García-Fortanet Jorge, Murga Juan, Carda Miguel, Marco J Alberto, Matesanz Ruth, Díaz J Fernando, Barasoain Isabel
Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Avda. Sos Baynat s/n, 12071 Castellón, Spain.
Chemistry. 2007;13(18):5060-74. doi: 10.1002/chem.200700342.
A total, stereoselective synthesis of the naturally occurring, cytotoxic macrolide FD-891 and of its non-natural (Z)-C12 isomer is described. Three fragments of the main carbon chain were stereoselectively prepared by using asymmetric aldol and allylation reactions as the key steps. The molecule was then assembled by using two Julia-Kocienski olefinations to connect the three fragments and a Yamaguchi reaction to close the macrolactone ring. Some specific biological properties (cytotoxicity, binding to tubulin) have been determined for both macrolides. The E configuration of the C12-C13 olefinic bond seems to be an important feature in determining the cytotoxicity but the precise biological mechanism of the latter still remains to be cleared.
本文描述了天然存在的细胞毒性大环内酯FD - 891及其非天然（Z）-C12异构体的全立体选择性合成。以不对称羟醛缩合反应和烯丙基化反应为关键步骤，立体选择性地制备了主碳链的三个片段。然后，通过两次Julia - Kocienski烯烃化反应连接这三个片段，并利用山口反应闭合大环内酯环，从而完成分子组装。已测定了这两种大环内酯类化合物的一些特定生物学性质（细胞毒性、与微管蛋白的结合）。C12 - C13烯键的E构型似乎是决定细胞毒性的一个重要特征，但后者的确切生物学机制仍有待阐明。
