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

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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.