Phosphorothioate oligonucleotides are routinely prepared as uncontrolled mixtures of diastereomers, using highly optimized P(III) based phosphoramidite chemistry. While methods for stereocontrolled synthesis using modified phosphoramidites have been described, these methods rely on non-commercially available reagents, and are technically complex to carry out. We developed a P(V) based platform to enable stereodefined oligonucleotide synthesis on solid phase, and extended that method to incorporate other types of oligonucleotide linkages, such as phosphodiesters and phosphorodithioates. The synthetic cycle for these transformations is simplified with respect to P(III) as the phosphorus is maintained in the desired P(V) oxidation state throughout. In order to enable widespread uptake of these methods, these reagents have been made commercially available.

Development of a P(V) method for stereocontrolled oligonucleotide synthesis

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