A Convergent Approach to the Synthesis of Auriculatol A

合成黑木醇A的收敛方法

• 批准号: 10334477
• 负责人: Conner Micheal Farley
• 金额: $ 2.75万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-05-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334477
• 关键词: Acetals; Anti-Inflammatory Agents; Area; Biological; Biological Models; Bromides; Cancerous; Carbonic Anhydrase Inhibitors; Catalysis; Complex; Coupling; Cycloheptanes; Development; Disease; Diterpenes; Drug Targeting; Enzymes; Epoxy Compounds; FDA approved; Family; Family member; Goals; HIV; Investigation; Laboratories; Learning; Mediating; Medicine; Natural Products; Nature; Periodicity; Pharmacology; Process; Reaction; Reporting; Research Personnel; Route; Skeleton; System; Therapeutic Agents; Time; Ursidae Family; Work; World Health Organization; analog; antimicrobial; base; diketone; enolate; human disease; hydroxyl group; immunoregulation; interest; overexpression; prevent; process optimization; tumor

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.

项目概要 灰烷二萜是一类结构复杂的天然产物，具有令人信服的功效 生物活性，但在实验室中从头合成具有挑战性。独特的结构特点 从自然界中分离出来的灰烷激发了药理学实验室的大量研究，最终 导致发现多种生物活性。在最近的一个值得注意的例子中，几种grayananes被 被鉴定为有效的碳酸酐酶抑制剂（CAI）。 FDA 批准的几种针对不同人类的药物 疾病属于 CAI，其中一些已被列入世界卫生组织的基本疾病清单 药物。此外，grayanane 天然产物还显示出抗 HIV、抗微生物和 免疫调节活性。这些生物学结果指出了开发基于grayanane的机会 跨越不同疾病领域的治疗剂。然而，为了完成这些研究，需要开发 使有机化学家能够快速合成结构衍生物的收敛全合成路线是 必要的。 也许反映了它们的立体化学复杂性和三环稠合[5-7-6]碳环骨架， 完成grayanane目标全合成的报道很少。此外，大部分已完成 合成的重点是一次构建每个环，防止合成同系物的快速合成 进一步探讨生物活性和作用机制。我们设想了一条总体趋同路线 通过将两个快速制备的周边环结合在一起来组装中央七元环 两个连续的偶联反应。在本提案中，我们将此策略应用于最近的首次全合成 分离出的grayanane天然产物Auriculatol A。在第一个关键步骤中，我们提出了化学选择性α-芳基化 五元环单元上的硅基烯醇化物与1-溴-2-三氟甲磺酸基芳烃的三氟甲磺酸基团之间的反应。 然后，剩余的芳基溴和环氧化物之间进行第二次分子内偶联反应，建立 提出了中心环庚烷环。总的来说，该提案旨在建立一条便捷途径 合成了Auriculatol A具有挑战性的核心，并为合成结构提供了模板 衍生物。该策略的成功开发将有助于进一步研究生物学 格雷烷的作用机制，以及潜在地揭示新的、多样化的生物活性。