Construction of challenging proline–proline junctions via diselenide–selenoester ligation chemistry

Polyproline sequences are highly abundant in prokaryotic 10 and eukaryotic proteins, where they serve as key components of 11 secondary structure. To date, construction of the proline−proline motif 12 has not been possible owing to steric congestion at the ligation junction, 13 together with an n → π* electronic interaction that reduces the 14 reactivity of acylated proline residues at the C-terminus of peptides. 15 Here, we harness the enhanced reactivity of prolyl selenoesters and a 16 trans-γ-selenoproline moiety to access the elusive proline−proline 17 junction for the first time through a diselenide−selenoester ligation− 18 deselenization manifold. The efficient nature of this chemistry is 19 highlighted in the high-yielding one-pot assembly of two proline-rich 20 polypeptide targets, submaxillary gland androgen regulated protein 3B 21 and lumbricin-1. This method provides access to the most challenging of ligation junctions, thus enabling the construction of 22 previously intractable peptide and protein targets of increasing structural complexity