Toward Safe, Sustainable Chemical Synthesis: Iron-Catalyzed C-C and C-N Cross-Coupling

迈向安全、可持续的化学合成：铁催化的 C-C 和 C-N 交叉偶联

基本信息

批准号：
9224997
负责人：
Jamie Marie Neely
金额：
$ 2.05万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-04 至 2017-06-03
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The advent of pharmaceutical drugs that prevent, diagnose and treat disease has facilitated a revolution in human health. The discovery and manufacture of these substances rely on chemical transformations. It is crucial to render these processes as safe, sustainable and cost-effective as possible and to develop novel synthetic methods to enable discovery of new medications. Of currently available methods, palladium-catalyzed C-C and C-N cross coupling reactions constitute two of the most widely practiced strategies in the pharmaceutical industry. While offering efficient transformations using easily handled, available starting materials, prominent drawbacks stem from a reliance on palladium catalysts. Palladium is considered toxic, making the removal of residual metal after a cross-coupling step a significant issue in the pharmaceutical industry. Moreover, taking its natural scarcity and growing consumption into account, dependence on palladium is detrimental to the sustainability of these processes. In contrast, iron is the fourth most abundant element on Earth and is classified as a metal with no significant toxicity, making it an ideal choice for the pharmaceutical industry. Indeed, Fe-catalyzed cross coupling is a primary initiative of the ACS Green Chemistry Institute Pharmaceutical Roundtable and is the long-term goal of this research. Furthermore, this work presents the opportunity to discover new reactivity with iron not available to less abundant catalysts. We have established a collaboration with the Catalysis Discovery Group of Bristol-Myers Squibb to develop Fe-catalyzed C-C and C-N cross coupling methodology. To be useful for pharmaceutical synthesis, these processes must incorporate stable carbon and nitrogen nucleophiles, reactivity that is currently unknown for iron catalysis. To overcome the considerable challenges associated with this transition, we will implement two parallel strategies - high throughput experimentation (HTE) and stoichiometric investigation. Rapid execution of considerable amounts of reactions enabled by HTE techniques will allow us to acquire extensive data regarding catalytic reactions in reasonable amounts of time. This information will be combined with fundamental knowledge gained in stoichiometric reactions of discrete, isolable iron complexes. A primary objective of the proposed research is the development of iron catalysts that engage in palladium-like behavior (two electron chemistry), efforts that will be facilitated by the preparation and observation of catalytically relevant iron complexes. The research described herein presents an innovative approach to solving the challenges of practical Fe-catalyzed cross coupling by capitalizing on the unique advantages offered by two distinct strategies, therefore maximizing the probability for success. Targeting the incorporation of stable coupling partners distinguishes this research from current Fe-catalyzed cross coupling efforts and, more importantly, will contribute safe, sustainable processes for large-scale chemical synthesis.

描述（由适用提供）：预防，诊断和治疗疾病的药物的进步已经准备了人类健康的革命。这些物质的发现和制造依赖于化学转化。至关重要的是，使这些过程尽可能安全，可持续和成本效益，并开发出新的合成方法来发现新药物。在当前可用的方法中，钯催化的C-C和C-N交叉耦合反应构成了制药行业中最广泛实践的两种策略。同时，使用易于处理的可用原材料进行有效的转换，但突出的缺点源于钯催化剂的缓解。钯被认为是有毒的，在交叉耦合步骤之后，将残留金属去除是制药行业的重大问题。此外，考虑到它的自然稀缺和不断增长的消费，对钯的依赖对这些过程的可持续性有害。相比之下，铁是地球上第四大元素，被归类为没有明显毒性的金属，使其成为制药行业的理想选择。实际上，Fe催化的交叉耦合是ACS绿色化学研究所制药圆桌会议的主要倡议，是这项研究的长期目标。此外，这项工作为发现新反应性的机会提供了一个机会，而铁无法获得较少的催化剂。我们已经与Bristol-Myers Squibb的催化发现组建立了合作，以开发Fe催化的C-C和C-N交叉耦合方法。为了对药物合成有用，这些过程必须结合稳定的碳和氮核pholipses，这对于铁催化剂目前未知的反应性。为了克服与此过渡相关的考虑挑战，我们将实施两种平行策略 - 高通量实验（HTE）和化学计量研究。 HTE技术启用的反应量的快速执行将使我们能够在合理的时间内获取有关催化反应的大量数据。这些信息将与离散的，可隔离的铁配合物的化学计量反应中获得的基本知识相结合。拟议研究的主要目的是开发从事钯样行为（两种电子化学）的铁催化剂，这将通过制备和观察催化相关的铁配合物来制备。此处描述的研究提出了一种创新的方法，可以通过利用两种不同的策略提供的独特优势来解决实用的Fe催化交叉耦合的挑战，从而最大程度地提高了成功的可能性。针对稳定耦合伙伴的就业，将这项研究与当前的FE催化交叉耦合工作区分开来，更重要的是，将为大型化学合成提供安全，可持续的过程。