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Catalytic Enantioselective Nucleophilic Desymmetrisation of Phosphonate Esters

Abstract

Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation
state are important to chemistry, biology and medicine. These include marketed
antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment
for Ebola which has also recently been approved for use against SARS-CoV-2 in the US.
Existing approaches for the stereoselective synthesis of P-stereogenic centers, while
elegant, remain mostly diastereoselective, with catalytic enantioselective approaches
remaining limited in application. Accordingly, conceptually novel, broad-scope, catalytic
strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing
compounds remain essential.
To this end, we describe a novel enantioselective two-stage strategy, exploiting the first catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages.

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