Total Synthesis of Bioactive Natural Products

描述（由申请人提供）：该计划的目标是定义合成含有七元环的生物活性天然产物的新策略和方法。我们制造的分子将为研究许多生物过程提供工具，并可能最终用于开发新的治疗方法，特别是癌症。具体而言，我们打算开发一个通用的策略，重排甾体化合物皮质抑素A和生物碱的石松家族的合成。皮质抑素是一种有效的血管生成抑制剂，可用于对抗肿瘤细胞转移。我们提出了一个策略，合成这些天然产物使用环庚三烯前体。这些环庚二烯又由新的金属介导的方法产生。我们期望这些新的七元环形成方法的发展将简化复杂分子的合成。皮质抑素和石松生物碱的全合成将推动新的发展，这反过来又将应用于其他生物和结构感兴趣的分子的合成。这些贡献将有助于利用小分子的人类医学和化学生物学的进步。 公共卫生相关性：寻找新的和更有效的方法来构建小的有机分子是一个重要的追求，这将为化学生物学和医学提供新的工具，并导致人类健康的改善。我们的目标是开发新的策略和方法，有效地构建小分子，包括具有药物重要性的天然产物。在这方面，我们对使用过渡金属的新的七元环形成反应特别感兴趣.

DESCRIPTION (provided by applicant): The goal of this program is to define new strategies and methods for the synthesis of bioactive natural products that contain a seven-membered ring. The molecules we make will provide tools to study many biological processes and may ultimately be used to develop new therapeutics, especially for cancer. Specifically, we intend to develop a general strategy for the synthesis of the rearranged steroidal compounds cortistatin A and alkaloids in the Lycopodium family. The cortistatins are potent angiogenesis inhibitors and should find use in combating tumor cell metastasis. We present a strategy to synthesize these natural products using cycloheptadiene precursors. These cycloheptadienes are in turn generated from novel metal-mediated methods. It is our expectation that these new methodological developments for seven-membered ring formation will streamline the synthesis of complex molecules. The total synthesis of the cortistatins and Lycopodium alkaloids will drive new developments, which will in turn, be applied to the synthesis of other molecules of biological and structural interest. These contributions will aid advances in human medicine and chemical biology using small molecules. PUBLIC HEALTH RELEVANCE: Finding new and more efficient ways to construct small organic molecules is an important pursuit that will provide new tools for chemical biology as well as medicine and lead to improvements in human health. Our goals are to develop new strategies and methods that efficiently build small molecules including natural products that are of pharmaceutical importance. In this regard, we are especially interested in new seven- membered ring forming reactions using transition metals.