NCα‐gem‐dimethylated peptoid side chains: A novel approach for structural control and peptide sequence mimetics

The design of linear peptoid oligomers adopting well‐defined secondary structures while mimicking defined peptide primary sequences is a major challenge in the context of drug discovery. To this end, chemists have developed cis‐inducing peptoid side chains to build robust polyproline type I helices. However, the number of efficient examples remains scarce and chemical diversity accessible through the use of these side chains is limited. Herein, we introduce an array of NCα‐gem‐dimethylated peptoid residues mimicking proteinogenic amino acids. Submonomer synthesis and block‐coupling approaches were explored to access heterooligomers incorporating these novel types of side chains. NMR studies of monomer and trimer models showed that the NCα‐gem‐dimethylated groups exert complete cis control on the backbone amide conformation. Lastly, a preliminary molecular modeling study gave an insight into the preferred orientation of the substituents of the NCα‐gem‐dimethyl side chains relative to the peptoid backbone