New Enantioselective Catalytic Desymmetrisation Reactions

前言和背景：P(V)氧化态中含有一个或多个磷原子的化合物在化学、生物和医学中具有重要的意义。这些药物包括市面上销售的抗病毒药物，例如替诺福韦丙氨酰胺、福司德韦林和索福布韦，后者被列入世界卫生组织治疗丙型肝炎的基本药物名单。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力除草剂赛特隆。因此，高效合成P(V)化合物，特别是以对映体选择性的方式合成P(V)化合物的新方法和改进方法是必不可少的。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，然后分离非对映异构体或通过拆分。尽管合成外消旋P(V)化合物的新方案已经开始出现，但立体选择性合成P-立体中心的新战略方法是有限的，催化对映体选择性方法在很大程度上仍然是未知的。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，允许在单一的对映选择性步骤中直接和对映选择性地合成手性磷酸盐、膦酸酯及其硫代和氮杂类似物。我们希望利用商业磷(V)原料的丰富，使适当的对称前手性反应前体的制备变得容易和可扩展，并通过适当的催化剂使能的去对称化生成高对映体过剩的合成相关的手性磷中间体，这些中间体可用于许多下游合成应用。我们将研究各种不同的脱对称底物，以及它们将进行的反应类型。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化。由于医药和农用化学领域大量具有生物相关性的手性磷(V)化合物，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在大规模合成、文库生成、后期官能化和药物分子合成等方面获得广泛应用。目的：上述初步研究成功的绝对关键是确定新的催化剂使能的反应活性。在第一种情况下，这是由于双官能团亚胺基膦超碱催化剂体系的独特性质，在对映体离开基团的直接对映体选择性取代反应中同时激活了苯酚亲核试剂。这些研究表明，我们提出的新的对映选择性反应开发研究具有合成实用价值和巨大潜力。在这个学生项目中，我们将：1)探索磷(V)催化的对映体选择性亲核去对称反应的全部范围和其他变体(例如，金属与有机金属试剂的催化取代反应)。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)利用手性Bronsted碱和/或相转移催化剂，探索新的有机催化中磷和膦二硫酸脱对称反应。4)使用物理有机方法和密度泛函理论来探索催化剂的活化和立体电子的起源。工业合作者：AstraZena与工业主管Thomas JamesesDr博士本项目属于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