A Convergent Approach to the Synthesis of Auriculatol A

项目总结 灰烷二萜类化合物是一类结构复杂的天然产物，具有 具有生物活性，但在实验室合成从头开始具有挑战性。的独特结构特征 从自然中分离出来的灰烷最终激发了药理实验室的大量研究。 导致各种生物活动被发现。在最近一个值得注意的例子中，几个灰烷是 被确认为有效的碳酸酐酶抑制剂(CAI)。几种FDA批准的针对各种人类的药物 疾病是CAI，其中一些被列入世界卫生组织的基本要素清单 药物。此外，灰色天然产物还显示出抗艾滋病毒、抗微生物和 免疫调节活性。这些生物学结果表明，有机会开发以灰烷为基础的 跨越不同疾病领域的治疗剂。然而，为了完成这些研究， 收敛的全合成路线，使有机化学家能够快速合成结构衍生物 这是必要的。 也许反映了它们的立体化学复杂性和三环融合的[5-7-6]碳环骨架， 完全全合成丙烷靶标的报道很少。此外，大部分已完成的 合成侧重于一次构建一个环，阻止合成同系物的快速合成 进一步探讨其生物活性和作用机制。我们设想了一条通向 通过将两个快速准备的周环通过连接来组装中心七元环 两个顺序的偶联反应。在这个建议中，我们将这一策略应用于最近一次的全合成 在第一个关键步骤中，我们提出了一种化学选择性的α芳基化反应。 五元环单元上的硅烯酸酯与1-溴-2-三氟基芳烃的三氟化基之间的反应。 然后，剩余的芳基溴与环氧化物之间的第二次分子内偶联反应建立 提出了中心环庚烷环的概念。总而言之，这项建议旨在建立一条权宜之路，以 合成具有挑战性的木耳醇A核心，并为合成结构化合物提供模板 衍生品。这一策略的成功开发将促进对生物的进一步研究 灰烷的作用机制，以及潜在地发现新的、多样化的生物活性。

PROJECT SUMMARY The grayanane diterpenoids are a class of structurally complex natural products that have compelling biological activity but are challenging to synthesize de novo in the laboratory. The unique structural features of the grayananes isolated from nature have inspired numerous studies in pharmacological laboratories, ultimately leading to diverse bioactivity being uncovered. In one recent notable example, several grayananes were identified as potent carbonic anhydrase inhibitors (CAIs). Several FDA-approved drugs that target various human diseases are CAIs, with some being included as entries in the World Health Organization's List of Essential Medicines. Additionally, grayanane natural products have also shown anti-HIV, anti-microbial, and immunomodulatory activity. These biological results point toward opportunities to develop grayanane-based therapeutic agents that span diverse disease areas. However, to accomplish these studies, the development of convergent total synthesis routes that allow organic chemists to rapidly synthesize structural derivatives is necessary. Perhaps reflective of their stereochemical complexity and tricyclic fused [5-7-6] carbocyclic skeleton, reports of completed total syntheses of grayanane targets are rare. Moreover, the majority of completed syntheses focus on building each ring one at a time, preventing the rapid synthesis of synthetic congeners to probe further into biological activity and mechanisms of action. We envisioned a general convergent route toward the assembly of the central seven-membered ring by uniting the two rapidly-prepared perimeter rings through two sequential coupling reactions. In this proposal, we apply this strategy to the first total synthesis of a recently isolated grayanane natural product, Auriculatol A. In the first key step, we propose a chemoselective α-arylation reaction between a silyl enolate on the five-membered ring unit and the triflate group of a 1-bromo-2-triflyl arene. Then, a second intramolecular coupling reaction between the remaining aryl bromide and an epoxide to establish the central cycloheptane ring is proposed. In total, this proposal aims to establish an expedient route to synthesize the challenging core of Auriculatol A, as well as provide a template for synthesizing structural derivatives. The successful development of this strategy would facilitate further studies into the biological mechanism of action of the grayananes, as well as potentially uncover new, diverse bioactivity.