A Sequenced [4+3] Cycloaddition Synthesis of the Endoperoxide (+)-Jungermatrobrunin A

内过氧化物 ( )-Jungermatrobrunin A 的顺序 [4 3] 环加成合成

• 批准号: 329618273
• 负责人: Dr. Magnus Pfaffenbach
• 金额: --
• 依托单位: Department of Chemistry
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/329618273?language=en
• 关键词: Sequenced; 4+3; Cycloaddition; Synthesis; Endoperoxide

This research project describes the first total synthesis of the natural products jungermatrobrunin A, diacetoxyjungermannenone C and acetoxyhydroxyjungermannenone C. Due to their low abundance and highly complex polycyclic carbon skeleton, the biological profile of these tetracyclic diterpenoids has yet to be explored. Related jungermannenones have shown promising cytotoxic activity against human leukemia cells. The endoperoxide jungermatrobrunin A is envisioned to serve as a hypoxia-activated prodrug for the treatment of solid tumors, which generally evade traditional chemotherapeutic agents.These highly oxidized jungermannenones have remained a formidable synthetic challenge. No total synthesis has been reported since their isolation in 2008. The complex framework is proposed to be rapidly established by a sequenced [4+3] cycloaddition. This process combines two powerful bond forming reactions generating a high level of structural complexity from relatively simple starting materials. The synthetic endeavor starts from commercially inexpensive carvone, which is available in both enantiomeric forms. Thus, a concise total synthesis of both natural product antipodes may be achieved.Given the efficiency of our proposed synthetic approach, the work will enable comprehensive structure-activity relationship studies by providing sufficient amounts of the natural products, eventually leading to the identification of future drug candidates.

本课题首次全合成了天然产物jungermatrobrunin A、二乙酰氧基jungermannenone C和乙酰氧基羟基jungermannenone C。由于它们的丰度低和高度复杂的多环碳骨架，这些四环二萜的生物概况还有待探索。相关的jungermannenones已经显示出对人白血病细胞有希望的细胞毒活性。内过氧化物jungermatrobrunin A被认为是一种低氧激活的前体药物，用于治疗实体瘤，这通常会逃避传统的化疗药物。自2008年分离以来，尚未报告全合成。复杂的框架，建议迅速建立一个有序的[4+3]环加成。该过程结合了两个强大的键形成反应，从相对简单的起始材料产生高水平的结构复杂性。合成奋进从商业上便宜的香芹酮开始，香芹酮有两种对映体形式。因此，一个简洁的全合成的天然产物的对映体may be achieved.Given的效率，我们提出的合成方法，工作将使全面的结构-活性关系的研究，通过提供足够量的天然产物，最终导致未来的候选药物的识别。