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

普林斯顿大学的Paul J. Chirik教授得到化学系化学催化项目的支持，从地球上丰富的金属中开发有效的催化剂，用于可持续地合成单一对映体药物样分子。 该资助机会与行业学术联络（GOALI）项目是与默克公司的Rebecca T Ruck博士合作进行的，Inc. 单一对映体化合物，那些可以像一双手一样与其镜像对应物区分开的化合物，通常表现出独特的生物功能，占2015年FDA批准药物的三分之二。将这些手性化合物制备为单一对映异构体或手，通常具有挑战性，但过渡金属催化通过提供从丰富的前体到这些化合物的直接路线而彻底改变了该领域。传统的催化剂通常依赖于地球上最稀有的元素，并引起人们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。该研究小组专注于地球上丰富的过渡金属所特有的新反应，这些反应是可持续反应所需的。 与默克团队的对接提供了高通量实验的机会，这是一种能够并行快速评估众多化学反应的技术。这种方法，再加上普林斯顿大学开发的分子理解，使合理的催化剂设计和产生的见解，使新的可持续的合成方法以及诊断，以探测药物的安全性和有效性在制药行业。通过工业和学术界的合作，取得进展是可能的，如果这两个团体独立行动，这是不可能的。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工业以外的其他催化领域。此外，参与该项目的学生和博士后还获得了与工业化学家合作的独特经验，并获得了传统研究生课程中通常没有的宝贵职业建议和指导。过渡金属催化已经彻底改变了化学合成，是可持续化学的关键组成部分。使用地球上丰富的而不是贵金属不仅在经济和环境上有利，而且第一行过渡金属可获得的可变电子结构、态密度和配位几何形状为新的化学反应性打开了途径。这一建议的智力价值在于合理应用电子结构控制，以解决在制药工业中应用的贱金属催化的长期挑战。描述了用于制备单一对映体化合物和还原杂环的可持续方法。加氢催化剂，通过3个不同的机制，区分的方法，在催化转换过程中的电子流，进行了研究。从类似的催化剂平台获得涉及均裂键和异裂键活化的不同反应通道是贱金属所独有的，并且提高了成功克服长期存在的挑战的可能性，例如对映选择性杂芳烃氢化和还原缺乏配位官能团的底物。高通量实验（HTE）与物理无机光谱学，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。在药学相关目标的指导下，重点关注地球上丰富的金属催化剂，这些催化剂可以提高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.