Catalytic Enantioselective Nucleophilic Desymmetrisation of Phosphonate Esters

22 July 2021, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

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 being 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 a catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the first 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.

Keywords

P(V)
Superbase
Enantioselective
Desymmetrisation

Supplementary materials

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Description
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Supporting Information
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Supporting Information including analytical data, NMR spectra and HPLC traces
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Crystallographic Data
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Crystallographic Data CIF file
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Checkcif
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Check cif file for single crystal X-ray structures.
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