Rapid Synthesis of Functionalized High-Generation Polyester Dendrimers via Strain-Promoted Alkyne–Azide Cycloaddition

Abstract

Preparation of structurally perfect high-generation dendrimer libraries with different peripheral groups is challenging as divergent synthesis introduces peripheral defects and convergent synthesis leads to low yields. Here, we prepare a third-generation polyester dendron based on the bisMPA monomer structure, having eight peripheral azide functionalities, as an “inner” dendron. We also prepare a series of low-generation “outer” dendrons (G2 and G3) with various peripheral groups, including aromatic, aliphatic, and polar structures, each having a single dibenzoaza­cyclooctyne (DIBAC) at the core. Efficient strain-promoted azide–alkyne cycloaddition (SPAAC) enables quantitative coupling between the outer and inner dendrons, producing high-generation (G5 and G6) dendrimers in a single coupling step. Characterization by NMR and mass spectrometry shows that the coupling products are structurally perfect. Using this strategy, we prepared a small dendrimer library that includes the first high-generation monodisperse peripherally PEGylated dendrimers as well as a structure bearing bulky protected amino acids at its periphery. This general strategy allows for rapid, efficient, and quantitative preparation of high-generation dendrimers with a variety of peripheral and core functional groups, starting from small, easily prepared fragments.

Globular Polymer Grafts Require a Critical Size for Efficient Molecular Sieving of Enzyme Substrates

“…To complement the α‐CT‐N 3 , a series of hydroxy periphery bis‐MPA dendrons were functionalized with DBCO at the core (Figure ). Dendron synthesis was completed according to modified literature procedures (see Supporting Information) …”

Synthetic Methodologies for Chelating Polymer Ligands: Recent Advances and Future Development

“…[206] It is of interest to use strain-promoted azide-alkyne cycloaddition, which provides a quantitative coupling of the outer and inner dendrons, leading to high-generation (G5 and G6) dendrimers in a single coupling step (Scheme 31). [207] It should be noted the solid-phase synthesis of G7 inverse PAMAM dendrimer using only 50% of available reactive centers and by selecting a large resin. [208]…”

“…It is of interest to use strain‐promoted azide‐alkyne cycloaddition, which provides a quantitative coupling of the outer and inner dendrons, leading to high‐generation (G5 and G6) dendrimers in a single coupling step (Scheme ) …”

Recent advances in development of dendritic polymer‐based nanomedicines for cancer diagnosis

“…Previously, strain‐promoted azide‐alkyne cycloaddition, a click chemistry method, was reported for rapid preparation of high‐generation ( G = 5, 6) polyester dendrimers. The low‐generation inner dendrons and outer dendrons could be efficiently coupled through the chemical reaction between azide‐terminated groups and active cyclooctyne groups in less than 5 min under mild ambient conditions (McNelles & Adronov, 2017). To date, one of the bottlenecks in application of dendrons/dendrimers is their multiple purification steps, resulting in poor scalability.…”