A S-Sn Lewis Pair-Mediated Ring-Opening Polymerization of α-Amino Acid N-Carboxyanhydrides: Fast Kinetics, High Molecular Weight, and Facile Bioconjugation

Abstract

The rapid and controlled generation of polypeptides with ultrahigh molecular weight (MW) and welldefined chain end functionality has been a great challenge.To tackle this problem, we report here an initiation system based on a S-Sn Lewis pair, trimethylstannyl phenyl sulfide (PhS-SnMe 3 ), for the ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs). This initiator displays a strong solvent effect, and can yield polypeptides with high MW (>1.0 × 10 5 g•mol −1 ) and low polydispersity index within a few hours. The MWs of the obtained polypeptides are strongly dependent on the THF/DMF ratio. The polymerization follows a typical first-order kinetic character with respect to the monomer concentration in mixed THF and DMF. Moreover, a highly reactive phenyl thioester is in situ generated at the C-terminus of the polypeptides, which is readily accessible for native chemical ligation affording high MW and site-specific protein−polypeptide conjugates. Together, this initiator sheds light on regulating the ROP of NCAs via appropriate Lewis pair and solvent selection, and is particularly useful in preparing ultrahigh MW polypeptides within a short period of time.

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.…”

“…Recently, the developments of accelerated polymerization of NCAs offered great opportunities to not only simplify the preparation process of polypeptides, but also access polymer materials that were difficult to prepare using conventional methods [18][19][20][21][22][23][24][25][26][27][28][29] . The fast polymerization kinetics outpaces various side reactions, enabling the polymerization in the presence of moisture and even aqueous phase 21,25,[27][28][29] .…”

Density Functional Theory Studies on the Synthesis of Poly(α-Amino Acid)s Via the Amine-Mediated Ring Opening Polymerizations of N-Carboxyanhydrides and N-Thiocarboxyanhydrides

“…The ring opening polymerization (ROP) of cyclic monomers is still the most promising synthetic route toward PAAs. Due to the existence of multiple active sites located on NCA or in the NTA ring, including carbonyl groups at 2- and 5-positions for nucleophilic attack and acidic protons of 3-NH and 4-CH groups, various initiators have been carried out for polymerization including amines ( Kricheldorf, 1987 ), trimethylsilyl (TMS) containing compounds, ( Lu and Cheng, 2007 , 2008 ; Yuan et al, 2016 ; Baumgartner et al, 2017 ; Yuan et al, 2018 ), salts ( Szwarc, 1965 ; Wu et al, 2018 ), (activated) alcohols ( Zhao et al, 2019 ; 2020 ), N -heterocyclic carbene ( Guo and Zhang, 2009 ; Falivene et al, 2016 ; Falivene and Cavallo, 2017 ), transition metal catalysts ( Deming, 1997 ), rare earth complexes ( Ling et al, 2012 ; Peng et al, 2012 ; Tao et al, 2014 ), and so on.…”

Poly(α-l-lysine)-based nanomaterials for versatile biomedical applications: Current advances and perspectives

“…In recent years, increasing efforts have been devoted to exploring new and efficient initiators and catalysts for NCA polymerization. Diverse initiators such as hexamethyldisilazane, used by Cheng [ 19 ], lithium hexamethyldisilazide, used by Liu [ 20 ]; trimethylsilyl and trimethylstannyl sulfide, used by Lu [ 21 , 22 ]; ammonium salts, used by Schlaad [ 23 , 24 ]; frustrated Lewis pairs, used by Yang [ 25 ]; catalysts such as cobalt and nickel organometallic catalysts, used by Deming [ 26 ]; organophosphates catalysts used by Yang [ 27 ]; and 1,1,3,3-tetramethylguanidine used by Cabral [ 28 ] have been reported for the controlled synthesis of PLL and other polypeptides. Very recently, Dong et al combined the inimer (initiator + monomer) ROP and photocaged chemistry to prepare hyperbranched and linear PLL.…”