Thermal Azide-Alkyne Cycloaddition (TAAC) as Efficient Clicked Chemistry Tool for the Functionalization of Dendrimers and Polymers

Zusammenfassung

Summary With the aim of exploring new methodologies for the functionalization of GATG dendrimers while taking advantage of their of peripheral decoration with terminal azides, we have focused on the thermal azide-alkyne cycloaddition (TAAC). Using internal alkynes activated with propargylic carbamates, reliable TAAC conditions (temperature, concentration, solvent and time) were optimized with a model system mimicking the GATG periphery. At the same time, a scaling up of the synthesis of GATG dendrimers of the 2G and 3G families was achieved that allowed preparation of G4 dendrimers of both families in high scale (< 600 mg). With these two pieces in hand, internal alkynes functionalized with several ligands of biomedical interest (anionic and cationic groups, biotin, carbohydrates, alcohols, phenol, catechol, fluorophores as FITC, and chelating agents such as DOTA) were efficiently synthesized and used for the TAAC functionalization of several generations of GATG dendrimers (3G1, 2G2, 3G3 and 3G4) and PEG-dendritic block copolymers. The resulting functionalized dendritic structures were reproducibly obtained in very high yields after heating at 120 ºC for 6-8 h followed by easy purifications by ultrafiltration, the dendrimer conjugates were full characterized by 1H NMR, 13C NMR, IR, DLS and GPC that confirmed their purity, monodispersity and size increasing. These materials are envisaged as promising tools for different biological applications, including drug delivery, multivalent recognition and cell internalization.