A novel mechanochemical approach is described for chloride-templated head-to-tail macrocyclization of a pentapeptide and a hexapeptide. This straightforward method allows the solvent-free preparation of cyclopeptides with yields comparable to solution-based approaches without the need for high dilution of the reaction mixture and with significantly reduced reaction times and organic waste amount.

Penicyclone A is a polyketide compound with a unique and intriguing structure recently isolated from the fungus Penicillium sp. F23-2 during an OSMAC (one-strain-many-compounds) campaign. The compound demonstrated significant antimicrobial activity without exhibiting any cytotoxic effects, which prompted us to pursue total synthesis of the reported enantiomer. Upon completion of the synthesis, we observed that our synthetic compound lacked antimicrobial activity. Further analysis suggested that the natural product may have, in fact, been the opposite enantiomer to that reported. This observation led us to synthesize the antipodal enantiomer using our previously developed synthetic sequence and to evaluate the biological activity (via antibacterial and cytotoxicity assays) of both the final compound and the selected intermediates from both enantiomeric series.