A P(V) platform for oligonucleotide synthesis.

The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food and Drug Administration approvals for therapeutic oligonucleotides, by far most of which contain modified phosphate linkages. These unnatural linkages have desirable biological and physical properties but are often accessed with difficulty using phosphoramidite chemistry. We report a flexible and efficient [P(V)]–based platform that can install a wide variety of phosphate linkages at will into oligonucleotides. This approach uses readily accessible reagents and can install not only stereodefined or racemic thiophosphates but any combination of (, or )–PS with native phosphodiester (PO) and phosphorodithioate (PS) linkages into DNA and other modified nucleotide polymers. This platform easily accesses this diversity under a standardized coupling protocol with sustainably prepared, stable P(V) reagents.