New Enantioselective Catalytic Desymmetrisation Reactions

简介和背景：含有一个或多个P(V)氧化态磷原子的化合物在化学、生物学和医学中具有重要意义。这些药物包括已上市的抗病毒药物，如替诺福韦、氟替韦林和索非布韦（后者被列入世卫组织治疗丙型肝炎基本药物清单）。其他相关化合物包括治疗高血压的福辛普利、化疗药物环磷酰胺和强效除草剂Zytron。因此，需要新的和改进的方法来高效地合成含P(V)的化合物，特别是以对映选择性的方式。传统上，它们的合成依赖于相应的P（III）物种的氧化，使用手性助剂，然后分离非对映体或通过拆分。虽然合成外消旋P(V)化合物的有希望的方案开始出现，但立体选择性合成P-立体中心的新策略方法有限，催化对映选择性方法在很大程度上仍然未知。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，这些系统和催化反应将允许在单个对映选择步骤中直接和对映选择性地合成手性磷酸盐，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，允许准备和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激活的去对称化，在高对映体过剩的情况下，合成相关的手性磷中间体，可用于许多下游合成应用。各种底物的不对称将被调查，将反应的类型，他们将参与。进一步的研究将探讨手性外消旋反应前体的动力学不对称转化。由于生物相关的手性磷(V)化合物在医药和农化领域的丰富，以及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、后期功能化和药物分子合成等方面找到大量应用。目的：上述初步研究成功的关键是确定新的催化剂激活反应性。首先，这是通过双功能亚磷烷超碱催化剂体系的独特性质而产生的，它可以在对映基离去基的直接对映选择性取代反应中同时激活酚亲核试剂。这些研究证明了我们在新的对映选择性反应开发方面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)催化的对映选择性亲核去对称反应的全部范围和其他变体（如金属催化与有机金属试剂的取代反应）。2)探索去对称取代反应的分子内变异，以获得各种循环化疗药物。3)利用手性Bronsted碱和/或相转移催化剂，探索新型有机催化中介磷和-磷二硫酸的脱对称反应。4)利用物理有机方法和DFT探索催化剂活化和立体选择性的机理。工业合作者：阿斯利康与工业主管Dr Thomas james该项目属于EPSRC物理科学研究领域

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