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A Type of Auxiliary for Native Chemical Peptide Ligation beyond Cysteine and Glycine Junctions
Author(s) -
Loibl Simon F.,
Harpaz Ziv,
Seitz Oliver
Publication year - 2015
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.201505274
Subject(s) - native chemical ligation , cysteine , morpholine , chemistry , combinatorial chemistry , tcep , thiol , steric effects , chiral auxiliary , peptide , reductive amination , glycine , amino acid , stereochemistry , organic chemistry , biochemistry , enantioselective synthesis , phosphine , enzyme , catalysis
Native chemical ligation enables the chemical synthesis of proteins. Previously, thiol‐containing auxiliary groups have been used to extend the reaction scope beyond N‐terminal cysteine residues. However, the N ‐benzyl‐type auxiliaries used so far result in rather low reaction rates. Herein, a new N α ‐auxiliary is presented. Consideration of a radical fragmentation for cleavage led to the design of a new auxiliary group which is selectively removed under mildly basic conditions (pH 8.5) in the presence of TCEP and morpholine. Most importantly and in contrast to previously described auxiliaries, the 2‐mercapto‐2‐phenethyl auxiliary is not limited to Gly‐containing sites and ligations succeed at sterically demanding junctions. The auxiliary is introduced in high yield by on‐resin reductive amination with commercially available amino acid building blocks. The synthetic utility of the method is demonstrated by the synthesis of two antimicrobial proteins, DCD‐1L and opistoporin‐2.