Accelerated polymerization of N-carboxyanhydrides catalyzed by crown ether

Abstract

The recent advances in accelerated polymerization of N-carboxyanhydrides (NCAs) enriched the toolbox to prepare well-defined polypeptide materials. Herein we report the use of crown ether (CE) to catalyze the polymerization of NCA initiated by conventional primary amine initiators in solvents with low polarity and low hydrogen-bonding ability. The cyclic structure of the CE played a crucial role in the catalysis, with 18-crown-6 enabling the fastest polymerization kinetics. The fast polymerization kinetics outpaced common side reactions, enabling the preparation of well-defined polypeptides using an α-helical macroinitiator. Experimental results as well as the simulation methods suggested that CE changed the binding geometry between NCA and propagating amino chain-end, which promoted the molecular interactions and lowered the activation energy for ring-opening reactions of NCAs. This work not only provides an efficient strategy to prepare well-defined polypeptides with functionalized C-termini, but also guides the design of catalysts for NCA polymerization.

N-Heterocyclic Carbene-Catalyzed Random Copolymerization of N-Carboxyanhydrides of α-Amino Acids

“…1 H NMR (fully deuterated dimethyl sulfoxide (DMSO-d 6 ), 400 MHz): δ (ppm) = 1.92 (m, 1H, γ-CH), 2.02(m, 1H, γ-CH), 2.52 (t, 2H, β-CH 2 ), 4.49 (dd, 1H, α-CH), 5.10 (s, 2H, -CH 2 Ar), 7.35 (m, 5H, ArH), and 9.11 (s, 1H, -NH-). 13 Ala NCA was synthesized by reacting L-alanine with triphosgene following the same procedure as that used for the synthesis of Bn-Glu NCA except that the reaction temperature was increased to 55 • C. 1 H NMR (CDCl 3 , 400 MHz): δ (ppm) = 1.58 (d, 3H, -CH 3 ), 4.42 (q, 1H, -CH-), and 6.30 (s, 1H, -NH-). 13 Bn-Cys NCA was synthesized by reacting S-benzyl-cysteine with triphosgene following the same procedure as that used for the synthesis of Bn-Glu NCA.…”

“…13 Ala NCA was synthesized by reacting L-alanine with triphosgene following the same procedure as that used for the synthesis of Bn-Glu NCA except that the reaction temperature was increased to 55 • C. 1 H NMR (CDCl 3 , 400 MHz): δ (ppm) = 1.58 (d, 3H, -CH 3 ), 4.42 (q, 1H, -CH-), and 6.30 (s, 1H, -NH-). 13 Bn-Cys NCA was synthesized by reacting S-benzyl-cysteine with triphosgene following the same procedure as that used for the synthesis of Bn-Glu NCA. 1 H NMR (CDCl 3 , 400 MHz): δ (ppm) = 2.80 (m, 2H, -CH 2 -), 3.77 (s, 2H, -CH 2 Ar), 4.33 (q, 1H, -CH-), 6.44 (s, 1H, -NH-), and 7.31 (m, 5H, ArH).…”

“…1 H NMR (CDCl 3 , 400 MHz): δ (ppm) = 2.80 (m, 2H, -CH 2 -), 3.77 (s, 2H, -CH 2 Ar), 4.33 (q, 1H, -CH-), 6.44 (s, 1H, -NH-), and 7.31 (m, 5H, ArH). 13 C NMR (CDCl 3 , 100 MHz): δ (ppm) = 2.6 (-CH 2 -), 37.0 (-CH 2 Ar), 57.7 (-CH-), 127.7, 128.1, 128.9, 137.0 (ArH), 152.1 (-NHC(O)O-), and 175.1…”

“…1 H NMR (CDCl 3 , 400 MHz): δ (ppm) = 2.80 (m, 2H, -CH 2 -), 3.77 (s, 2H, -CH 2 Ar), 4.33 (q, 1H, -CH-), 6.44 (s, 1H, -NH-), and 7.31 (m, 5H, ArH). 13…”

“…Synthetic peptide-based polymers are a class of promising materials that exhibits interesting self-assembly behaviors and shows promise for applications in drug release, gene delivery, tissue engineering, and regenerative medicine [1][2][3][4][5] as well as metal-free polypeptide-based battery applications [6]. In recent decades, improved methods in the ring-opening polymerization (ROP) of α-amino acid-N-carboxyanhydrides (NCAs) have enabled the preparation of increasingly complex copolypeptide sequences having controlled molecular weights (MWs) that display properties far superior to those of illdefined homo-and copolypeptides, which are difficult to prepare using conventional methods owing to the slow polymerization rate (typically requiring hours to days to finish) and suffering from various side reactions, including chain termination, chain transfer, and water-induced NCA degradation [5,[7][8][9][10][11][12][13]. Fortunately, well-defined polypeptides with complex structures, high MWs, and unique block sequences are now accessible in an efficient manner even in the presence of moisture.…”