New Enantioselective Catalytic Desymmetrisation Reactions

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


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 James
This project falls within the EPSRC Physical Sciences research area


10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/T517811/1 30/09/2020 29/09/2025
2446223 Studentship EP/T517811/1 30/09/2020 31/03/2024 Thomas Marsh