A Concise, Enantioselective Approach to the Synthesis of (-)-Rhodomollanol-A

(-)-红多酚-A 的简洁、对映选择性合成方法

• 批准号: 10436840
• 负责人: Simon Joynson Cooper
• 金额: $ 6.72万
• 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: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436840
• 关键词: 3-hydroxybutanal; Acute Pain; Aldehydes; Alder plant; Alkaloids; Alkenes; Ammonia; Antibiotics; Benzofurans; Benzoquinones; Betula Genus; Biological; Carboxylic Acids; Chemistry; Coal; Coal Tar; Communities; Diamines; Diels Alder reaction; Disease; Electrons; Ethers; Event; Exhibits; Fluorides; Future; Iodine; Life; Masks; Medicine; Methanol; Methodology; Morphine; Naloxone; Naltrexone; Natural Products; Nitrogen; Opioid Antagonist; Overdose; Patients; Process; Public Health; Reaction; Reagent; Reporting; Research; Role; Savings; Side; Solvents; Source; Structure; Substance abuse problem; System; The Sun; Yang; anti-cancer; carbon skeleton; carboxylation; chronic pain; combat; dibenzofuran; diene; functional group; problem drinker; protonation; success; tetrabutylammonium

PROJECT SUMMARY The number of people suffering with type II diabetes has nearly quadrupled in the past four decades. While many treatments exist, new biological targets for small molecule therapeutic development are needed. In this regard, a promising target is protein tyrosine phosphatase 1B, which is overexpressed in obese/diabetic individuals, weakening the effects of insulin for these people. Inhibition of this enzyme would be an attractive option for a diabetes drug, however selective inhibition without off-target activity is a difficult problem. Recently, a new diterpenoid possessing a previously unknown carbon skeleton was isolated and characterized, and was found to exhibit notable protein tyrosine phosphatase 1B inhibition. This new diterpenoid, rhodomollanol A, shares many structural features with the well-known grayanane diterpenoid class, though the right hand portion of the molecule is significantly rearranged, changing its shape substantially. Despite these structural differences, grayanane diterpenoids have also been reported to exhibit protein tyrosine phosphatase 1B inhibitory activity on par with that reported for rhodomollanol A. The discovery of rhodomollanol A provides a new structural class upon which to base the search for a safe, selective protein tyrosine phosphatase 1B inhibitor, and given the reported inhibitory activity for the structurally distinct grayanane diterpenoids, represents a unique opportunity to better understand the structural criteria required for inhibition of this important target. Only six milligrams of pure rhodomollanol A was isolated from twenty-five kilograms of plant material, making obtaining the requisite material for studies a significant barrier to fully evaluating the potential of this structural class. Herein, we propose a total synthesis of rhodomollanol A. A linear sequence of twenty- one steps is proposed starting from 2,2-dimethylcyclopent-4-ene-1,3-dione, featuring a proposed intramolecular Pauson-Khand reaction and an oxyallyl cation [3+2] as the key steps to rapidly assemble the rhodomollane skeleton. The proposed route allows for ample modification to the core structure, providing opportunities to synthesize derivatives of rhodomollanol-A with potentially more potent protein tyrosine phosphatase 1B inhibition. The inhibitory activity of these derivatives will be studied in collaboration with the research group of Professor Eli Chapman, whose lab has developed several types of assays to examine protein tyrosine phosphatase inhibition, and has demonstrated expertise in this area through their recent publication (Biochemistry, 2019, 58, 3225).

项目摘要 在过去的四十年中，患有II型糖尿病的人数几乎三倍。尽管 存在许多治疗方法，需要用于小分子治疗性发育的新生物学靶标。在这个 注意，一个有希望的靶标是蛋白质酪氨酸磷酸酶1B，在肥胖/糖尿病中过表达 个人，削弱胰岛素对这些人的影响。抑制这种酶将是一种有吸引力的 糖尿病药物的选择，但是没有脱靶活动的选择性抑制是一个困难的问题。最近， 隔离并表征了一种具有先前未知的碳骨架的新的二萜类化合物，并且是 发现表现出显着的蛋白酪氨酸磷酸酶1B抑制。这个新的二萜，若多光子醇A， 尽管右手部分 分子的重新排列显着重新排列，大大改变了其形状。尽管有这些结构性 差异，灰烷二萜类化合物也据报道表现出蛋白酪氨酸磷酸酶1B 与Rhodomollanol的报道A的抑制活性A. Rhodomollanol A的发现提供了A 新的结构类别，以搜索安全，选择性蛋白酪氨酸磷酸酶1B 抑制剂，并给出了据报道的抑制活性，用于结构上不同的灰色二萜， 代表了一个独特的机会，可以更好地理解抑制所需的结构标准 重要目标。从二十五公斤的植物中分离出六毫克的纯若多莫洛醇A 材料，使得获得必要的研究材料成为充分评估潜力的重大障碍 这个结构类别。本文中，我们提出了Rhodomollanol A的总合成。 从2,2-二甲基环甲基-4-ene-1,3-二酮开始提出一个步骤，以提议 分子内Pauson-Khand反应和氧阳离子[3+2]，作为快速组装的关键步骤 Rhodomollane骨骼。提议的路线允许对核心结构进行充分的修改，提供 与可能更有效的蛋白酪氨酸合成Rhodomollanol-A衍生物的机会 磷酸酶1B抑制。这些衍生物的抑制活性将与 埃利·查普曼（Eli Chapman）教授的研究小组，其实验室已经开发了几种类型的测定 蛋白质酪氨酸磷酸酶抑制作用，并通过其最近的 出版（生物化学，2019，58，3225）。