Photocatalytic synthesis of phosphorothioates by 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 has proven to be an effective strategy, since this linkage often provides increased metabolic stability and beneficial activity compared to phosphates. Herein, we describe that visible-light photocatalysis allows the generation of phosphorothioates by an exceptionally mild and general sulfurization with conventional thiosulfate as a benign sulfur source. The method was applied to efficiently prepare DNA and RNA phosphorothioates, phosphoramidothioate, phosphine sulfides and phosphoramidodithioate. Furthermore, the protocol was translated to the synthesis of phosphoroselenoates using selenosulfate and was integrated into standard solid-phase phosphoramidite oligonucleotide synthesis to form phosphorothioates with riboflavin (vitamin B2) as a photocatalyst in water, representing a sustainable means for the synthesis of DNA and RNA phosphorothioates.