A conceptually novel macrolactonization technology is described. A strategically positioned 5-aminooxazole served as an internal traceless activator of the neighboring C-terminal carboxylic acid allowing the occurrence of macrolactonization under mild acidic conditions. It is a domino process involving a sequence of: a) protonation of 5-amino oxazole leading to an electrophilic iminium salt; b) trapping the iminium species by the neighboring C-terminal carboxylic acid leading to a putative spirolactone; c) intramolecular nucleophilic addition of the tethered alcohol onto the spirolactone followed by fragmentation to afford the macrolactone. No coupling reagent is required and the entire sequence is triggered by trifluoroacetic acid under very mild conditions (MeCN, room temperature). By combining with a three-component synthesis of 5-aminooxazole, a two-step synthesis of structurally complex cyclodepsipeptides from readily accessible starting materials is developed.