Backbone-Enabled Directional Peptide Macrocyclization through Late-Stage Palladium-Catalyzed δ-C(sp² )-H Olefination

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Chemistry

Background:

• Peptide macrocyclization is crucial for developing novel peptidomimetics and cyclic peptides.
• Expanding structural diversity in cyclic peptides remains a key challenge in drug discovery.

Purpose of the Study:

• To develop a versatile peptide macrocyclization strategy using late-stage palladium-catalyzed C-H activation.
• To enable facile macrocyclization in the N-to-C direction via δ-C(sp2)-H olefination.

Main Methods:

• Utilized palladium-catalyzed δ-C(sp2)-H olefination of phenylalanine residues.
• Employed peptide backbone amides as internal directing groups for macrocyclization.
• Integrated this method with a previously established β-C(sp3)-H arylation for orthogonal synthesis.

Main Results:

• Demonstrated a highly versatile peptide macrocyclization strategy.
• Achieved facile N-to-C direction macrocyclization using C-H olefination.
• Showcased the first one-pot synthesis of bicyclic peptides via directionally orthogonal Pd-catalyzed C-H activation.

Conclusions:

• Developed a novel and versatile palladium-catalyzed C-H olefination for peptide macrocyclization.
• Established a pair of directionally orthogonal C-H activation methods for peptide synthesis.
• Enabled efficient synthesis of complex bicyclic peptides through a one-pot strategy.