Convergent Total Synthesis of the Complex Non‐Ribosomal Peptide Polytheonamide B

Abstract

AbstractPolytheonamide B, isolated from the Japanese marine sponge Theonella swinhoei, is by far the largest non‐ribosomal peptide known to date, and displays potent cytotoxicity. Its 48 amino acid residues include a variety of non‐proteinogenic D‐ and L‐amino acids, and the chiralities of these amino acids alternate in sequence. These structural features induce the formation of a stable β6.3‐helical structure in the hydrophobic environment, giving rise to an overall tubular structure of 45 Å in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore with an inner diameter of 4 Å, thereby acting as an ion channel. In this account, we describe in detail our total synthetic route to polytheonamide B. The total synthesis relies on a combination of four key stages: synthesis of eight non‐proteinogenic amino acids and an N‐terminus moiety, a solid phase assembly of four fragments of polytheonamide B, three Ag+‐mediated couplings of the fragments, and finally, acid‐promoted global deprotection. The generality and modularity of the developed strategy will enable future studies of the chemical and biological properties of this unusual ion‐channel‐forming peptide and its synthetic analogues.