title: The first total synthesis of the cyclodepsipeptide pipecolidepsin A.
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.
authors.affiliation: 1] Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona, Spain [2] CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, 08028 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pelay-Gimeno
authors.forename: Yésica
authors.initials: Y
authors.lastname: García-Ramos
authors.forename: Maria
authors.initials: M
authors.lastname: Jesús Martin
authors.forename: Jan
authors.initials: J
authors.lastname: Spengler
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Molina-Guijarro
authors.forename: Simon
authors.initials: S
authors.lastname: Munt
authors.forename: Andrés M
authors.initials: AM
authors.lastname: Francesch
authors.forename: Carmen
authors.initials: C
authors.lastname: Cuevas
authors.forename: Judit
authors.initials: J
authors.lastname: Tulla-Puche
authors.forename: Fernando
authors.initials: F
authors.lastname: Albericio
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D010875:Pipecolic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011161:Porifera / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047630:Depsipeptides; D010875:Pipecolic Acids; C587510:pipecolidepsin A