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

Lead Research Organisation: University of Nottingham
Department Name: Sch of Chemistry


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.

Planned Impact

This CDT will deliver impact aligned to the following agendas:

A2P will provide over 60 PhD graduates with the skill sets required to deliver innovative sustainable products and processes into the UK chemicals manufacturing industry. A2P will inspire and develop leaders who will:
- understand the needs of industrial end-users;
- embed sustainability across a range of sectors; and
- catalyse the transition to a more productive and resilient UK economy.

A2P will promote a step change towards a circular economy that embraces resilience and efficiency in terms of atoms and energy. The benefits of adopting more sustainable design principles and smarter production are clear. For example, the global production of active pharmaceutical ingredients (APIs) has been estimated at 65,000-100,000 tonnes per annum. The scale of associated waste is > 10 million tonnes per annum with a disposal cost of more than £15 billion. Consequently, even a modest efficiency increase by applying new, more sustainable chemical processes would deliver substantial economic savings and environmental wins. A2P will seek and deliver systematic gains across all sectors of the chemicals manufacturing industry. Our goals of providing cross-scale training in chemical sciences with economic and life- cycle awareness will drive uptake of sustainable best practice in UK industry, leading to improved economic competitiveness.

This CDT will deliver significant new knowledge in the development of more sustainable processes and products. It will integrate the philosophy of sustainability with catalysis, synthetic methodology, process engineering, and scale-up. Critical concepts such as energy/resource efficiency, life cycle analysis, recycling, and sustainability metrics will become seamlessly joined to what is considered a 'normal' approach to new molecular products. This knowledge and experience will be shared through publications, conferences and other engagement activities. A2P partners will provide efficient routes to market ensuring the efficient translation and transferal of new technologies is realised, ensuring impact is achieved.

The chemistry-using industries manufacture a rich portfolio of products that are critical in maintaining a high quality of life in the UK. A2P will provide highly trained people and new knowledge to develop smarter, better products, whilst increasing the efficiency and sustainability of chemicals manufacture.
To amplify the impacts of our CDT, effective public engagement and technology transfer will become crucially important. As a general comment, 'sustainability' styled research is often regarded in a positive light by society, however, the science that underpins its effective implementation is often poorly appreciated. The University of Nottingham has developed an effective communication portfolio (with dedicated outreach staff) to tackle this issue. In addition to more traditional routes of scientific communication and dissemination, A2P will develop a portfolio of engagement and outreach activities including blogs, webpages, public outreach events, and contribution of material to our award-winning YouTube channel, www.periodicvideos.com.

A2P will build on our successful Sustainable Chemicals and Processes Industry Forum (SCIF), which will provide entry to networks with a wide range of chemical science end-users (spanning multinationals through to speciality SMEs), policy makers and regulators. We will share new scientific developments and best practice with leaders in these areas, to help realise the full impact of our CDT. Annual showcase events will provide a forum where knowledge may be disseminated to partners, we will broaden these events to include participants from thematically linked CDTs from across the UK, we will build on our track record of delivering hi-impact inter-CDT events with complementary centres hosted by the Universities of Bath and Bristol.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S022236/1 01/10/2019 31/03/2028
2606406 Studentship EP/S022236/1 01/10/2021 04/08/2023 Hannah Simpson