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

项目摘要/摘要（来自母公司奖项GM124234） 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。在复杂的核心结构的可达性方面， 开发和获得尚未成为众多专利主题的核心结构。这一差距 将通过确定新的合成方法来解决，这些方法可以实现两个目标， 同时也探索以前无法进入的"化学空间"。"长期目标是 了解不稳定卡宾及其直接前体的反应性。的目的 应用是探索铑催化的碳烯的C-H插入反应，该反应在没有 分离重氮化合物，同时还探索新的串联环加成/重排方法。的 中心假设是，将两个"供体"基团附加到卡宾前体上将开辟新的途径， 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） 的供体/供体卡宾参与高度对映选择性的C-H插入反应和B）一个显着的 环加成/重排序列，其产生药物样杂环核心结构，所述药物样杂环核心结构不存在于 专利文献!小分子药物构成了治疗急性和慢性疾病的绝大多数药物 在发达国家和发展中国家。这项应用的研究将为拯救生命奠定基础 并通过推进三个特定目标来实现下一代药物发现。1)合成 氧和硫杂环的催化C-H插入。这一目标将探索不对称卡宾反应 在避免分离危险中间体的条件下， 耐受性，并导致共同的核心结构的药物发现线索和天然产物，调节 生物现象。2)密集取代的吲哚啉、茚满和四氢异喹啉的组装 （THIQs）通过催化C-H插入。该插入技术将成为一个平台，发现在大会上 氮基和碳基多环系统代表了药物发现的有用起点。3)快速 由新的一锅偶极环加成-[1，5]移位序列构建复杂杂环。我们的一锅 用于生成和立即反应的重氮中间体的系统将被用于构建复杂的螺环， 在一个步骤中合成杂环，产生用于制药和生物医学应用的未开发分子。 拟议的方法是创新的，因为它是基于一个新的方法平台， 以前无法达到的化学反应。这项研究意义重大，因为它将改变合成 化学家接近目标，同时为发现有用的分子开辟了新的前景， 医学和其他领域。最终，从我们的研究中出现的发现将代表一个垂直的步骤， 在分子结构的组装中，这将转化为新药，以解决我们社会最严重的问题， 紧迫的健康挑战。

Project Summary/Abstract (from parent award GM124234) 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.