Improved Strategy for the Synthesis of the Anticancer Agent Culicinin D

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.