GOALI: SusChEM: An Industrial-Academic Collaboration for High Throughput Discovery of Base Metal Catalysis

普林斯顿大学的Paul J.Chirik教授得到了化学系化学催化项目的支持，该项目旨在从地球上丰富的金属中开发高效催化剂，用于可持续地合成单一对映体类药物分子。GOALI学术联系机会(GOALI)项目是与默克公司的丽贝卡·T·拉克博士合作进行的。单一对映体化合物可以与镜像化合物区分开来，就像一双手一样，通常具有独特的生物学功能，占FDA 2015年批准的药物的三分之二。将这些手性化合物作为单一对映体或手性化合物制备往往是具有挑战性的，但过渡金属催化通过从丰富的前体直接获得这些化合物而彻底改变了这一领域。传统催化剂通常依赖于地球上最稀有的元素，并引发了对这些过程的整体可持续性、二氧化碳(CO2)足迹和毒性的担忧。研究小组专注于地球上独特的新反应，丰富的过渡金属对可持续反应是可取的。与默克团队的接口提供了高通量实验的途径，这是一项能够快速评估众多并行化学反应的技术。这种方法与普林斯顿大学开发的分子理解相结合，使合理的催化剂设计成为可能，并产生洞察力，使新的可持续合成方法以及诊断方法能够探索制药行业内的药物安全性和有效性。通过产学研合作，如果这两个团队独立行动，就有可能取得进展。这些研究还提供了基本的催化剂设计原则，这些原则最终可能会转化为制药行业以外的其他催化领域。此外，参与该项目的学生和博士后将获得与工业化学家合作的独特经验，并获得传统研究生课程中所没有的宝贵的职业建议和指导。过渡金属催化使化学合成发生了革命性的变化，是可持续化学的重要组成部分。使用地球上丰富的金属而不是贵金属不仅对经济和环境有利，而且第一排过渡金属提供的可变电子结构、态密度和配位几何结构为新的化学反应开辟了途径。这一建议的智力优势在于合理应用电子结构控制，以解决贱金属催化在制药工业中的应用中长期存在的挑战。描述了制备单一对映体化合物和还原杂环的可持续方法。研究了三种不同机理的加氢催化剂，并用催化剂周转过程中的电子流方法进行了区分。从类似的催化剂平台上访问涉及均解键和异解键激活的不同反应通道是贱金属独有的，并提高了成功克服长期存在的挑战的可能性，如对映体选择性杂芳烃氢化和底物缺乏配位官能团的还原。高通量实验(HTE)与物理无机光谱、结构化学和磁学相结合，为解决化学催化中的基础和应用问题提供了独特的机会。在药物相关目标的指导下，重点放在地球上丰富的金属催化剂上，这些催化剂提高了药物发现中使用的转化的速度、多样性、复杂性和可持续性。

Professor Paul J. Chirik of Princeton University is supported by the Chemical Catalysis program in the Division of Chemistry to develop efficient catalysts from Earth-abundant metals for the sustainable synthesis of single enantiomer drug-like molecules. This Grant Opportunities for Academic Liaisons with Industry (GOALI) project is conducted in collaboration with Dr. Rebecca T Ruck of Merck & Co., Inc. Single enantiomer compounds, those that can be distinguished from their mirror image counterparts much like a pair of hands often exhibit unique biological function and constituted two-thirds of FDA drugs approved in 2015. Preparing these chiral compounds as single enantiomers, or hands, is often challenging but transition metal catalysis has revolutionized the field by providing direct routes to these compounds from abundant precursors. Traditional catalysts often rely on the rarest elements on Earth and raise concerns about the overall sustainability, carbon dioxide (CO2) footprint and toxicity of these processes. The research team focuses on new reactions unique to Earth abundant transition metals that are desirable for sustainable reactions. Interfacing with the Merck team provides access to high throughput experimentation, a technique that enables rapid evaluation of numerous chemical reactions in parallel. This approach, coupled with molecular understanding developed at Princeton, enables rational catalyst design and generates insights that enables new sustainable synthetic methods as well as diagnostics to probe drug safety and efficacy within the pharmaceutical industry. Through an industrial-academic partnership advances are possible that would not be had the two group acted independently. These studies also provide fundamental catalyst design principles that may ultimately translate to other areas of catalysis beyond of the pharmaceutical industry. In addition, students and postdocs involved in the project gain unique experience working with industrial chemists and gain invaluable career advice and mentorship not typically found in traditional graduate programs. Transition metal catalysis has revolutionized chemical synthesis and is a key component of sustainable chemistry. Use of Earth-abundant rather than precious metals is not only economically and environmentally advantageous but the variable electronic structures, density of states, and coordination geometries that are available with first row transition metals open pathways for new chemical reactivity. The intellectual merit of this proposal lies in the rational application of electronic structure control to address long-standing challenges in base metal catalysis with applications in the pharmaceutical industry. Sustainable methods for the preparation of single enantiomer compounds and the reduction of heterocycles are described. Hydrogenation catalysts that operate by 3 distinct mechanisms, differentiated by the method of electron flow during catalytic turnover, are investigated. Access to distinct reaction channels involving both homolytic and heterolytic bond activation from similar catalyst platforms is unique to base metals and improves the likelihood for success to overcome long-standing challenges such as enantioselective heteroarene hydrogenation and reduction of substrates lacking coordinating functionality. High throughput experimentation (HTE) coupled with physical inorganic spectroscopy, structural chemistry and magnetism provide a unique opportunity to solve fundamental and applied problems in chemical catalysis. Guided by pharmaceutically relevant targets, focus is devoted to Earth-abundant metal catalysts that improve the speed, diversity, complexity and sustainability of transformations used in drug discovery.