Native chemical ligation at a base-labile 4-mercaptobutyrate Nα-auxiliary

Native chemical ligation (NCL) proceeds via a S–N acyl shift and, therefore, requires N-terminal cysteine. Nα-auxiliaries have long been used to enable NCL beyond cysteine. However, the reversibility of the S–N acyl shift under the acidic conditions used to remove the commonly applied N-benzyl auxiliaries limits the scope of this reaction. Herein, we introduce a new class of Nα-auxiliary which is designed for removal under mild basic conditions. The 3-N-linked 4-mercaptobutyrate auxiliary is readily synthesized in a single step and enables introduction on solid phase by means of reductive amination. The usefulness of the new auxiliary was demonstrated in the synthesis of the anti-microbial C-terminal domain of Dermicidine-1L.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide