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

 描述(申请人提供)：预防、诊断和治疗疾病的药物的出现促进了人类健康的一场革命。这些物质的发现和制造依赖于化学转化。关键是使这些过程尽可能安全、可持续和具有成本效益，并开发新的合成方法，使新药物的发现成为可能。在目前可用的方法中，钯催化的C-C和C-N交叉偶联反应构成了制药行业中应用最广泛的两种策略。虽然使用易于处理的、可获得的起始材料提供了高效的转化，但突出的缺点源于对钯催化剂的依赖。钯被认为是有毒的，使交叉偶合步骤后残留金属的去除成为制药业的一个重大问题。此外，考虑到钯的自然稀缺性和日益增长的消费量，对钯的依赖不利于这些进程的可持续性。相比之下，铁是地球上第四丰富的元素，被归类为无重大毒性的金属，使其成为制药行业的理想选择。事实上，铁催化的交叉偶联是美国化学学会绿色化学研究所药物圆桌会议的主要倡议，也是这项研究的长期目标。此外，这项工作提供了发现铁与铁的新反应性的机会，这是不太丰富的催化剂所没有的。 我们已经与百时美施贵宝的催化发现小组建立了合作关系，以开发铁催化的C-C和C-N交叉偶联方法。为了用于药物合成，这些过程必须包含稳定的碳和氮亲核试剂，这是目前铁催化未知的反应性。为了克服与这一过渡相关的相当大的挑战，我们将实施两个并行战略-高通量实验(HTE)和化学计量调查。通过HTE技术实现的大量反应的快速执行将使我们能够在合理的时间内获得关于催化反应的大量数据。这些信息将与在离散的、可分离的铁络合物的化学计量反应中获得的基本知识相结合。拟议研究的一个主要目标是开发具有类钯行为(双电子化学)的铁催化剂，这将通过制备和观察催化相关的铁配合物来促进这一努力。 这里描述的研究提出了一种创新的方法，通过利用两种不同策略提供的独特优势来解决实用的铁催化交叉偶联的挑战，从而最大化成功的可能性。以稳定偶联伙伴的加入为目标使这项研究有别于目前铁催化的交叉偶联努力，更重要的是，将有助于安全、可持续的大规模化学合成过程。

 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.