New Directions in Nickel and Photoredox Catalysis

项目摘要/摘要 新的救命药物的发现和制造需要开发新的和 改进的合成工具，可以选择性和可持续地访问复杂的生物活性化学结构 举止。拟议的研究计划试图通过设计新的化学反应和 阐述了过渡金属和可见光氧化还原催化领域的新催化原理。 研究表明，在化学结构中添加饱和碳原子可以提高生物活性。 对候选药物的性质，促使需要发明改进的C(SP3)-C成键 反应。我们实验室和其他人的早期工作表明，镍和镍/光氧化还原催化 提出了一个通用的平台来产生和官能化C(Sp3)-C(Sp2)交叉中的碳中心自由基。 耦合。这些反应正越来越多地被学术界和制药业的化学家采用 工业。然而，重要的挑战和机遇依然存在，本提案力求 地址。这些包括：1)交叉选择性C(SP3)-C(SP3)偶联反应的发展，与 最终目标是提供一条连接两个饱和环系的路线，该环系与传统的交叉环系一样用途广泛。 用于组装联芳基结构的偶联；2)模板式手性配体骨架的鉴定 对映体选择性和催化剂控制的非对映选择性偶联反应；3)策略的设计 这颠覆了生物活性小分子C(SP3)-H/O/N官能化的共同位置选择性。 鉴于镍和镍/光氧化还原催化领域的大部分努力都集中在反应发现上，我们的 该计划还将通过配基设计和机理研究来推动该领域的发展。我们会研究这些措施的影响 关于催化相关氧化态的结构和反应性的新的和已建立的配体类别 NI(0/I/II/III)，目标是提高现有方法的效率，并能够设计新的 反应。最后，尽管在化学催化领域取得了许多进展，但直接均裂激活 存在于丰富的原料化学品中的强且不能氧化还原的C-O、O-H和N-H键，以及 阶段生物活性化合物仍然是一个突出的挑战。我们的计划正在通过以下方式解决这一差距 开发一种利用可见光光氧化还原催化和单电子氧化还原的策略 磷化氢对N-H杂环、脂肪族和(杂型)芳香醇的活化过程 新的成键反应。综上所述，这些努力将提供有价值的新反应和 对从事生物活性物质发现和合成的化学团体的认识 小分子。该项目还将为科学培养和专业人才提供一个平台 培养一支研究生、博士后研究人员和本科生研究助理队伍。

Project Summary/Abstract The discovery and manufacture of new life-saving medicines necessitates the development of new and improved synthetic tools that can access complex, bioactive chemical structures in a selective and sustainable manner. The proposed research program seeks to address this need by devising novel chemical reactions and elucidating new principles of catalysis in the fields of transition metal and visible light photoredox catalysis. The addition of saturated carbon atoms into chemical structures has been shown to confer improved bioactive properties to drug candidates, prompting a need for the invention of improved C(sp3)–C bond-forming reactions. Early work from our laboratory and others demonstrated that Ni and Ni/photoredox catalysis present a versatile platform to generate and functionalize carbon-centered radicals in C(sp3)–C(sp2) cross- coupling. These reactions are being increasingly adopted by chemists in academia and the pharmaceutical industry. Nevertheless, important challenges and opportunities remain, which the current proposal seeks to address. These include: 1) the development of cross-selective C(sp3)–C(sp3) coupling reactions, with the ultimate goal of affording a route to joining two saturated ring systems that is as versatile as traditional cross- coupling for the assembly of biaryl architectures; 2) the identification of modular chiral ligand frameworks for enantioselective and catalyst-controlled diastereoselective coupling reactions; and 3) the design of strategies that overturn common site-selectivity for C(sp3)–H/O/N functionalization of small bioactive molecules. Whereas most effort in the field of Ni and Ni/photoredox catalysis has focused on reaction discovery, our program will also advance the field through ligand design and mechanistic studies. We will study the impact of novel and established ligand classes on the structure and reactivity of catalytically relevant oxidation states of Ni (0/I/II/III) with the goal of improving the efficiency of existing methods and enabling the design of new reactions. Finally, despite numerous advances in the field of chemical catalysis, direct homolytic activation of strong and redox-inaccessible C–O, O–H, and N–H bonds present in abundant feedstock chemicals and late- stage bioactive compounds remains an outstanding challenge. Our program is addressing this gap by developing a strategy that makes use of visible light photoredox catalysis and the single-electron redox processes of phosphines for the activation of N–H heterocycles and aliphatic and (hetero)aromatic alcohols in new bond-forming reactions. Taken together, these efforts will provide valuable new reactions and understanding for the chemistry communities engaged in the discovery and synthesis of biologically active small molecules. This program will also provide a platform for the scientific training and professional development of a team of graduate students, postdoctoral researchers, and undergraduate research assistants.