Bughin Carine, Zhao Gang, Bienaymé Hugues, Zhu Jieping
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France.
Chemistry. 2006 Jan 23;12(4):1174-84. doi: 10.1002/chem.200500703.
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.
一种概念全新的大环内酯化方法已经被开发出来。这是一个多米诺过程，包括以下一系列步骤：1）5-氨基恶唑质子化生成亲电亚胺盐；2）相邻的C端羧酸捕获亚胺物种生成假定的螺内酯；3）连接的醇对螺内酯进行分子内亲核加成，随后发生断裂。策略性引入的5-氨基恶唑作为相邻C端羧酸的内部无痕活化剂，因为它在环化后成为肽主链的一个组成部分。无需偶联试剂，在非常温和的条件下（以乙腈为溶剂，室温），只需几当量的三氟乙酸就能引发整个反应序列。通过硫迁移实验证明了螺内酯是羧酸的活化形式。通过与5-氨基恶唑的三组分合成相结合，从易于获得的起始原料开发出了一种两步合成结构复杂的环缩肽的方法。
