Studies in the Synthesis of Complex Organic Molecules with Donor-Donor Carbenes

项目摘要/摘要 迫切需要新的方法来快速制备具有成为新分子的潜力的复杂分子 毒品。难以开发的复杂核心结构的可达性和难以开采的复杂核心结构的可达性之间的差距越来越大 在核心结构的可用性方面，这些结构已经不是许多专利的主题。这一差距将是 通过确定新的合成方法来解决，这些方法实现了实现有效获取有用的 并探索以前无法进入的“化学空间”。我们研究计划的长期目标是 了解不稳定金属卡宾的反应性。这个应用程序的目标是探索 此外，我们还开发了一种新型的铑供体-供体卡宾化合物，使其具有广泛的有用的新应用。中心假说 将两个“供体”基团加到一个卡宾上，为有机化学开辟了新的反应性途径。 这一假设得到了关于a)供体/供体卡宾的独特能力的初步结果的支持 进行高对映选择性的C-H插入反应，以及b)一种温和的催化新工艺 用于环加成反应的活性双烯的形成！小分子构成了绝大多数的治疗方法。 无论是发达国家还是发展中国家的急性和慢性病。对这一应用的研究 将为拯救生命和实现下一代药物发现奠定基础 研究的三个领域。首先，我们将探索新的C-H插入反应，使配合物的合成成为可能 碳环和杂环结构，最终得到多环生物碱天然产物的有效合成 这将是关于诱导神经可塑性的能力的研究，用于治疗创伤后应激障碍、抑郁症和其他 神经紊乱。第二，我们将探索Rg供体-供体卡宾的新反应 形成C-H插入到获得新化学类型的新反应中。最后，我们将第一次建立一个 QSSR模型，使定制设计的新催化剂的设计、合成和探索成为可能 以提高供体-供体卡宾的反应性。建议的方法是创新的，因为它基于 一种新的方法平台，使以前无法获得的化学反应成为可能。这项研究是 意义重大，因为它将改变合成化学家接近目标的方式，同时打开 为发现医学和其他领域有用的分子开辟了新的前景。最终，这些发现 我们的研究成果将代表着在组装分子结构方面迈出的垂直一步 转化为新药，以应对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 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 and exploring previously inaccessible "chemical space." The long-term goal of our research program is to understand the reactivity of unstabilized metal carbenes. The objective of this application is to explore the ability of rhodium donor-donor carbenes to engage in a wide variety of useful new applications. The central hypothesis is that appending two "donor" groups to a carbene opens 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 new mild and catalytic process for the formation of reactive dienes for cycloaddition reactions! 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 focusing on three areas of research. First, we will explore new C–H insertion reactions the enable the synthesis of complex carba- and heterocyclic structures, culminating in an efficient synthesis of polycyclic alkaloid natural products that will be studies for the ability to induce neuroplasticity for the treatment of PTSD, depression and other neurological disorders. Second, we will explore new reactions of rhodium donor-donor carbenes that branch out form C–H insertion into new reactions that access new chemotypes. Finally, we will, for the first time, build a QSSR model that will enable the design, synthesis and exploration of new catalysts that are custom-designed to enhance the reactivity of donor-donor carbenes. The proposed approach is innovative because it is based on a new methodological platform that enables 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.