Construction of Challenging Proline–Proline Junctions via Diselenide–Selenoester Ligation Chemistry

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