Epimerization-free C-term Activation of Peptide Fragments by Ball-Milling

02 July 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Ball-milling enabled to perform [2+1], [2+2], and [2+3] peptide couplings with high yields and, if any, very low epimerization. Very good results were obtained with peptide fragments containing highly epimerization-prone and/or highly hindered amino acids at C-term such as phenylglycine, cysteine and valine. Ball-milling was clearly identified as the key element to obtain both high yield and purity along with low epimerization. Indeed, the ball-milling conditions proved to be superior to the classical solution synthesis approach on a various array of widely used coupling agents. These results open avenues for the development of highly efficient, convergent and flexible peptide synthesis strategies based on peptide fragment couplings mediated by ball-milling.


Mechanochemistry Mechanical forces
Mechanochemistry vs Solution Methods
peptide synthesis
Ball-Milling Method
epimerization-free segment condensation reaction

Supplementary materials

20200701 Experimental part fragment coupling


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