The first total synthesis of the cyclodepsipeptide pipecolidepsin A

Nature Communications; 4,
Article number:: 2352; doi:10.1038/ncomms3352

Received: 28 April 2013
Accepted: 24 July 2013
Published: 30 August 2013

Abstract

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 () residue, placed at the branching ester position and surrounded by the four demanding residues , (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, and . Here we describe the first total synthesis of a -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.