Boronic-Acid-Accelerated Electrophilic Activation of Unprotected Maltols to N-Substituted Hydroxypyridinones in Water.

doi:10.1021/acs.orglett.1c03833

Paper

Boronic-Acid-Accelerated Electrophilic Activation of Unprotected Maltols to N-Substituted Hydroxypyridinones in Water.

Published Feb 5, 2022 · Di Ke, Lei Zhang, Xiuwen Zhong

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Abstract

3,4-Hydroxypyridinone (3,4-HOPO) is a vital metal-chelating pharmacophore. However, the efficient synthesis has been a long-standing problem in drug development. In this paper, we report an efficient electrophilic activation of unprotected maltols via reversible covalent bonds between boronic acid and 3-hydroxyl/4-carbonyl. This one-pot reaction proceeded well on a gram scale in water with excellent efficiencies up to 97%. Moreover, taking advantage of the covalent interactions via the transient boronate, most of the previously tough amine donors, including sterically hindered amines, aromatic amines, and amino acids and amino alcohols, were well-tolerated. Importantly, the potential of this strategy in the pharmaceutical industry was highlighted with a successful synthesis of 3,4-HOPOs containing iron-chelating active pharmaceutical ingredients on 10 g and kilogram scales.

Study Snapshot

Boronic acid-accelerated electrophilic activation of unprotected maltols in water enables efficient synthesis of 3,4-hydroxypyridinones with up to 97% efficiency, potentially benefiting drug development.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Boronic-Acid-Accelerated Electrophilic Activation of Unprotected Maltols to N-Substituted Hydroxypyridinones in Water.

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References

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Hydroxypyridinones (HOPOs) are effective building blocks for developing metal chelation agents, enabling efficient applications in biological, environmental, and clinical sciences.

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Boronic acid catalysis allows for the efficient synthesis of various cyclopentenones and azaspirocycles with excellent diastereoselectivity.

Citations

Bioinspired Metal–Ligand Networks with Enhanced Stability and Performance: Facile Preparation of Hydroxypyridinone (HOPO)-Functionalized Materials

Bioinspired hydroxypyridinone (HOPO)-functionalized materials can be easily synthesized and incorporated into PEG-acrylate networks, enabling diverse physical properties and chelation of metal ions.

Synthesis, X-ray characterization, and DFT study of six deferiprone analogues

This study reveals new insights into the structural and electronic properties of six deferiprone analogues, highlighting their potential applications in various fields.

Synthesis and structure-activity optimization of hydroxypyridinones against rhabdomyolysis-induced acute kidney injury.

Hydroxypyridinones, specifically 6k, show potential as a safe and effective treatment for rhabdomyolysis-induced acute kidney injury by chelating iron and inhibiting ferroptosis.

Synthesis of γ-Pyrones and N-Methyl-4-pyridones via the Au Nanoparticle-Catalyzed Cyclization of Skipped Diynones in the Presence of Water or Aqueous Methylamine.

Au nanoparticles on TiO2 catalyze the hydration/6-endo cyclization of skipped diynones to -pyrones and N-methyl-4-pyridones in aqueous dioxane, with N-methyl-4-pyridone