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

本课题首次实现了天然产物jungermatrobrunin A、diacetoxyjungermannenone C和acetoxyhydroxyjungermannenone C的全合成。由于这些四环二萜类化合物丰度低，多环碳骨架高度复杂，其生物学特性尚不明确。相关的jungermannenones已显示出对人白血病细胞有良好的细胞毒活性。内过氧化物jungermatrobrunin A被设想为一种缺氧激活的前药，用于治疗通常逃避传统化疗药物的实体肿瘤。这些高度氧化的jungermannenones仍然是一个巨大的合成挑战。自2008年分离以来，没有报道过它们的全合成。提出了通过序列[4+3]环加成快速建立复合骨架的方法。这个过程结合了两种强大的成键反应，从相对简单的起始材料产生高水平的结构复杂性。合成努力从商业上便宜的香芹酮开始，它有两种对映体形式。因此，可以实现两种天然产物对映体的简洁全合成。鉴于我们提出的合成方法的效率，这项工作将通过提供足够数量的天然产物来实现全面的结构-活性关系研究，最终导致未来候选药物的鉴定。

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.