title: A CuAAC-Hydrazone-CuAAC Trifunctional Scaffold for the Solid-Phase Synthesis of Trimodal Compounds: Possibilities and Limitations.
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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, 16610 Praha 6, Czech Republic. fabre@uochb.cas.cz.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fabre
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, 16610 Praha 6, Czech Republic. picha@uochb.cas.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Pícha
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, 16610 Praha 6, Czech Republic. vasek@uochb.cas.cz.
authors.forename: Václav
authors.initials: V
authors.lastname: Vaněk
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, 16610 Praha 6, Czech Republic. budesinsky@uochb.cas.cz.
authors.forename: Miloš
authors.initials: M
authors.lastname: Buděšínský
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, 16610 Praha 6, Czech Republic. jiracek@uochb.cas.cz.
authors.forename: Jiří
authors.initials: J
authors.lastname: Jiráček
mesh_terms: D001386:Azides / Q000737:chemistry; D002384:Catalysis; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry*; D061565:Cycloaddition Reaction; D006835:Hydrazones / Q000737:chemistry*; D018716:Molecular Mimicry; D011092:Polyethylene Glycols / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques
chemical_list: D001386:Azides; D006835:Hydrazones; D011092:Polyethylene Glycols; D003300:Copper
keywords: click chemistry; copper; hydrazide; hydrazone; multifunctional scaffold; protein mimics; solid-phase synthesis