Sequence-defined l-glutamamide oligomers with pendant supramolecular motifs via iterative synthesis and orthogonal post-functionalization

Abstract

One of the great challenges in polymer chemistry is to achieve discrete and sequence-defined synthetic polymers that fold in defined conformations and form well-defined three-dimensional structures. Here, we present our progress to arrive at functional, sequence-defined and discrete oligomers by selecting a synthetic approach based on oligo-L-glutamamides. We introduce a solution-based iterative approach and start with an orthogonally protected L-glutamic acid derivative with an alkene or alkyne side chain. Using subsequent deprotection, activation and coupling steps, discrete, sequence-defined octamers were prepared with alkene or alkyne pendants at defined positions. Benzene-1,3,5-tricarboxamide (BTA) was selected as the supramolecular motif and decyl side chains for enhancing solubility. Full functionalization of the octamer was achieved with subsequent Cu(I)-catalyzed alkyne–azide and thiol–ene “click” chemistry, affording octamers with two BTA motifs at pre-defined positions. The octamers show a strong propensity to form hydrogen bonds in bulk as evidenced by infrared spectroscopy. In dilute solution, intermolecular aggregation of the amides present in the backbone and/or BTAs is observed. Our work shows that the iterative method serves as an reliable strategy for the synthesis of functionalized sequence-defined, discrete oligomers comprising side chain supramolecular motifs, although further optimizations are required.