Preparation and Application of an Inexpensive ?-Formylglycine Building Block Compatible with Fmoc Solid-Phase Peptide Synthesis

alpha-Formylglycine (fGly) is a rare residue located in the active site of sulfatases and serves as a precursor to pharmaceutically relevant motifs. The installation of fGly motifs into peptides is currently challenging due to degradation under the acidic and nucleophile-rich conditions accompanying resin cleavage during solid-phase peptide synthesis. We report the synthesis of acid-and nucleophile-tolerant alpha- formylglycine building blocks from vitamin C and use them to prepare callyaerin A, a macrocyclic peptide containing an fGly-derived motif.

Automated summary

alpha-Formylglycine (fGly) is a rare residue used as a precursor for pharmaceutically relevant motifs. However, the installation of fGly motifs into peptides is challenging due to degradation during solid-phase peptide synthesis. In this study, acid- and nucleophile-tolerant alpha-formylglycine building blocks were synthesized from vitamin C and successfully used to prepare callyaerin A, a macrocyclic peptide containing an fGly-derived motif.