A milestone advance in peptide synthesis was the development of native chemical ligation (NCL) by Kent and co-workers in 1994. In this ligation approach, a C-terminal thioester peptide and an N-terminal cysteine peptide are selectively coupled to generate a “native” peptide bond (Xaa-Cys) at the ligation site. Our group has recently reported a new approach to amide bond formation utilizing β-hydroxyamines and mildly activated esters. We suggest the reaction pathway for these ligations involves initial trans-esterfication of the alcohol followed by an acyl transfer to give the more stable hydroxy amide. This reaction pathway mimics the NCL mechanism utilizing the hydroxyl group of serine, which is more abundant than cysteine in natural peptides, as opposed to the thio group of cysteine. Studies of this technology have been expanded to amide condensations of activated native amino acids with β-hydroxyamines and serine residues. These studies have provided more support for the earlier proposed trans-esterfication/acyl transfer reaction pathway, as well as, uncovered a superior C-terminal activating group, namely the 1,1,1,3,3,3-hexafluoro-2-propanol (HIP) ester.

Serine peptide ligations

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.