Thioimidate Protection Enables Amide, Thioamide, and Amidine Installation at Aspartic Acid Residues

Area of Science:

• Peptide chemistry and synthesis
• Medicinal chemistry
• Organic synthesis

Background:

• Peptide-bond isosteres are crucial for studying peptide backbone interactions.
• Thioamides are susceptible to aspartimide formation during peptide synthesis, complicating their incorporation.
• Conventional methods struggle to efficiently synthesize thioamide-containing peptides.

Purpose of the Study:

• To elucidate the reasons behind thioamide's propensity for aspartimide formation.
• To develop a robust strategy for incorporating thioamides and their derivatives into peptides.
• To establish a modular approach for accessing novel peptide backbone structures.

Main Methods:

• Investigation of thioamide reactivity during peptide elongation.
• Utilizing thioimidates as protecting groups for thioamides in solid-phase peptide synthesis (SPPS).
• Selective deprotection and conversion of thioimidates to amides and amidines.

Main Results:

• Thioimidate protecting groups effectively prevent aspartimide formation at aspartic acid residues.
• Thioimidates can be selectively converted to amides (native control) or amidines (backbone modification).
• A modular strategy was developed for incorporating amidine isosteres into peptides via a single SPPS precursor.

Conclusions:

• Thioimidates are superior protecting groups for thioamides, preventing aspartimide side-products.
• This method provides access to both native peptides and novel backbone-modified analogues.
• The successful incorporation of amidines represents a significant advancement in peptide isostere chemistry.