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Late‐Stage Functionalization of Histidine in Unprotected Peptides
Author(s) -
Noisier Anaïs F. M.,
Johansson Magnus J.,
Knerr Laurent,
Hayes Martin A.,
Drury William J.,
Valeur Eric,
Malins Lara R.,
Gopalakrishnan Ranganath
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201910888
Subject(s) - surface modification , chemistry , histidine , combinatorial chemistry , peptide , chemical modification , oxime , ketone , alkylation , selectivity , hydrazone , organic chemistry , polymer chemistry , catalysis , biochemistry , enzyme
Abstract The late‐stage functionalization (LSF) of peptides represents a valuable strategy for the design of potent peptide pharmaceuticals by enabling rapid exploration of chemical diversity and offering novel opportunities for peptide conjugation. While the C(sp 2 )−H activation of tryptophan (Trp) is well documented, the resurgence of radical chemistry is opening new avenues for the C−H functionalization of other aromatic side‐chains. Herein, we report the first example of LSF at C2 of histidine (His) utilizing a broad scope of aliphatic sulfinate salts as radical precursors. In this work, the exquisite selectivity for histidine functionalization was demonstrated through the alkylation of complex unprotected peptides in aqueous media. Finally, this methodology was extended for the installation of a ketone handle, providing an unprecedented anchor for selective oxime/hydrazone conjugation at histidine.