General and Facile Route to Isomerically Pure Tricyclic Peptides Based on Templated Tandem CLIPS/CuAAC Cyclizations

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...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2018-01, Vol.57 (2), p.501-505
Main Authors: Richelle, Gaston J. J., Ori, Sumeet, Hiemstra, Henk, van Maarseveen, Jan H., Timmerman, Peter
Format: Article
Language:English
Subjects:
Alkynes
Amino acids
Benzyl bromide
Clips
CuAAC
cyclization
Functional groups
one-pot processes
Peptides
Scaffolds
Tricycles
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Summary: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 T41 and T42 mostly promote the formation of single isomeric tricycles while the rigid scaffolds T43 and T44 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. Rotatable tetravalent scaffolds containing two bromomethyl and two alkyne moieties are reported that enable the locking of linear peptides containing two cysteine and two azidohomoalanine (Aha) residues into tricyclic topologies via one‐pot ligation/cyclization (CLIPS=chemical linkage of peptides onto scaffolds).
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201709127