The Art Of Phosphitylation

Phosphorylation is a critical process in preparing new biologically active molecules like oligonucleotides, phosphopeptides, carbohydrate phosphates, and phospholipids. Oligonucleotides are an important emerging class of drugs in clinical trials for treating various conditions, including cancers, viral infections, and inflammatory disorders. The introduction of a pentavalent phosphorus P^v reagent or phosphitylation with trivalent phosphorus P^III reagents followed by oxidation are the two primary methods for phosphorylation.

Phosphitylation using phosphoramidites and chlorophosphoramidites is widely used due to the enhanced reactivity of P^III reagents compared to less reactive P^v reagents. Phosphoramidites are particularly useful as they do not react with alcohols or other H-nucleophiles unless specifically activated. The choice of protecting groups on the P^III reagent, particularly the amino and alkoxy groups, is critical for tuning the reaction's efficiency and coupling selectivity. Explore the benefits of P^III reagents, protecting group selection, and key synthesis schemes for phosphorylation in the full technical note.