期刊
MOLECULES
卷 20, 期 10, 页码 19310-19329出版社
MDPI AG
DOI: 10.3390/molecules201019310
关键词
click chemistry; multifunctional scaffold; solid-phase synthesis; protein mimics; copper; hydrazone; hydrazide
资金
- Grant Agency of the Czech Republic [14-17305S]
- Academy of Sciences of the Czech Republic (Research Project RVO) [6138963]
- Institute of Organic Chemistry and Biochemistry (IOCB)
- Czech Academy of Sciences
- Medical Research Council [MR/K000179/1]
- Medical Research Council [MR/K000179/1] Funding Source: researchfish
- MRC [MR/K000179/1] Funding Source: UKRI
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 F-19-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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