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

项目总结 在过去的40年里，患有II型糖尿病的人数几乎翻了两番。而当 存在多种治疗方法，需要新的生物靶点用于小分子治疗的开发。在这 考虑到，一个有希望的靶点是蛋白酪氨酸磷酸酶1B，它在肥胖/糖尿病患者中过度表达 个体，削弱了胰岛素对这些人的影响。抑制这种酶将是一个有吸引力的 作为糖尿病药物的选择，然而，没有靶向活性的选择性抑制是一个困难的问题。最近， 分离和鉴定了一个新的具有未知碳骨架的二萜类化合物，并对其结构进行了表征。 发现具有显著的蛋白酪氨酸磷酸酶1B抑制作用。这种新的二萜类化合物--月见草醇A， 与广为人知的灰烷二萜类化合物有许多相同的结构特征，尽管右侧部分 分子的结构发生了显著的重排，实质上改变了它的形状。尽管有这些结构性的 不同的是，灰烷二萜类化合物也被报道展示了蛋白酪氨酸磷酸酶1B 抑制活性与已报道的月见草醇A相当。月见草醇A的发现提供了 寻找安全、选择性蛋白酪氨酸磷酸酶1B的新结构类 抑制剂，并给出了所报道的结构不同的灰烷二萜类化合物的抑制活性， 是一个独特的机会，可以更好地理解抑制这一现象所需的结构标准 重要目标。从25公斤的植物中只分离出6毫克的纯品杜鹃花醇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 这一结构类的。在此，我们提出了一种全合成月见草醇A的方法，其线性序列为20- 提出了以2，2-二甲基环戊烯-4-烯-1，3-二酮为起始原料的一步反应。 分子内Pauson-Khandd反应和氧烯丙基阳离子[3，2]作为快速组装的关键步骤 罗多莫兰的骨架。提议的路线允许对核心结构进行充分修改，提供 合成可能具有更强蛋白质酪氨酸活性的月见草醇-A衍生物的机会 磷酸酶1B抑制作用。这些衍生物的抑制活性将与 伊莱·查普曼教授的研究小组，他的实验室开发了几种类型的分析方法来检查 蛋白酪氨酸磷酸酶抑制，并通过他们最近的研究展示了这一领域的专业知识 发表(《生物化学》，2019，58,3225)。

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).