Protein subunits that have been constructed or modified to highly exacting specifications are a critical resource for many fields of scientific research. It is of critical importance that these proteins are enantiomerically pure. Therefore synthetic methodology for producing peptide chains in a way that is stereospecific is a critical endeavor. Unfortunately, the formation of amide bonds during peptide synthesis, or ligation, is achieved via a mechanistic pathway in which epimerization of the chiral centers in the peptide subunits is possible. 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 an added amino acid and peptide chain through a weaker electrophile, which itself is not susceptible to epimerization. Once the peptide chain and amino acid are linked via the auxiliary molecule, intramolecular acyl substitution to form peptide bond between the peptide chain and new amino acid becomes energetically favorable. In the current work, progress in the synthesis towards novel salicylaldehyde peptide auxiliary, which prevents epimerization through bulky substituents, 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.

Synthesis of novel auxiliary molecules for stereospecific peptide ligation

2019 Spring National Meeting

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