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

项目背景（确定问题及其重要性和与可持续性的相关性）氨基磷酸酯是磷酸的酰胺，是一类特别重要的有机磷化合物。含有该基团的分子在广泛的化学领域中具有各种商业应用。氨基磷酸酯中存在的P-N键赋予它们高度期望的药理学性质，例如与带有磷酸酯基团的那些相比改善的亲脂性、生物利用度和结合亲和力。因此，磷酰胺可以在磷酰胺酯前药（Pronucleotide）药物中找到。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，氨基磷酸酯还存在于杀虫/杀线虫化合物和用于普通家用织物的商业化防火涂料中。尽管它们丰富，但只有少数反应用于大规模合成这些化合物。许多方法涉及使胺与合适的有害磷酰卤物质反应。这些试剂不仅不受欢迎，而且它们往往是由化学武器前体磷酰亚胺制备的。有一些经常使用的合成路线可以避免处理磷酰卤化物，其中之一是Atherton-Todd反应。该反应涉及在碱存在下使H-膦酸酯与高毒性、化学计量量的卤化剂反应。氯代磷酸酯原位生成并与适当的胺亲核试剂反应以产生氨基磷酸酯产物。虽然这种方法避免了处理危险的磷酰基试剂的需要，但它仍然需要使用有毒的卤化剂和苛刻的反应条件。Staundinger-亚磷酸酯反应提供了合成氨基磷酸酯的替代途径。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期望的有机叠氮化物和有毒溶剂。 为了避免使用化学计量试剂，将使用催化氧化工艺。在这种合成中将使用H-膦酸酯，因为它们不是从化学武器的前体磷衍生的。工作包将首先集中在金属催化氧化条件下各种H-膦酸酯的活化。地球丰富的金属的有效性将在这些反应中探索，因为它们是廉价的，比稀有过渡金属更丰富。围绕这些金属的主要问题是，机械细节没有得到很好的理解。因此，这项工作的一部分将涉及详细的动力学和机理研究，这将有助于使用技术，如循环伏安法，EPR光谱，晶体学和HPLC，以进一步了解反应中真正发生的事情。这项工作不仅限于氨基磷酸酯的合成，因为同样可以应用于其他修饰的磷键，如硫代磷酸酯等。由于这些反应将应用于磷酰胺酯前药和寡核苷酸的合成，该项目的下一阶段将是合成P-立体纯氨基磷酸酯产品。在过去，立体化学已经通过使用手性助剂来控制。该研究的这一要素将涉及催化反应的开发，其中氨基磷酸酯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。工作包的这一要素将从合成用于预期不对称偶联反应的P-手性H-膦酸酯试剂开始。

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.