A P(V) platform for oligonucleotide synthesis

Huang, Yande; Knouse, Kyle W.; Qiu, Shenjie; Wei, Hao; Padial, Natalia M.; Vantourout, Julien C.; Zheng, Bin; Mercer, Stephen E.; López-Ogalla, Javier; Narayan, Rohan; Olson, R. E.; Blackmond, Donna G.; Eastgate, Martin D.; Schmidt, Michael A.; McDonald, Ivar M.; Baran, Phil S.

doi:10.1126/science.abi9727

Cited by 58 publications

(34 citation statements)

References 41 publications

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“…This was the pivaloyloxymethyl (POM) protecting group, comprised of a formyl acetal and the pivaloyl group capping the distal hydroxy functionality. The POM protecting group is known from the phosphonate prodrug adefovir dipivoxyl, [29,30] as well as from protected forms of uridine, thymidine, [31][32][33][34] imidazole C-nucleosides, and pseudouridine. [35,36] In the latter cases, the nucleobases are N-protected, though, and it was unclear what the chemoselectivity would be for ethynylpyridones.…”

Section: Resultsmentioning

confidence: 99%

Acid‐Stable Nucleobase Protection for a Strongly Pairing Pyridone C‐Nucleoside Suitable for Solid‐Phase Synthesis of Oligonucleotides

et al. 2022

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Oligonucleotides are indispensable tools in diagnostics, therapeutic applications and molecular biology. The low base pairing strength of thymine with adenine complicates their use. Ethynylpyridone C-nucleosides are analogs of thymidine that pair more strongly and with improved base selectivity, and sequences containing these analogs show improved target affinity and selectivity, but their routine use is hampered by diminished yields of solid-phase syntheses with the known building blocks. A partial loss of base protecting groups during the acidic deblocking step of chain extension cycles was identified as the cause of lower yields. Here we report the synthesis of an improved phosphoramidite building block featuring a pivaloyloxymethyl (POM) base protecting group. This building block gives oligonucleotides containing the strongly pairing ethynylmethylpyridone C-nucleoside in high yield and purity via solid-phase synthesis.

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Section: Resultsmentioning

confidence: 99%

Acid‐Stable Nucleobase Protection for a Strongly Pairing Pyridone C‐Nucleoside Suitable for Solid‐Phase Synthesis of Oligonucleotides

et al. 2022

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“…A newly developed suite of reagents based off of the Ψ platform now allows for access to all common linkages found in current ASOs. Moreover, these reagents display kinetics on-par with phosphoramidite chemistry . The utility of the Ψ reagent suite is demonstrated by a few selected examples in which ASOs are synthesized in exquisite crude purity.…”

Section: Putting It All Together: Chimeric Oligonucleotides Using a P...mentioning

confidence: 99%

Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods Can Augment Existing Strategies

et al. 2021

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Phosphate linkages govern life as we know it. Their unique properties provide the foundation for many natural systems from cell biology and biosynthesis to the backbone of nucleic acids. Phosphates are ideal natural moieties; existing as ionized species in a stable P(V)-oxidation state, they are endowed with high stability but exhibit enzymatically unlockable potential. Despite intense interest in phosphorus catalysis and condensation chemistry, organic chemistry has not fully embraced the potential of P(V) reagents. To be sure, within the world of chemical oligonucleotide synthesis, modern approaches utilize P(III) reagent systems to create phosphate linkages and their analogs. In this Outlook, we present recent studies from our laboratories suggesting that numerous exciting opportunities for P(V) chemistry exist at the nexus of organic synthesis and biochemistry. Applications to the synthesis of stereopure antisense oligonucleotides, cyclic dinucleotides, methylphosphonates, and phosphines are reviewed as well as chemoselective modification to peptides, proteins, and nucleic acids. Finally, an outlook into what may be possible in the future with P(V) chemistry is previewed, suggesting these examples represent just the tip of the iceberg.

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“…Phosphormonoamidites (P-amidites), introduced by Marvin Caruthers in 1981, are best known for enabling automated DNA/RNA synthesis by providing a storable yet easily activatable form of a reactive P(III) electrophile. This breakthrough technology marks the advent of modern molecular biology, and it has been so successful that only very recently have alternative, potentially competitive, approaches based on P(V) chemistry been introduced …”

Section: P-amidite Chemistrymentioning

confidence: 99%

Lost in Condensation: Poly-, Cyclo-, and Ultraphosphates

et al. 2021

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Conspectus Much like linear, branched, and cyclic alkanes, condensed phosphates exist as linear, branched, and cyclic structures. Inasmuch as alkanes are the cornerstone of organic chemistry, generating an inexplorably large chemical space, a comparable richness in structures can be expected for condensed phosphates, as also for them the concepts of isomerism apply. Little of their chemical space has been charted, and only a few different synthesis methods are available to construct isomers of condensed phosphates. Here, we will discuss the application of phosphoramidites with one, two, or three P–N bonds that can be substituted selectively to access different condensed phosphates in a highly controllable manner. Work directed toward the further exploration of this chemical space will contribute to our understanding of the fundamental chemistry of phosphates. In biology, condensed phosphates play important roles in the form of inorganic representatives, such as pyrophosphate, polyphosphate, and cyclophosphate, and also in conjugation with organic molecules, such as esters and amidates. Phosphorus is one of the six biogenic elements; the omnipresence of phosphates in biology points toward their critical involvement in prebiotic chemistry and the emergence of life itself. Indeed, it is hard to imagine any life without phosphate. It is therefore desirable to achieve through synthesis a better understanding of the chemistry of the condensed phosphates to further explore their biology. There is a rich but underexplored chemistry of the family of condensed phosphates per se, which is further diversified by their conjugation to important biomolecules and metabolites. For example, proteins may be polyphosphorylated on lysins, a very recent addition to posttranslational modifications. Adenosine triphosphate, as a representative of the small molecules, on the other hand, is well known as the universal cellular energy currency. In this Account, we will describe our motivations and our approaches to construct, modify, and synthetically apply different representatives of the condensed phosphates. We also describe the generation of hybrids composed of cyclic and linear structures of different oxidation states and develop them into reagents of great utility. A pertinent example is provided in the step-economic synthesis of the magic spot nucleotides (p)ppGpp. Finally, we provide an overview of 31P NMR data collected over the years in our laboratories, helping as a waymarker for not getting lost in condensation.

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A P(V) platform for oligonucleotide synthesis

Cited by 58 publications

References 41 publications

Acid‐Stable Nucleobase Protection for a Strongly Pairing Pyridone C‐Nucleoside Suitable for Solid‐Phase Synthesis of Oligonucleotides

Acid‐Stable Nucleobase Protection for a Strongly Pairing Pyridone C‐Nucleoside Suitable for Solid‐Phase Synthesis of Oligonucleotides

Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods Can Augment Existing Strategies

Lost in Condensation: Poly-, Cyclo-, and Ultraphosphates

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