Asymmetric Nucleophilic Aromatic Substitution Enabled by Hydrogen-Bonding Catalysis

项目总结/摘要 立体生成的磷（P-手性）P（V）化合物在生命设计中越来越重要， 节省药物，如广谱抗病毒药物（Remdesivir，Sofosbuvir，Tenofovir 阿拉芬酰胺）治疗B和C型肝炎以及埃博拉和COVID-19。尽管作为一个 能够将P-手性中心引入化合物中，以开发新的药物来对抗现有的和新出现的药物。 尽管这些疾病的发病率很高，但由于缺乏有效的化学方法，获得这种化学基序的途径仍然受到限制。结果导致 在药物化学研究中可以有效探索和产生的结构的多样性相对较少。 有限公司现有的方法受到几个限制：1）依赖于非选择性合成路线， 需要额外的解析步骤，从而限制了这些方法的效率，以及2） 亲电子P（V）底物，其需要预活化步骤以安装适当的反应性离去基团。 催化交叉偶联方法获得P-手性化合物目前具有相对狭窄的产品范围 并且通常依赖于昂贵的过渡金属催化剂，其必须在生物测试之前被费力地除去。 一种有吸引力的新方法是有机催化的不对称鳞脱烷基化反应， 通过偶联P（III）亲核试剂和亲电活化剂产生P-手性立体异构中心。这 这种方法将解决前面提到的关键限制，同时使化学家能够催化和 选择性地控制已知通过磷物种进行的大范围的强反应。 氢键给体（HBD）有机催化剂已知催化阴离子通过阴离子交换形成离子物种。 结合，同时还控制这些物质的亲核捕获的立体化学结果。通过利用 强大过渡态稳定和协同双重亲核和亲电活化能力 独特的HBD催化剂，这种方法应该能够实现鳞去对称化， 精确的对映选择性。 该提议的目标是设计一种阴离子对结合有机催化剂，以促进第一催化反应。 能够产生P-手性产物的对映选择性鳞脱烷基化反应。研究计划 概述了一个战略，以发展这样的催化剂系统的指导下，假设驱动的实验，计算 建模和结构活性研究。为了增加反应开发中获得的信息，详细的 HBD有机催化剂活化简单磷（III）底物如亚膦酸酯和 亚磷酸盐将使用数据密集的多维相关性进行。这项研究将使简单 用于以新的方式生产医学相关的对映体富集的化合物的试剂， 对医学研究、催化剂开发以及对科学知识的重大贡献做出了巨大的贡献。

Project Summary/Abstract Stereogenic-at-phosphorus (P-chiral) P(V) compounds are an increasingly important motif in the design of life- saving pharmaceuticals such as broad spectrum anti-viral medications (Remdesivir, Sofosbuvir, Tenofovir Alafenamide) to treat hepatitis B and C as well as Ebola and COVID-19. Despite the enormous importance of being able to introduce P-chiral centers into compounds to develop new medications to combat existing and emergent diseases, access to this chemical motif remains constrained by a lack of efficient chemical methods. As a result, the diversity of structures that can be efficiently explored and produced in medicinal chemistry research is relatively limited. Existing methods suffer from several limitations: 1) reliance on non-selective synthesis routes, which require additional resolution steps, thus limiting the efficiency of these approaches and 2) the predominant use of electrophilic P(V) substrates that required pre-activation steps to install an appropriately reactive leaving group. Catalytic cross coupling approaches to access P-chiral compounds currently have relatively narrow product scopes and often rely on expensive transition metal catalysts that must be removed assiduously before biological testing. An attractive new approach would be an organocatalytic asymmetric phosphonium dealkylation reaction that generates P-chiral stereogenic centers by coupling P(III) nucleophiles and electrophilic activating agents. This approach would address the previously mentioned key limitations while enabling chemists to catalytically and selectively control the wide range of powerful reactions know to proceed through phosphonium species. Hydrogen-bond donor (HBD) organocatalysts are known to catalyze the formation of ionic species by anion binding while also controlling the stereochemical outcome of nucleophilic trapping of these species. By leveraging the powerful transition state stabilization and synergistic dual nucleophilic and electrophilic activation capabilities unique to HBD catalysts, this approach should enable phosphonium desymmetrization to be accomplished with exquisite enantioselectivity. The goal of this proposal is to design an anion pair binding organocatalyst to promote the first catalytic enantioselective phosphonium dealkylation reaction capable of producing P-chiral products. The research plan outlines a strategy to develop such a catalyst system guided by hypothesis-driven experimentation, computational modeling, and structure-activity studies. To add to the information gained in the reaction development, a detailed mechanistic study of HBD organocatalyst activation of simple phosphorus (III) substrates such as phosphonites and phosphites will be undertaken using data-intensive multi-dimensional correlation. This study will enable simple reagents to be utilized to produce medicinally relevant enantioenriched compounds in a novel manner, contributing enormously to medicinal research, catalyst development, and substantially contributing to scientific knowledge.