Organophosphonates are common motifs in nucleotides, pesticides, herbicides, and flame retardants. Commonly, phosphate mimics possess four unique substituents, and thereby a chirality centre. These chiral phosphate mimics are useful in transition metal catalysis and as nucleotide therapeutics. Use of phosphorus-stereogenic analogues in antisense therapy improves potency, stability toward enzymatic degradation, and bioavailability. The catalytic, stereocontrolled synthesis of phosphorous-stereogenic centres is challenging, and traditionally, depends on resolution or use of stochiometric auxiliaries. Herein, enantioenriched phosphorous centres have been synthesized using nucleophilic catalysis. A racemic H-Phosphonate species were coupled to the nucleophilic alcohols under halogenating conditions. Chiral phosphonate products were synthesized in modest yield and enantioselectivity (62% ee) after identification of an appropriate chiral catalyst and optimization of the solvent, base and temperature. These products could be significantly utilized as phosphonate prodrugs and/or analogues for studies in a biological system.

Asymmetric synthesis of stereogenic phosphorous centers using chiral nucleophilic catalysis

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.