Development of a nitrogen-bound hydrophobic auxiliary: application to solid/hydrophobic-tag relay synthesis of calpinactam.

In the last couple of decades, technologies and strategies for peptide synthesis have advanced rapidly. Although solid-phase peptide synthesis (SPPS) and liquid-phase peptide synthesis (LPPS) have contributed significantly to the development of the field, there have been remaining challenges for C-terminal modifications of peptide compounds in SPPS and LPPS. Orthogonal to the current standard approach that relies on installation of a carrier molecule at the C-terminus of amino acids, we developed a new hydrophobic-tag carbonate reagent which facilitated robust preparation of nitrogen-tag-supported peptide compounds. This auxiliary was easily installed on a variety of amino acids including oligopeptides that have a broad range of noncanonical residues, allowing simple purification of the products by crystallization and filtration. We demonstrated a solid/hydrophobic-tag relay synthesis (STRS) strategy using the nitrogen-bound auxiliary for total synthesis of calpinactam.