Synthetic Studies on Antitumor Antibiotics Mitomycin C and its Congeners

丝裂霉素C目前被用作癌症的化疗药物。藤泽制药株式会社分离的FR900482也具有平行的抗肿瘤活性。我们以前以外消旋的形式实现了这两个化合物的全合成。然而，这些合成方法还不够实用，不能用于大规模生产。本研究的一个主要建议是开发实用、灵活的合成路线，适用于丝裂霉素C、FR900482及其同系物。经过逆合成分析，我们选择了8元环化合物作为关键中间体。为了构建8元关键中间体，我们首先测试了阴离子与环氧化物之间的分子内烷基化反应。由于分子内烷基化方法没有得到成功的结果，我们接着研究了使用丁腈氧化物的分子内1，3-偶极环加成方法。在苯环上没有取代基的模型化合物的丁腈氧化物环加成反应，以合理的产率得到了所需的8元环加成产物。然而，出乎意料的是，由于改变了环加成反应的区域化学，FR900482的底物在苯环上含有适当的取代基，得到了不需要的9元环化合物。进一步的研究发现，肉桂酸酯类底物即使在苯环上具有适当的官能团也能提供所需的8元环产品。从环加合物到FR900482及其同系物的进一步阐述正在研究中。

Mitomycin C is currently used as chemotherapeutic agent for the treatment of cancer. FR900482 isolated by Fujisawa Pharmaceutical Co., Ltd also possesses parallel antitumore activity as well. We previously achieved total syntheses of both compounds in racemic form. These syntheses, however, is not practical enough to apply these for large-scale production. A main proposes of this research is development of practical and flexible synthetic routes, which would be applicable for mitomycin C, FR900482 and their congeners. After retrosynthetic analysis, we chose 8-membered ring compound as a key intermediate. For the construction of the 8-membered key intermediate, we initially tested intramolecular alkylation reaction between anion and epoxides. Since the intramolecular alkylation approach gave no successful results, we then investigated intramolecular 1,3-dipolar cycloaddition approach using nitrile oxides. Nitrile oxide cycloaddition of the model compounds which is lacking substituents on benzene ring afforded the desired 8-membered ring cycloadducts in reasonable yield. Unexpectedly, however, the substrate for FR900482 bearing appropriate substituents on benzene ring gave an undesired 9-membered ring compound due to changing the regiochemistry of cycloaddition reaction. After further investigations, it was found that cinnamate type substrate afforded the desired 8-membered ring product even with appropriate functionality on benzene ring. Further elaboration from the cycloadduct to FR900482 and its congeners is under investigation.