Synthesis of phosphorothioates by photocatalytic sulfur transfer from thiosulfate

With therapeutic oligonucleotides progressing from the treatment of rare genetic diseases to the medication of common disorders, the synthesis of modified oligonucleotides is gaining considerable significance. To improve pharmacokinetic and pharmacodynamic properties, chemical modifications to the nucleotide backbone are thereby especially advantageous. In particular the incorporation of phosphorothioate moieties have proven to be an effective strategy, since this linkage often provides increased metabolic stability and beneficial activity compared to regular phosphates. Herein, we now establish that visible-light photocatalysis for oligonucleotide synthesis allows to generate phosphorothioates by an exceptionally mild and general sulfurisation with conventional thiosulfate as a benign sulfur source. The method was applied to efficiently prepare DNA and RNA phosphorothioates, phosphoramidothioate and phosphine sulfides. Furthermore, the protocol was integrated into standard solid-phase phosphoramidite oligonucleotide synthesis using riboflavin (vitamin B2) as photocatalyst in water, representing a sustainable means for the synthesis of DNA and RNA phosphorothioates.