Combinatorial, Catalytic Functionalization of Alkenes and Alkynes

烯烃和炔烃的组合催化官能化

基本信息

批准号：
10451983
负责人：
Keary Mark Engle
金额：
$ 9.89万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

项目摘要

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-difunctionaliztion 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.

项目概要/摘要从根本上讲，所有医学适应症的药物发现过程中的一个主要瓶颈是这反过来又说明了合成拓扑复杂的小分子用于生物测试的困难。合成工具包的局限性，特别是缺乏可以快速部署的反应从简单的起始材料合成结构复杂的化合物系列我的研究实验室。试图通过开发一系列新的反应来加速有机合成来解决这个问题。我们的方法是使用过渡金属催化剂，它为主族提供正交反应性元素并可以实现其他方式不可能实现的债券构建模式。开发综合可行且可持续的催化反应，符合绿色目标我们的观点是独特的，因为我们是一个从事研究的反应发现小组。生态系统专注于生物医学问题，我们与免疫学研究人员密切合作，化学生物学和药物发现，以确定合成方法中未满足的需求并进行新的部署开发了反应来制备用于生物筛选的小分子文库。本研究提案的总体目标是开发一种机械上统一且本质上组合催化循环，可实现烯烃和炔烃（两类高度催化的化合物）的 1,2-双官能化我们提出了一种 π-路易斯酸活化方法，因此原料丰富且廉价。过渡金属催化剂与底物的碳-碳π键配位并促进添加接下来，用亲电子试剂拦截所得有机金属中间体以形成最终的产物。结合并关闭催化循环。在运营的前 17 个月里，我们制定了可更换的指导小组策略烯烃和炔烃的氢官能化，最近成功捕获了核钯化的烷基钯(II)中间体与碳亲电子试剂实现1,2-双官能化，如下所示。迄今为止已在 4 篇研究出版物中进行了描述，为 NIH R35 期间的未来工作奠定了坚实的基础在接下来的五年里，我们打算沿着三个方向建立这个研究计划。探究：（1）扩大底物、反应伙伴和键合构建模式的范围，（2）追求控制区域选择性和促进反应性的新策略，包括可移动的设计三齿定向基团、催化定向基团和促进非定向反应的配体，以及(3) 通过计算和动力学研究核钯化机制。该研究计划意义重大，因为它涉及合成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验证药物和其他生物活性化合物的核心结构。