Α-amino Acid N-carboxyanhydrides Research Articles

Investigation of the solid-state polymerization of N-carboxy α-amino acid anhydrides with reference to their crystal structures

Solid-state polymerizations of N-carboxy anhydrides (NCAs) of α-amino acids ( l-leucine, l-alanine, γ-benzyl- l-glutamate and glycine) were carried out using butylamine as initiator in hexane at 20–50°C. The results were compared with those for polymerization in acetonitrile solution. l-Leucine NCA was the most reactive among the NCAs examined, and formed high-molecular-weight polypeptide in the solid state. In contrast, l-alanine NCA polymerized faster than any other NCAs examined and formed high-molecular-weight polypeptide in acetonitrile compared to the solid-state polymerization. X-ray analysis, electron microscopy and infra-red spectroscopy revealed that l-leucine NCA polymerized to form α-helical polypeptide predominantly along the c axis in the crystal, while the α-helical polymer grows in random directions in the crystal of L-alanine NCA. Although γ-benzyl- l-glutamate NCA polymerized a little slower in the solid state than in acetonitrile, its polymerization reached 100% conversion and formed polypeptide with higher molecular weight than the value expected from the molar ratio of the monomer to the initiator. Glycine NCA polymerized very slowly in the solid state. These differences could be explained by their crystal structures. Favourable features for solid-state polymerization were found in the crystal of l-leucine NCA : five-membered rings of the NCA make a layer sandwiched by two hydrophobic side-chain layers and the NCA molecules polymerize to form the a-helical polypeptide in a layer without any interference from the other layers. On the other hand, such a layer structure was not seen in the crystal structure of l-alanine NCA. In the crystal of γ-benzyl- l-glutamate NCA, the layer structure similar to l-leucine NCA was observed and this seemed to activate the polymerization of the NCA, while the long side chains were considered to make molecular rotation difficult to some extent in the crystal. Glycine NCA seemed to be stable because of the dimer structure in the crystal.

Synthesis and Properties of High Molecular Weight Polypeptides Containing of Tryptophan

Abstract High purity N-carboxy-Dl-tryptophan anhydride (Dl-4-indoylmethyl-2,5-oxazolidinedione, Dl-Trp NCA) was synthesized in good yield. Copolypeptides with a random sequence of Dl-Trp with l-alanine (Ala) and Dl-alanine (Dl-Ala) were synthesized by copolymerization of the corresponding N-carboxy-α-amino acid anhydrides (NCA) in solution. Copolypeptides of Dl-Trp with l-Ala and Dl-Ala were partially soluble in water. The water-soluble copolypeptides of Dl-Trp and l-Ala mostly gave disordered conformations, while the water-insoluble copolypeptides were found in a mixture of α- and disordered conformations. The solubility of the copolypeptides was not influence by the tryptophan content in the polypeptides but, rather, by the conformation of the polypeptides.

ChemInform Abstract: A New Method for the Stepwise Synthesis of Depsipeptides.

Depsipeptides have been prepared in a stepwise fashion by a method using the dichloroacetyl (Dca) group as a suitable protecting group for the hydroxy group of hydroxy acids and 2-nitrophenylsulphenyl (Nps)N-carboxy α-amino acid anhydrides (NCAs) as a highly reactive amino acid derivative to acylate the hydroxy compounds.

A new method for the stepwise synthesis of depsipeptides

Depsipeptides have been prepared in a stepwise fashion by a method using the dichloroacetyl (Dca) group as a suitable protecting group for the hydroxy group of hydroxy acids and 2-nitrophenylsulphenyl (Nps)N-carboxy α-amino acid anhydrides (NCAs) as a highly reactive amino acid derivative to acylate the hydroxy compounds.

Synthesis of sequential polydepsipeptides involving depsipeptide formation by the 2-nitrophenylsulphenyl N-carboxy α-amino acid anhydride (Nps–NCA) method

Sequential polydepsipeptides containing a tripeptide sequence Ala-Ala-Glu(OEt) and various α-hydroxy acids have been successfully prepared by polycondensation of tetradepsipeptide pentachlorophenyl esters. The latter were synthesized by preparation of didepsipeptide free acids by the Nps-NCA method followed by active esterification and peptide chain elongation by the so-called ‘back-up’ procedure.

Secondary structure of peptides: 19. Primary/secondary structure relationships of leucine/valine copolypeptides prepared from α-amino acid N-carboxyanhydrides

l-Leucine -N- carboxyanhydride ( l-Leu-NCa) and l-valine -N- carboxyanhydride ( l-Val-NCA) were copolymerized under various conditions. In addition to the initiators benzylamine, triethylamine, pyridine), temperature, solvent and molar ratio of the co-monomers were varied. The molar composition of the isolated copolypeptides were determined from 1H n.m.r. spectra. The sequences were analysed by means of 15N n.m.r. spectroscopy and characterized by average block lengths. By means of 13C n.m.r. CP/MAS spectroscopy of the solid ‘as polymerized’ copolypeptides it was feasible to quantify the α-helix/β-sheet ratio of both Leu and Val units separately. In all copolypeptides with Leu/Val ratios 1 2 a substantial fraction of the Val units adopts the α-helical conformation. Upon reprecipitation the α-helix/β-sheet ratio changed, indicating that most ‘as polymerized’ samples possess a kinetically controlled, thermodynamically unstable secondary structure. In several samples the percentage of α-helical Val units reached 90% after reprecipitation. At constant Leu/Val ratios the percentage of α-helical Val units decreases with increasing blockiness of the sequence.

Block copolymerization of α-amino acid N-carboxyanhydride initiated by vinyl polymers having a terminal amino group and the characterization of the block copolymers

Poly(methyl methacrylate) and polystyrene having terminal amino groups were synthesized by the radical polymerization of those monomers in the presence of 2-mercaptoethylammonium chloride as a chain-transfer agent. By the terminal group analysis and the molecular weight determination of the polymers, 0.5–1.3 amino groups were found in a chain of poly(methyl methacrylate) and 0.5–2.5 amino groups in a chain of polystyrene. Using these polymers having a terminal amino group as an initiator, the block polymerization of α-amino acid N-carboxyanhydride (NCA) was carried out. In the polymerizations of Glu(OBzl) NCA and Lys(Z) NCA by the poly(methyl methacrylate) initiator, the terminal amino group underwent a nucleophilic addition reaction to NCA and initiated the polymerization, yielding A-B-type block copolymers in a high yield. The same was observed in the polymerizations of Gly(OBzl) NCA and Lys(Z) NCA by the polystyrene initiator. By eliminating the protecting groups of the side chains of the polypeptide segment, the block copolymers poly(methyl methacrylate)-poly(Glu), poly(methyl methacrylate)-poly(Lys), polystyrene-poly(Glu) and polystyrene-poly(Lys) were synthesized with little side reactions. The side chain amino groups of poly(Lys) segment in the poly(methyl methacrylate)-poly(Lys) block copolymers were sulphonated or stearoylated successfully.

ChemInform Abstract: SYNTHESIS OF N‐TRIPEPTIDYL‐D‐GLUCOSAMINE BY THE STEPWISE REACTION OF N‐CARBOXY α‐AMINO ACID ANHYDRIDE

AbstractAus dem Glucosamin (IV) erhält man durch Reaktion mit den Anhydriden (Ia) bzw. (Ib) und (IIa) die Derivate (V) bzw. (VI).

Fusibility of Poly(N-carboxy α-Amino Acid Anhydride) Materials Treated under Pressure-Heat Conditions and in Vitro-in Vivo Degradation of Hot-Pressed Materials

Abstract Powdered poly(N-carboxy α-amino acid anhydride) materials were treated at temperatures of 50, 100, 150, and 200°C under a pressure of 150 kg/cm2. A number of hot-pressed materials showed simultaneous fusion and contraction in volume. The fusion temperature of the hot-pressed materials was generally lower than the true melting point of the powdered materials at atmospheric pressure (determined with a Differential Scanning Calorimeter). The hot-pressed materials had high rigidity and transparency. The in vitro-in vivo degradation of hot-pressed materials was also investigated. The homo- and copoly(α-amino acid) materials used in this study were scarcely degraded, though debenzylated t e rpolymers such as β-benzyl-L-aspartate/aspartic acid/L-leucine and γ -benzyl-L- glutamate/glutamic acid/L - leucine we re significantly degraded in both the in vitro and in vivo experiments. It was found that the in vivo degradation profile of hot-pressed terpolymer materials corresponds relatively well to degradati...

Synthesis of N-Tripeptidyl-d-glucosamine by the Stepwise Reaction of N-Carboxy α-Amino Acid Anhydride

Abstract N-Peptidyl-d-glucosamines were synthesized by the stepwise reaction of N-carboxy α-amino acid anhydrides (4-alkyl-2,5-oxazolidinediones) with d-glucosamine hydrochloride in the presence of equimolar sodium methoxide in a mixture of acetonitrile and methanol, or in methanol, at a low temperature. Polymerization reaction of N-carboxy α-amino acid anhydrides (NCAs) did not occur at −50 °C. The mechanism of the reaction was then studied.

Polymerization of α=Aminoisobutyric Acid NCA: Interpretation According to the Hypothesis of a Multiple Mechanism

Abstract The basic salt-initiated polymerization of α-aminoisobutyric acid NCA in acetonitrile was studied using various alkaline alcoholates and in the presence or absence of various protic (very weak acid) additives. The cation effect observed was the one expected from either the N-carboxy-α-amino acid anhydride (NCA) anion mechanism (activated monomer mechanism) or the alcoholate anion mechanism (Blout's mechanism). The anion effect appeared to be abnormal for the former mechanism, but did not agree nor disagree substantially with the latter. Furthermore, such additives as methanol (conjugate acid of the initiator), 3-methylhydantoin, 2-oxazolidone, and N-acetylglycine NCA (prototype of the chain growing through the NCA anion mechanism) considerably enhanced the rate of initiation. A still higher rate of initiation could be obtained by the combined use of two additives. IR and DTA analyses of the polymerization products showed the formation of 5,5-dimethylhydan-toin-3-isobutyric acid in the sample usin...

New polymer syntheses

L-Lactic acid O-carboxyanhydride (L-Lac-OCA) was prepared by phosgenation of L-lactic acid lithium salt. Its polymerization was conducted using a variety of initiators, and the resulting poly(L-lactides) were characterized by 1H-and 13C-NMR spectra, by vapor pressure osmometry (VPO) and by optical rotation. Number average molecular weights > 3 000 were never obtained. Also polymerizations of D,L-Lac-OCA did not give higher Mn's. The formation of isotactic triads was favored under all conditions. Furthermore, copolymerizations of L-Lac-OCA and various α-amino acid N-carboxyanhydrides (NCAs) only yielded low molecular weight poly(depsipeptides). The polymerization mechanism is discussed.

Stereoselectivity in the nucleophilic addition-type polymerization of α-amino acid N-caboxyanhydride initiated by diastereomeric dipeptide amines

In order to investigate the effect of the chiral penultimate unit on the stereoselection of α-amino acid N-carboxyanhydride (NCA) by the terminal unit of a growing chain in the nucleophilic addition-type polymerization, the diastereomers of dipeptide amines, H-( R)-Phe-( S)-Phe-Mo and H-( S)-Phe-( S)-Phe-Mo, in which Mo represents a morpholine residue, were synthesized, and the stereoselectivity in their nucleophilic addition reactions to NCA was investigated and compared with that of a monopeptide amine H-( S)-Phe-OEt. In the reaction with Phe NCA in nitrobenzene, either of the dipeptide amines reacted preferentially with an enantiomer of NCAs having a configuration opposite to the N-terminal unit of the dipeptide amine. The preference of enantiomeric NCA and the extent of stereoselectivity were nearly the same as those found with H-( S)-PheOEt. The opposite-enantiomer selectivity of the dipeptide amines was also observed in the reaction with N-MePhe NCA, and the extent of stereoselectivity was found to increase very much in the reaction of H-( R)-PHe-( S)-Phe-Mo compared with that of H-( S)-Phe-OEt. Therefore, the enhancement of the stereoselectivity of the N-terminal unit by the penultimate unit was shown experimentally. On the other hand, the stereoselectivity of H-( S)-Phe-( S)-Phe-Mo was not very different from that of H-( S)-Phe-OEt. These results were obtained either in nitrobenze or in m-dimethoxybenzene. H-( S)-Phe-( S)-Phe-OEt tends to aggregate by an intermolecular hydrogen bond in aqueous and tetrahydrofuran solutions. Its p K a value and nucleophilicity towards NCA were much lower than H-( R)-Phe-( S)-Phe-Mo, which was free from the aggregation under similar conditions. These experimental results suggest that the major product in the polymerization of ( RS)-Phe NCA by amine should be an alternating copolymer. However, this prediction was not verified experimentally, and the important contributions from the aggregation and the molecular weight distribution of growing chains were suggested.

The Steric Hindrance of the Stepwise Reaction of N-Carboxy α-Amino Acid Anhydride with the α-Amino Acid Ester

Abstract The mechanisms of the reactions of 4-alkyloxazolidinediones (1) (N-carboxy α-amino acid anhydrides(NCAs)) with α-amino acid benzyl ester p-toluenesulfonates (2) were investigated in acetonitrile containing triethylamine at low and room temperatures. Two types of reactions were observed: (1) the polymerization of NCAs was initiated with a small amount of 2 to produce polypeptides (6), and (2) the dipeptide benzyl esters (4) were produced by the stepwise reaction of NCAs with the esters. Both the polymerization and the dipeptide formation (1+2) seemed to be initiated by the nucleophilic attack of the amino group of the ester on the C-5 carbon of NCAs. The polymerization proceeded when the side chains of the amino acid esters (R2) were more bulky than those of the NCAs (R1). On the contrary, dipeptide esters were produced when the side chains of the NCAs (R1) were more bulky than those of the esters (R2).

Solvent effect on the stereoselective addition reaction of optically active amines to N-methylphenylalanine N-carboxyanhydride

The effect of solvent on stereoselectivity in the nucleophilic addition reaction of various optically active amines to N-methylphenylalanine N-carboxyanhydride has been investigated. In m-dimethoxybenzene as solvent, ( S)-valine, ( S)-leucine, and ( S)-phenylalanine ethyl esters reacted preferentially with ( R)- N-methylphenylalanine N-carboxyanhydride, but the stereoselectivity decreased considerably in nitrobenzene and dimethylacetamide as solvents. In the latter solvents, the dipolar interactions between an amine and an N-carboxyanhydride and the orientation of the substituent of N-carboxyanhydride were seriously affected, hence the stereoselectivity decreased. As a consequence, the enantiomer selection by the terminal amine of a growing chain in the nucleophilic addition-type polymerization of α-amino acid N-carboxyanhydride can be controlled by the choice of solvent. ( S)-Proline ethyl ester and ( S)- α-phenylethylamine reacted preferentially with ( S)- N-methylphenylalanine N-carboxyanhydride in m-dimethoxybenzene, and this type of selectivity did not change in nitrobenzene. But in dimethylacetamide the stereoselectivity decreased. In the transition state of the reaction of these amines and N-methylphenylalanine N-carboxyanhydride dipolar interactions are operating, which should be destroyed by dimethylacetamide but may not be affected by nitrobenzene.

Polymerization of α-amino acid N-carboxyanhydride in the presence of preformed poly(α-amino acid) - from chain effect to stereoselective polymerization

Abstract

Stereoselective and Asymmetric-Selective Polymerization of α-Amino Acid N-Carboxyanhydride

Abstract The enantiomer selectivity in the propagation reaction of NCA was investigated by using suitable model reactions. Contrary to the assumption usually made, the enantiomer selectivity in the nucleophilic addition of chiral amines to NCA depended strongly on the structure of amine or NCA and the solvent. In the polymerization by an activated-NCA mechanism, the addition of activated NCA to NCA was found for the first time to be enantiomer-selective. In addition to this, the chiral penultimate unit was found to participate in the enantiomer selection. Structures of the transition states leading to the different types of enantiomer selection were proposed.

On the polymerization mechanism of alpha-amino acid N-carboxyanhydrides initiated by sodium hydride.

On the polymerization mechanism of alpha-amino acid N-carboxyanhydrides initiated by sodium hydride.

ChemInform Abstract: SYNTHESIS OF POLYAMINO ACIDS. II. SYNTHESIS OF α‐AMINO ACID N‐CARBOXY ANHYDRIDE

Chemischer InformationsdienstVolume 7, Issue 2 Heterocyclic Compounds ChemInform Abstract: SYNTHESIS OF POLYAMINO ACIDS. II. SYNTHESIS OF α-AMINO ACID N-CARBOXY ANHYDRIDE Y. KOIWA, Search for more papers by this authorK. TATSUKAWA, Search for more papers by this authorA. MIIKE, Search for more papers by this authorM. TERANISHI, Search for more papers by this authorY. FUJIMOTO, Search for more papers by this author Y. KOIWA, Search for more papers by this authorK. TATSUKAWA, Search for more papers by this authorA. MIIKE, Search for more papers by this authorM. TERANISHI, Search for more papers by this authorY. FUJIMOTO, Search for more papers by this author First published: January 13, 1976 https://doi.org/10.1002/chin.197602182Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume7, Issue2January 13, 1976 RelatedInformation

Anionic polymerization mechanism of n‐carboxy‐α‐amino acid anhydrides

AbstractThe anionic polymerization mechanism of N‐carboxy‐α‐amino acid anhydrides (NCAs) is studied. Polymerization of α‐aminoisobutyric acid NCA in the presence of triethylamine as catalyst is fairly accelerated by addition of ring amide compounds, namely 2‐oxazolidone and 3‐methyl hydantoin. Similar effects are noted when N‐acetyl derivatives of such compounds are used. This observation corroborates the usual hypothesis which presumes a N‐acylated NCA ring structure for the growing chain end.By comparing this polymerization with that of lactams, one reveals some common features as well as differences between these two reactions. Theoretical considerations supported by some experimental data lead us to assume two hypotheses in interpreting the anionic polymerization of NCAs: first, the 2‐carbonyl group is the most electrophilic of the three carbonyls present at the active site of chain growth, and second, the NCA anion has a pronounced oxanionic character.Thus, the anionic polymerization mechanism of NCAs we propose, involves attack of the 2‐carbonyl group of the terminal ring unit by NCA oxanion. In the resulting reaction intermediate, the attacking unit then swings to the 5‐carbonyl through a series of electron transfers by mesomerism, helped by the release of carbon dioxide after the neutralization of the ionic charge of the polymer chain.This mechanism is an improved version of the “activated monomer” mechanism, and is based on the same principle as the latter. Thus, not only can our own results be explained without difficulty by this mechanism, but also the experimental facts presented in support of the conventional mechanism in the literature agree with it.