H-Phosphonates as Green Starting Materials in the Synthesis of Phosphoramidates.

项目背景（查明问题及其对可持续性的重要性和相关性）磷酰胺是磷酸的酰胺，是一类特别重要的有机磷化合物。含有这一基团的分子在广泛的化学领域中得到了各种各样的商业应用。磷酸酯中存在的P-N键使它们具有非常理想的药理学特性，例如与具有磷酸酯基团的磷酸酯相比，具有更好的亲脂性、生物利用度和结合亲和力。因此，可以在ProTide（原核苷酸）药物中发现磷酰胺。一个关键的例子是Remdesivir，这是一种广谱抗病毒化合物，与最近的COVID-19大流行有关。除医药产品外，在普通家用织物的杀虫/杀线虫化合物和商业化阻燃涂料中也可以看到磷酰胺基团。尽管这些化合物丰富，但只有少数反应被用于大规模合成这些化合物。许多方法涉及胺与适当的危险卤化磷的反应。这些试剂不仅不受欢迎，而且它们通常是由化学武器前体三氯化磷制备的。有一些常用的合成路线可以避免处理磷酰卤化物，其中之一是阿瑟顿-托德反应。这个反应包括h -膦酸盐在碱的存在下与剧毒的、化学计量量的卤化剂反应。氯磷酸盐在原位生成，并与适当的胺亲核试剂反应生成酰胺化产物。虽然这种方法避免了处理危险的磷酰剂的需要，但仍然需要使用有毒的卤化剂和恶劣的反应条件。斯坦丁格-亚磷酸酯反应为合成氨基磷提供了另一种途径。然而，从可持续化学的角度来看，这种方法也是不利的，因为它依赖于使用不良的有机叠氮化物和有毒溶剂。建议的解决方案和方法为了避免使用化学计量试剂，将使用催化氧化过程。h -膦酸盐将用于这种合成，因为它们不是从化学武器的前驱物三氯化磷中提取的。该工作包将首先关注各种h -膦酸盐在金属催化氧化条件下的活化。在这些反应中，将探索富含地球元素的金属的有效性，因为它们比稀有的过渡金属更便宜且更丰富。围绕这些金属的主要问题是，人们对其机理细节还没有很好地了解。因此，这项工作的一部分将涉及详细的动力学和机理研究，并将使用循环伏安法、EPR光谱、晶体学和HPLC等技术来辅助研究，以进一步了解反应的真实情况。这项工作不仅局限于磷酰胺的合成，同样可以应用于其他修饰的磷键，如磷硫酸盐等。由于这些反应将用于合成ProTide和寡核苷酸，本项目的下一阶段将是合成p -立体纯磷酸酰胺产品。在过去，立体化学是通过使用手性助剂来控制的。研究的这一要素将涉及一种催化反应的发展，在这种催化反应中，磷酸酰胺产物的立体化学可以通过使用金属催化剂和手性配体来控制。工作包的这一部分将从p手性h -膦酸盐试剂的合成开始，用于未来的不对称偶联反应。

Project background (identification of the problem and its importance and relevance to sustainability) Phosphoramidates are the amides of phosphoric acid and are a particularly important class of organophosphorus compounds. Molecules containing this group have found various commercial applications within a wide range of chemical fields. The P-N bond present in phosphoramidates gives them highly desirable pharmacological properties such improved lipophilicity, bioavailability and binding affinity compared to those bearing phosphate ester groups. As a result of this, phosphoramidates can be found in ProTide (Pronucleotide) drugs. A key example being Remdesivir, a broad-spectrum antiviral compound which has been implicated in the recent COVID-19 pandemic. In addition to medicinal products, phosphoramidate groups are seen in insecticidal/nematocidal compounds and commercialised fire-retardant coatings for common household fabrics. Despite their abundance, only a few reactions are used to synthesise these compounds on a large scale. Many of the methods involve reacting an amine with a suitable hazardous phosphoryl halide species. Not only are these reagents undesirable but they are often prepared from the chemical weapons precursor phosphorous trichloride. There are synthetic routes that are frequently used that avoid the handling of phosphoryl halides, one of which is the Atherton-Todd reaction. This reaction involves reacting H-phosphonates with highly toxic, stoichiometric amounts of halogenating agents in the presence of a base. Chlorophosphates are generated in-situ and react with an appropriate amine nucleophile to produce the phosphoramidate product. Although this method avoids the need to handle the hazardous phosphoryl agents it still requires the use of toxic halogenating agents and harsh reaction conditions. The Staundinger-phosphite reaction provides an alternative route of synthesising phosphoramidates. However, this method is also unfavourable from the perspective of sustainable chemistry as it relies on the use of undesirable organic azides and toxic solvents. Proposed solution and methodology In order to avoid the use of stoichiometric reagents, a catalytic oxidation process will be used. H-Phosphonates will be used in this synthesis as they are not derived from the chemical weapon's pre-cursor phosphorus trichloride. The work package will first focus on the activation of various H-Phosphonates in metal catalysed oxidation conditions. The effectivity of earth abundant metals will be explored in these reactions as they are inexpensive and more abundant than the rare transition metals. The main issue surrounding these metals is that the mechanistic details are not well understood. Thus, part of this work will involve a detailed kinetic and mechanistic study which will be assisted using techniques such as cyclic voltammetry, EPR spectroscopy, crystallography and HPLC to gain further understand what is truly going on in the reaction. This work is not solely limited to phosphoramidate synthesis as the same could be applied to other modified phosphorous linkages such as phosphorothioates etc. As these reactions will be applied in the synthesis of ProTide and oligonucleotides, the next stage of this project will be the synthesis of P-stereogenically pure phosphoramidate products. In the past, the stereochemistry has been controlled via the use of a chiral auxiliary. This element of the research will involve the development of a catalytic reaction in which the stereochemistry of the phosphoramidate product can be controlled by use of a metal catalyst and chiral ligands. This element of the work package will commence with the synthesis of the P-chiral H-Phosphonate reagents for use in the prospective asymmetric coupling reactions.