A conceptually novel macrolactonization protocol has been developed. It is a domino process involving a sequence of: (1) protonation of 5-aminooxazole leading to the electrophilic iminium salt; (2) trapping of the iminium species by the neighboring C-terminal carboxylic acid leading to a putative spirolactone; and (3) intramol. nucleophilic addn. of the tethered alc. to the spirolactone followed by fragmentation. The strategically incorporated 5-aminooxazole serves as an internal traceless activator of the neighboring C-terminal carboxylic acid, since it became an integral part of the peptide backbone after cyclization. No coupling reagent is required and the entire sequence is triggered by just a few equiv. of trifluoroacetic acid under very mild conditions (MeCN as the solvent at room temp.). The spirolactone as an activated form of the carboxylic acid has been evidenced by a sulfur-migration expt. By combining with a three-component synthesis of 5-aminooxazole, a two-step synthesis of structurally complex cyclodepsipeptides from readily accessible starting materials was developed. [on SciFinder (R)]