The first total synthesis of the cyclodepsipeptide pipecolidepsin A

Marta Pelay-Gimeno, Yésica García-Ramos, Maria Jesús Martin, Jan Spengler, José Manuel Molina-Guijarro, Simon Munt, Andrés M. Francesch, Carmen Cuevas (), Judit Tulla-Puche () and Fernando Albericio ()
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Marta Pelay-Gimeno: Institute for Research in Biomedicine
Yésica García-Ramos: Institute for Research in Biomedicine
Maria Jesús Martin: Pharma Mar S. A., Avda de los Reyes 1
Jan Spengler: Institute for Research in Biomedicine
José Manuel Molina-Guijarro: Pharma Mar S. A., Avda de los Reyes 1
Simon Munt: Pharma Mar S. A., Avda de los Reyes 1
Andrés M. Francesch: Pharma Mar S. A., Avda de los Reyes 1
Carmen Cuevas: Pharma Mar S. A., Avda de los Reyes 1
Judit Tulla-Puche: Institute for Research in Biomedicine
Fernando Albericio: Institute for Research in Biomedicine

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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 D -allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-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.

Date: 2013
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DOI: 10.1038/ncomms3352

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