Phosphorus(V) Umpolung Converts Electrophilic Phosphates into Nucleophilic H-Phosphonates
Abstract
Ubiquitous in chemistry, biology and medicine, phosphate groups form the backbone of DNA and RNA, and their analogues like phosphorothioate antisense oligonucleotides provide frontier therapies for challenging genetic disorders. However, the inherent electrophilicity of phosphorus(V) and thermodynamic stability of native P–OH bonds preclude their direct, latestage conversion into phosphate analogues. Here, we introduce a polarity-reversal (umpolung) strategy for converting electrophilic phosphates into nucleophilic H-phosphonates. This approach proceeds through two stages: P–OH thiolation into a thiophosphate followed by radical P–S cleavage, which generates the P–H bond. This sequence converts diverse phosphate substrates, such as complex drug scaffolds and nucleotides, into H-phosphonates that can undergo further phosphorus functionalization. The thiolation step also enables direct, one-pot conversion of P–OH into P–SH in nucleotides, providing a chemical route to the phosphorothioation of native phosphate backbones associated with bacterial and archaeal DNA defense. Therefore, phosphorus(V) umpolung reverses the polarity of phosphate chemistry, transforming otherwise stable P–OH bonds into synthetically versatile phosphorus functionalities.
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BibTeX
@misc{oeser2026phosphorusv,
title = {{Phosphorus(V) Umpolung Converts Electrophilic Phosphates into Nucleophilic H-Phosphonates}},
author = {Petr Oeser and Petr Šimon and Kristýna Kellovská and Matthew Z. Todd and Rafael Navrátil},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010278/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010278/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Phosphorus(V) Umpolung Converts Electrophilic Phosphates into Nucleophilic H-Phosphonates
AU - Petr Oeser
AU - Petr Šimon
AU - Kristýna Kellovská
AU - Matthew Z. Todd
AU - Rafael Navrátil
PY - 2026
DA - 2026/10/12
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010278/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010278/v1
AB - Ubiquitous in chemistry, biology and medicine, phosphate groups form the backbone of DNA and RNA, and their analogues like phosphorothioate antisense oligonucleotides provide frontier therapies for challenging genetic disorders. However, the inherent electrophilicity of phosphorus(V) and thermodynamic stability of native P–OH bonds preclude their direct, latestage conversion into phosphate analogues. Here, we introduce a polarity-reversal (umpolung) strategy for converting electrophilic phosphates into nucleophilic H-phosphonates. This approach proceeds through two stages: P–OH thiolation into a thiophosphate followed by radical P–S cleavage, which generates the P–H bond. This sequence converts diverse phosphate substrates, such as complex drug scaffolds and nucleotides, into H-phosphonates that can undergo further phosphorus functionalization. The thiolation step also enables direct, one-pot conversion of P–OH into P–SH in nucleotides, providing a chemical route to the phosphorothioation of native phosphate backbones associated with bacterial and archaeal DNA defense. Therefore, phosphorus(V) umpolung reverses the polarity of phosphate chemistry, transforming otherwise stable P–OH bonds into synthetically versatile phosphorus functionalities.
ER -