Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan.
J Org Chem. 2012 Jan 6;77(1):388-99. doi: 10.1021/jo2019762. Epub 2011 Dec 6.
The total synthesis of (-)-apicularen A (1), a highly cytostatic 12-membered macrolide, and its analogues is described. The convergent and distinct approach not only provides 1, but also opens the opportunity to synthesize C10-C11 functional analogues of 1. The key steps of the total synthesis include assembling of iodoalkene 12 and aldehyde 13by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. The (17E,20Z,22Z)-heptadienoylenamine moiety in the side chain is installed by an efficient Cu(I)-mediated coupling to complete the synthesis. Analogues of C11-epi-, C11-deoxy-C10-α-hydroxy-, and C10-C11 dehydrated apicularen A 3-5 were also prepared. Cytostatic activities of (-)-apicularen A and the three analogues for three different cancer cell lines are described.
（-）-尖尾藻烯 A（1）是一种具有高度细胞抑制活性的 12 元大环内酯，其全合成及类似物的合成方法被描述。这种收敛而独特的方法不仅提供了 1，还为 1 的 C10-C11 功能类似物的合成开辟了机会。全合成的关键步骤包括：通过 Nozaki-Hiyama-Kishi（NHK）偶联反应将碘代烯烃 12 和醛 13 组装在一起，通过 Pd（II）催化的 1,3-手性转移反应立体特异性构建 2,6-反式-二取代二氢吡喃，以及 Yamaguchi 大环内酯化。通过高效的 Cu（I）介导的偶联反应将侧链中的（17E,20Z,22Z）-庚二烯酰亚胺部分安装到位，完成合成。还制备了 C11-epi-、C11-去氧-C10-α-羟基-和 C10-C11 脱水尖尾藻烯 A 3-5 的类似物。描述了（-）-尖尾藻烯 A 和三种类似物对三种不同癌细胞系的细胞抑制活性。
