Synthetic Studies of Anti-tumor Natural Products Based on the Carbohydrate Transformation

开发高效的合成生物活性天然产物的化学工艺是现代合成有机化学的重要任务。本研究以糖类转化为基础，合成了紫杉醇、放线菌素和延胡索醇等具有显著抗肿瘤活性的天然产物。在紫杉醇合成项目中，利用费里尔的碳环化反应，将最易获得的碳水化合物之一D-葡萄糖转化为高功能化的环己酮衍生物。环己酮与乙烯基金属物种和甲醛的三组分偶联反应有效地合成了紫杉醇的C环。C环与A环的偶联反应，然后进一步操纵Gav…更多的是具有醛功能的环己酮衍生物。SmI2催化的还原环化反应以较高的产率合成了紫杉烷骨架。在放线菌素的合成研究中，成功地实现了目标化合物的两个对映体的全合成，以D-葡萄糖衍生的环己酮与乙烯基金属物种和羟醛的三组分偶联反应为关键转化反应。研究发现，通过选择羟醛和溶剂的保护基团，可以对羟醛反应过程进行立体化学控制。在延胡索醇的合成中，D-葡萄糖衍生的环己烯醇的Claisen重排反应有效地立体选择性地生成了碳-碳键。重排产物的进一步转化为富马吉洛提供了索伦森中间体，完成了形式上的全合成。目前正在进行反应条件的优化。较少

The development of efficient chemical process for the synthesis of biologically active natural product is highly important task in modern synthetic organic chemistry. In this study, synthesis of natural products possessing significant anti-tumor activities, such as taxol, actinobolin and fumagillol based on the carbohydrate transformation was investigated. Carbohydrates have been produced by plants in huge quantities without causing any negative effect to the environment of the earth and thus are considered to be important carbon resources.In the project of taxol synthesis, D-glucal which is one of the most readily available carbohydrates, was converted into the highly functionalized cyclohexenone derivative utilizing Ferrier's carbocyclization reaction as the key step. Three-component coupling reaction of the cyclohexenone with vinyl metal species and formaldehyde effectively afforded the C-ring of taxol.Coupling reaction of the C-ring with A-ring, followed by further manipulation gav … More e the cyclohexenone derivative possessing an aldehyde function. SmI2 mediated reductive cyclization successfully afforded the taxane skeleton in good yield. Introduction of the carbon-carbon double bond, which would complete the total synthesis, is now under investigation.In the synthetic study of actinobolin, total synthesis of both enantiomers of the target compound was successfully achieved.Three-component coupling reaction of the cyclohexenone derived from D-glucose with vinyl metal species and hydroxyaldehyde was employed as the key transformation. It was found that the stereochemical control of the aldol reaction process was possible by the choice of the protecting group of the hydroxyaldehyde and the solvents.In fumagillol synthesis, Claisen rearrangement of the cyclohexenol derived from D-glucose effectively generated the carbon-carbon bond stereoselectively. Further transformation of the rearranged product provided the Sorensen's intermediate for fumagillol, completing the formal total synthesis. Optimization of the reaction conditions is currently under way. Less