Straightforward access to linear and cyclic polypeptides

Abstract

Ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs) is a powerful synthetic methodology for generating well-defined functional polypeptides. However, conventional procedures require a compromise between obtaining controlled microstructures and employing the optimized polymerization conditions. Specifically, a versatile method to access sequenced cyclic polypeptides remains challenging due to the difficulty in site-specific cyclization. Here we describe a general and straightforward method for the synthesis of both linear and cyclic polypeptides using organocatalytic living polymerization of NCAs. The use of an air-stable organocatalyst, imidazolium hydrogen carbonate, allows for the rapid and controlled polymerization of a variety of NCAs, leading to high conversion within a few minutes under mild conditions. Linear and cyclic block copolypeptides are also accessible simply by controlling the type of initiators and the order of addition of NCA monomers.

Accelerated polymerization of N-carboxyanhydrides catalyzed by crown ether

“…The fast polymerization kinetics outpaces various side reactions, enabling the polymerization in the presence of moisture and even aqueous phase 21 , 25 , 27 – 29 . Well-defined polypeptides with complex structures 19 , 20 , 23 , high MWs 20 , 22 , 26 , and unique block sequences 27 were therefore synthesized in an efficient manner, which is difficult, if not impossible, with conventional NCA ROP methods.…”

Amphiphilic Nucleobase-Containing Polypeptide Copolymers—Synthesis and Self-Assembly

“…[21,22] Herein, pursuing a macromolecular engineering design, we contemplated an introduction of such thymidine nucleobases onto multiblock polymeric backbone incorporating one clickable poly(γ-propargyl-L-glutamate) segment (Scheme 1). The first step of our nucleopolypeptide design involved the synthesis of the polypeptide backbone [27,28]. Two copolymers with different architectures, diblock and triblock, were prepared in order to investigate the influence of the architecture on the morphology of nanoobjects formed by self-assembly in water.…”

“…Both diblock and triblock copolymers, PBLG-b-PPLG and PPLG-b-PBLG-b-PPLG respectively, were achieved using a two-step ring-opening polymerization approach. First, macroinitiators were obtained by initiating the ring-opening polymerization of BLG-NCA in DMF at 0 °C, as a means to achieved controlled ROP with either hexylamine (PBLG) or The first step of our nucleopolypeptide design involved the synthesis of the polypeptide backbone [27,28]. Two copolymers with different architectures, diblock and triblock, were prepared in order to investigate the influence of the architecture on the morphology of nanoobjects formed by self-assembly in water.…”

“…The first step of our nucleopolypeptide design involved the synthesis of the polypeptide backbone [ 27 , 28 ]. Two copolymers with different architectures, diblock and triblock, were prepared in order to investigate the influence of the architecture on the morphology of nanoobjects formed by self-assembly in water.…”

Accelerated Polypeptide Synthesis via N‐Carboxyanhydride Ring Opening Polymerization in Continuous Flow

“…Zhang et al proposed the introduction of imidazolium hydrogen carbonates to accelerate the rate of reaction in DMF, accessing linear and cyclic topologies through the dosage of organocatalyst, and optional addition of amine initiator. [32] Hadjichristidis and coworkers recently reported a substantial increase in polymerization rate afforded by the use of a fluorinated alcohol catalyst in chlorinated solvents. [33] The organocatalyst was found to form multiple cooperative hydrogen bonds, activating the NCA monomers and simultaneously protecting the initiator/growing polymer chain ends, resulting in a polymerization with high activity and selectivity.…”