Polymerization of α‐amino acid N‐carboxyanhydrides catalyzed by rare earth tris(borohydride) complexes: Mechanism and hydroxy‐endcapped polypeptides

In this work, rare earth tris(borohydride) complexes, Ln(BH₄)₃(THF)₃ (Ln = Sc, Y, La, and Dy), have been used to catalyze the ring‐opening polymerization of γ‐benzyl‐L ‐glutamate N‐carboxyanhydride (BLG NCA). All the catalysts show high activities and the resulting poly(γ‐benzyl‐L ‐glutamate)s (PBLGs) are recovered with high yields (≥90%). The molecular weights (MWs) of PBLG can be controlled by the molar ratios of monomer to catalyst, and the MW distributions (MWDs) are relatively narrow (as low as 1.16) depending on the rare earth metals and reaction temperatures. Block copolypeptides can be easily synthesized by the sequential addition of two monomers. The obtained P(γ‐benzyl‐L ‐glutamate‐b‐ε‐carbobenzoxy‐L ‐lysine) [P(BLG‐b‐BLL)] and P(γ‐benzyl‐L ‐glutamate‐b‐alanine) [P(BLG‐b‐ALA)] have been well characterized by NMR, gel permeation chromatography, and differential scanning calorimetry measurements. A random copolymer P(BLG‐co‐BLL) with a narrow MWD of 1.07 has also been synthesized. The polymerization mechanisms have been investigated in detail. The results show that both nucleophilic attack at the 5‐CO of NCA and deprotonation of 3‐NH of NCA in the initiation process take place simultaneously, resulting in two active centers, that is, an yttrium ALA carbamate derivative [H₂BOCH₂(CH)NHC(O)OLn? ] and a N‐yttriumlated ALA NCA. Propagation then proceeds on these centers via both normal monomer insertion and polycondensation. After termination, two kinds of telechelic polypeptide chains, that is, α‐hydroxyl‐ω‐aminotelechelic chains and α‐carboxylic‐ω‐aminotelechelic ones, are formed as characterized by MALDI‐TOF MS, ¹H NMR, ¹³C NMR, ¹H–¹H COSY, and ¹H–¹³C HMQC measurements. By decreasing the reaction temperature, the normal monomer insertion pathway can be exclusively selected, forming an unprecedented α‐hydroxyl‐ω‐aminotelechelic polypeptide. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Cyclic polypeptides by thermal polymerization of α‐amino acid N‐carboxyanhydrides

The NCAs of the following five amino acids were polymerized in bulk at 120 °C without addition of a catalyst or initiator: sarcosine (Sar), L ‐alanine (L ‐Ala), D ,L ‐phenylalanine (D ,L ‐Phe), D ,L ‐leucine (D ,L ‐Leu) and D ,L ‐valine (D,L ‐Val). The virgin reaction products were characterized by viscosity measurements ¹³C NMR spectroscopy and MALDI‐TOF mass spectrometry. In addition to numerous low molar mass byproducts cyclic polypeptides were formed as the main reaction products in the mass range above 800 Da. Two types of cyclic oligo‐ and polypeptides were detected in all cases with exception of sarcosine NCA, which only yielded one class of cyclic polypeptides. The efficient formation of cyclic oligo‐ and polypeptides explains why high molar mass polymers cannot be obtained by thermal polymerizations of α‐amino acid NCAs. Various polymerization mechanisms were discussed. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4012–4020, 2008     

Deprotonation reaction of α‐amino acid N‐carboxyanhydride at 4‐CH position by yttrium tris[bis(trimethylsilyl)amide]

Reaction of yttrium tris[bis(trimethylsilyl)amide] [(TMSN)₃Y] with equivalent L ‐alanine N‐carboxyanhydride (ALA NCA) yields yttrium α‐isocyanato carboxylate ( II ), yttrium ketenyl carbamate ( III ), and hexamethyldisilazane ( V ). The products indicate that 4‐CH group of ALA NCA monomer is deprotonated in addition to 3‐NH group, which has been neglected in NCA chemistry for decades. This result proves the acidity of 4‐CH in NCA and provides the first direct evidence for racemization phenomenon of NCA in strong base in microscopic aspect. Rare earth tris[bis(trimethylsilyl)amide] (TMSN)₃Ln (Ln = Sc, Y, La, Dy, and Lu) compounds are high efficient catalysts for ring‐opening polymerizations of NCAs. Polypeptides can be produced in quantitative yields with narrow molecular weight distributions below 1.3, and block copolypeptides can be facilely prepared by sequential addition method. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Optimization of an α‐(Amino acid)‐N‐carboxyanhydride polymerization using the high vacuum technique: Examining the effects of monomer concentration,polymerization kinetics,polymer molecular weight,and monomer purity

l ‐Ornithine‐based poly(peptides) have been widely utilized in the field of drug delivery, however few studies have been conducted examining the details of polymerization. In this article, the effects of monomer concentration, polymerization kinetics, polymer molecular weight and monomer purity were investigated using l ‐carboxybenzyl (Cbz)‐ornithine as a model monomer. The mechanism of polymerization herein follows the normal amine mechanism to produce poly(peptides) having controlled molecular weights, known chain ends and a narrow polydispersity index (PDI). A preferred monomer concentration range was determined, which required minimal polymerization times and allowed for predictable and reproducible molecular weights with narrow PDIs. The impact of monomer purity on the polymerization was established and monomer purification conditions are reported, which produce high‐purity monomer after a single recrystallization. Additionally, the optimized polymerization conditions and monomer purification protocol were combined with a sequential monomer addition technique to produce high molecular weight poly(ornithine) with a narrow PDI and known chain ends. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1385–1391     

Living polymerization of α‐amino acid‐N‐carboxyanhydrides

This article reviews recent developments in the polymerization of α‐amino acid‐ N‐carboxyanhydrides (NCAs) to form polypeptides. Traditional methods used to polymerize these monomers are described, and limitations in the utility of these systems for the preparation of polypeptides with controlled molecular weights and narrow molecular weight distributions are discussed. The development of transition‐metal‐based initiators, which activate the monomers to form covalent active species, permits the formation of polypeptides via the living polymerization of NCAs. In these systems, polymer molecular weights are controlled by monomer‐to‐initiator stoichiometry, polydispersities are low, and block copolypeptides can be prepared. The scope and limitations of these initiators and their key features and mode of operation are described in detail in this highlight. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3011–3018, 2000     

Tertiary amine catalyzed polymerizations of α‐amino acid N‐carboxyanhydrides: The role of cyclization

Sarcosine N‐carboxyanhydride, D,L ‐alanine N‐carboxyanhydride, D,L ‐phenylalanine N‐carboxyanhydride, and D,L ‐leucine N‐carboxyanhydride were polymerized with pyridine or N‐ethyldiisopropylamine as the catalyst. With pyridine, cyclic oligo‐ and polypeptides were obtained in addition to water‐initiated or water‐terminated chains. The cyclopeptides were the main products in the case of sarcosine N‐carboxyanhydride and D,L ‐phenylalanine N‐carboxyanhydride. The fraction of cycles was particularly high when N‐methylpyrrolidone was used as the reaction medium. These results suggested the existence of a pyridine‐catalyzed zwitterionic mechanism. However, cyclopeptides were also obtained with N‐ethyldiisopropylamine as the catalyst. In this case, N‐deprotonation of N‐carboxyanhydrides, followed by the formation of N‐acyl N‐carboxyanhydride chain ends, was the most likely initiation mechanism. Various chain‐growth mechanisms were examined. In the case of γ‐benzyl ester‐L ‐glutamate N‐carboxyanhydride, side reactions such as the formation of pyroglutamoyl end groups were detected. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4680–4695, 2006     

Imidazole‐initiated polymerizations of α‐amino acid N‐carboxyanhydrides – simultaneous chain‐growth and step‐growth polymerization

The N‐carboxyanhydrides (NCAs) of sarcosine (Sar), D ,L ‐leucine (D ,L ‐Leu), D ,L ‐phenylalanine (D ,L ‐Phe), and L ‐alanine (L ‐Ala) were polymerized in dioxane. Imidazole served as initiator and the NCA/initiator ratio was varied from 1/1 to 40/1. The isolated polypeptides were characterized by ¹H NMR spectroscopy, by MALDI‐TOF mass spectrometry, by viscosity measurements, and by SEC measurements in the case of poly(sarcosine). Cyclic oligopeptides were found in all reaction products and in the case of polySar, poly(D ,L ‐Leu), and poly(D ,L ‐Phe) the cycles were the main products. In the case of poly(L ‐Ala), rapid precipitation of β‐sheet lamellaes prevented efficient cyclizations and stabilized imidazolide endgroups. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5690–5698, 2005     

Synthesis and ring‐opening (co)polymerization of L‐lysine N‐carboxyanhydrides containing labile side‐chain protective groups

This contribution describes the synthesis and ring‐opening (co)polymerization of several L ‐lysine N‐carboxyanhydrides (NCAs) that contain labile protective groups at the ?‐NH₂ position. Four of the following L ‐lysine NCAs were investigated: N^?‐trifluoroacetyl‐L ‐lysine N‐carboxyanhydride, N^?‐(tert‐butoxycarbonyl)‐L ‐lysine N‐carboxyanhydride, N^?‐(9‐fluorenylmethoxycarbonyl)‐L ‐lysine N‐carboxyanhydride, and N^?‐(6‐nitroveratryloxycarbonyl)‐L ‐lysine N‐carboxyanhydride. In contrast to the harsh conditions that are required for acidolysis of benzyl carbamate moieties, which are usually used to protect the ?‐NH₂ position of L ‐lysine during NCA polymerization, the protective groups of the L ‐lysine NCAs presented here can be removed under mildly acidic or basic conditions or by photolysis. As a consequence, these monomers may allow access to novel peptide hybrid materials that cannot be prepared from ?‐benzyloxycarbonyl‐L ‐lysine N‐carboxyanhydride (Z‐Lys NCA) because of side reactions that accompany the removal of the Z groups. By copolymerization of these L ‐lysine NCAs with labile protective groups, either with each other or with γ‐benzyl‐L ‐glutamate N‐carboxyanhydride or Z‐Lys NCA, orthogonally side‐chain‐protected copolypeptides with number‐average degrees of polymerization ≤20 were obtained. Such copolypeptides, which contain different side‐chain protective groups that can be removed independently, are interesting for the synthesis of complex polypeptide architectures or can be used as scaffolds for the preparation of synthetic antigens or protein mimetics. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1167–1187, 2003     

Ring opening insertion polymerization of ε‐caprolactone with hydrogen phosphonate initiators

In this work, ring opening insertion polymerization (ROIP) of ε‐caprolactone (ε‐CL) using a series of hydrogen phosphonates (H‐phosphonates) as initiators was investigated. The ROIP occurred by a coordination‐insertion mechanism containing two steps. First, the carbonyl carbon was attacked by the phosphorus atom of the H‐phosphonate tautomerization (a phosphine‐like structure) and the acyl‐oxygen bond was broken. An intermediate was formed by the coordination of the former carbonyl carbon and acyl‐oxygen of ε‐CL to phosphorus atom. Then the phosphorus‐alkoxide of H‐phosphonate was cleavaged to form acyl‐alkoxide bond. Poly(ε‐caprolactone) (PCL)‐inserted H‐phosphonates (PCL‐HPs), which was not only the product of the occurred ROIP but also the initiator for the next ROIP, were produced. After 60 min of microwave irradiation (510 W), PCL with a number‐average molar mass of 7800 g/mol and monomer conversion over 92% was obtained. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 6214–6222, 2009     

Ring‐opening polymerization of 1‐methyltrimethylene carbonate by rare earth initiators

Ring‐opening polymerization of 1‐methyltrimethylene carbonate (MTMC) initiated by highly active single‐component rare earth tris(2,6‐di‐tert‐butyl‐4‐methylphenolate)s [Ln(OAr)₃, Ln = La, Dy, Y] or yttrium isopropoxide [Y(OiPr)₃] is reported for the first time. PolyMTMC (M_w = 8.4 × 10⁴, molecular weight distributions = 1.5) initiated by La(OAr)₃ at [MTMC]/[initiator] = 1000 was obtained with the yield over 99% in toluene within 1 h at 30 °C. Random and block copolymers of MTMC with ε‐caprolactone (CL), 2,2‐dimethyltrimethylene carbonate (DTC) or polyethylene glycol (PEG) including poly(MTMC‐r‐CL), poly(MTMC‐b‐CL), poly(MTMC‐r‐DTC), poly(MTMC‐b‐DTC), and poly(MTMC‐b‐PEG‐b‐MTMC) were synthesized. The differential scanning calorimetry results show that thermal behaviors of the polymers sensitively depend on their compositions and chain structures. Furthermore, the measurements of ¹H‐¹H COSY and density functional theory calculation are applied to investigate the mechanism. The polymerization of MTMC takes place according to a coordination‐insertion mechanism, and the ring is opened via acyl‐oxygen bond cleavage resulting in a Ln? O active center. There exist two ring‐opening modes of MTMC in which mode b , breaking the CH₂O? CO bond, is the major pathway. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3807–3815, 2010     

Hydroxyl‐tolerated polymerization of N‐phenoxycarbonyl α‐amino acids: A simple way to polypeptides bearing hydroxyl groups

Differing from the moisture‐sensitive α‐amino acid N‐carboxyanhydrides (AA‐NCAs) monomers, N‐phenoxycarbonyl α‐amino acids (AA‐NPCs) can be prepared and stored in open air. In this contribution, we report that the controlled polymerizations of AA‐NPC monomers of O‐tert‐butyl‐dl ‐serine (BRS‐NPC), N^ε‐benzyloxycarbonyl‐l ‐lysine (ZLL‐NPC) and N^ε‐trifluoroacetyl‐l ‐lysine (FLL‐NPC) initiated by amines are surprisingly able to tolerate common nucleophilic impurities such as water and alcohols at a level of monomer concentration. The structures of polypeptides synthesized in the presence of water or alcohols agree well with the designed ones in the case of repeated chain extensions. Detailed mechanism study and density functional theory calculation reveal that the low concentration of AA‐NCA and the high activity of amines are the key factors to the controllability of AA‐NPC polymerizations. The water‐ and alcohol‐tolerant property in polymerizations of AA‐NPCs encourages the following studies on unprotected (phenolic) hydroxyl groups containing AA‐NPCs. The controllable polymerizations of N‐phenoxycarbonyl l ‐tyrosine (LT‐NPC) and N‐phenoxycarbonyl S‐(3‐hydroxypropyl)‐l ‐cysteine (HLC‐NPC) initiated by amines are confirmed and reported for the first time, which extends the library of AA‐NPCs and polypeptides as well. All the universality of library, the convenience of monomer preparation, and the controllability and water‐ and alcohol‐tolerant property of polymerization of AA‐NPCs significantly enhance the feasibility of polypeptide synthesis, making AA‐NPC approach a promising synthetic method of polypeptides. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 907–916     

Convenient synthesis of poly(γ‐benzyl‐L‐glutamate) from activated urethane derivatives of γ‐benzyl‐L‐glutamate

A series of activated urethane‐type derivatives of γ‐benzyl‐L ‐glutamate were synthesized, and their potential as monomers for polypeptide synthesis was investigated. The derivatives of the focus of this work were a series of N‐aryloxycarbonyl‐γ‐benzyl‐L ‐glutamate 1 , of which aryl groups were phenyl, 4‐chlorophenyl, and 4‐nitrophenyl. These urethanes 1 were reactive in polar solvents such as dimethylsulfoxide, N,N‐dimethylformamide (DMF), and N,N‐dimethylacetamide (DMAc), and were efficiently converted into poly(γ‐benzyl‐L ‐glutamate) (poly(BLG)) under mild conditions; at 60 °C without addition of any catalyst. Among the three urethanes, that having 4‐nitrophenoxycarbonyl group 1c was the most reactive to give poly(BLG) efficiently, as was expected from the highly electron deficient nature of the nitrophenoxycarbonyl group. On the other hand, the urethane 1a having phenoxycarbonyl group was also efficiently converted into poly(BLG), in spite of the intrinsically less electrophilicity of the phenoxycarbonyl group. In addition, the successful formation of poly(BLG) by the reaction of 1a favored its diluted concentration (0.1 M) much more than 2.0 M, the optimum initial concentration for 1c . ¹H NMR spectroscopic analyses of the reactions in situ revealed that the predominant pathway from 1 to poly(BLG) involved the intramolecular cyclization of 1 into the corresponding N‐carboxyanhydride, with release of phenol and its successive ring‐opening polymerization with release of carbon dioxide. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2649–2657, 2008     

Ring‐opening polymerization of lactide, ε‐caprolactone and their copolymerization catalyzed by β‐diketiminate zinc complexes

A series of zinc silylamido complexes bearing non‐symmetric β ‐diketiminate ligands were synthesized and structurally characterized. Ring‐opening polymerization (ROP) of rac ‐lactide catalyzed by these zinc complexes afforded heterotactic polylactides at room temperature (P _r = 0.79 ~ 0.83 in THF). The steric and electronic characteristics of the ancillary ligands showed significant influence on the polymerization performance of the corresponding zinc complexes. All these zinc complexes also showed moderate activities toward the polymerization of ε ‐caprolactone at ambient temperature in toluene, producing polycaprolactones (PCLs) with high molecular weights and moderate polydispersities. PCL‐b ‐PLLA copolymers could be obtained via three different copolymerization strategies (one‐pot polymerization, and sequential addition of the two monomers in either order) by adopting complex 6 as the initiator through the adjustment of reaction temperatures. The diblock nature of the copolymers was confirmed by ¹³C NMR spectroscopy and DSC analysis.     

Efficient catalysts for ring‐opening polymerization of ε‐caprolactone and β‐butyrolactone: Synthesis and characterization of zinc complexes based on benzotriazole phenoxide ligands

A series of efficient zinc catalysts supported by sterically bulky benzotriazole phenoxide ( BTP ) ligands are synthesized and structurally characterized. The reactions of diethyl zinc (ZnEt₂) with ^CMe2PhBTP ‐H, ^t‐BuBTP ‐H, and ^TMClBTP ‐H yield monoadduct [(μ‐ BTP )ZnEt]₂ ( 1 – 3 ), respectively. Bisadduct complex [( ^t‐BuBTP )₂Zn] ( 4 ) results from treatment of ZnEt₂ with ^t‐BuBTP ‐H (2 equiv.) in toluene, but treatment of ^TMClBTP ‐H with ZnEt₂ in the same stoichiometric proportion in Et₂O produces five‐coordinated monomeric complex [( ^TMClBTP )₂Zn(Et₂O)] ( 5 ). The molecular structures of compounds 1 , 4 , and 5 are characterized by X‐ray crystal structure determinations. All complexes 1 – 5 are efficient catalysts for the ring‐opening polymerization of ε‐caprolactone (ε‐CL) in the presence of 9‐anthracenemethanol. Experimental results indicate that complex 3 exhibits the greatest activity with well‐controlled character among these complexes. The polymerizations of ε‐CL and β‐butyrolactone catalyzed by 3 are demonstrated in a “living” character with narrow polydispersity indices (monomer‐to‐initiator ratio in the range of 25–200, PDIs ≤ 1.10). The “immortal” character of 3 provides a way to synthesize as much as 16‐fold polymer chains of poly(ε‐CL) (PCL) with narrow PDI in the presence of a catalyst in a small proportion. The controlled fashion of complex 3 also enabled preparation of the PCL‐b‐poly(3‐hydroxybutyrate) copolymer. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Self‐assembly of star‐shaped polystyrene‐block‐polypeptide copolymers synthesized by the combination of atom transfer radical polymerization and ring‐opening living polymerization of α‐amino acid‐N‐carboxyanhydrides

The self‐assembling nature and phase‐transition behavior of a novel class of triarm, star‐shaped polymer–peptide block copolymers synthesized by the combination of atom transfer radical polymerization and living ring‐opening polymerization of α‐amino acid‐N‐carboxyanhydride are demonstrated. The two‐step synthesis strategy adopted here allows incorporating polypeptides into the usual synthetic polymers via an amido–amidate nickelacycle intermediate, which is used as the macroinitiator for the growth of poly(γ‐benzyl‐L ‐glutamate). The characterization data are reported from analyses using gel permeation chromatography and infrared, ¹H NMR, and ¹³C NMR spectroscopy. This synthetic scheme grants a facile way to prepare a wide range of polymer–peptide architectures with perfect microstructure control, preventing the formation of homopolypeptide contaminants. Studies regarding the supramolecular organization and phase‐transition behavior of this class of polymer‐block‐polypeptide copolymers have been accomplished with X‐ray diffraction, infrared spectroscopy, and thermal analyses. The conformational change of the peptide segment in the block copolymer has been investigated with variable‐temperature infrared spectroscopy. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 2774–2783, 2006     

A convenient synthesis of α,α′‐ homo‐ and α,α′‐hetero‐bifunctionalized poly(ε‐caprolactone)s by ring opening polymerization: The potentially valuable precursors for miktoarm star copolymers

Two new ring opening polymerization (ROP) initiators, namely, (3‐allyl‐2‐(allyloxy)phenyl)methanol and (3‐allyl‐2‐(prop‐2‐yn‐1‐yloxy)phenyl)methanol each containing two reactive functionalities viz. allyl, allyloxy and allyl, propargyloxy, respectively, were synthesized from 3‐allylsalicyaldehyde as a starting material. Well defined α‐allyl, α′‐allyloxy and α‐allyl, α′‐propargyloxy bifunctionalized poly(ε‐caprolactone)s with molecular weights in the range 4200–9500 and 3600–10,900 g/mol and molecular weight distributions in the range 1.16–1.18 and 1.15–1.16, respectively, were synthesized by ROP of ε‐caprolactone employing these initiators. The presence of α‐allyl, α′‐allyloxy and α‐allyl, α′‐propargyloxy functionalities on poly(ε‐caprolactone)s was confirmed by FT‐IR, ¹H, ¹³C NMR spectroscopy, and MALDI‐TOF analysis. The kinetic study of ROP of ε‐caprolactone with both the initiators revealed the pseudo first order kinetics with respect to ε‐caprolactone consumption and controlled behavior of polymerization reactions. The usefulness of α‐allyl, α′‐allyloxy functionalities on poly(ε‐caprolactone) was demonstrated by performing the thiol‐ene reaction with poly(ethylene glycol) thiol to obtain (mPEG)₂‐PCL miktoarm star copolymer. α‐Allyl, α′‐propargyloxy functionalities on poly(ε‐caprolactone) were utilized in orthogonal reactions i.e copper catalyzed alkyne‐azide click (CuAAC) with azido functionalized poly(N‐isopropylacrylamide) followed by thiol‐ene reaction with poly(ethylene glycol) thiol to synthesize PCL‐PNIPAAm‐mPEG miktoarm star terpolymer. The preliminary characterization of A₂B and ABC miktoarm star copolymers was carried out by ¹H NMR spectroscopy and gel permeation chromatography (GPC). © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 844–860