A Facile Glovebox-Free Strategy To Significantly Accelerate the Syntheses of Well-Defined Polypeptides by N-Carboxyanhydride (NCA) Ring-Opening Polymerizations

Abstract

A facile N2 flow-accelerated N-carboxyanhydride ring opening polymerization (NCA ROP) is demonstrated, herein, with rigorous kinetic studies to evaluate the methodology in detail. By using n-hexylamine as initiator and γ-benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) as monomer, the NCA ROP via a normal amine mechanism (NAM) reached 90% conversion in 2 h under N2 flow at room temperature in a fume hood, much shorter than the time required for the same polymerization conducted in a glove box (14 h). The efficient removal of CO2 from the reaction by N2 flow drove the carbamic acid-amine equilibrium toward the formation of active nucleophilic amino termini and promoted polymerization. The detailed kinetic studies of the polymerization with different feed ratios and N2 flow rates were conducted, demonstrating the living feature of the NCA ROP and the tuning of the polymerization rate by simply changing the flow rate of N2. Maintenance of the reactivity of the amino ω-chain terminus and control during a subsequent polymerization were confirmed by performing chain extension reactions. The N2 flow method provides a new straightforward strategy to synthesize well-defined polypeptides with predictable molecular weights and narrow molecular weight distributions (PDI < 1.19).

Multi-responsive polypeptide hydrogels derived from N-carboxyanhydride terpolymerizations for delivery of nonsteroidal anti-inflammatory drugs

“…35-41 In fact, NCA ROP can be conducted using normal Schlenk techniques, with the enhancement of polymerization rate and retention of controlled features achieved through a straightforward N 2 flow method. 40, 42 Using this technique, the methoxy poly(ethylene glycol)- block -poly( l -alanine- co -glycine- co - l -isoleucine) (mPEG- b -P(A-G-I)) was synthesized by statistical copolymerization of l -alanine (Ala), glycine (Gly) and l –isoleucine (Ile) NCAs, initiated by monomethoxy monoamino-terminated poly(ethylene glycol) (mPEG 45 -NH 2 , M n = 2000 g/mol) as the macroinitiator under continuous N 2 flow (100 mL/min), as shown in Scheme 1. A series of block polymers with polypeptide segments of various lengths was synthesized by varying the ratio of NCA monomers to the macroinitiator, while maintaining the ratio of three NCA monomers at 1 : 1 : 1 (Table 1).…”

Reversible photo-patterning of soft conductive materials via spatially-defined supramolecular assembly

“…10 Synthesis of a series of three PEG- b -PDLAGs was performed through polymerization of the N -carboxyanhydride (NCA) of DL-allylglycine via a N 2 flow method (Figure S1), to tune the hydrophilic-hydrophobic balance and optimize the gel transition temperature ( T gel ) to be slightly above room temperature. 11 Reversible and responsive hydrogelations of PEG- b -PDLAG were confirmed (Figure S3). The heat-induced sol-to-gel transitions were attributed to the constrution of β sheets and dehydration of PEG, resulting in the formation of β-sheet-rich peptide nanofibrils (Scheme 1a); while the sonication-triggered gel-to-sol transitions were assigned to the disruption of long range interactions between these nanofibrils.…”

Synthesis and structure formation of block copolymers of poly(ethylene glycol) with homopolymers and copolymers of l-glutamic acid γ-benzyl ester and l-leucine in water

“…Depending on the PAA block length, reaction times ranged between 24 and 48 h per block with a total reaction time of 72-96 h and with the triblock copolymers with a total of 40 amino acid units taking the longer times. The polymerization method used here is similar to that described by Wooley [46], but polymerizations were performed under an argon blanket, in the presence of urea, and the progress of the ROPs was monitored via the CO 2 development. Reactions were considered complete when no more CO 2 was released from the reaction mixtures.…”