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

项目总结 过渡金属催化的交叉偶联反应是应用最广泛的策略之一 生物医学研究用小分子合成过程中C-C和C-N键的形成。 尽管它们被广泛使用，但这些方法的局限性往往可以归因于控制不善 在催化循环的关键基本步骤中对金属的反应性或选择性的影响。在……里面 特别是，氧化加成问题可能会限制可访问的化学空间 通过交叉耦合的方法。在这一基本步骤中，一种过渡金属氧化 插入亲电试剂的键中(通常是碳-杂原子键)。与以下方面相关的挑战 这一步骤包括(1)当两个或更多相同的卤化物时颠覆传统的位置选择性 存在于芳香族底物上，(2)利用相对不稳定的苯酚衍生物作为 以及(3)发展选择性、温和的交叉偶联反应 由低毒的贱金属，如铁和钴催化。这项建议旨在发展 通过实验和计算相结合的方法解决这些挑战。 这项工作的完成将有助于简化获取药用相关化合物的途径 通过更有效的催化方法。此外，深入了解 这些体系中选择性和反应性的机制起源将为未来奠定基础 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.