Combinatorial, Catalytic Functionalization of Alkenes and Alkynes

项目摘要/摘要 从根本上说，在所有医学适应症的药物发现过程中的一个主要瓶颈是 为生物测试合成拓扑复杂的小分子的难度。这反过来又指向 合成工具包中的限制，特别是可用于快速合成的反应的匮乏 由简单的起始材料组成的结构复杂的化合物家族。我的研究实验室试图解决 通过开发一系列新的反应来加速有机合成来解决这一问题。我们的方法的核心 是使用过渡金属催化剂，它与主族元素具有正交反应性，并能够 债券构建的模式，否则是不可能的。此外，我们还努力开发催化反应。 这既是综合的，也是可持续的，符合绿色化学的目标。我们的观点是 独特之处在于，我们是一个反应发现小组，在专注于生物医学的研究生态系统中运作 问题，我们与免疫学、化学生物学和药物研发方面的研究人员密切合作 确定合成方法学中未满足的需求，并部署新开发的反应来制备小分子 用于生物筛选的分子文库。 这项研究提案的总体目标是开发一个机械上统一和内在的 使烯烃和炔烃的1，2-去功能化成为可能的组合催化循环，这是两类高度 原料丰富，价格低廉。我们提出了一种π-Lewis酸活化方法，其中一个 过渡金属催化剂与底物的碳-碳π-键配位，并促进了 亲核分子。接下来，用电泳剂截取所得的有机金属中间体以形成最终的 键合并关闭催化循环。 在我们运营的头17个月里，我们制定了一套可拆卸的指导小组战略， 烯烃和炔烃的氢官能化作用，最近成功地捕获了一种核钯 烷基钯(II)中间体与碳亲电体实现1，2-二官能化。这些结果，如 到目前为止在4个研究出版物中描述的内容，为NIH R35期间的未来工作奠定了坚实的基础 资助期。在接下来的五年里，我们打算沿着三条研究路线建立这个研究计划： (1)扩大底物、反应伙伴和键构建方式的范围；(2)追求新的 控制区域选择性和促进反应性的战略，包括可拆卸三齿的设计 用于促进非定向反应的导向基团、催化导向基团和配体，以及(3)研究 通过计算和动力学研究了核配位的机理。 这项研究计划意义重大，因为它涉及到发明新的反应来合成 难以或不可能制备的产品，包括全新的化学类型和经过验证的 药物和其他生物活性化合物的核心结构。

Project Summary/Abstract Fundamentally, a major bottleneck in the drug discovery process across all medical indications is the difficulty of synthesizing topologically complex small molecules for biological testing. This, in turn, points back to limitations in the synthetic toolkit, specifically the paucity of reactions that can be deployed to rapidly synthesize families of structurally intricate compounds from simple starting materials. My research laboratory seeks to solve this problem by developing a collection of novel reactions to expedite organic synthesis. Central to our approach is the use of transition metal catalysts, which offer orthogonal reactivity to main group elements and can enable modes of bond construction that are otherwise impossible. Moreover, we strive to develop catalytic reactions that are both synthetically enabling and sustainable, in line with goals of green chemistry. Our perspective is unique in that we are a reaction discovery group operating in a research ecosystem focused on biomedical problems, and we collaborate closely with researchers in immunology, chemical biology, and drug discovery to identify unmet needs in synthetic methodology and to deploy newly developed reactions to prepare small molecule libraries for biological screening. The overall goal of this research proposal is to develop a mechanistically unified and inherently combinatorial catalytic cycle that enables 1,2-difunctionalization of alkene and alkynes, two classes of highly abundant and inexpensive starting materials. We propose a π-Lewis acid activation approach, whereby a transition metal catalyst coordinates to the carbon–carbon π-bond of the substrate and facilitates addition of a nucleophile. Next, the resulting organometallic intermediate is intercepted with an electrophile to form the final bond and close the catalytic cycle. During our first 17 months in operation, we have developed a removable directing group strategy for alkene and alkyne hydrofunctionalization and have recently succeeded in trapping a nucleopalladated alkylpalladium(II) intermediate with a carbon electrophile to achieve 1,2-difunctionalization. These results, as described in 4 research publications to date, establish a firm foundation for future work during the NIH R35 funding period. During the next five years, we intended to build this research program along three lines of inquiry: (1) expanding the scope of substrates, reaction partners, and modes of bond construction, (2) pursuing new strategies for controlling regioselectivity and promoting reactivity, including the design of removable tridentate directing groups, catalytic directing groups, and ligands to promote non-directed reactions, and (3) studying the mechanism of the nucleopalladation through computation and kinetics. This research program is significant because it involves the invention of new reactions to synthesize products that are otherwise difficult or impossible to prepare, including completely new chemotypes and validated core structures of drugs and other biologically active compounds.