Synthesis of Diverse Natural Products and Complex Heterocycles with Donor/Donor Carbenoids

项目总结/摘要 迫切需要新的方法来快速制备复杂的有机分子， 成为新的毒品。有一个日益扩大的差距，在访问复杂的核心结构， 很难开发，并且核心结构的可用性还不是许多专利的主题。 这一差距将通过确定新的合成方法来解决，这些方法可以实现以下双重目标 有效地获得有用的核心，同时还探索以前无法进入的“化学空间”。“长期 目的是了解不稳定卡宾及其直接前体的反应性。的目标 本申请是探索铑催化的卡宾的C-H插入反应，该反应在没有 重氮化合物的分离，同时也探索新的串联环加成/重排方法。 核心假设是在卡宾前体上附加两个“供体”基团将开辟新的途径 有机化学的反应性。这一假设得到了以下初步结果的支持：a） 供体/供体卡宾参与高度对映选择性C-H插入反应的能力，和B）a 不存在产生药物样杂环核心结构的显著环加成/重排序列 从专利文献中！小分子药物包括绝大多数急性和慢性的治疗方法。 疾病在发达国家和发展中国家。这项应用的研究将奠定基础， 通过推进三个特定目标，拯救生命并实现下一代药物发现。第一章 通过催化C-H插入合成氧和硫杂环。这一目标将探索不对称 在避免分离危险中间体的条件下的卡宾反应，表现出前所未有的 官能团的耐受性，并导致核心结构共同的药物发现线索和天然 调节生物现象的产品。2)密集取代的二氢吲哚、茚满和 四氢异喹啉（THIQs）通过催化C-H插入。插入技术将成为一个平台， 在氮基和碳基多环系统的组装中发现， 药物发现的要点。3)由新偶极一锅法快速合成复杂杂环化合物 环加成-[1，5]移位序列。我们的一锅系统用于重氮的生成和立即反应 中间体将用于在一个步骤中构建复杂的螺杂环， 用于制药和生物医学应用的分子。所提出的方法是创新的，因为它是 基于一种新的方法平台，可以访问以前无法访问的化学反应性。这 这项研究意义重大，因为它将改变合成化学家接近目标的方式， 为发现医药和其他领域的有用分子开辟了新的前景。最终 从我们的研究中出现的发现将代表分子组装的垂直步骤。 这些架构将转化为新的药物，以解决我们社会最紧迫的健康挑战。

Project Summary/Abstract An urgent need exists for new methods to rapidly prepare complex organic molecules with the potential to become new drugs. There is a widening gap in both the accessibility of complex core structures that are difficult to exploit and in the availability of core structures that are not already the subject of numerous patents. This gap will be addressed by identifying new synthetic methods that achieve the dual goals of enabling efficient access to useful cores while also exploring previously inaccessible "chemical space." The long-term goal is to understand the reactivity of unstabilized carbenes and their immediate precursors. The objective of this application is to explore rhodium-catalyzed C–H insertion reactions of carbenes that are generated without the isolation of diazo compounds while also exploring new tandem cycloaddition/rearrangement processes. The central hypothesis is that appending two "donor" groups to a carbene precursor will open up new avenues of reactivity for organic chemistry. This hypothesis is supported by preliminary results regarding a) the unique ability of donor/donor carbenes to engage in highly enantioselective C–H insertion reactions and b) a remarkable cycloaddition/ rearrangement sequence that produces drug-like heterocyclic core structures absent from the patent literature! Small molecules comprise the vast majority of treatments for both acute and chronic diseases in both the developed and developing world. Research in this application will lay the groundwork to save lives and enable the next generation of pharmaceutical discovery by advancing three Specific Aims. 1) Synthesis of oxygen and sulfur heterocycles by catalytic C–H insertion. This aim will explore asymmetric carbene reactions under conditions that avoid isolation of dangerous intermediates, exhibit unprecedented functional group tolerance, and lead to core structures common to both drug discovery leads and natural products that modulate biological phenomena. 2) Assembly of densely-substituted indolines, indanes and tetrahydro-isoquinolines (THIQs) by catalytic C–H insertion. The insertion technology will become a platform for discovery in the assembly of nitrogen- and carbon-based polycyclic systems representing useful starting points for drug discovery. 3) Rapid construction of complex heterocycles from new one-pot dipolar cycloaddition-[1,5] shift sequence. Our one-pot system for the generation and immediate reaction of diazo intermediates will be used to construct complex spiro-heterocycles in a single step, yielding unexplored molecules for pharmaceutical and biomedical applications. The proposed approach is innovative because it is based on a new methodological platform that accesses previously inaccessible chemical reactivity. This research is significant because it will change the way synthetic chemists approach targets while at the same time opening up new vistas for discovery of useful molecules for medicine and other fields. Ultimately, the discoveries emerging from our research will represent a vertical step in the assembly of molecular architectures that will translate into new medicines to address our society's most pressing health challenges.