Combinatorial, Catalytic Functionalization of Alkenes and Alkynes

项目总结/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 难以合成拓扑复杂的小分子用于生物测试。这反过来又指向 合成工具包的局限性，特别是缺乏可以快速合成的反应 从简单的起始原料合成结构复杂的化合物。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，解决了这个问题。我们方法的核心 使用过渡金属催化剂，其提供与主族元素正交的反应性，并且可以使 其他方式无法实现的结合模式。此外，我们努力开发催化反应， 这些都是综合性的和可持续的，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，在一个专注于生物医学的研究生态系统中运作。 我们与免疫学、化学生物学和药物发现领域的研究人员密切合作， 确定合成方法中未满足需要，并利用新开发的反应制备小分子化合物， 用于生物筛选的分子文库。 本研究提案的总体目标是开发一种机械统一的、内在的 组合催化循环，其能够使烯烃和炔的1，2-双官能化，两类高度 丰富和廉价的起始原料。我们提出了一种π-刘易斯酸活化方法， 过渡金属催化剂与基底的碳-碳π-键配位，并有助于添加 亲核试剂接下来，将所得有机金属中间体与亲电试剂截取以形成最终的有机金属化合物。 结合并关闭催化循环。 在我们的头17个月的运作，我们已经制定了一个可移动的指导小组的战略， 烯烃和炔烃的氢官能化，最近成功地捕获了核钯化的 烷基钯（II）中间体与碳亲电试剂反应以实现1，2-双官能化。这些结果，如 迄今为止，在4篇研究出版物中描述了这一点，为NIH R35期间的未来工作奠定了坚实的基础。 融资期。在接下来的五年里，我们打算沿着沿着三条调查路线建立这个研究计划： (1)扩大底物，反应伙伴和键结构模式的范围，（2）追求新的 控制区域选择性和促进反应性的策略，包括可移除三齿的设计 定向基团、催化定向基团和配体以促进非定向反应，以及（3）研究 通过计算和动力学的核钯化机制。 这项研究计划意义重大，因为它涉及到新反应的发明， 难以或不可能制备的产品，包括全新的化学型和经过验证的产品。 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.