Hypervalent Iodine Amino Acid Building Blocks for Bioorthogonal Peptide Macrocyclization

• Published in: Angewandte Chemie International Edition 2024-08, Vol.63 (33), p.e202404747-n/a
• Main Authors: Liu, Xing‐Yu, Mykhailenko, Olha, Faraone, Adriana, Waser, Jerome
• Format: Article
• Language: English
• Subjects: Amino acids; Amino Acids - chemistry; bioorthogonal functionalization; Cyclization; hypervalent iodine; Iodine; Iodine - chemistry; macrocyclization; Molecular Structure; non-proteogenic amino acids; Peptide synthesis; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Reagents; Solid phases; Solid-Phase Synthesis Techniques; Synthesis
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202404747

Ethynylbenziodoxol(on)es (EB(X)xs) reagents have emerged as useful reagents for peptide/protein modification due to their versatile reactivity and high selectivity. Herein, we report the successful introduction of ethynylbenziodoxoles (EBxs) on different amino acid building blocks (Lys/Orn/Dap), and show their compatibility with both solid phase peptide synthesis (SPPS) and solution phase peptide synthesis (SPS). The selective incorporation of the EBx core into peptide sequences enable efficient macrocyclizations under mild conditions for the synthesis of topologically unique cyclic and bicyclic peptides. The development of non‐proteogenic amino acids (NPAAs) containing hypervalent iodine reagents ‐ethynylbenziodoxoles (EBxs)‐ is described. These NPAAs were compatible with both solid phase peptide synthesis (SPPS) and solution peptide synthesis (SPS), allowing the introduction of reactive handles on specific sites in the presence of multiple identical residues. The obtained peptide‐EBXs can be applied to the synthesis of cyclic peptides with unique topological properties.