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Stapled Peptides by Late‐Stage C(sp 3 )−H Activation
Author(s) -
Noisier Anaïs F. M.,
García Jesús,
Ionuţ Ioana A.,
Albericio Fernando
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201608648
Subject(s) - peptide , combinatorial chemistry , chemistry , molecule , structural motif , stereochemistry , amino acid , functional diversity , biochemistry , biology , organic chemistry , ecology
Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross‐linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C−H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C−H functionalization of amino acids, examples of post‐synthetic peptide C−H modification are rare and comprise almost only C(sp 2 )−H activation. Herein, we report the development of a palladium‐catalyzed late‐stage C(sp 3 )−H activation method for peptide stapling, affording an unprecedented hydrocarbon cross‐link. This method was first employed to prepare a library of stapled peptides in solution. The compatibility with various amino acids as well as the influence of the size ( i , i +3 and i , i +4) and length of the staple were investigated. Finally, a simple solid‐phase procedure was also established.