Cooperative Covalent Polymerization of N-carboxyanhydrides: from Kinetic Studies to Efficient Synthesis of Polypeptide Materials

Conspectus Polypeptides, as the syntheticanalogues of natural proteins, arean important class of biopolymers that are widely studied and usedin various biomedical applications. However, the preparation of polypeptidematerials from the polymerization of N-carboxyanhydride(NCA) is limited by various side reactions and stringent polymerizationconditions. Recently, we report the cooperative covalent polymerization(CCP) of NCA in solvents with low polarity and weak hydrogen-bondingability (e.g., dichloromethane or chloroform). The polymerizationexhibits characteristic two-stage kinetics, which is significantlyaccelerated compared with conventional polymerization under identicalconditions. In this Account, we review our recent studies on the CCP,with the focus on the acceleration mechanism, the kinetic modeling,and the use of fast kinetics for the efficient preparation of polypeptidematerials. By studying CCP with several initiating systems,we found thatthe polymerization rate was dependent on the secondary structure aswell as the macromolecular architecture of the propagating polypeptides.The molecular interactions between the alpha-helical, propagatingpolypeptide and the monomer played an important role in the acceleration,which catalyzed the ring-opening reaction of NCA in an enzyme-mimetic,Michaelis-Menten manner. Additionally, the proximity betweeninitiating sites further accelerated the polymerization, presumablydue to the cooperative interactions of macrodipoles between neighboringhelices and/or enhanced binding of monomers. A two-stage kinetic modelwith a reversible monomer adsorption process in the second stage wasdeveloped to describe the CCP kinetics, which highlighted the importanceof cooperativity, critical chain length, binding constant, [M](0), and [M](0)/[I](0). The kinetic model successfullypredicted the polymerization behavior of the CCP and the molecular-weightdistribution of resulting polypeptides. The remarkable rateacceleration of the CCP offers a promisingstrategy for the efficient synthesis of polypeptide materials, sincethe fast kinetics outpaces various side reactions during the polymerizationprocess. Chain termination and chain transfer were thus minimized,which facilitated the synthesis of high-molecular-weight polypeptidematerials and multiblock copolypeptides. In addition, the acceleratedpolymerization enabled the synthesis of polypeptides in the presenceof an aqueous phase, which was otherwise challenging due to the water-induceddegradation of monomers. Taking advantage of the incorporation ofthe aqueous phase, we reported the preparation of well-defined polypeptidesfrom nonpurified NCAs. We believe the studies of CCP not only improveour understanding of biological catalysis, but also benefit the downstreamstudies in the polypeptide field by providing versatile polypeptidematerials.