Nitrogen- and Oxygen-Radicals-Based Strategies for the Divergent Assembly of Novel Building Blocks by Strain-Release

基于氮和氧自由基的策略，用于通过应变释放来不同组装新型构件

• 批准号: EP/T016019/1
• 负责人: Stephen Liddle
• 金额: $ 49.92万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FT016019%2F1
• 关键词: Nitrogen; Oxygen; Radicals; Based; Strategies

The invention of chemical reactions that form C-N and C-O bonds in novel ways is of strategic importance to discover and evolve molecules that impact our society. As the pharmaceutical and agrochemical sectors are now aware of the greater clinical success of sp3-rich molecules, developing methods to prepare 3D-shaped and saturated building blocks is fundamental to our well-being.The small and strained bicyclo[1.1.1]pentyl motif has been identified as a powerful bioisostere to replace flat (2D) aromatics and improve the potency of lead molecules. However, difficulties in preparing and modifying this structural element have severely limited its use in biological and medicinal chemistry. There is an urgent need to develop novel methods that can effectively manipulate and introduce this motif into organic compounds.The overarching aim of this project is to exploit the generation of nitrogen-radicals using the visible-light-mediated approach developed in our group and then use these species in "radical strain-release reactions". This reactivity mode will explore the ability of nitrogen-radicals to react with propellane (a highly strained hydrocarbon) by cleaving a strong sp3-sp3 C-C bond. This reactivity will then be harnessed as part of a radical multicomponent strategy to access poly-functionalised bicyclo[1.1.1]pentylamines and, using oxygen-radicals, bicyclo[1.1.1]penthanols.In this way, we will provide unique reactions streamlining the synthesis of N- and O-containing sp3-rich molecules currently very difficult to prepare but highly sought after by pharmaceutical and agrochemical discovery programs.The project is divided in three Aims that will address specific challenges relevant to the preparation of bioisosteres of anilines and phenols.Aim 1. We will use our knowledge in nitrogen-radical generation using photocatalysis to develop unprecedented radical-strain-release cascades. The chemistry involves the generation of amidyl radicals, which subsequently react with propellane by strain-release and then are diversified by a final atom/group-transfer reaction with a broad range of radical trapping agents. We will evaluate the scope and limitations of this strategy and we will apply it to the preparation of novel and currently elusive bioisosteres of frequently prescribed drugs.Aim 2. This photocatalytic strategy for nitrogen-radical strain-release will be expanded by merging it with nickel catalysis. Thus, we will provide an innovative dual photoredox-nickel platform for the preparation of valuable building blocks containing both N- and C-based substituents across the bicyclo[1.1.1]pentyl core.Aim 3. The strategy for radical strain-release will then be extended to oxygen-radicals. This will enable fast and divergent access to a broad range of poly-functionalised bicyclo[1.1.1]penthanols. These molecules have application as phenol bioisosteres but they are currently very difficult to prepare even through lengthy synthetic sequences.A relevant aspect of this research project will be investigating the scalability of these processes that we will develop. This will be evaluated through a collaboration with AstraZeneca (Macclesfield) that has agreed to host the PDRA associated to the project in their state-of-the-art flow-chemistry facilities.Overall, this project will develop an innovative strategy for the fast, selective and divergent preparation of sp3-rich building blocks containing nitrogen- and oxygen-based functionalities. The possibility to access these high-value materials will facilitate the discovery, development and manufacture of therapeutic agents and agrochemicals with overall impact to the well-being of UK society.

以新的方式形成C-N和C-O键的化学反应的发明对于发现和进化影响我们社会的分子具有战略重要性。随着制药和农用化学品部门现在意识到富含sp3的分子在临床上取得了更大的成功，开发制备3D形状和饱和结构单元的方法对我们的福祉至关重要。小而紧张的双环[1.1.1]戊基基序已被确定为强大的生物电子等排体，可取代平面（2D）芳烃并提高铅分子的效力。然而，制备和修饰这种结构元件的困难严重限制了其在生物和药物化学中的应用。因此，迫切需要开发新的方法，可以有效地操纵和引入到有机化合物的motif。本项目的总体目标是利用氮自由基的产生使用可见光介导的方法在我们的小组开发，然后使用这些物种在“自由基应变释放反应”。该反应模式将探索氮自由基通过断裂强sp3-sp3 C-C键与螺桨烷（一种高度应变的烃）反应的能力。然后将利用该反应性作为自由基多组分策略的一部分以获得多官能化的双环[1.1.1]戊胺，并且使用氧自由基获得双环[1.1.1]戊醇。我们将提供独特的反应，简化合成含N和O的sp3-丰富的分子，目前很难制备，但高度追捧的药物和农用化学品发现计划。该项目分为三个目的是解决与苯胺和苯酚的生物电子等排体的制备相关的具体挑战。我们将利用我们在氮自由基生成方面的知识，使用NH 4来开发前所未有的自由基应变释放级联。化学涉及生成酰胺基自由基，其随后通过应变释放与螺桨烷反应，然后通过与广泛的自由基捕获剂的最终原子/基团转移反应而多样化。我们将评估这一策略的范围和局限性，并将其应用于制备新的和目前难以捉摸的常用处方药的生物电子等排体。这种氮自由基应变释放的光催化策略将通过将其与镍催化剂合并来扩展。因此，我们将提供一种创新的双光氧化还原-镍平台，用于制备在双环[1.1.1]戊基核上含有N-和C-基取代基的有价值的结构单元。然后将自由基应变释放的策略扩展到氧自由基。这将使得能够快速和分散地获得广泛的多官能化双环[1.1.1]戊醇。这些分子具有作为苯酚生物电子等排体的应用，但它们目前非常难以制备，即使是通过冗长的合成序列。本研究项目的一个相关方面将调查我们将开发的这些过程的可扩展性。这将通过与阿斯利康（Macclesfield）的合作进行评估，阿斯利康已同意在其最先进的流动化学设施中主持与该项目相关的PDRA。总的来说，该项目将开发一种创新策略，用于快速，选择性和多样化制备含有氮基和氧基功能的富含sp3的构建模块。获得这些高价值材料的可能性将促进治疗剂和农用化学品的发现、开发和制造，对英国社会的福祉产生全面影响。

项目成果

A Desaturative Approach for Aromatic Aldehyde Synthesis via Synergistic Enamine, Photoredox and Cobalt Triple Catalysis.

• DOI: 10.1002/anie.202201870
• 发表时间: 2022-04-25
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Zhao, Huaibo;Caldora, Henry P.;Turner, Oliver;Douglas, James J.;Leonori, Daniele
• 通讯作者: Leonori, Daniele

Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer

• DOI: 10.1038/s41929-021-00652-8
• 发表时间: 2021-07-12
• 期刊: NATURE CATALYSIS
• 影响因子: 37.8
• 作者: Gorski, Bartosz;Barthelemy, Anne-Laure;Leonori, Daniele
• 通讯作者: Leonori, Daniele

A Desaturative Approach for Aromatic Aldehyde Synthesis via Synergistic Enamine, Photoredox and Cobalt Triple Catalysis

烯胺、光氧化还原和钴三重协同催化去饱和合成芳香醛的方法

• DOI: 10.1002/ange.202201870
• 发表时间: 2022
• 期刊: Angewandte Chemie
• 作者: Zhao H