Cyclization Cascades to Access Bioactive Diterpenoids

项目摘要 多环萜类天然产物具有广泛的药用价值。 活动。紫杉醇和青蒿素是两个主要的救命萜类化合物；前者用于临床 用于治疗几种癌症，而后者是全世界使用的一种关键的抗疟疾药物。化学合成 获得天然产品的方法提供了制造可能很难获得的化合物的机会 从自然界中产生只有通过全合成才能获得的类似物，并制造用于 增加了对潜在生物学的理解。创新战略和新化学品的平衡 方法论承诺有效地合成小分子，可以为重要的生物学问题提供答案 不容易用其他方法解决的问题。 作为我们实验室提高复杂天然产物合成效率的长期目标的一部分 为了方便重要的生物学研究，拟议研究的目标是开发简明的 以及创造性的合成设计和授权的方法进步，以允许获得许多生物活性 二萜类天然产物。这项工作的基本原理是，合成化学是发展的关键 通过模拟生产，将天然产物“分子”转化为合法的临床前先导化合物，由 通过合成化学探针分子鉴定其作用机理的构效关系 行动研究，等等。目标天然产物的高效全合成提供了一个平台 来解决这些关键研究领域中的每一个。我们的具体目标包括(1)合成 Lissosteide家族的细胞毒性翻译抑制物，有助于完善我们对分子基础的理解 利用生物和生化分析以及结构生物学工具抑制蛋白质合成； (2)应用为LissoClimate开发的方法学，以开发一系列有效的合成 其他复杂的多环二萜类化合物；以及(3)开发新的自由基自行车化策略 两种结构复杂的抗感染天然产物的合成。 这项拟议的研究意义重大，因为化学合成将提供广泛的 生物上重要的次生代谢物和类似物，用来询问关键过程； 同时，基本的综合设计和方法学将导致垂直领域的进步 有机化学。这些贡献是创新的，得益于化学驱动的、多方面的 链球菌核糖体抑制机制的研究、新核糖体的开发 立体控制的多烯环化策略，以获得特别具有挑战性的二萜类天然产物， 以及新的激进自行车战略的阐述，使复杂的多循环建筑与 生物活性天然产物。

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 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 of small molecules that can provide answers to important biological questions that are not easily solved by other means. 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 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. Our specific aims include (1) the synthesis of the lissoclimide family of cytotoxic translation inhibitors, to aid in refining our understanding of the molecular basis of protein synthesis inhibition using biological and biochemical assays, as well as the tools of structural biology; (2) the application of methodology developed for the lissoclimides to develop efficient syntheses of a range of other complex, polycyclic diterpenoids; and (3) the development of new radical bicyclization strategies for the synthesis of two architecturally complex anti-infective natural products. 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 mechanism of ribosome inhibition by the lissoclimides, the development of new stereocontrolled polyene cyclization strategies to access particularly challenging diterpenoid natural products, and the elaboration of new radical bicyclization strategies to make complex polycyclic architectures relevant to bioactive natural products.