Stereoselective Synthesis via Metallacycle-Mediated Bond Construction

： 使复杂偶联伙伴之间的片段结合成为可能的化学过程定义了 反应异常强烈。虽然它们可以帮助定义通往复杂环境的有效途径 除了分子，它们对组合化学和药物化学也是至关重要的。尽管 这种偶联反应在化学合成中的重要性，令人惊讶的是，只有少数人健壮 在高度官能化的偶联伙伴之间形成双分子C-C键的途径是可用的。 这项提案中概述的研究计划的重点是建立一种新的立体选择方法 新型金属环介导型双分子碳链化合物的发现与应用 天然产物合成中的C键形成反应。 我们为GM080266提供的第一阶段资金主要集中在方法开发上，以及许多 在过去的五年里，人们已经发现/报道了这些反应。我们现在有能力开发这些 在以目标为导向的合成背景下的独特的反应模式。这是 我们的目标是取得科学进展，因为反应方法需要在复杂的环境中进行审查，以探索其 在影响医学相关追求方面的真正潜力。因此，我们将继续应用我们的 合成一系列结构多样的稀有天然产物(生物碱、脂肪酸)的技术 和聚酮)，已知具有显著的和医学上相关的生物活性。 总体而言，提出的方案将导致：(1)确认金属环介导的交叉反应的效用。 复杂分子合成中的偶联技术，(2)一系列新型逆合成化合物的阐明 目标导向合成中的策略，以及(3)一系列天然化合物的第一次或最简明的合成 产品包括生物碱205B、瑞波他丁A、冬凌草素和肯德霉素。因此，我们建议 研究的目的将是推动GM080266支持的新的化学反应模式从 一类功能强大的立体选择性片段偶联反应方法学的建立 在面向目标的合成中具有深远的实用价值。因此，该计划的成功开发将提供 立体选择性合成对药物相关研究有很大影响的研究进展 通过在化学、生物和医学的界面上实现未来的科学发现，实现小分子。 二、

: Chemical processes that enable fragment union between complex coupling partners define a subset of reactions that are exceptionally powerful. While they can help to define efficient pathways to complex molecules, they are also of central importance to combinatorial and medicinal chemistry. Despite the importance of such coupling reactions in chemical synthesis, it is surprising that only a handful of robust pathways are available for bimolecular C-C bond formation between highly functionalized coupling partners. The research program outlined in this proposal is focused on establishing a new approach to stereoselective chemical synthesis that derives from discovery and application of novel metallacycle-mediated bimolecular C- C bond forming reactions in natural product synthesis. Our first phase of funding for GM080266 was focused on methods development, and a great many reactions have been discovered/reported over the last five years. We are now in a position to develop these unique modes of reactivity in the context of target-oriented synthesis. This is a critical component of the scientific advance we aim to make, as reaction methods need to be vetted in complex settings to explore their true potential in impacting medicinally relevant pursuits. As such, we will pursue the application of our technology to the syntheses of a range of structurally diverse and rare natural products (alkaloids, fatty acids and polyketides) that are known to possess significant and medicinally relevant biological activities. Overall, the program proposed will result in: (1) confirming the utility of metallacycle-mediated cross- coupling technology in complex molecule synthesis, (2) the elucidation of a range of novel retrosynthetic strategies in target-oriented synthesis, and (3) the first, or the most concise, syntheses of a range of natural products including, the alkaloid 205B, ripostatin A, borrelidin and kendomycin. Therefore, our proposed studies will aim to advance the emerging modes of chemical reactivity supported by GM080266 from a foundation of reaction methodology to a powerful class of stereoselective fragment coupling reactions of profound utility in target-oriented synthesis. As such, successful development of this program will offer advances in stereoselective synthesis that have great potential to impact the search for medicinally relevant small molecules via enabling future scientific discovery at the interface of chemistry with biology and medicine. II.