A Synthetic Method for Site‐Specific Functionalized Polypeptides: Metal‐Free, Highly Active, and Selective at Room Temperature

Abstract

Functionalized polypeptides have attracted tremendous interest in recent years and found many stimulating applications owing to their tunable physicochemical characteristics including hydrophilicity and stimuli‐responsive behavior. The development of new strategies to produce these polymers without metallic contaminants is crucial for their applications in high‐value and sensitive domains, such as biomedical, microelectronic, food‐packaging, and personal beauty care fields. Herein, a highly efficient strategy to access well‐defined site‐specific functionalized polypeptides is developed by combining Michael reaction with hydrogen‐bonding organocatalytic ROP of NCA. A library of chain‐end and chain‐middle functionalized polypeptides (14 examples) with predesigned molecular weights and low polydispersities are readily prepared with this approach. Specifically, the whole synthetic process is metal‐free, fulfilling high activity and selectivity at room temperature.

Organobase 1,1,3,3-tetramethyl guanidine catalyzed rapid ring-opening polymerization of α-amino acid N-carboxyanhydrides adaptive to amine, alcohol and carboxyl acid initiators

“…Tertiary amino groups were required to enhance the nucleophilicity of the hydroxyl group. 33,41 Developing new catalysts to increase the NCA polymerization rates and to obtain polypeptides with low dispersity for initiators with low nucleophilicity and high (macro)initiator versatility is highly desired. In this work, we demonstrated that TMG as an organobase can significantly increase the initiation and propagation rate of NCAs.…”

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.…”

“…For linear substituted secondary amines such as propagation end in NNCA polymerization, good controllability and pseudo first kinetics are confirmed, but for some α-branched substituted secondary amines such as diisopropylamine obeys AMM. The nucleophilicity and basicity of amines are also influenced by interaction with other groups, especially in α,ω-telechelic initiators such as α,ω-alcohol/thiol amine ( Tao et al, 2017 ; Tao et al, 2018b ; Zhao et al, 2019 ; 2020 ).…”

An Inspection into Multifarious Ways to Synthesize Poly(Amino Acid)s

“…[52] Zhao et al used fluorinated alcohol as an organocatalyst to enable alcohol-initiated NCA polymerizations. [53,54] Liu and co-workers reported alkali hexamethyldisilazide saltinitiated NCA polymerizations, which produced polypeptides with medium dispersities in open air. [55,56] Cheng and co-workers reported crown ether as a catalyst to accelerate polymerizations of NCAs initiated by primary amine in low polar solvents.…”