Oligonucleotide-based medicines are an exciting and proven therapeutic modality whereby the production of specific proteins can be controlled through selective binding to mRNA using Watson-Crick-Franklin base pairing. In principle, this approach can tackle the root causes of disease, offer prolonged therapeutic benefits, and be effective against seemingly intractable indications. For example, nusinersen (Spinraza), the first oligonucleotide FDAapproved drug for the treatment of spinal muscular atrophy, consists of 18 nucleosides linked by phosphorothioate (PS) bonds , enhancing its metabolic stability and cellular uptake (known as the "thio-effect"). Now considered an essential component of therapeutic oligonucleotides, the PS modification is present in nearly every FDA-approved oligonucleotide therapeutic. Through traditional solid-phase oligonucleotide synthesis (SPOS), PS linkages are introduced with uncontrolled stereochemistry, creating 2 n isomers (where n is the number of PS linkages), often resulting in mixtures of over 100,000 diastereoisomers. This long-standing synthetic challenge in the field was the inspiration to develop a new approach to oligonucleotide synthesis using the P(V)-oxidation state featuring exquisite control of stereochemistry. In contrast to widely used P(III)based protocols (Figure ), P(V) reduces the step count per synthesis cycle and provides complete stereocontrol rather than stereorandom or stereoenriched products. Although initial findings in this area were promising, the developed synthesis cycle suffered from the use of an expensive reagent, an unstable linker system, and bespoke nucleobase protecting groups (Figure ). This letter describes several improvements to this technique that ameliorate those shortcomings thus paving the way to more widespread adoption of the P(V)-platform for the discovery and development of therapeutic oligonucleotides (Figure ). Nature's approach of creating oligonucleotides utilizes the P(V) rather than the P(III) oxidation state to form the phosphate linkages. Although early laboratory techniques for forming these P-O bonds also employed P(V), the approach was largely abandoned in the 1970s in favor of the superior coupling efficiency provided by P(III)-based reagents. It wasn't until nearly a decade later that Beaucage and Caruthers (1981) enhanced the coupling efficiency of P(III) reagents, leading to the development of what is now known as "Phosphoramidite" chemistry that can be summarized in 4 synthetic steps (1) coupling, (2) capping, (3) oxidation and ( ) deprotection (Figure ). In 2018, the introduction of the Phosphorus-Sulfur Incorporation (PSI, Y) platform simplified the control of stereochemistry in oligonucleotides, and reduced the SPOS cycle to 3 steps. The platform quickly garnered attention from the scientific community and gained popularity in the oligonucleotide and medicinal chemistry fields. this innovation has since enabled access to stereodefined CDNs, nucleotides, and phosphonates. In 2021, the Ψ-platform was expanded to install a wide variety of phosphate linkages into oligonucleotides. This approach can install stereodefined and racemic phosphorothioates (PS) as well as native phosphodiester (PO) and phosphorodithioate (PS2) linkages into oligonucleotides utilizing an automated oligonucleotide synthesizer albeit with noncanonical base protecting groups [Pivaloyloxymethyl (Pom) and 1-methylpyrrolidin-2-imine (Pya)] and a modified linker support to improve stability towards DBU(Figure ), none of which are commercially available. It was found that the P(V) platform resulted in lower isolated yields when using a sequence-and linkage-agnostic protocol. In direct comparison, the P(III) synthesized constructs were generally produced with double the yield. This is not surprising as P(III)-methods have undergone decades of evolution and optimization. Indeed, commercial oligonucleotide synthesizers are already tailored to the P(III) platform. In this context, our efforts focused on optimizing three key components of the P(V) oligonucleotide platform whilst preserving all the advantages of the Ψ-platform: nucleobase protecting group chemistry, linker support optimization, and reducing the cost of the phosphorylation reagent, (Figure ).