The 2-acetylthioethyl ester group: A versatile protective group for P-OH-groups

Phosphodiesters are bridging elements in nucleic acids. In nature and synthesis, their negative charge protects them from hydrolysis and controls their solubility profile. RNA is a promising material for gene technology but cellular uptake is low due to negative charges. Synthetic oligonucleotides were delivered into cells by a prodrug approach relying on the enzymatic release of the polyphosphodiester oligonucleotides. In synthetic chemistry, a protective group for the P–OH functionality is often necessary, e.g. due to solubility or chemical incompatibility. Several methods for P–OH protection were proposed, but often with low selectivity or harsh conditions. Here, we present the 2-acetylthioethyl group as a versatile protective group for low molecular weight or polymeric phosphodiesters, which can be cleaved under acidic conditions in water or by hydrazine in THF to release the P–OH-functionality, but olefins remain intact. This straightforward use allows designing various synthetic polyphosphodiesters, e.g. for flame-retardant or dispersants.