Organoborane-catalysed approaches to biologically active amines

为了发现一种新药，学术和工业研究人员需要获得不同的分子集合。然而，药物发现的缓慢步骤是从更简单的构建块合成这些生物活性分子。在许多情况下，目前的技术无法获得关键分子，这阻碍了研究人员探索理解和开发新药所需的全部化学结构。在药物发现过程中使用的大约80%的分子含有氮原子（以胺的形式），因此产生新胺结构的新方法在药物发现领域受到高度重视。在这个项目中，我们将探索有机硼烷的独特反应性，以开发一个新的和通用的胺合成催化平台。有机硼烷具有从胺中提取氢化物的特殊能力，生成活性阳离子中间体和与硼结合的氢化物。这种独特的反应性将允许在新工艺中使用常见的和现成的构建块。在项目中发现的方法将很容易使用，不需要特殊培训。它还将通过高原子经济性产生低废物。该项目将通过解决药物发现中的具体挑战，向学术界、制药和支持合同研究行业的目标最终用户展示这些新工具的实用性。例如，通过解决含氮分子合成的限制，我们将能够获得新的和以前无法获得的结构。这将改变药物和生物化学家的能力，使他们能够清晰地描绘出结构-活性关系，这对研究疾病和开发新的治疗方法至关重要。该项目分为三个目标，代表三个反应类别，我们将利用有机硼烷的独特能力来解决挑战。- Aim 1将首次直接和模块化合成在治疗各种精神疾病的血清素能/多巴胺能药物中发现的特殊芳基烷基胺。这一目标将使芳烷基胺的有效获取成为可能，并允许对结构如何影响活性进行全面和系统的研究，从而导致更有效的治疗。- Aim 2将开发一种新的方法来催化胺的- CH基化。我们将展示该方法在各种经过验证的药物的后期功能化中的实用性，以便可以从已知的分子模板中有效地发现新的或改进的生物活性。-目标3将开发一种合成一类常见的生物活性N-杂环，四氢喹啉的新方法。我们将解决当前方法的具体局限性，并将使化学空间快速探索与癌症，疼痛，骨质疏松症，寄生虫感染和过敏治疗相关的结构活性关系。

In order to discover a new medicine, academic and industrial researchers require access to diverse collections of molecules. However, the slow step in medicine discovery is the synthesis of these biologically active molecules from simpler building blocks. In many cases, key molecules are inaccessible with current technologies, which prevents researchers exploring the full range of chemical structures required to understand and develop a new medicine. Around 80% of the molecules used in the drug discovery process contain a nitrogen atom (in the form of amines), and therefore novel methods that generate new amine structures are highly valued in the drug discovery arena. In this project, we will explore the unique reactivity of organoboranes to develop a novel and general catalytic platform for the synthesis of amines. Organoboranes have an unusual ability to abstract hydride from amines, generating a reactive cationic intermediate and a hydride bound to boron. This unique reactivity will allow common and readily available building blocks to be used in novel processes. The methods discovered in the project will be easy to use and not require special training. It will also generate low waste through high atom economy. The project will demonstrate the utility of these new tools to targeted end-users in academia, and pharmaceutical and supporting Contract Research industries, by solving specific challenges in drug discovery. For example, by addressing limitations in the synthesis of nitrogen-containing molecules, we will enable access to new and previously inaccessible structures. This will transform medicinal and biological chemists' abilities by enabling them to develop clear pictures of structure-activity relationships that are critical for studying disease and developing new treatments.The project is divided into three Aims that represent the three reaction classes where we will employ the unique abilities of organoboranes to solve challenges.- Aim 1 will target the first direct and modular synthesis of privileged aryl alkyl amines found in serotonergic/dopaminergic pharmaceuticals that treat a variety of mental illnesses. This Aim will enable efficient access to aryl alkyl amines and allow a full and systematic study of how structure affects activity and therefore lead to more efficacious treatments.- Aim 2 will develop a new approach to the catalytic alpha CH arylation of amines. We will demonstrate utility of this method in the late-stage-functionalisation of a variety of validated medicines so that new or improved bioactivity can be efficiently discovered from known molecular templates.- Aim 3 will develop a new approach to the synthesis of a common class of bioactive N- heterocycles, tetrahydroquinolines. We will address specific limitations of current methods and will enable the rapid exploration of chemical space for structure activity relationships related to treatments for cancer, pain, osteoporosis, parasite infections and allergies for the first time.