Native Serine Peptide Assembly: Scope and Utility.

This work develops serine peptide assembly (SPA), which complements and contrasts with classic native chemical ligation (NCL). Advances in reagent-less peptide bond formation have been applied to serine (and serine models) and a range of C-terminal amino acids, including bulky residues that are not amenable to NCL. The particular appeal of SPA is preparative-scale segment condensations with zero racemization risk and favourable process mass intensity (PMI). Mechanistic studies support a previously proposed reaction pathway via an initial trans-esterification step. An understanding of the factors favouring this pathway relies on hard-soft acid-base theory, where mildly activated esters with the largest carbonyl positive charge are most reactive with hydroxy amines. Novel C-terminal activators have been discovered that enhance reactivity and give harmless by-products.