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General and Facile Route to Isomerically Pure Tricyclic Peptides Based on Templated Tandem CLIPS/CuAAC Cyclizations
Author(s) -
Richelle Gaston J. J.,
Ori Sumeet,
Hiemstra Henk,
van Maarseveen Jan H.,
Timmerman Peter
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201709127
Subject(s) - chemistry , combinatorial chemistry , peptide , native chemical ligation , peptidomimetic , alkyne , click chemistry , tandem , amino acid , bromide , cysteine , yield (engineering) , cycloaddition , organic chemistry , catalysis , biochemistry , materials science , composite material , metallurgy , enzyme
We report a one‐pot ligation/cyclization technology for the rapid and clean conversion of linear peptides into tricyclic peptides that is based on using tetravalent scaffolds containing two benzyl bromide and two alkyne moieties. These react via CLIPS/CuAAC reactions with cysteines and azides in the peptide. Flexibility in the scaffolds is key to the formation of isomerically pure products as the flexible scaffolds T4 1 and T4 2 mostly promote the formation of single isomeric tricycles while the rigid scaffolds T4 3 and T4 4 do not yield clean products. There seems to be no limitation to the number and types of amino acids present as 18 canonical amino acids were successfully implemented. We also observed that azides at the peptide termini and cysteine residues in the center gave better results than compounds with the functional groups placed the other way round.