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 在过去的四十年里，患有II型糖尿病的人数几乎翻了两番。而 存在许多治疗方法，需要用于小分子治疗开发的新的生物靶点。在这 在这方面，一个有希望的靶点是蛋白酪氨酸磷酸酶1B，它在肥胖/糖尿病患者中过表达， 这会削弱胰岛素对这些人的作用。抑制这种酶将是一个有吸引力的 然而，没有脱靶活性的选择性抑制是一个难题。最近， 分离并表征了一种具有先前未知碳骨架的新的二萜类化合物， 发现显示出显著的蛋白酪氨酸磷酸酶1B抑制。这种新的二萜类化合物，rhodomollanol A， 与众所周知的grayanane二萜类化合物具有许多结构特征，尽管右手部分 分子的结构发生了显著的重排，其形状发生了显著的变化。尽管这些结构 不同之处在于，还报道了grayanane二萜类化合物表现出蛋白酪氨酸磷酸酶1B 抑制活性与报道rhodomollanol A相当。rhodomollanol A的发现提供了 一种新的结构类型，用于寻找安全、选择性的蛋白酪氨酸磷酸酶1B 抑制剂，并且考虑到所报道的对结构上不同的grayanane二萜类化合物的抑制活性， 代表了一个独特的机会，以更好地了解所需的结构标准，抑制这种 重要目标。从25公斤的植物中只分离出6毫克纯的杜鹃花醇A 材料，使得获得研究所需的材料成为充分评估潜力的重大障碍 这个结构类。在此，我们提出了一个全合成的rhodomollanol A。一个线性序列的20- 提出了从2，2-二甲基环戊二烯-4-烯-1，3-二酮开始的一个步骤， 分子内Pauson-Khand反应和氧烯丙基阳离子[3+2]作为快速组装 rhodomollane骨架。拟议的路线允许对核心结构进行大量修改， 合成具有潜在更有效的蛋白酪氨酸的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 Eli Chapman教授的研究小组，他的实验室已经开发了几种类型的检测方法， 蛋白酪氨酸磷酸酶抑制，并已证明在这一领域的专业知识，通过他们最近的 出版物（Biochemistry，2019，58，3225）。