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：含有一个或多个 P(V) 氧化态磷原子的化合物对于化学、生物学和医学都很重要。其中包括市售抗病毒药物，如替诺福韦艾拉酚胺、福斯德韦林和索磷布韦，后者被列入世界卫生组织治疗丙型肝炎基本药物清单。其他相关化合物包括用于治疗高血压的福辛普利、化疗药物环磷酰胺和强效除草剂齐创。因此，有效合成含 P(V) 化合物的新方法和改进方法，特别是以对映选择性方式，是至关重要的。传统上，它们的合成依赖于相应 P(III) 物质的氧化、使用手性助剂，然后分离非对映体或通过拆分。尽管用于合成外消旋 P(V) 化合物的有希望的方案已经开始出现，但用于 P-立体中心立体选择性合成的新战略方法仍然有限，并且催化对映选择性方法仍然很大程度上未知。提案愿景：我们的计划是设计、发现和开发新的催化剂系统和催化反应，从而在一个对映选择性步骤中直接对映选择性合成手性磷酸酯、膦酸酯及其硫杂和氮杂类似物。我们希望利用丰富的商业磷（V）起始材料来快速且可扩展地制备合适的对称前手性反应前体，并通过合适的催化剂去对称化产生高对映体过量的合成相关的手性磷中间体，该中间体可以可用于众多下游合成应用。将研究用于去对称化的各种底物以及它们将参与的反应类型。进一步的研究将探索手性外消旋反应前体的动力学不对称转变。由于医药和农业化学领域生物相关的手性磷 (V) 化合物丰富，并且未来几年对此类化合物的需求可能会增加，新的选择性和催化合成方法可能会在大规模合成、文库生成等领域得到广泛应用、后期功能化和药物分子合成等。目标：我们上述初步研究成功的绝对关键是识别新的催化剂驱动的反应性。首先，这是通过双功能亚氨基正膦超强碱催化剂系统的独特性质产生的，可在对映体离去基团的直接对映选择性取代反应中同时活化苯酚亲核试剂。这些研究证明了我们提出的新对映选择性反应开发研究的合成效用和巨大潜力。在这个学生项目中，我们将：1）探索磷（V）催化对映选择性亲核去对称反应的完整范围和其他变体（例如有机金属试剂的金属催化取代反应）。2）探索去对称取代反应的分子内变体以获得各种循环化疗药物。3）探索介观磷酸和-使用手性布朗斯台德碱和/或相转移催化剂的膦二硫酸。4) 使用物理有机方法和 DFT 探测机制，以揭示催化剂活化和立体选择性的起源。工业合作者：阿斯利康与工业主管 Thomas James 博士该项目属于 EPSRC 物理科学研究领域