Synthetic Studies toward the Total Synthesis of the Isoryanodane Diterpenes

项目摘要 尽管RyR在心脏功能中普遍存在，但只有少数治疗方法已经被证实。 开发用于预防和治疗针对兰尼碱受体的心脏病 （RyR）.为了确定这种疗法是否可以从异柳烷中发展出来， 框架内，我们建议完成天然异柳烷perseanol的全合成 和18-羟基perseanol。获得异柳烷将使我们能够评估 这些二萜与RyR结合，特别是通过制备非天然的 带有关键的吡咯-2-羧酸酯的异氰烷。 两个高度收敛的战略，旨在有效地建立多环 详细介绍了这些天然产物的结构。在第一种策略中，Heck环化/Stille 提出了交叉耦合级联。由此产生的烯丙基作为一个手柄，以伪造7- 在涉及高度化学选择性的斯塔尔的两步序列中， 好氧氧化在第二种策略中，晚期SmI 2介导的酮基自由基环化是 设想，锻造，一次，C8-C9键和一个关键的全碳季中心。的 制定一个有效和普遍的方法将有助于全面评价 这些小分子用于制备RyR异构体选择性分子探针。结果 这种系统方法的一个重要特点是能够合理地设计小分子， 心脏病的治疗。在这样做的时候，我们相信新颖和潜在的更有效的 将进行心脏治疗。

Project Summary Despite the prevalence of the RyR in cardiac function, only a few therapies have been developed for the prevention and treatment of cardiac disease that target the ryanodine receptor (RyR). To determine whether or not such therapies might be developed from the isoryanodane framework, we propose to complete a total synthesis of the natural isoryanodanes perseanol and 18-hydroxyperseanol. Access to the isoryanodanes will position us to assess the ability of these diterpenes to bind to the RyR, specifically, through the preparation of unnatural isoryanodanes bearing the critical pyrrole-2-carboxylate ester. Two highly convergent strategies aimed at efficiently establishing the polycyclic framework of these natural products are detailed. In the first strategy, a Heck cyclization/Stille cross-coupling cascade is proposed. The resulting allyl group serves as a handle to forge the 7- membered D-ring lactone in a two-step sequence involving a highly chemoselective Stahl aerobic oxidation. In the second strategy, a late-stage SmI2-mediated ketyl radical cyclization is envisioned to forge, at once, the C8–C9 bond and a critical all-carbon quaternary center. The development of an efficient and general approach will allow a comprehensive evaluation of these small molecules for the preparation of RyR isoform-selective molecular probes. The result of such a systematic approach will be the ability to rationally design small molecules for the treatment of cardiac disease. In doing so, we believe novel and potentially more effective cardiac treatments will be produced.