Stereoselective Synthesis via Metallacycle-Mediated Bond Construction

通过金属环介导的键构建进行立体选择性合成

• 批准号: 8372060
• 负责人: GLENN C MICALIZIO
• 金额: $ 40.59万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-12 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372060
• 关键词: Address; Affect; Alcohols; Alkaloids; Alkenes; Alkynes; Amines; Antifungal Antibiotics; Biological; Biological Factors; Biology; Chemicals; Chemistry; Complex; Coupling; Data; Dependence; Development; Fatty Acids; Foundations; Funding; Future; Imines; Laboratories; Mediating; Medicine; Methodology; Methods; Nicotinic Receptors; Organic Chemistry; Organic Synthesis; Oxidation-Reduction; Pathway interactions; Pharmaceutical Chemistry; Phase; Play; Positioning Attribute; Process; Program Development; Property; Rana; Reaction; Reporting; Research; Role; Route; Scheme; Scientific Advances and Accomplishments; Technology; base; carbonyl group; chemical reaction; chemical synthesis; combinatorial chemistry; cycloaddition; design; diene; kendomycin; method development; nitrone; novel; novel strategies; programs; small molecule

: 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.

： 化学过程使复杂耦合伙伴之间的碎片结合能够定义 反应异常强大。虽然他们可以帮助定义复杂的有效途径 分子，它们对于组合化学和药物化学也至关重要。尽管有 这种耦合反应在化学合成中的重要性，令人惊讶的是只有少数鲁棒 高度功能化耦合伙伴之间的双分子C-C键形成途径。 该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 化学合成源自发现和应用新型金属叶子介导的双分子c-的化学合成 C在天然产物合成中形成键反应。 我们针对GM080266的第一阶段资金集中在方法开发上，很多 在过去的五年中，已经发现/报道了反应。我们现在可以开发这些 在目标综合的背景下，反应性的独特模式。这是 我们旨在进行科学进步，因为需要在复杂的环境中审查反应方法以探索其 真正影响与药物相关的追求的真正潜力。因此，我们将追求我们的应用 一系列结构多样和稀有天然产物的合成技术（生物碱，脂肪酸 众所周知具有重要且与药物相关的生物学活性的聚酮化合物。 总体而言，提出的计划将导致：（1）确认金属囊性介导的跨界的效用 复杂分子合成中的耦合技术，（2）阐明了一系列新型弯曲 面向目标综合的策略，以及（3）一系列自然的第一或最简洁的合成 包括生物碱205b，Ripostatin A，硼替丁和肯多霉素在内的产品。因此，我们提出了 研究将旨在提高GM080266支持的新兴化学反应模式 反应方法对强大的一类立体选择性片段耦合反应的基础 面向目标的合成中的深刻效用。因此，该计划的成功开发将提供 立体选择性合成的进步，具有影响对药物相关的搜索的巨大潜力 小分子通过在化学与生物学和医学的界面上实现未来的科学发现。 ii。