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

Polytheonamide 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 nonproteinogenic d- and l-amino acids, and the chiralities of these amino acids alternate in sequence. These structural features induce the formation of a stable beta(6.3)-helical structure in the hydrophobic environment, giving rise to an overall tubular structure of 45 angstrom 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 angstrom, 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.