Aziridine based electrophilic handle for aspartic acid ligation

Area of Science:

• Organic Chemistry
• Peptide Chemistry
• Synthetic Chemistry

Background:

• Peptide synthesis is crucial for drug discovery and development.
• Existing ligation strategies can be complex and time-consuming.
• Developing efficient and regioselective peptide bond formation is an ongoing challenge.

Purpose of the Study:

• To develop a novel one-pot ligation strategy for synthesizing native peptides.
• To utilize aziridine chemistry for regioselective peptide coupling.
• To demonstrate the versatility of the method using aspartame-based peptides.

Main Methods:

• Incorporation of aziridin-2,3-dicarboxylate to peptide fragments to form N-aziridine appended peptides.
• Solution-phase ligation of N-aziridine appended peptides with peptide thio acids.
• Employing a ring-opening/peptidyl migration/desulfurization strategy.
• Synthesis of various aspartame-based peptides.

Main Results:

• Successful development of a one-pot ligation strategy at aspartic acid junctions.
• N-aziridine appended peptides were ligated with peptide thio acids to yield native peptides.
• The reaction demonstrated high regioselectivity and provided short native peptides in good yields.
• Generality of the aziridine-based ligation was showcased through the synthesis of aspartame-based peptides.

Conclusions:

• The developed one-pot ligation strategy provides an efficient and regioselective method for synthesizing native peptides.
• This aziridine-based approach offers a valuable tool for peptide synthesis, particularly for short peptide fragments.
• Further computational studies can provide deeper insights into the reaction mechanism.