A CuAAC-Hydrazone-CuAAC Trifunctional Scaffold for the Solid-Phase Synthesis of Trimodal Compounds: Possibilities and Limitations

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Benjamin FabreJiří Jiráček

Abstract

We present a trifunctional scaffold designed for the solid-phase synthesis of trimodal compounds. This scaffold holds two alkyne arms in a free and TIPS-protected form for consecutive CuAAC (copper(I)-catalyzed azide-alkyne cycloaddition), one Fmoc-protected hydrazide arm for reaction with aldehydes, and one carboxylic acid arm with CF₂ groups for attachment to the resin and (19)F-NMR quantification. This scaffold was attached to a resin and derivatized with model azides and aliphatic, electron-rich or electron-poor aromatic aldehydes. We identified several limitations of the scaffold caused by the instability of hydrazones in acidic conditions, in the presence of copper during CuAAC, and when copper accumulated in the resin. We successfully overcame these drawbacks by optimizing synthetic conditions for the derivatization of the scaffold with aromatic aldehydes. Overall, the new trifunctional scaffold combines CuAAC and hydrazone chemistries, offering a broader chemical space for the development of bioactive compounds.

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Citations

Dec 10, 2019·Chembiochem : a European Journal of Chemical Biology·Lukasz SygaBert Poolman
Oct 24, 2020·Chemical Communications : Chem Comm·Norikazu TerashimaSuguru Yoshida
Nov 27, 2020·Chemical Communications : Chem Comm·Hinano TakemuraSuguru Yoshida
Dec 29, 2020·Chemical Communications : Chem Comm·Suguru YoshidaTakamitsu Hosoya
Dec 29, 2020·Bioorganic Chemistry·Jan HajduchJiří Jiráček
Feb 12, 2021·Organic Letters·Kohei SatoNobuyuki Mase

Related Concepts

Azides
Catalysis
Copper
Hydrazones
Vigilon
Molecular Mimicry
Click Chemical Reactions
Solid-Phase Nucleotide Synthesis Techniques
Cycloaddition Reaction
Acids

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