An Orthogonal Synthetic Platform for the Construction of Structurally Diverse Disubstituted Polypeptoids

The synthesis of disubstituted polypeptoids, or N-substituted polypeptides, remains challenging due to steric hindrance. Here, a synthetic platform, with orthogonal functional side chains, was developed for the construction of structurally diverse disubstituted polypeptoids. Poly(N-allyl S-methyl cysteine) was synthesized by acetic acid-catalyzed controlled ring-opening polymerization. Subsequent methylation yielded the sulfonium-pendant polymer, which underwent base-catalyzed elimination of sulfonium groups to generate well-defined poly(N-allyl dehydroalanine). This polymer features two orthogonal reactive sites, electrophilic α,β-unsaturated carbons and N-allyl groups, which could undergo selective modification through sequential orthogonal reactions. Michael addition reaction preferentially functionalized the α,β-unsaturated sites while preserving allyl groups for subsequent thiol-ene click chemistry. This strategy enabled precise installation of alternating functional side chains, yielding structurally diverse disubstituted polypeptoids with high functional group density and programmable side-chain sequences. The combination of efficient orthogonal functionalization, tunable side-chain arrangement, and dense functionality establishes these disubstituted polypeptoids as versatile scaffolds for different applications.