Synthesis of Complex Terpenes From Simple Precursors

项目摘要 从Taxol™到青蒿素，复杂的萜烯对治疗和治疗产生了深远的影响。 了解人类疾病。尽管它们具有巨大的药用价值，然而， 萜烯结构不是详尽的医学和化学生物学研究的最佳起点， 与许多小分子药物发现计划不同，很难简单地混合和匹配结构 片段拟议的研究计划旨在发现和开发简单的，模块化的合成 途径获得复杂的，药用相关的萜类天然产物。该提案的核心是 希望通过使用简单的异戊二烯基衍生的单元和手性池材料大大简化萜烯合成， 与受控的非仿生环化事件和多加氧策略一致。选择的目标 对于这个计划代表了复杂分子合成的最新挑战以及潜在的 新一代的治疗方法具有5/8/n-稠环系统（n = 5，6）的复杂萜烯具有吸引人的 和有效的抗癌，抗菌和免疫抑制特性，但缺乏有效的合成 构建这种系统的方法极大地阻碍了深入的结构/功能研究。蛇孢菌素 特别是二倍半萜家族几十年来一直抵抗有效的化学合成， 需要策略来有效地构建这种多样化和不断增长的天然产品类别。这项工作将 毫无疑问地导致关于与它们抗癌相关的结构和功能的增强的SAR图像 特性. Periconicins代表了一类新兴的（并且在很大程度上未开发的）抗菌剂， 抗革兰氏阳性和阴性菌株的活性。尽管努力，复杂的免疫抑制剂 Variecolin尚未被合成，这表明当前技术中存在差距。高氧愈创木酚 萜烯代表了有机合成和潜在的下一代治疗剂的现有技术的挑战。 最后，萜类过氧化物代表用于治疗疟疾的已被证实的疗法，并且正在作为治疗疟疾的药物出现。 有希望的一类用于治疗各种疾病的促凋亡剂。我们已经开发出一种 一种非常简单的方法来构建萜烯过氧化物支架， 反应.总的来说，该计划旨在利用合成化学的进步， 天然产物结构以前所未有的效率构建生物活性小分子， 多样性在这项工作的过程中，学生将提供严谨和智力刺激 合成化学的培训。

PROJECT SUMMARY From Taxol™ to artemisinin, complex terpenes have had a profound impact on both the treatment and understanding of human disease. Despite their enormous medicinal relevance, however, most complex terpene architectures are not optimal starting points for exhaustive medicinal and chemical biological studies, and unlike many small molecule drug discovery programs, it is difficult to easily mix- and-match structural fragments. The proposed research program seeks to discover and develop simple, modular synthetic pathways to access complex, medicinally relevant terpenoid natural products. At the core of this proposal is the desire to greatly simplify terpene synthesis by using simple prenyl-derived units and chiral pool materials in concert with controlled, non-biomimetic cyclization events and polyoxygenation strategies. The targets chosen for this program represent both state of the art challenges for complex molecule synthesis as well as potential next-generation therapeutics. Complex terpenes featuring 5/8/n-fused ring systems (n = 5,6) have attractive and potent anticancer, antibacterial, and immunesuppressant properties, yet the lack of efficient synthetic methods to construct such systems has greatly hampered in-depth structure/function studies. The ophiobolin family of sesterterpenes in particular has resisted efficient chemical synthesis for several decades and new strategies are needed to efficiently construct this diverse and growing class of natural products. This work will undoubtedly lead to an enhanced SAR picture with respect to structure and function relating to their anticancer properties. Periconicins represent an emerging (and largely unexplored) class of antibacterial agents with activity against both gram positive and negative strains. Despite effort, the complex immunosuppressant variecolin has not been synthesized signifying a gap in current technologies. Highly oxygenated guaianolide terpenes represent state of the art challenges for organic synthesis and potential next generation therapeutics. Finally, terpenoid peroxides represent proven therapeutics for the treatment of malaria and are emerging as a promising class of pro-apoptotic agents for the treatment of various diseases. We have developed a remarkably simple way to construct terpene peroxide scaffolds using efficient, metal-catalyzed tandem reactions. Overall this program seeks to use advances in synthetic chemistry coupled with the inspiration of natural product architectures to construct biologically active small molecules with unprecedented efficiency and diversity. In the process of this work, students will be provided with rigorous and intellectually stimulating training in synthetic chemistry.