Nakada M
School of Science and Engineering, Waseda University, Tokyo, Japan.
Yakugaku Zasshi. 1997 Aug;117(8):486-508. doi: 10.1248/yakushi1947.117.8_486.
The first total synthesis of the antitumor macrolide rhizoxin in a highly stereo-controlled manner was described. The construction of the key building fragments required for the total synthesis of the antitumor macrolide rhizoxin, that arose from our retrosynthetic analysis of rhizoxin in an optically pure form by concise and efficient sequence analyses was described. Synthesis of the right-wing was started from the chiral half-ester generated by asymmetric hydrolysis of the corresponding meso-diester using pig liver esterase. The remaining chiral centers of the fragment was constracted by cyclic hydroboration. Synthesis of the left-wing was also accomplished starting from (S)-methyl 3-hydroxy-2-methylpropionate which had been prepared by enzyme mediated transformation. Coupling of the right-wing and the left-wing was accomplished by Julia coupling, and the macrocyclic lactone was constructed by the intramolecular Horner-Emmons reaction. The control of the stereoselective epoxidations was well achieved after the formation of an unsaturated 16-membered macrocyclic lactone. Chromophore-side-chain moiety was constructed at the final stage by the reaction of the phosphineoxide in 80% yield with high selectivity (E/Z = > 20/1). The present methodology will be useful for the synthesis of the homologues and man-made rhizoxin.
描述了以高度立体控制的方式首次全合成抗肿瘤大环内酯类根霉素。描述了通过简洁高效的序列分析对光学纯形式的根霉素进行逆合成分析后，全合成抗肿瘤大环内酯类根霉素所需关键构建片段的构建。右翼的合成从使用猪肝酯酶对相应内消旋二酯进行不对称水解生成的手性半酯开始。片段其余的手性中心通过环硼氢化构建。左翼的合成也从通过酶介导转化制备的(S)-3-羟基-2-甲基丙酸甲酯开始。右翼和左翼的偶联通过Julia偶联完成，大环内酯通过分子内霍纳-埃蒙斯反应构建。在形成不饱和十六元大环内酯后，立体选择性环氧化的控制得到了很好的实现。在最后阶段，通过氧化膦的反应以80%的产率和高选择性（E/Z>20/1）构建了发色团侧链部分。本方法将有助于合成根霉素的同系物和人工合成根霉素。
