Chemical Synthesis of Bioactive Diterpenoids

项目摘要 多环萜类天然产物具有广泛的药用相关生物活性， 活动紫杉醇和青蒿素是拯救生命的萜类化合物的两个主要例子;前者用于临床 用于治疗几种不同的癌症，而后者是全世界使用的关键抗疟剂。化学 天然产物的合成方法提供了制造化合物的机会， 可从自然界中获得，以产生仅可通过全合成获得的类似物，并制备探针。 分子来增加对潜在生物学的理解。创新战略与新的 化学方法保证了有效的合成，可以用来回答重要的生物学问题 通常只能用小分子来探测。 作为我们实验室的长期目标的一部分，以提高效率，在合成复杂的自然 产品，以促进生物学的重要研究，拟议的研究计划的目标是开发 简明和创造性的综合设计，并赋予方法上的进步， 生物活性二萜类天然产物。这项工作的基本原理是，合成化学是至关重要的， 通过类似物将天然产物“命中分子”开发成合法的临床前先导化合物 生产，通过鉴定结构-活性关系，通过合成化学探针分子 行动机制研究等等。目标天然产物的有效全合成提供了一种 平台，以解决这些关键领域的研究。 拟议的研究是重要的，因为化学合成将提供一个广泛的 生物学上重要的次级代谢产物和类似物，用于询问关键过程; 与此同时，潜在的合成设计和方法学将导致该领域的垂直发展， 有机化学这些贡献是创新的凭借化学驱动的，多方面的 研究了二萜类化合物的免疫抑制、抗病毒、抗生素和 神经活性;开发新的立体控制多烯环化策略，以获得 多环二萜类天然产物;和制定新的自由基双环化策略， 与生物活性天然产物相关的复杂结构。

Project Summary Polycyclic terpenoid natural products are endowed with a broad range of medicinally relevant biological activities. Taxol and artemisinin are two premier examples of life-saving terpenoids; the former is used clinically to treat several different cancers, while the latter is a critical antimalarial agent used worldwide. Chemical synthesis approaches to natural products provide opportunities to make compounds that might be scarcely available from nature, to generate analogues that are only available by total synthesis, and to make probe molecules for increased understanding of the underlying biology. A balance of innovative strategy and new chemical methodology promises efficient syntheses that can serve to answer important biological questions that often can only be probed with small molecules. As part of our laboratory’s long-term goal to enhance efficiency in the synthesis of complex natural products to facilitate important studies in biology, the objective of the proposed research program is to develop concise and creative synthesis designs and empowering methodological advances to permit access to many bioactive diterpenoid natural products. The rationale for this work is that synthetic chemistry is critical to the development of natural product “hit molecules” into legitimate preclinical lead compounds by analogue production, by identification of structure-activity relationships, by the synthesis of chemical probe molecules for mechanism of action studies, and more. An efficient total synthesis of targeted natural products provides a platform from which to address each of these key areas of research. The proposed research is significant because chemical synthesis will provide access to a broad range of biologically important secondary metabolites and analogues with which to interrogate key processes; at the same time, the underlying synthesis designs and methodologies will lead to vertical advancement of the field of organic chemistry. These contributions are innovative by virtue of the chemistry-driven, multi-faceted investigations into the biological activity of diterpenoids with immunosuppressive, antiviral, antibiotic, and neurological activity; the development of new stereocontrolled polyene cyclization strategies to access polycyclic diterpenoid natural products; and the elaboration of new radical bicyclization strategies to make complex architectures relevant to bioactive natural products.