Advancing sustainable alcohol phosphorylation through acid-base catalysis

Nucleosides, containing a five-carbon sugar and a nitrogenous base, are essential for antiviral and cancer therapy. Before they can be active in vivo, they need to be phosphorylated at the 5’-OH group of the sugar moiety. These compounds are administered as neutral, phosphoramidate precursors (pronucleotides). Current standard methods for preparing prodrug phosphoramidates start from chlorinated precursors and face problems concerning chloride wastes, chemo- or regioselectivity at the nucleoside and difficult stereochemical control of the chiral P-atom. The proposed research will use Zr-containing metal-organic frameworks (MOF) for the synthesis of phosphoramidates and pronucleotides. We will aim for selective formation of P-O and P-N bonds starting from P(V)- precursors. We hypothesize that rates and selectivities of the so far known homogeneous catalysts can be surpassed by a double activation, both of the P=O compound and the nucleophile. To start, suitable MOFs with coordinatively unsaturated Zr sites will be identified for catalyzing nucleophilic substitution reactions of phosphate esters and phosphoramidates. Next, we will maximize positional and stereoselectivity of the P-O and P-N bond formation. Spectroscopic and kinetic studies will give insight in the reaction mechanisms. Eventually, the reaction will be upscaled and the solid catalysts will be demonstrated with practical cases.