A Combined Rhodium-Photoredox-Catalyzed Approach to Alkene Carbofunctionalization by Carbon-Hydrogen Bond Activation

项目摘要 开发新治疗剂的主要挑战是发现和生产 这些物质。大多数药物中的活性成分是复杂的小分子， 大规模合成困难且昂贵。正因为如此，化学合成的新策略 有益的是提供了从简单、丰富的化学物质到这些分子的替代和有效的途径， 原料。在有机分子中最普遍但多样的键是碳-氢键， 有机分子还具有这样的特征，即它们的骨架结构主要由碳组成， 碳键，影响三维相互作用的分子受体负责其 精确的生物活性。因此，利用选择性碳-氢键活化事件并 将它们直接应用于受控的碳-碳键形成， 实施新的小分子疗法。 这项研究将有机化学中的两个概念结合到一种新的化学合成模式中， 以立体控制的方式将碳-氢键转化为碳-碳键。过渡金属， 特别是铑，长期以来已知选择性地裂解未活化碳-氢键，但通常 在过程中形成惰性络合物，从而阻碍催化。光催化剂是一种强大的新兴工具 利用可见光的能量，并利用它来促进过渡金属络合物的反应性。具体 这项研究的目的是使用光催化剂诱导新的反应与铑络合物，激活 碳-氢键通过三种不同的模式。将这种反应性与大量烯烃的使用相结合， 提供了一种高效合成具有生物活性的复杂骨架的简便方法， 分子。 这项研究的产品将是一种新的合成工具，能够快速发现和生产 生物活性小分子。这将最终通过促进设计和 生产负担得起的药物来诊断、治疗和预防人类疾病。

PROJECT SUMMARY The major challenges in the development of new therapeutic agents are the discovery and production of these substances. The active ingredients in most pharmaceuticals are complex small molecules that can be difficult and expensive to synthesize on scale. Because of this, new strategies for chemical synthesis are beneficial in providing alternative and efficient routes to these molecules from simple, abundant chemical feedstocks. The most ubiquitous yet diverse linkage in organic molecules is the carbon-hydrogen bond, and organic molecules also share the characteristic that their skeletal structure is predominantly composed of carbon- carbon linkages that affect the three-dimensional interactions with molecular receptors responsible for their precise biological activity. Hence, methods that harness selective carbon–hydrogen bond activation events and apply them directly toward controlled carbon–carbon bond-formation are transformative for the discovery and implementation of new small molecule therapeutics. This research combines two concepts in organic chemistry into a new mode of chemical synthesis that converts carbon-hydrogen bonds into carbon-carbon bonds in a stereocontrolled fashion. Transition metals, specifically rhodium, have long been known to selectively cleave unactivated carbon-hydrogen bonds but often form inert complexes in the process, thereby impeding catalysis. Photocatalysts are a powerful emerging tool that harness the energy of visible light and use it to promote reactivity in transition metal complexes. The specific aims of this research are to use photocatalysts to induce new reactivity with rhodium complexes that activate carbon-hydrogen bonds by three distinct modes. Coupling this reactivity with the use of abundant alkenes will provide a convenient method for the efficient synthesis of the complex frameworks of biologically active molecules. The product of this research will be a new synthetic tool that enables the rapid discovery and production of biologically active small molecules. This will ultimately improve public health by facilitating the design and production of affordable medicines to diagnose, treat, and prevent human disease.