Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 145, Issue 25, Pages 13968-13978Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.3c03512
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In this study, a broadly applicable strategy to remodel the structure of homodetic peptides by cross-linking the aromatic side chains of Trp, His, and Tyr residues with various aryl linkers is reported. The aryl linkers can be easily installed via copper-catalyzed double heteroatom-arylation reactions of peptides with aryl diiodides. These aromatic side chains and aryl linkers can be combined to form a large variety of assemblies of heteroatom-linked multi-aryl units. The assemblies can serve as tension-bearable multi-joint braces to modulate the backbone conformation of peptides as an entry to previously inaccessible conformational space.
The three-dimensional structure of medium-sized cyclicpeptidesaccounts for their biological activity and other important physiochemicalproperties. Despite significant advances in the past few decades,chemists' ability to fine-tune the structure, in particular,the backbone conformation, of short peptides made of canonical aminoacids is still quite limited. Nature has shown that cross-linkingthe aromatic side chains of linear peptide precursors via enzyme catalysiscan generate cyclophane-braced products with unusual structures anddiverse activities. However, the biosynthetic path to these naturalproducts is challenging to replicate in the synthetic laboratory usingpractical chemical modifications of peptides. Herein, we report abroadly applicable strategy to remodel the structure of homodeticpeptides by cross-linking the aromatic side chains of Trp, His, andTyr residues with various aryl linkers. The aryl linkers can be easilyinstalled via copper-catalyzed double heteroatom-arylation reactionsof peptides with aryl diiodides. These aromatic side chains and aryllinkers can be combined to form a large variety of assemblies of heteroatom-linkedmulti-aryl units. The assemblies can serve as tension-bearable multijointbraces to modulate the backbone conformation of peptides as an entryto previously inaccessible conformational space.
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