Repetitive Thiazolidine Deprotection Using a Thioester-Compatible Aldehyde Scavenger for One-Pot Multiple Peptide Ligation

Angew Chem Int Ed Engl. 2022 Sep 26;61(39):e202206240. doi: 10.1002/anie.202206240. Epub 2022 Aug 19.


Strategies for one-pot peptide ligation enable chemists to access synthetic proteins at a high yield in a short time. Herein, we report a novel one-pot multi-segments ligation strategy using N-terminal thiazolidine (Thz) peptide and a newly designed formaldehyde scavenger. Among the designed 2-aminobenzamide-based aldehyde scavengers, 2-amino-5-methoxy-N',N'-dimethylbenzohydrazide (AMDBH) can remarkably convert Thz into unprotected cysteine at pH 4.0. Furthermore, AMDBH degrades Thz at a considerably low rate at pH 7.5, and thioester degradation caused by this scavenger is negligible. As a result, we have developed an efficient one-pot peptide ligation strategy by simply repetitively changing the pH with AMDBH. Finally, we synthesize mono-ubiquitinated histone H2A.Z (209 amino acids) via AMDBH-mediated one-pot four-segment peptide ligation in good yield.

Keywords: Chemical Protein Synthesis; Native Chemical Ligation; Peptides; Protecting Groups; Thiazolidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes
  • Amino Acids
  • Cysteine* / chemistry
  • Formaldehyde
  • Histones*
  • Peptides / chemistry
  • Thiazolidines / chemistry


  • Aldehydes
  • Amino Acids
  • Histones
  • Peptides
  • Thiazolidines
  • Formaldehyde
  • Cysteine