Fluoride-Promoted Esterification (FPE) Chemistry: A Robust Route to Bis-MPA Dendrons and Their Postfunctionalization

Abstract

Bifunctional dendrons based on 2,2-bis(methylol)propionic acid (bis-MPA) are highly desirable scaffolds for biomedical applications. This is due to their flawless nature and large and exact number of functional groups as well as being biodegradable and biocompatible. Herein, we describe a facile divergent growth approach to their synthesis from monobenzylated tetraethylene glycol and post functionalization utilizing fluoride-promoted esterification (FPE) chemistry protocols. The scaffolds, presenting selectively deprotectable hydroxyls in the periphery and at the focal point, were isolated on a multigram scale with excellent purity up to the fourth generation dendron with a molecular weight of 2346 Da in seven reactions with a total yield of 50%. The third generation dendron was used as a model compound to demonstrate its functionalizability. Selective deprotection of the dendron's focal point was achieved with an outstanding yield of 94%, and biotin as well as azido functionalities were introduced to its focal point and periphery, respectively, through FPE chemistry. Bulky disperse red dyes were clicked through CuAAC to the dendron's azido groups, giving a biotinylated dendron with multivalent dyes with a molecular weight of 6252 Da in a total yield of 37% in five reactions with an average yield of 82% starting from the third generation focally and peripherally protected dendron. FPE chemistry proved to be a superb improvement over previous protocols towards bis-MPA dendrons as high purity and yields were obtained with less toxic solvents and greatly improved monomer utilization.

Design of multivalent fluorescent dendritic probes for site‐specific labeling of biomolecules

“…First, Boc‐hydrazine‐TEG‐OH 4 was synthesized in four consecutive reaction steps. The synthesis was initiated by the derivatization of TEG as benzyl protected TEG ( 1 ) . Then after, a succinic moiety was incorporated to yield the carboxylic acid functional 2 that facilitated covalent coupling of amino‐protected diboc‐2‐hydroxyethylhydrazine, via fluoride promoted esterification (FPE) chemistry resulting in 3 .…”

“…S5, S7, and S8]. In contrast to the G1 9 , the G3 15 was synthesized as previously reported prior to the deprotection by palladium‐catalyzed hydrogenation, introduction of succinic modified diboc‐2‐hydroxyethylhydrazine, and finally the functionalization with peripheral alkynes. The synthesis of the three alkyne decorated molecules ( 5 , 9, and 15 ) and their intermediates were monitored by matrix‐assisted laser desorption ionization time of flight (MALDI‐TOF) mass spectrometry (MS) [Fig.…”

“…In this context, dendrons, as highly branched and monodisperse wedge‐shaped scaffolds with multiple peripheral end‐groups and a single reactive functionality at the focal point, bring the option of orthogonal reactions suited for site‐specific labeling of biomolecules . For instance, Wängler et al synthesized a library of polyamidoamine (PAMAM) dendrons being peripherally decorated with various fluorescent dyes and encompassing a single thiol functionality at the focal point.…”

Dendrimers: syntheses, toxicity, and applications toward catalysis, environmental sciences, and nanomedecine

“…[5][6][7] The latter are now classified in different types according to a series of criteria. [8][9][10][11][12][13][14][15][16][17] The intrinsic properties of the dendritic organic moiety 10,[18][19][20] are designed according to the targeted applications [21][22][23][24] or to confer specific features to the hybrid materials when supported on inorganic supports. [25][26][27][28][29][30][31][32][33][34] In the area including energy and green chemistry, recently, major advances have been made in this regard by synthesizing metalorgano-aluminosilicates through in-situ synthesis of metal nanoparticles within the entanglements of supported dendrimers.…”

Special Issue: “Functional Dendrimers”

“…An article by M. Malkoch et al [24] describes the use of synthetic green chemistry protocols involving protect/deprotect, click and novel fluoride-assisted esterification chemistry (FPE), wherein either biotin or azido moieties could be readily introduced at the focal point or on the dendritic surface in high yield to produce monodispersed bis-MPA dendrons using less toxic solvents.…”