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Improved Strategy for the Synthesis of the Anticancer Agent Culicinin D
Author(s) -
Stach Michaela,
Weidkamp Andreas J.,
Yang SungHyun,
Hung Kuoyuan,
Furkert Daniel P.,
Harris Paul W. R.,
Smaill Jeff B.,
Patterson Adam V.,
Brimble Margaret A.
Publication year - 2015
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201500872
Subject(s) - chemistry , alcohol , peptide , amino acid , cleavage (geology) , residue (chemistry) , chloride , peptide synthesis , yield (engineering) , diastereomer , stereochemistry , intramolecular force , combinatorial chemistry , organic chemistry , biochemistry , materials science , geotechnical engineering , fracture (geology) , engineering , metallurgy
Abstract The anticancer peptaibol culicinin D was synthesised via a newly developed pathway. This route included an improved attachment of a C‐terminal amino acid alcohol building block to 2‐chlorotrityl chloride resin. A model system utilising readily available Fmoc‐alaninol as the substitute for the unusual APAE building block was developed to investigate the resin‐loading by N ‐anchoring of the first C‐terminal residue and an intramolecular O–N acyl shift. The use of both Fmoc SPPS and the crucial O–N acyl transfer afforded a C‐terminal alcohol that enabled the synthesis of a library of five related peptaibols. This model system was then applied to the synthesis of culicinin D. The C‐terminal APAE building block was anchored to 2‐chlorotrityl chloride resin in 67 % loading yield using the optimised conditions, and culicinin D (6.31 mg, 4 %) was prepared by SPPS prior to peptide cleavage and O–N acyl shift. This synthetic strategy was also used to prepare a diastereomer of culicinin D containing the unnatural ( S )‐AHMOD amino acid.