Synthesis and study of oxo-bridged taxanes by C-C activation/cross-coupling of carvone-derived cyclobutanols

项目摘要/摘要 癌症是严重和高度流行的疾病，估计有1400万新病例和820万 2012年全球范围内的死亡人数。在各种各样的化疗药物中，紫杉醇等紫杉烷类药物 紫杉醇(Taxol®)已成为某些癌症治疗的标准护理。不幸的是， 这些药物受到它们显著的亲脂性和最近出现的耐药癌症的限制，产生了 迫切需要新的紫杉烷化疗药物。该提案描述了一种合成紫杉烷的计划 分子紫杉烷，以及结构上相关的天然和非天然紫杉烷，努力提供新的 用于生物学研究的化合物。泰索吉芬具有良好的微管稳定和细胞毒特性 并显示了潜在的抗耐药癌症活性，但在结构上与紫杉醇在几个方面不同 位置，包括一个不寻常的C17-C12氧桥官能团，这可能会增加水 相对于紫杉醇的溶解度。由于缺乏资料，对泰索吉芬的进一步研究一直受挫： 与世隔绝是极其低效的，而C17-C12氧桥对任何 半合成路线。 这项提案描述了第一种紫杉醇及相关化合物的全合成方法， 香芹酮类环丁醇的Sarpong C-C活化/芳基化反应扩展假说 将使紫杉醇的合成简明、收敛和可扩展。这项建议的具体目标是： 1)将Sarpong和同事最近开发的C-C活化/芳基化方法扩展到 允许使用合成的多功能乙烯基亲电体，2)应用C-C活化/乙烯基化反应 开发的目的是构建氧桥联A环，并随后进行全合成 紫杉烷，以及3)使用在AIM II中开发的合成紫杉烷的简明路线来制造其他天然紫杉烷 含有C17-C12氧桥，以及用于结构活性的非天然紫杉烷衍生物- 关系(SAR)研究。我们对非自然类似物的合成将集中在利用合成路线来 在Taxagifine框架上未被开发的位置安装功能化。紫杉醇的合成 还将对紫杉醇杂交物进行研究，以探索紫杉醇的结合构象。 C-C活化/乙烯基化反应的发展将允许构建不同的 萜类支架，在药物化学和天然产物全合成中具有潜在的用途。使用这个 合成紫杉酯以及天然和非天然类似物的反应将使SAR和机制 行动研究，加深我们对微管-相互作用的理解，并帮助识别潜在的秒 代用紫杉烷类治疗剂。

PROJECT SUMMARY/ABSTRACT Cancers are serious and highly prevalent diseases, with an estimated 14 million new cases and 8.2 million deaths worldwide in 2012. Among the wide variety of chemotherapeutic agents, taxane drugs like paclitaxel (Taxol®) have emerged as standards of care for the treatment of certain cancers. Unfortunately, the utility of these drugs is limited by their pronounced lipophilicity and the recent emergence of resistant cancers, creating an urgent need for novel taxane chemotherapeutics. This proposal describes a plan to synthesize the taxane molecule taxagifine, as well as structurally related natural and unnatural taxanes, in an effort to provide new compounds for biological study. Taxagifine exhibits promising microtubule-stabilizing and cytotoxic properties and demonstrates potential activity against resistant cancers, but differs structurally from paclitaxel at several positions, including an unusual C17–C12 oxo-bridge functionality which will likely impart increased aqueous solubility relative to paclitaxel. Further studies of taxagifine have been frustrated by a lack of material: isolation from nature is extremely inefficient, and the C17–C12 oxo-bridge poses a significant challenge to any semi-synthetic routes. This proposal describes the first total synthetic approach to taxagifine and related compounds, with the hypothesis that the expansion of Sarpong's C–C activation/arylation reaction of carvone-derived cyclobutanols will enable a concise, convergent, and scalable synthesis of taxagifine. The Specific Aims of the proposal are: 1) Expansion of the C–C activation/arylation methodology recently developed by Sarpong and co-workers to allow for the use of synthetically versatile vinyl electrophiles, 2) Apply the C–C activation/vinylation reaction developed in Aim I to the construction of the oxo-bridged A ring and subsequently the total synthesis of taxagifine, and 3) Use the concise route to taxagifine developed in Aim II to make other natural taxanes containing the C17–C12 oxo-bridge, as well as unnatural taxagifine derivatives for structure-activity- relationship (SAR) studies. Our syntheses of unnatural analogs will focus on exploiting the synthetic route to install functionalization at underexplored positions on the taxagifine framework. The synthesis of paclitaxel- taxagifine hybrids will also be investigated to probe the taxagifine binding conformation. The development of a C–C activation/vinylation reaction will allow for the construction of a diverse array of terpenoid scaffolds, with potential use in medicinal chemistry and natural products total synthesis. Use of this reaction to synthesize taxagifine as well as natural and unnatural analogs will enable SAR and mechanism of action studies, furthering our understanding of microtubule-interactions and helping to identify potential second generation taxane therapeutic agents.