The first total synthesis of the cyclodepsipeptide pipecolidepsin A

• Published in: Nature communications Vol. 4; no. 1; p. 2352
• Main Authors: Pelay-Gimeno, Marta, García-Ramos, Yésica, Jesús Martin, Maria, Spengler, Jan, Molina-Guijarro, José Manuel, Munt, Simon, Francesch, Andrés M., Cuevas, Carmen, Tulla-Puche, Judit, Albericio, Fernando
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.08.2013; Nature Publishing Group
• Subjects: 631/67; 639/638/309; 639/638/403/937; Amino acids; Animals; Cell Line, Tumor; Chemistry; Cytotoxicity; Depsipeptides - chemical synthesis; Depsipeptides - chemistry; Depsipeptides - pharmacology; Female; Hep G2 Cells; HT29 Cells; Humanities and Social Sciences; Humans; Male; MCF-7 Cells; multidisciplinary; Neoplasms - drug therapy; Peptides; Pipecolic Acids - chemical synthesis; Pipecolic Acids - chemistry; Pipecolic Acids - pharmacology; Porifera - metabolism; Science; Science (multidisciplinary); Structure-Activity Relationship; Spain
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3352

Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa . This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered γ-branched β-hydroxy-α-amino acid D -allo -(2 R ,3 R ,4 R )-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L -(2 S ,3 S ,4 R )-3,4-dimethylglutamine, (2 R ,3 R ,4 S )-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D -allo -Thr and L -pipecolic acid. Here we describe the first total synthesis of a D -allo -AHDMHA-containing peptide, pipecolidepsin A, thus allowing chemical structure validation of the natural product and providing a robust synthetic strategy to access other members of the relevant head-to-side-chain family in a straightforward manner. Pipecolidepsin A—commonly isolated from a marine sponge—is a promising anticancer agent but is challenging to synthesise in the lab. Here the authors describe the first total synthesis of this cyclodepsipeptide using a versatile strategy applicable to other similar compounds.