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. 65 donors have been reported to react with N-terminal Cys-66 containing peptides, albeit in the presence of a selenol catalyst 67 and a large molar excess of the acyl donor fragment. More 68 recently, Dong et al. have designed a prolyl thioester whereby 69 the γ-position of the Pro ring is functionalized with a thiol 70 moiety (Scheme 1B). 17 This modified Pro thioester reacts via a 71 bicyclic thiolactone intermediate, which leads to activation of 72 the carbonyl through the generation of a highly strained cyclic 73 thioester. While this is a very elegant strategy, the γ-thiol
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