(Radio)Fluorination and Other Nucleophilic Functionalizations Enabled by Photocatalytic Radical-Polar Crossover

在化学系化学合成(SYN)计划的支持下，加州大学洛杉矶分校的阿比盖尔·道尔教授正在开发新的化学反应，使有机氟化合物的合成成为可能；即那些含有C-F键的化合物。随着C-F键在下一代药物、农用化学品和生物医学显像剂中的发现，这种键结构的需求很大。这里正在开发的化学反应使用一种催化剂，它可以利用可见光中的能量来产生高能的活性中间体，碳阳离子，通常只有在恶劣的(热的或强酸的或路易斯酸的)条件下才能接触到。由于Doyle教授和她的学生正在追求的策略是在与可见光照射相关的温和条件下访问这种中间体，因此正在开发的反应产生了以前难以获得的化学结构，从丰富而廉价的试剂开始。研究人员将使用各种工具帮助他们在分子水平上了解反应是如何工作的，这样这些知识就可以用来发现新的过程和设计改进的反应。开展这些研究活动的学生将有机会发展广泛的技能，既有科学性质的，也有关于沟通、指导、领导能力的，以及拥抱和建立多样性、公平、包容和归属感的技能，这将帮助他们成为独立职业生涯的领导者。这项工作的更广泛影响还包括开展旨在招收和留住人数不足群体中的学生进入科学、技术、工程和数学(STEM)的活动。例如，该计划包括开发本科教材，以突出不同背景、经验和观点的研究人员的科学贡献，并设计研讨会，让研究生学习引用偏差、冲突管理和微攻击等主题。碳正离子是广泛的合成转化中的活性中间体，因为它们与水、醇、卤化物、胺和烯烃等丰富而稳定的亲核试剂发生反应。然而，碳阳离子中间体的生成通常需要苛刻的反应条件，并需要使用预氧化的前体，如烷基卤化物。这些限制排除了在更复杂的环境中的应用，例如生物活性化合物的合成或放射性标记，以及获得所需的产品。该计划旨在通过使用光催化剂和光将丰富和稳定的C(SP3)-OH、-NH2和-H前体转化为自由基，然后转化为碳阳离子(所谓的自由基-极性交叉)来应对这些挑战。这些努力的重点将是使用氟化物捕获碳阳离子中间体，以生产在制药和农用化学工业中有用的有机氟产品。机制研究将伴随着这些合成努力，最有效的策略也将用于合成18-氟标记小分子，用于正电子发射断层扫描(PET)，正电子发射断层扫描(PET)是检测疾病的重要诊断工具。这项研究将为不同的研究生、本科生和博士后研究员提供一个严格的、多学科的培训环境。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Abigail Doyle of University of California, Los Angeles is developing new chemical reactions that will enable the synthesis of organofluorine compounds; namely those that contain a C-F bond. Such bond constructions are in high demand as C-F bonds are found in next-generation medicines, agrochemicals, and biomedical imaging agents. The chemical reactions under development here use a catalyst that can harness the energy in visible light to generate a high-energy reactive intermediate, a carbocation, that is most often only accessible under harsh (thermal or strongly acidic or Lewis-acidic) conditions. Because the strategy being pursued by Professor Doyle and her students accesses this intermediate under the mild conditions associated with visible light irradiation, reactions are being developed that generate chemical structures that were previously challenging to access, starting from abundant and inexpensive reagents. The researchers will use a variety of tools to help them understand how the reactions work at the molecular level such that this knowledge can be used to discover new processes and design improved reactions. Students conducting these research activities will have the opportunity to develop a broad skill set, both scientific in nature and with respect to communication, mentorship, leadership, and also with respect to embracing and building diversity, equity, inclusion and belonging, that will help them become leaders in their independent careers. Broader impacts of this work also include the development of activities directed at recruitment and retention of students from underrepresented groups to science, technology, engineering, and mathematics (STEM). For example, the program includes the development of undergraduate teaching material to highlight scientific contributions from researchers of diverse backgrounds, experiences and perspectives and the design of workshops for entering graduate students on topics such as citation bias, conflict management, and micro-aggression.Carbocations are reactive intermediates in a broad range of synthetic transformations because they undergo reaction with abundant and stable nucleophiles like water, alcohols, halides, amines, and olefins. Nevertheless, the generation of carbocation intermediates typically requires harsh reaction conditions and requires use of pre-oxidized precursors such as alkyl halides. These limitations preclude applications in more complex settings, such as in the synthesis of bioactive compounds or radiolabelling, and access to desirable products. This program seeks to address these challenges by using a photocatalyst and light to convert abundant and stable C(sp3)–OH, –NH2 and –H precursors to radicals and then to carbocations (a so-called radical-polar crossover). A focus of these efforts will be to use fluoride to trap the carbocation intermediates in order to generate organofluorine products that are useful in the pharmaceutical and agrochemical industries. Mechanistic studies will accompany these synthetic efforts and the most efficient strategies will also be adapted for the synthesis of 18-fluorine-radiolabelled small molecules for use in positron emission tomography (PET), an important diagnostic tool for detecting disease. This research will provide a rigorous and multi-disciplinary training environment for a diverse group of graduate and undergraduate students and postdoctoral fellows.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.