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Molecules 2015, 20(10), 19310-19329; doi:10.3390/molecules201019310

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

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, 16610 Praha 6, Czech Republic
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Academic Editor: Fernando Albericio
Received: 28 August 2015 / Revised: 14 October 2015 / Accepted: 16 October 2015 / Published: 23 October 2015
(This article belongs to the Section Organic Synthesis)
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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 19F-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. View Full-Text
Keywords: click chemistry; multifunctional scaffold; solid-phase synthesis; protein mimics; copper; hydrazone; hydrazide click chemistry; multifunctional scaffold; solid-phase synthesis; protein mimics; copper; hydrazone; hydrazide
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Fabre, B.; Pícha, J.; Vaněk, V.; Buděšínský, M.; Jiráček, J. A CuAAC–Hydrazone–CuAAC Trifunctional Scaffold for the Solid-Phase Synthesis of Trimodal Compounds: Possibilities and Limitations. Molecules 2015, 20, 19310-19329.

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