Methods for Late-Stage Nucleophilic Fluorination and Radiofluorination

美国国家科学基金会化学部的化学合成项目支持普林斯顿大学化学系Abigail G. Doyle教授的研究。Doyle教授和她的学生开发了亲核氟化的新试剂和策略。氟是对公共保健和工业至关重要的无数药物、农用化学品和材料的重要组成部分。然而，选择性地将氟植入有机分子的工具要么有限，要么在某些情况下根本不存在。具体而言，目前的亲核氟化方法往往依赖于传统试剂的恶劣条件，导致对其他官能团的反应性、选择性和/或耐受性低。这项研究导致了用于催化的新的潜在HF源的发明，设计了能够温和和选择性形成C-F键的一般策略，并制备了用于化学合成的有价值的含氟合成子。这些策略也适用于合成用于正电子发射断层扫描（PET）的放射性标记小分子，这是一种重要的脑成像诊断工具。这项计划支持的学生接受研究、写作、沟通技巧和指导方面的培训。通过各种项目，Doyle教授从传统上在STEM学科中代表性不足的群体中招募和指导学生。Doyle教授组织了普林斯顿大学学生邀请讲座系列；她和她的学生参加推广活动，以鼓励早期参与科学。本研究的重点是通过从丰富、稳定的氟化物试剂中原位生成HF的新策略，开发亲核C-F键形成的新方法。这些合成方法提供了高效、温和、选择性和环境友好的途径，利用有机催化或过渡金属催化。Doyle小组和更大的化学社区的研究人员能够应用这些方法构建对制药和生物医学领域感兴趣的难以捉摸和理想的化合物。该研究项目还通过参与多样性研究项目、女性参与科学活动以及面向服务不足社区儿童的拓展活动，为科学领域中代表性不足的群体创造了成长机会，促进了他们的进步。

The Chemical Synthesis Program of the NSF Chemistry division supports the research of Professor Abigail G. Doyle of the Department of Chemistry at Princeton University. Professor Doyle and her students develop new reagents and strategies for nucleophilic fluorination. Fluorine is an essential constituent of myriad drugs, agrochemicals and materials that are crucial to public healthcare and industry. However, the tools to selectively install fluorine into organic molecules are either limited or in some cases nonexistent. Specifically, current methods for nucleophilic fluorination often rely on harsh conditions with traditional reagents resulting in low reactivity, selectivity and/or tolerance to other functional groups. This research leads to the invention of new latent HF sources for catalysis, the design of general strategies that enable mild and selective C-F bond formation, and the preparation of valuable fluorine-containing synthons for chemical synthesis. These strategies are also adapted for the synthesis of radiolabeled small molecules for use in positron emission tomography (PET), an important diagnostic tool for imaging the brain. The students supported under this program receive training in research, writing, communication skills, and mentoring. Through various programs, Professor Doyle recruits and mentors students from groups traditionally underrepresented in the STEM disciplines. Professor Doyle organizes the Princeton University Student Invited Lecture Series; she and her students participate in outreach activities to encourage early engagement in the sciences.The key focus of this research is the development of new methods for nucleophilic C-F bond formation enabled by novel strategies for in situ generation of HF from abundant, stable fluoride reagents. These synthetic methods offer routes that are efficient, mild, selective, and environmentally benign, utilizing either organocatalysis or transition metal catalysis. Researchers in the Doyle group and in the greater chemical community are able to apply these methods to construct elusive and desirable compounds of interest to the pharmaceutical and biomedical fields. This research program also creates opportunities for growth and promotes the advancement of underrepresented groups in the sciences through participation in diversity research programs, women in science events, and outreach activities to children from underserved communities.