Synthesis of Fluorescent Lanthipeptide Cytolysin S Analogues by Late-Stage Sulfamidate Ring Opening

Abstract

Nucleophilic ring opening of cyclic sulfamidates derived from amino acids is a common strategy for the synthesis of lanthionine derivatives. In this work, we report the regio-, chemo-, and stereoselective intramolecular S-alkylation of a cysteine residue with N-sulfonyl sulfamidates for the synthesis of cyclic lanthionine-containing peptides. The strategy involves the solid-phase synthesis of sulfamidate-containing peptides followed by late-stage intramolecular cyclization. This protocol allowed for the synthesis of four full-length cytolysin S (CylLS″) analogues, two α-peptides and two hybrid α/β-peptides. Their conformational preferences and biological activities were assessed and compared with those of wild-type CylLS″.

Natural products from the human microbiome: an emergent frontier in organic synthesis and drug discovery

“…53 Interestingly, some lantionine rings in cytolysin peptides show an unusual ll -stereochemistry which, via diverted total synthesis of all possible Lan/MeLan stereoisomeric peptides, were shown to be crucial for their antibiotic activities. 54…”