Synthesis of Complex Terpenes From Simple Precursors

描述(申请人提供)：从紫杉醇(TM)到青蒿素，复杂的萜类化合物对人类疾病的治疗和理解都产生了深远的影响。然而，尽管它们具有巨大的药用价值，但大多数复杂的萜类结构并不是详尽的药物和化学生物学研究的最佳起点，而且与许多小分子药物发现计划不同，很难轻松地混合和匹配结构片段。拟议的研究计划寻求发现和开发简单、模块化的合成途径，以获得复杂的、具有医学意义的萜类天然产物。这一提议的核心是希望通过使用简单的戊烯基衍生单元和手性池材料，结合受控的、非仿生的环化事件和多加氧策略，大大简化萜烯的合成。为该计划选择的目标既代表了复杂分子合成的最先进挑战，也代表了潜在的下一代疗法。具有5/8/n-稠环体系(n=5，6)的复杂萜类化合物具有诱人而有效的抗癌、抗菌和免疫抑制性能，但缺乏有效的合成方法来构建这类体系，极大地阻碍了对其结构/功能的深入研究。特别是二十四烯类的蛇床子素家族，几十年来一直抵制有效的化学合成，需要新的策略来有效地构建这一多样化和不断增长的天然产品类别。这项工作无疑将导致与其抗癌特性相关的结构和功能方面的增强的SAR图像。培立康星代表了一类新兴的(且大部分未被开发的)抗菌剂，对革兰氏阳性和阴性菌株都有活性。尽管做出了努力，但复杂的免疫抑制剂Varieclin尚未合成，这意味着目前的技术存在缺口。高含氧愈创木内酯萜类化合物代表了有机合成和潜在的下一代疗法的最新挑战。最后，萜类过氧化物类代表了治疗疟疾的有效疗法，并成为治疗各种疾病的一类有前途的促细胞凋亡剂。我们开发了一种非常简单的方法，使用高效的金属催化串联反应来构建过氧化萜支架。总体而言，该计划寻求利用合成化学的进步，结合天然产品结构的灵感，以前所未有的效率和多样性构建具有生物活性的小分子。在这项工作的过程中，将为学生提供严格的、激发智力的合成化学培训。

DESCRIPTION (provided by applicant): From Taxol(tm) 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. Periconicin 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.