Total Synthesis of Highly Oxygenated Icetexane Diterpenoids

描述（由申请人提供）：开发生物活性天然产物和药用重要化合物的全合成新策略和新方法对普通医学的研究很重要。通过构建复杂的分子，我们可以获得大量具有生物活性的天然产物，以供进一步测试。此外，我们获得了获得这些化合物类似物的能力，试图提高生物活性。本课题的研究重点是开发和利用一种新的七元环环异构化反应及其在一类重要的天然产物的全合成中的应用。具体而言，本项目侧重于A)使用比其他常用的环异构化金属催化剂更便宜且毒性更小的镓盐来激活独立中间体异构化中的炔形成七元环，以及B)该方法在具有生物活性的天然产物的全合成中的应用。这种方法可以应用于从鼠尾草属的各种成员中分离出来的冰己烷天然产物的全合成。这个家族的成员表现出有趣的生物活动。例如，从科马罗维龙头菌中分离出来的科马罗维醌显示出对传染性克氏锥虫（恰加斯病的病原体）的锥虫杀灭活性。komaroviquinone显示的另一个重要生物活性是抑制趋化因子受体CCR5，这在HIV感染中起着至关重要的作用。抑制CCR5可能导致抑制感染的通用方法。冰替酮、吻合苷和二氢吻合苷是这个家族中尚未被合成的三种化合物。它们与家族中其他成员的不同之处在于包含了一个额外的5元内酯环。这些化合物的生物活性尚未得到充分研究；然而，初步研究表明，冰替酮的C5外显体具有与科马罗醌相当的杀锥虫活性。对方法和全合成的研究有利于公共卫生，因为它允许分子的合成，从而可以更有效地治疗常见疾病，如南美锥虫病。这些研究也可以导致分子类似物的合成，可能会改善目前的疾病治疗方法。

DESCRIPTION (provided by applicant): The development of new strategies and methods for the total synthesis of biologically active natural products and medicinally important compounds are important for the study of general medicine. By building complex molecules, we gain access to significant quantities of natural products with biological activity for further testing. In addition, we gain the ability to access analogs of these compounds in an attempt to improve bioactivity. The focus of the research is the development and utilization of a new cycloisomerization reaction or the synthesis of seven-membered rings and its application to the total synthesis of a biologically important family of natural products. Specifically, this project focuses on A) the use of gallium salts, which are cheaper and less toxic than other commonly used cycloisomerization metal catalysts, to activate alkynes in the isomerization of indene intermediates to form seven-membered rings as well as, B) the utilization of this methodology in the total synthesis of natural products with biological activity. This methodology can be applied to the total synthesis of the icetexane natural products, isolated from various members belonging to the Salvia genus. The members of this family have been shown to exhibit interesting biological activities. For example, komaroviquinone, isolated from Dracocephalum komarovi, shows trypanocidal activity against the infectious form of Trypanosoma cruzi, the causative agent for Chagas' disease. Another important bioactivity displayed by komaroviquinone is inhibition of the chemokine receptor CCR5, which plays a vital role in HIV infection. Inhibition of CCR5 could lead to a general method for curbing infection. Icetexone, anastomosine, and dihydroanastomosine are three compounds in this family that have yet to be synthesized. They differ from other members in the family through the inclusion of an additional 5- membered lactone ring. The bioactivity of these compounds has not been fully studied; however, preliminary accounts suggest that the C5 epimer of icetexone displays trypanocidal activity comparable to that found in komaroviquinone. The study of methodology and total synthesis benefits public health by allowing for the synthesis of molecules that can lead to more effective treatments for common diseases, such as Chagas' disease. These studies can also lead to the synthesis of analogs of molecules that may improve on current treatments of disease.