Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Chiyoda-ku, Tokyo 101-0062, Japan.
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
J Org Chem. 2021 Apr 2;86(7):5091-5101. doi: 10.1021/acs.joc.0c03019. Epub 2021 Mar 18.
Improved methods of convergent synthesis for peptidomimetic utilizing a chloroalkene dipeptide isostere (CADI) are reported. In this synthesis, Fmoc- or Boc-protected carboxylic acids can be produced from - and -terminal analogues corresponding to each amino acid starting material via an Evans aldol reaction, followed by a [3.3] sigmatropic rearrangement utilizing the Ichikawa allylcyanate rearrangement reaction. With this strategy, an Fmoc-protected CADI can be directly applied for solid-phase peptide synthesis. Using this approach, we have also identified the CADI-containing [-Lys-Leu-Val-Phe-Phe-] peptidomimetic, which is a superior inhibitor of amyloid-β aggregation than the parent peptide.
报道了一种利用氯烯二肽等价物（CADI）进行肽模拟物的收敛合成的改良方法。在该合成中，Fmoc-或 Boc 保护的羧酸可以通过 Evans 醛醇反应从每个氨基酸起始原料的 - 和 - 末端类似物中产生，然后利用 Ichikawa 烯丙基氰酸盐重排反应进行 [3.3] 西格玛重排。利用该策略，可以直接将 Fmoc 保护的 CADI 应用于固相肽合成。使用这种方法，我们还鉴定了含有 CADI 的 [-Lys-Leu-Val-Phe-Phe-] 肽模拟物，它是比母体肽更好的淀粉样蛋白-β聚集抑制剂。
