CAREER: Establishing Ligand Platforms to Enable Selective, Catalytic Olefin Difunctionalization Reactions for Constructing Diverse Heterocyclic Scaffolds

在化学系化学合成项目的支持下，罗彻斯特大学的Shauna Paradine正在研究新的金属催化化学工艺，该工艺可能会更有效地制备重要类别的所谓“杂环”分子。所针对的杂环化合物在治疗剂、农用化学品和先进材料方面具有潜在的应用前景，因此研究结果可能具有各种社会效益。随着钯具有非常规性质的新配体的设计，提供的潜在进展成为可能。通过假设驱动和数据驱动的配体设计策略，Paradine实验室希望发现选择性和广泛有用的反应，这将允许对感兴趣的分子的性质进行精细调整。在开展研究活动的同时，帕拉丁博士将扩大罗切斯特大学化学研究生的指导经验，并为本科生和研究生开设一门正式的科学交流课程。这些活动旨在支持化学学生的个人和专业发展，特别注重解决边缘群体学生的需求，并使所有背景的学生具备在广泛的环境和媒体中成为有效的科学传播者的能力。钯形成广泛反应的有机金属物种的能力导致了合成有机化学的各种实用方法的引入。事实上，钯催化的方法已经普遍用于构建富含sp2杂化碳原子的分子支架。配体的开发一直是这一创新的关键驱动因素，富含电子且体积庞大的配体，如膦和n杂环羰基，主要用于发现新的pd催化反应性。然而，这些配体家族的成功导致钯的配体空间的其他领域在很大程度上未被探索，为反应发现留下了相当大的机会，特别是在sp3杂化富碳结构域的构建方法方面。为了解决这一不平衡问题，该资助项目涉及研究从尿素和膦衍生的非常规配体平台，以促进pd催化的选择性烯烃双官能化反应，重点研究导致非平面杂环支架的杂环过程。该研究分为四个目的：(1)开发尿素配体激活的杂环反应，涉及两亲性物质（例如，2-溴苯胺）和1,3-二烯；(2)探索新的pi偶联伙伴与尿素激活Pd催化的反应性；(3)尿素配体的基本性质及其催化作用的阐明；(4)在烯烃功能化反应中实现配体控制的位点选择性。追求这些目标将包括数据驱动的基础，预测配体设计模型，预计将促进过渡金属催化领域配体开发的一般策略，并为未来的反应发现带来相关好处。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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 Program in the Division of Chemistry, Shauna Paradine of the University of Rochester is studying new metal-catalyzed chemical processes that may enable more efficient preparation of important classes of so-called 'heterocyclic' molecules. The kinds of heterocycles being targeted have potential applications as therapeutic agents, agrochemicals, and advanced materials, and as such the outcome of the research could have a variety of societal benefits. The potential advances being offered are made possible with the design of new ligands for palladium that possess unconventional properties. Through both hypothesis-driven and data-driven ligand design strategies, the Paradine laboratory expects to discover selective and broadly useful reactions that will allow for refined tuning of the properties of the molecules of interest. In parallel with research activities, Dr. Paradine will expand mentoring experiences for chemistry graduate students at the University of Rochester and develop a formal course in scientific communication for undergraduate and graduate students. These activities are designed to support the personal and professional development of chemistry students, with a special focus on addressing the needs of students from marginalized groups, and to equip students of all backgrounds with the capacity to be effective scientific communicators in a broad range of contexts and media.The ability of palladium to form broadly reactive organometallic species has led to the introduction of a diverse array of practical methodologies for synthetic organic chemistry. Indeed, Pd-catalyzed methods have become ubiquitous for the construction of molecular scaffolds rich in sp2-hybridized carbon atoms. Ligand development has been a key driver of this innovation, with electron-rich and bulky ligands such as phosphines and N-heterocyclic carbenes being predominantly used in efforts to uncover new Pd-catalyzed reactivity. However, the success of these ligand families has led to other areas of ligand space for palladium being left largely unexplored, leaving considerable opportunities for reaction discovery, particularly in regard to methods for the construction of sp3-hybridized carbon-rich domains. To address this imbalance, the funded project involves study of unconventional ligand platforms derived from ureas and phosphines to facilitate Pd-catalyzed selective olefin difunctionalization reactions, with an emphasis on heteroannulation processes leading to non-planar heterocyclic scaffolds. The investigation is divided across four aims: (1) development of urea ligand-enabled heteroannulation reactions involving ambiphiles (e.g., 2-bromoanilines) and 1,3-dienes; (2) exploration of the reactivity of new pi-coupling partners with urea-enabled Pd catalysis; (3) elucidation of the fundamental properties of urea ligands and their role in catalysis; and, (4) realization of ligand-controlled site-selectivity in olefin functionalization reactions. Pursuit of these aims will include the foundation of data-driven, predictive models for ligand design that are anticipated to facilitate general strategies for ligand development in the field of transition metal catalysis with associated benefits for future reaction discovery.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.