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.

: 使复杂偶联配偶体之间的片段结合成为可能的化学过程定义了 异常强烈的反应虽然它们可以帮助确定复杂的有效途径， 分子，他们也是至关重要的组合和药物化学。尽管 尽管这种偶联反应在化学合成中的重要性，但令人惊讶的是，只有少数强有力的偶联反应在化学合成中具有重要意义。 在高度官能化的偶联配偶体之间形成双分子C-C键的途径是可用的。 该提案中概述的研究计划侧重于建立一种新的立体选择性方法， 化学合成，源于新的金属环介导的双分子C- 天然产物合成中的C键形成反应。 我们对GM 080266的第一阶段资助集中在方法开发上， 在过去五年中发现/报告了反应。我们现在能够开发这些 在靶向合成的背景下，独特的反应模式。这是一个关键的组成部分， 我们的目标是取得科学进步，因为反应方法需要在复杂的环境中进行审查，以探索其 真正有潜力影响医学相关的追求。因此，我们将继续实施我们的 技术，以合成一系列结构多样和稀有的天然产物（生物碱，脂肪酸 和聚酮化合物），其已知具有显著的和医学相关的生物活性。 总体而言，提出的方案将导致：（1）确认金属环介导的交叉- 偶联技术在复杂分子合成中的应用;（2）阐明了一系列新型逆合成 策略在目标导向的合成，和（3）第一，或最简洁，一系列的自然合成 产品包括生物碱205 B、利泊他汀A、疏螺旋体素和肯多霉素。因此，我们建议 研究的目的是推进由GM 080266支持的化学反应性的新兴模式， 反应方法学的基础，一类强大的立体选择性片段偶联反应， 在以目标为导向的合成中具有深远的效用。因此，该计划的成功开发将提供 立体选择性合成的进展，有很大的潜力影响医学相关的搜索 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来开发小分子。 二.