Improving Small Molecule Synthesis by Controlling Reactions between Transition Metals and Carbon-Heteroatom Electrophiles

项目摘要 过渡金属催化的交叉偶联反应是最广泛使用的策略之一， 生物医学研究用小分子合成过程中C-C和C-N键的形成。 尽管这些方法被广泛使用，但它们的局限性通常可归因于控制不佳 在催化循环的关键基本步骤中，金属的反应性或选择性。在 特别是，氧化加成的问题会限制可以进入的化学空间， 通过交叉耦合方法。在这个基本步骤中，过渡金属氧化 插入亲电试剂的键（通常为碳-杂原子键）中。方面的挑战 该步骤包括：（1）当两个或多个相同卤化物 存在于芳族底物上，（2）利用相对不稳定的苯酚衍生物作为 亲电偶联配偶体，和（3）开发选择性的温和的交叉偶联反应 由低毒性贱金属如铁和钴催化。该提案旨在发展 通过结合实验和计算的方法来解决这些挑战。 这项工作的完成将有助于简化获得与生物多样性有关的化合物的途径 通过更有效的催化方法。此外，深入了解 这些系统中选择性和反应性的机械起源将为未来的研究奠定基础。 合理设计新的催化体系。

PROJECT SUMMARY Transition metal-catalyzed cross coupling reactions are among the most widely used strategies for C—C and C—N bond formation during the synthesis of small molecules for biomedical research. Despite their widespread use, limitations to these methods can often be attributed to poor control over the metal's reactivity or selectivity during key elementary steps of the catalytic cycle. In particular, problems with oxidative addition can limit the chemical space that can be accessed through cross coupling methods. During this elementary step, a transition metal oxidatively inserts into a bond of an electrophile (typically a carbon–heteroatom bond). Challenges related to this step include (1) subverting conventional site selectivity when two or more identical halides are present on aromatic substrates, (2) exploiting relatively non-labile phenol derivatives as electrophilic coupling partners, and (3) developing selective, mild cross-coupling reactions catalyzed by low-toxicity base metals such as iron and cobalt. This proposal seeks to develop solutions to these challenges through a combined experimental and computational approach. Completion of this work will help to streamline access to pharmacologically relevant compounds through more efficient catalytic methods. Furthermore, an in-depth understanding of the mechanistic origin of selectivity and reactivity in these systems will lay the groundwork for future rational design of new catalytic systems.