New Enantioselective Catalytic Desymmetrisation Reactions
新的对映选择性催化去对称反应
基本信息
- 批准号:2446223
- 负责人:
- 金额:--
- 依托单位:
- 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:
- 关键词:
项目摘要
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
导言和背景:含有一个或多个P(V)氧化态磷原子的化合物对化学、生物学和医学都很重要。这些包括市售的抗病毒药物,例如替诺福韦艾拉酚胺,Fosdevirine和Sofosbuvir,后者在WHO治疗丙型肝炎的基本药物清单上。其他相关化合物包括用于治疗高血压的福辛普利、化疗剂环磷酰胺和强效除草剂Zytron。因此,有效合成含P(V)的化合物的新的和改进的方法,特别是以对映选择性方式合成含P(V)的化合物的新的和改进的方法是必要的。传统上,它们的合成依赖于相应的P(III)物质的氧化,使用手性助剂,然后分离非对映异构体或通过拆分。虽然有前途的协议开始出现外消旋P(V)化合物的合成,新的战略方法的立体选择性合成的P-立体中心是有限的,催化对映体选择性的方法仍然在很大程度上未知。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,这将允许直接和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,在一个单一的对映选择性步骤。我们希望利用商业磷(V)起始材料的丰富性,以允许容易且可规模化地制备合适的对称前手性反应前体,并通过合适的催化剂使能的去对称化以高对映体过量产生合成相关的手性磷中间体,其可用于许多下游合成应用。各种基板去对称化将被调查,因为将类型的反应,他们将从事。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。由于在医药和农业化学领域中生物相关的手性磷(V)化合物的丰富性以及未来几年对此类化合物的需求可能增加,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得到许多应用。目的:我们上述初步研究成功的绝对关键是鉴定新的催化剂激活的反应性。在第一种情况下,这是通过双官能亚氨基膦超强碱催化剂体系的独特性质而产生的,该催化剂体系在对映异构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。这些研究表明,我们提出的研究新的对映选择性反应的发展的合成效用和巨大的潜力。在这个学生项目中,我们将:1)探索完整的范围和其他变量(如金属催化的取代反应)的催化对映选择性亲核去对称化反应在磷(V)。2)探索去对称化取代反应的分子内变体,以获得各种环状化学疗法。3)探索使用手性布朗斯台德碱和/或相转移催化剂的新型有机催化的中磷酸和膦基二磺酸的去对称化反应。4)使用物理有机方法和DFT探索机制,以揭示催化剂活化和立体选择性的起源。阿斯利康与工业主管托马斯詹姆斯博士该项目属于EPSRC物理科学研究领域的福尔斯
项目成果
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其他文献
吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
- DOI:
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LiDAR Implementations for Autonomous Vehicle Applications
- DOI:
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2021 - 期刊:
- 影响因子:0
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吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
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