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

Molecules

Benjamin Fabre²  Jan Pໜha²  Vผlav Vaněk²  Miloš Buděšínský²  Jiří Jiráპk¹ 

[1] Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, 16610 Praha 6, Czech Republic;

关键词: click chemistry;    multifunctional scaffold;    solid-phase synthesis;    protein mimics;    copper;    hydrazone;    hydrazide;   

DOI  :  10.3390/molecules201019310

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.