✍ Scribed by Carine Bughin; Gang Zhao; Hugues Bienaymé; Jieping Zhu
No coin nor oath required. For personal study only.
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) intramolecular nucleophilic addition of the tethered alcohol 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 equivalents of trifluoroacetic acid under very mild conditions (MeCN as the solvent at room temperature). The spirolactone as an activated form of the carboxylic acid has been evidenced by a sulfur‐migration experiment. 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.
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