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HF‐Free Boc Synthesis of Peptide Thioesters for Ligation and Cyclization
Author(s) -
Raz Richard,
Burlina Fabienne,
Ismail Mohamed,
Downward Julian,
Li Jiejin,
Smerdon Stephen J.,
Quibell Martin,
White Peter D.,
Offer John
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201607657
Subject(s) - chemistry , peptide , chemical ligation , combinatorial chemistry , native chemical ligation , cleavage (geology) , peptide synthesis , chemical synthesis , biochemistry , materials science , fracture (geology) , in vitro , composite material
We have developed a convenient method for the direct synthesis of peptide thioesters, versatile intermediates for peptide ligation and cyclic peptide synthesis. The technology uses a modified Boc SPPS strategy that avoids the use of anhydrous HF. Boc in situ neutralization protocols are used in combination with Merrifield hydroxymethyl resin and TFA/TMSBr cleavage. Avoiding HF extends the scope of Boc SPPS to post‐translational modifications that are compatible with the milder cleavage conditions, demonstrated here with the synthesis of the phosphorylated protein CHK2. Peptide thioesters give easy, direct, access to cyclic peptides, illustrated by the synthesis of cyclorasin, a KRAS inhibitor.