Many fields of chemical research rely on a ready source of enantiomerically pure protein subunits that have been constructed and modified to highly exacting specifications. Therefore, the stereospecific synthesis of peptide chains is a critical endeavor. This is challenging, however, due to the epimerization of amino acid side chains that often accompanies amide bond formation, or ligation. Epimerization is particularly common when overly reactive electrophiles, such as acid chloride derivatives of the <i>C-</i>terminus, are used during the ligation step. Synthetic peptide auxiliaries have been developed to support epimerization-free ligation, by providing a way to facilitate amide bond formation between the amino acid and peptides through a weak electrophile, which itself is not susceptible to epimerization. Once the peptide and amino acid are linked via the auxiliary molecule, intramolecular amide bond formation between the peptide and amino acid becomes energetically favorable. In the current work, progress in the synthesis towards an aromatic peptide auxiliary, which prevents epimerization through steric bulk, is described. The long-term goal of the project is to develop an auxiliary that will make epimerization-free ligation between any two peptides possible.

Progress towards the synthesis of auxiliary molecules for stereospecific peptide ligation

256th National Meeting (2018)

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