Simplifying Synthesis Through Base Metal Catalysis

项目摘要 化学家需要更可靠、更简洁的方法来评估结构的复杂性。减少时间， 优化化合物的性质需要与药物相容的反应， 比如建筑物。许多基于贵金属的最先进的催化反应需要高度专业化的 条件和外来配体，同时保持与临床上发现的常见刘易斯碱性位点不相容， 候选人相比之下，贱金属催化，虽然大大欠发达，是理想地适合于克服 这些问题通过它们的快速逐步氧化加成来解决，这使得基于Csp 3的交叉偶联变得容易。 此外，贱金属提供长期可持续性、低成本和相对于金属的上级环境特性。 贵金属对应物。尽管有这种潜力，只有小的，孤立的努力存在，以建立和探索 交叉耦合过程中贱金属的反应性。实验室的目标是开发和 了解新的合成策略，使复杂分子的直接建设。的 本申请的目的是发明不同种类的贱金属催化的交叉偶联反应， 为药物化学提供获得新试剂、药效团和SAR的机会。的 开发拟议的化学物质的理由是，它将为后期阶段提供新的途径 药物样分子的功能化以及获得新的化学物质。凭借强大的 根据初步数据，目标将在两个具体目标下追求：1）锰催化的烷基硼基化 氯化物;和2）烯烃的1，2-双官能化。在第一个目标下，将使用新的锰系统 以解决由烷基卤化物合成复合硼酸烷基酯的关键空白，从而产生新的硼- 包含药物发现的结构。在第二个目标下，提出了一种新的1，2-碳硼化和1，2- 烯烃的碳芳基化将提供独特的区域选择性并提供获得新的氟化化合物的途径， 生物活性分子，以及药物样分子后期功能化的机会。两 拟议目标针对目前不可能实现的变革。无处不在的转换 官能团（卤化物和烯烃）转化为复杂的功能允许直接合成关键的 医药中间体、药物和生物工具分子。

Project Abstract Chemists need more reliable, concise methods for accessing structural complexity. Decreasing the time to optimize the properties of a compound en route to the clinic requires reactions that are compatible with drug- like structures. Many state-of-the-art catalytic reactions based on the noble metals require highly specialized conditions and exotic ligands while remaining incompatible with common Lewis basic sites found in clinical candidates. In contrast, base metal catalysis, although vastly less developed, is ideally suited to overcome these issues through their rapid stepwise oxidative addition that enables facile Csp3-based cross couplings. Moreover, base metals offer long-term sustainability, low costs, and superior environmental profiles relative to their noble metal counterparts. Despite this potential, only small, isolated efforts exist to establish and explore the reactivity of base metals in cross-coupling processes. The goal of the laboratory is to develop and understand new synthetic strategies that enable the straightforward construction of complex molecules. The objective of this application is to invent different classes of base metal-catalyzed cross-coupling reactions that provide access to new reagents, pharmacophores, and SAR opportunities for medicinal chemistry. The rationale for developing the proposed chemistry is that it will offer new avenues for the late-stage functionalization of drug-like molecules as well as access to new chemical matter. With the benefit of robust preliminary data, the goals will be pursued under two specific aims: 1) manganese-catalyzed borylation of alkyl chlorides; and 2) 1,2-difunctionalization of alkenes. Under the first aim, novel manganese systems will be used to address key gaps in the synthesis of complex alkyl boronates from alkyl halides, leading to new boron- containing structures for drug discovery. Under the second aim, a new route to the 1,2-carboboration and 1,2- carboarylation of alkenes will offer unique regioselectivity and provide access to new fluorinated compounds, biologically active molecules, and opportunities in late-stage functionalization of drug-like molecules. Both of the proposed aims target transformations that are not currently possible. The conversion of ubiquitous functional groups (halides and alkenes) into complex functionality allows the direct synthesis of key pharmaceutical intermediates, drugs, and biological tool molecules.