Accessing sequence specific hybrid peptoid oligomers with varied pendant group spacing

The synthesis of beta-peptoids (i.e., N-substituted beta-alanine oligomers) 10 or more residues in length has proven challenging owing to poor coupling efficiency even after extended reaction times, resulting in the substantial generation of deletion sequences and consequently making purification of the target oligomer challenging. To overcome the limitations of conventional approaches, here we examine a synthetic method to rapidly yield sequence specific beta- and gamma-peptoids with 4-20 repeat units in high purity via alternating monomer addition and deprotection reactions using Fmoc-protected, N-substituted beta-alanine- and gamma-aminobutyric acid-based monomers in conjunction with microwave-assisted automated solid phase synthesis. By decoupling the secondary amine generation and the oligomer synthesis, this approach circumvents the relatively low reaction efficiency of primary amine alkylation with halogenated propionic or butyric acid to afford secondary amines while retaining the pendant group chemical diversity offered by alpha-peptoids. We establish the compatibility of this technique with conventional Fmoc-peptide and 'submonomer' peptoid syntheses by fabricating several hybrid oligomer sequences including long beta- and gamma-peptoid oligomers in addition to hybrid alpha/beta, beta/peptide, and alpha/beta/gamma-systems, thereby confirming the capacity for this approach to yield oligomers with a backbone spacing of three or more atoms between any two residues. Additionally, we demonstrate that mixtures of aromatic amine- and aldehyde-bearing beta-peptoids undergo rapid dynamic covalent assembly to afford oligomeric molecular ladders.