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，但只有少数几种治疗方法被 针对兰尼定受体的心脏病的预防和治疗 (RyR)。以确定这种疗法是否可以从异氰烷开发出来 框架下，我们建议完成天然异氰酸酯的全合成。 和18-羟基香豆醇。接近异氰烷将使我们能够评估 这些二萜类化合物要结合到RyR上，特别是通过制备非天然的 含有临界吡咯-2-羧酸酯的异氰酸酯。 两种高度收敛的策略，旨在有效地建立多环 对这些天然产物的结构进行了详细的描述。在第一种策略中，a Heck环化/Stille 提出了交叉耦合级联的概念。由此产生的烯丙基作为柄来锻造7- 具有高度化学选择性的两步序列中的成员D-环内酯 好氧氧化。在第二种策略中，后期SmI2介导酮自由基环化是 设想同时打造C8-C9键和一个关键的全碳四元中心。这个 制定一种有效和全面的方法将能够全面评估 这些小分子用于制备RyR异构体选择性分子探针。结果 这种系统化的方法将是能够合理地为 心脏病的治疗。在这样做的时候，我们相信新奇的和潜在的更有效 心脏治疗将被开发出来。

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.