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Synthetic Studies on Antitumor Antibiotics Mitomycin C and its Congeners

抗肿瘤抗生素丝裂霉素C及其同系物的合成研究

基本信息

批准号：
08557121
负责人：
FUKUYAMA Tohru
金额：
$ 8.45万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

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.

丝裂霉素C目前用作治疗癌症的化学治疗剂。FR 900482由Fujisawa Pharmaceutical Co.分离，Ltd.还具有平行的抗肿瘤活性。我们以前实现了这两种化合物的外消旋形式的全合成。然而，这些合成不足以实际应用于大规模生产。本研究的主要目的是开发一条实用、灵活的合成路线，适用于丝裂霉素C、FR 900482及其同系物的合成。经过逆合成分析，我们选择了八元环化合物作为关键中间体。为了构建八元关键中间体，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，我们然后研究了分子内1，3-偶极环加成方法使用腈氧化物。苯环上没有取代基的模型化合物进行腈氧环加成反应，以合理的产率得到了所需的八元环环加合物。然而，出乎意料的是，在苯环上带有适当取代基的FR 900482的底物由于改变了环加成反应的区域化学而产生了不期望的9元环化合物。在进一步研究之后，发现肉桂酸酯型底物甚至在苯环上具有适当的官能度也提供所需的8元环产物。正在研究从环加合物到FR 900482及其同系物的进一步加工。