New Enantioselective Catalytic Desymmetrisation Reactions

新的对映选择性催化去对称反应

• 批准号: 2446223
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2446223
• 关键词: New; Enantioselective; Catalytic; Desymmetrisation; Reactions

Introduction and background: Compounds containing one or more phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as such as Tenofovir alafenamide, Fosdevirine, and Sofosbuvir the latter being on the WHO list of essential medicines for the treatment of Hepatitis C. Other relevant compounds include Fosinopril for the treatment of hypertension, chemotherapy agent Cyclophosphamide and potent herbicide Zytron. Accordingly, new and improved methods for the efficient synthesis of P(V) containing compounds, especially in an enantioselective fashion are essential. Classically, their synthesis has relied on oxidation of the corresponding P(III) species, use of chiral auxiliaries followed by separation of diastereomers or via resolution. Although promising protocols are beginning to arise for the synthesis of racemic P(V) compounds, new strategic approaches for the stereoselective synthesis of P-stereogenic centres are limited and catalytic enantioselective approaches remain largely unknown. Proposal vision: Our plan is to design, discover and develop new catalyst systems and catalysed reactions that will allow the direct and enantioselective synthesis of chiral phosphates, phosphonates and their thia and aza analogues, in a single enantioselective step. We wish to capitalise on the abundance of commercial phosphorous (V) starting materials to allow the ready and scalable preparation of suitable symmetric prochiral reaction precursors and through a suitable catalyst-enabled desymmetrization generate, in high enantiomeric excess, synthetically relevant chiral phosphorous intermediates that can be employed in numerous downstream synthetic applications. Various substrates for desymmetrization will be investigated as will the types of reaction they will engage in. Further studies will explore kinetic asymmetric transformations of chiral racemic reaction precursors. Owing to the abundance of biologically relevant chiral phosphorous (V) compounds across medicinal and agrochemical sectors and the likely increase in the demand for such compounds over the coming years new selective and catalytic synthetic approaches would likely find numerous applications in large scale synthesis, library generation, late stage functionalisation, and drug molecule synthesis alike. Objectives: Absolutely key to the success of our preliminary studies described above is the identification of new catalyst-enabled reactivity. In the first instance this has arisen through the unique properties of the bifunctional iminophosphorane superbase catalyst system to simultaneously activate the phenol nucleophile in the direct enantioselective substitution reaction of enantiotopic leaving groups. These studies demonstrate the synthetic utility and great potential of our proposed research into new enantioselective reaction development. During this studentship project we will:1) Explore the full scope and other variants (such as metal catalysed substitution reactions with organometallic reagents) of the catalytic enantioselective nucleophilic desymmetrization reaction at phosphorous(V).2) Explore intramolecular variants of the desymmetrizing substitution reaction to access various cyclic chemotherapeutics.3) Explore novel organocatalyzed desymmetrization reactions of meso-phosphoric and -phosphinodithionic acids using chiral Bronsted base and/or phase transfer catalysts.4) Probe mechanism using physical organic methods and DFT to uncover origins of the catalyst activation and stereoselectivity.Industrial Collaborators: AstraZeneca with industrial supervisor Dr Thomas JamesThis project falls within the EPSRC Physical Sciences research area

简介和背景：P（V）氧化态中包含一个或多个磷原子的化合物对化学，生物学和医学很重要。其中包括诸如Tenofovir Alafenamide，Fosdevirine和Sofosbuvir之类的销售抗病毒药物，后者在WHO中是WHO乙型肝炎的基本药物清单。其他相关化合物包括fosinerpril治疗高压治疗高压治疗，化学疗法剂环磷有磷酸胺和potentsententsententsherbicididididiide和Potent Zytron。因此，有效合成含有化合物的P（V）的新方法和改进的方法，尤其是在对映选择性方面。从经典上讲，它们的合成依赖于相应的P（iii）物种的氧化，使用手性辅助机，然后通过分离来映异构体或通过分辨率进行分离。尽管对于外消旋P（V）化合物的合成而开始出现有希望的方案，但p-螺旋中心的立体选择性合成的新战略方法有限，并且催化对映射方法仍然在很大程度上未知。提案视觉：我们的计划是在一个对映选择性步骤中设计，发现和开发新的催化剂系统和催化反应，以允许直接和对映选择性合成手性磷酸盐，磷酸盐，磷酸盐及其Thia和Aza类似物。我们希望利用丰富的商业磷（V）起始材料，以允许准备合适的对称性手术反应前体，并通过适当的启用催化剂的DESMOMEMEMEMEMERIZER产生，以高映体过量的过量，合成相关的手性磷磷中的中介体，这些中介具有许多在多种下属的应用中。将研究各种底物进行脱位，以及它们将参与的反应类型。进一步的研究将探索手性的外星人反应前体的动力学不对称转化。由于跨药物和农业化学领域的生物学相关性手性磷（V）化合物的丰富性，并且在未来几年内对此类化合物的需求的可能增加可能会增加新的选择性和催化合成方法，这可能会发现大规模合成，图书馆合成，晚期功能和药物分解的大规模合成中的众多应用。目标：上述初步研究成功的绝对关键是鉴定了新的催化剂反应性。首先，这是通过双功能亚氨基磷酸酯超级碱催化剂系统的独特特性而产生的，可以同时激活映射离开组的直接对映选择性取代反应中的苯酚亲核试剂。这些研究表明，我们对新的对映选择性反应发展的拟议研究的合成效用和巨大潜力。在此学生验证项目中，我们将：1）探索催化型对映射的亲核脱素化反应（V）在磷（V）.2）的全部范围和其他变体（例如与有机金属试剂的金属催化取代反应）。使用手性培养基碱和/或相位转移催化剂对中磷酸和磷酸化的脱磷酸反应。4）使用物理有机方法和DFT进行探测机制，并探测催化剂激活和立体选择的催化剂的起源。工业合作者与工业主管：experrial jamas jamas jamas projecthmas jamas projecthmas jamamas jamamas dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr dr.科学研究领域