Cyclotetrapeptides are important bioactive lead drug molecules that display a wide spectrum of pharmacological activities. However, the synthesis of cyclotetrapeptides from their linear precursors is challenging due to the highly constrained conformation required for cyclisation, thus hampering their progress to a clinical setting. This review provides an account of the reported methods used for the synthesis of cyclotetrapeptides.

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.

The development and application of a transfer hydrochlorination reagent based on a trichlorinated bicyclo[3.1.0]hexane core that transfers two molecules of HCl per molecule of surrogate to a π-basic substrate under...

Review: 83 refs.