Total Synthesis of Bioactive Natural Products

描述(申请人提供)：该项目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，并最终可能被用于开发新的疗法，特别是对癌症的治疗。具体地说，我们打算开发一种合成重排的甾体化合物皮质素A和石蒜属生物碱的一般策略。皮质酮是有效的血管生成抑制剂，应该可以用来对抗肿瘤细胞的转移。我们提出了一种利用环庚二烯前体来合成这些天然产物的策略。这些环庚二烯是通过新的金属介导法生成的。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。皮质酮和石松生物碱的全合成将推动新的发展，进而将应用于其他具有生物和结构兴趣的分子的合成。这些贡献将有助于使用小分子的人类医学和化学生物学的进步。 与公共卫生相关：寻找新的和更有效的方法来构建有机小分子是一项重要的追求，将为化学生物学和医学提供新的工具，并导致改善人类健康。我们的目标是开发新的战略和方法，有效地制造小分子，包括具有制药重要性的天然产品。在这方面，我们特别感兴趣的是使用过渡金属的新的七元环形成反应。

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.