Kinetically Controlled Approach for One-Pot Synthesis of Poly(peptide-b-peptoid) Exhibiting Well-Defined Secondary Structure and Thermal Stability.

Sequence-controlled polymerization aims to bridge the gap between biopolymers and synthetic macromolecules. In a kinetically controlled approach, the inherent reactivity differences among monomers determine the primary structure or sequence of the monomers linked within the resulting copolymer chains. This report outlines a one-pot synthesis of polypeptide-b-polypeptoid by choosing a suitable pair of N-carboxy anhydride (NCA) monomers with significant reactivity differences. We have demonstrated the preparation of well-defined block copolymers, including polyproline-b-polysarcosine (PLP-b-PSar) and poly(propargyl proline)-b-polysarcosine (PLPP-b-PSar) in a single step. ¹H NMR kinetic studies confirmed the sequence-controlled primary structures of these block copolymers. The NMR analysis indicated a striking reactivity ratio difference (r_PLP = 925 and r_PSar = 0.0014; r_PLPP = 860 and r_PSar = 0.0015) between the selected monomer pairs, which was crucial for a one-pot block copolymer synthesis. Notably, these sequence-controlled copolymers' secondary structures and stability were remarkably similar to those of block copolymers synthesized through conventional sequential addition methods. This further underscores the practicality of this kinetically controlled approach.