesis of bioactive and stabilized cyclic peptides by macrocyclization using C(sp³)-H activation

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Biochemistry

Background:

• Cyclic peptides are crucial for inhibiting protein-protein interactions.
• Existing methods for cyclic peptide synthesis are limited in structural diversity.
• Novel strategies are needed to expand the accessible chemical space of cyclic peptides.

Purpose of the Study:

• To develop a versatile peptide macrocyclization strategy.
• To synthesize cyclic peptides with unique hydrocarbon linkages.
• To explore the biological properties and applications of these novel cyclic peptides.

Main Methods:

• Utilized palladium-catalyzed C(sp3)-H activation for macrocyclization.
• Synthesized cyclic peptides incorporating hydrocarbon linkages between amino acid β-carbons and aromatic side chains (Phe, Trp).
• Applied the developed method to synthesize the natural product celogentin C.

Main Results:

• Successfully developed a highly versatile macrocyclization strategy.
• Created cyclic peptides with unique β-carbon to aromatic side chain hydrocarbon linkages.
• Demonstrated improved biological properties of the synthesized cyclic peptides compared to acyclic analogs.
• Achieved the synthesis of the natural product celogentin C using this method.

Conclusions:

• The novel palladium-catalyzed method offers a versatile approach to cyclic peptide synthesis.
• This strategy expands structural diversity by forming unique hydrocarbon linkages.
• The synthesized cyclic peptides show promising biological properties and potential for natural product synthesis.