Twisted Amide-Mediated Peptide Synthesis.

Area of Science:

• Organic Chemistry
• Peptide Chemistry
• Synthetic Methodology

Background:

• Peptide synthesis is crucial for developing therapeutics and understanding biological processes.
• Maintaining stereochemical purity during peptide bond formation is a significant challenge, particularly for complex structures.
• Existing methods often suffer from epimerization, limiting their applicability and efficiency.

Purpose of the Study:

• To develop a robust, practical, and sustainable method for peptide bond formation that suppresses isomerization.
• To explore the utility of acyl sulfonamides as activated intermediates in peptide synthesis.
• To investigate the potential of this method for synthesizing complex macrocyclic peptides and its broader applications in chemical synthesis.

Main Methods:

• Activation of the peptide C-terminus using tosyl isocyanate and pentafluorobenzyl bromide.
• Reaction of the activated intermediate with an amine to form an elongated peptide.
• Analysis of the active intermediate using Nuclear Magnetic Resonance (NMR) spectroscopy to identify structural features responsible for isomerization suppression.

Main Results:

• A novel peptide bond formation method via acyl sulfonamide (a twisted amide) was successfully developed.
• The method yields elongated peptides with high stereochemical purity, effectively suppressing Cα-epimerization.
• An intramolecular hydrogen bond in the active intermediate was identified as the key factor for isomerization suppression.

Conclusions:

• The developed method provides a powerful tool for synthesizing complex macrocyclic peptides, even under high dilution conditions.
• The synthetic route to twisted amides has broader applications, including the investigation of transition metal-catalyzed N-C bond activation.
• Sulfonamides can serve as orthogonally removable protecting groups for carboxylic acids in peptide synthesis.