Α-amino Acid N-carboxyanhydrides Research Articles

Friedel-Crafts α-Aminoacylation of Aromatic Compounds with a Chiral N-Carboxy-α-amino Acid Anhydride (NCA); Part 2

The N-carboxy-α-amino acid anhydrides (NCA) derived from L-Asp(OEt), L-Glu(OMe), L-Met, and L-Pro reacted with aromatic compounds (toluene or benzene) in the presence of AlCl3, to afford the corresponding α-aminoalkyl aryl ketones as hydrochloride salts in moderate yields. The β- and γ-amino acid esters, which were obtained from the reaction of the aromatic compounds with L-Asp(OEt)- and L-Glu(OMe)-NCA, were hydrolyzed by hydrochloric acid to the corresponding β- and γ-amino acids as hydrochloride salts. L-Phe-NCA did not react with benzene in the presence of AlCl3, instead an intramolecular acylation occurred to afford (S)-2-aminoindanone hydrochloride. The chiralities of the original L-α-amino acids were most retained during these α-aminoacylation.

Coordination polymerization of heterocyclic and heterounsaturated monomers

Polymerizations and copolymerizations of non-hydrocarbon monomers, such as heterocyclic and heterounsaturated monomers, in the presence of coordination catalysts constitute a distinct group of coordination polymerization processes which differ essentially from the coordination polymerization of unsaturated hydrocarbon monomers in terms of the kinds of catalyst applicable and the polymerization mechanism. While the coordination polymerization and copolymerization of numerous hydrocarbon monomers with catalysts based on transition metals have become the backbone of several significant branches of the plastics and rubber industries, the coordination polymerization and copolymerization of heterocyclic and heterounsaturated monomers (carried out mainly in the presence of catalysts based on main group metals) have been restricted in industry within a much smaller volume. However, the latter polymerizations are of great significance for extensive mechanistic studies and exploratory investigations to obtain more efficient catalysts, as well as for the discovery of novel synthetic routes for polymers, new polymers or for improving existing polymers. In this review, coordination polymerization and copolymerization of heterocyclic and heterounsaturated monomers are presented in terms of the type of monomer, type of catalyst, structure of the active sites and polymerization mechanism. Attention has been paid to the coordination homopolymerization of oxacyclic, thiacyclic, azacyclic, and phosphacyclic monomers, the coordination copolymerization of oxacyclic monomers with other heterocyclic monomers or heterounsaturated monomers, and the coordination homopolymerization of heterounsaturated monomers. Coordination polymerizability of heterocyclic monomers such as epoxides, episulfides, oxetanes, lactones, alkylene carbonates, alkylene thiocarbonates, dicarboxylic acid anhydrides and α-aminoacid N-carboxyanhydrides, morpholinedione, oxyphosphonoyloxytrimethylene, as well as heterounsaturated monomers like carbon dioxide, carbon disulfide, sulfur dioxide, isocyanates, aldehydes, ketones and ketenes, has been taken into consideration. The mechanisms of propagation operating in the coordination polymerization of the heteroatom-containing cyclic and acyclic monomers mentioned above have all been shown to be analogous, irrespective of the type of catalyst (containing mononuclear or multinuclear active species), and a general scheme concentrating on similarities of these mechanisms is proposed and discussed.

Synthesis of cyanoketophosphoranes, precursors of β-amino-α-keto-esters from UNCAs

Cyanomethylene triphenylphosphoranes of N-protected amino acids were synthesized from the corresponding N-urethane protected α-amino acid N-carboxyanhydrides (UNCAs) by reaction with cyanomethyltriphenylphosphonium chloride in good yields. These compounds are precursors of α-keto esters which are candidates for mimicking the tetrahedric transition state in enzyme inhibitors.

15N chemical shift tensors and conformation of solid polypeptides containing 15N-labeled glycine residue by 15N NMR

The correlation between the isotropic 15N chemical shift ( δ iso) and 15N chemical shift tensor components ( δ 11, δ 22 and δ 33) and the main-chain conformation such as the polyglycine I (PGI: β-sheet), II (PGII: 3 1-helix), α-helix and β-sheet forms of solid polypeptides [Gly∗,X] n consisting of 15N-labeled glycine (Gly∗) and other amino acids (X: natural abundance of 15N) has been studied by solid-state 15N NMR method. A series of polypeptides [Gly∗,X] n (X = glycine, l-alanine, l-leucine, l-valine, l-isoleucine, β-benzyl l-aspartate, γ-benzyl l-glutamate, ϵ-carbobenzoxy l-lysine, and sarcosine) were synthesized by the α-amino acid N-carboxy anhydride (NCA) method. Conformations of these polypeptides in the solid state were characterized on the basis of conformation-dependent 13C chemical shifts in the 13C cross-polarization-magic angle spinning (CP-MAS) NMR spectra and by the characteristic bands in the IR and far-IR spectra. The δ iso, δ 11, δ 22 and δ 33 of the polypetides were determined from the 15N CP-MAS and 15N CP-static (powder pattern) spectra. It was found that the δ iso, δ 11, δ 22 and δ 33 in the PGI form (δ 83.5, 185, 40.7 and 25 ppm, resp.) are upfield from those in the PGII form (88.5, 194, 42.1 and 29 ppm, resp.), which were reproduced by the calculated 15N shielding constants using the finite perturbation theory (FPT)-INDO method. It was also found that the δ 22 of the Gly∗ of [Gly∗,X] n is closely related to the main-chain conformation and the neighboring amino acid sequence, although the δ iso is almost independent of the glycine content and conformation. Consequently, the δ 22 value of Gly∗ containing copolypeptides is useful for the structural (main-chain conformation and neighboring amino acid sequence) analysis in the solid state by 15N NMR, if the 15N-labeled copolypeptide or natural protein can be provided. In addition, it is shown that the δ iso of the glycine residue is useful for the conformational study of some fibrous proteins such as silk fibroins and collagen fibrils in the solid state.

Vapor Deposition−Polymerization of α-Amino Acid N-Carboxy Anhydride on the Silicon(100) Native Oxide Surface

In this study, we introduce a novel dry process for surface deposition−polymerization of vapor phase α-amino acid N-carboxy anhydride (NCA) from a surface-immobilized initiator layer. In particular, the NCA of γ-benzyl-l-glutamate is initiated from (1-aminopropyl)triethoxysilane-modified silicon(100) native oxide substrates to form poly(γ-benzyl-l-glutamate) (PBLG). The progress of the reaction is monitored by the thickness change measured with ellipsometry, the surface composition is analyzed by X-ray photoelectron spectroscopy, the secondary conformation is characterized by attenuated total reflection Fourier transform infrared spectroscopy, and the surface roughness is examined by atomic force microscopy. Under an optimal reaction condition with temperature from 95 to 125 °C in vacuo, PBLG films of 40 nm thickness have been prepared in 4 h with surface roughness rms within 3.5 nm. All films above 4 nm thickness adopt the α-helical conformation.

Globular carbohydrate macromolecule “sugar balls”, 2. Synthesis of mono(glycopeptide)-persubstituted dendrimers by polymer reaction with sugar-substituted α-amino acid N-carboxyanhydrides (glycoNCAs)

Globular carbohydrate macromolecule “sugar balls”, 2. Synthesis of mono(glycopeptide)-persubstituted dendrimers by polymer reaction with sugar-substituted α-amino acid N-carboxyanhydrides (glycoNCAs)

Globular carbohydrate macromolecule "Sugar Balls", 2. Synthesis of mono(glycopeptide)-persubstituted dendrimers by polymer reaction with sugar-substitutedα-amino acidN-carboxyanhydrides (glycoNCAs)

Sugar-substituted α-amino acid N-carboxyanhydrides (glycoNCAs), i.e., O-(tetra-O-acetyl-β-D-glucopyranosyl)-L-serine NCA (2a) and O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-L-serine NCA (2b), were successfully used for the introduction of a mono(glycopeptide) unit into each terminal primary amino group of a dendrimer. Well-defined dendrimer-based artificial glycoconjugates, O-(β-D-glucopyranosyl)-L-serine-persubstituted poly(amido amine) (PAMAM) dendrimer (3a) and O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-L-serine-persubstituted PAMAM dendrimer (3b), were synthesized by polymer reaction of PAMAM dendrimer with 2a and 2b, respectively, followed by deacetylation with hydrazine monohydrate.

A concise synthesis of piperazine-2-carboxylic acids via β-lactam-derived α-amino acid N-carboxy anhydrides

A route to piperazine-fused 3-hydroxy β-lactams was accomplished via [2+2] cycloaddition of alkoxyketenes with imines derived from chiral α-amino aldehydes and chiral β-aminoalcohols. The resulting β-lactams on exposure to 0.55M NaOCl and a catalytic amount of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) afforded α-amino acid N-carboxy anhydrides formally derived from piperazine-2-carboxylic acids.

Synthesis of (S)- and (R)- tert Leucine Enabling Direct Coupling with α-Amino Acid Esters via β-Lactam-Derived α-Amino Acid N-Carboxy Anhydrides.

(3S, 4R)- and (3R, 4S)-3-hydroxy-4- tert-butyl β-lactams on exposure to 1M NaOCl and a catalytic amount of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) afforded α-amino acid N-carboxy anhydrides formally derived from both (S)- and (R)- tert-leucine amino acids. © 1997 Published by Elsevier Science Ltd.

Well defined polymer structures by ionic ring‐opening polymerization of cyclic monomers comprising the respective structure

AbstractRing‐opening polymerization of cyclic monomers is the method of choice when tailor‐made polymers and copolymers with heteroatoms in the main chain are to be prepared. Triblock copolymers comprising a poly(ethylene oxide) block [poly(EO)] and two poly(2,2‐dimethyltrimethylene carbonate) blocks [poly(DTC)] were prepared using a telechelic poly(EO) as initiator for the DTC polymerization. These block copolymers dissolve suitable salts leading to solid polymeric electrolytes. The thermal properties and the ionic conductivity of these materials are presented. Block copolymers comprising a poly(tetrahydrofuran) block [poly(THF)] and a poly(trimethylene urethane) block [poly(TU)] were obtained by sequential cationic polymerization of THF and TU with methyl trifluoromethane‐sulfonate as initiator. Mechanistic and kinetic aspects of the TU polymerization are discussed. To achieve the synthesis of block copolymers with a poly(L‐lactide) block [poly(LLA)] and a poly(α‐amino acid) block [poly(AA)] amino‐terminated poly(LLA) was prepared which served as initiator for the polymerization of α‐amino acid N‐carboxyanhydrides.

Synthesis and Properties of High-Molecular-Weight Polypeptides Containing Tryptophan II. Copolypeptides of Tryptophan with Various Amino Acids

Abstract High-purity N-carboxyl l-tryptophan anhydride (l-4-indoylmethyl-2,5-oxazolidinedione) was synthesized in good yield. Copolypeptides with a random sequence of l-trypophan (Trp) with glycine (Gly), l-alanine (Ala), l-α-amino-n-butyric acid (Abu), l-n-valine (Nval), l-n-leucine (Nleu), l-leucine (Leu), l-γ-methylglutamate (Glu(OMe)), and l-methionine (Met) were synthesized by the copolymerization of the corresponding N-carboxy-α-amino acid anhydrides (NCA) in solution. The rate of polymerization of Trp NCA was less than that of the other amino acid NCAs. The helix contents of the formed copolypeptides, estimated by the circular dichroism (CD) spectra, were remarkably decreased at a content of about 8% of Trp involved in poly(Trp-co-Nval) (poly(Trp,Nval)), poly(Trp-co-Leu) (poly(Trp,Leu)), poly(Trp-co-Nleu) (poly(Trp,Nleu)), and poly(Trp-co-Glu(OMe)) (poly(Trp,Glu(OMe))), but was not decreased at that percentage in poly(Trp-co-Met) (poly(Trp,Met)).

Spinning silk at Maidenhead: the polypeptide project

This paper reviews the research programme of the Maidenhead Laboratory of Courtaulds Ltd. devoted to the synthesis of textile fibres based on poly(α-amino acids), regarded as models for natural silk. The work involved studies of the preparation, properties and structures of the polymers and development of suitable fibre-spinning techniques. Polymers were prepared from N-carboxy-α-amino acid anhydrides (NCAs); the reactions involved, following initiation by protic or aprotic bases, are outlined. Applications of polarized infra-red radiation in elucidating polymer structure were pioneered at Maidenhead, and played a major role in the recognition of the α and β modifications of poly (α-amino acids) and their similarities to the fibrous proteins. The two forms show differences in properties, notably solubility, arising from different patterns of hydrogen bonding. X-ray diffraction patterns of oriented fibres of β-poly- l-alanine are remarkably similar to those of many silk fibroins. Solution-spinning is the only suitable process for fibre production from these polymers, and a novel method, permitting relatively high speeds, is described. Finished fabrics woven from 100 denier/60 filament yarn of poly (γ-methyl- l-glutamate) were found to possess many of the distinctive silk-like properties, together with a few additional easy-care features. Some costing details of the overall process are given; for 10 × 10 6 lb per year production, l-glutamic acid costs just exceeded 30% of the total.

Concise synthesis of α-alkyl α-amino acids and their incorporation into peptides viaβ-lactam-derived α-amino acid N-carboxy anhydrides

α-Hydroxy β-lactams in which C4 exists as a quaternary carbon are transformed in a single one-pot operation into α,α-dialkyl α-amino acid N-carboxy anhydrides providing a new approach to conformationally restricted peptide segments from non α-amino acid precursors.

Derivatisation of DL-amino acids by urethane — Protected α-amino acidN-carboxyanhydrides for separation by LC

Using a robotic autosampler, free DL-amino acids were derivatized with highly reactive, urethane-protected, L-α-amino acidN-carboxyanhydrides (NACs) with structures: Boc-Phe-NCA, Boc-Asn(Trt)-NCA, Fmoc-Lys(Boc)-NCA, Fmoc-Met-NCA, Fmoc-Ala-NCA, Z-Ala-NCA, Z-Val-NCA and Z-Leu-NCA (Boc=tert-butyloxycarbonyl, Trt=trityl, Fmoc=9-(fluor-enylmethyl)oxycarbonyl, Z=benzyloxycarbonyl). Using sodium borate buffer and acetonitrile solvent, derivatization was complete in 3.5 min at room temperature. By selection of an appropriate reagent, the resulting diastereomeric,N-protected dipeptides were separated on an octylsilica stationary phase using mixtures of sodium acetate buffer and acetonitrile as eluents.

A facile access to peptides containingD-α-methyl β-alkylserines by coupling of α-branched leuchs anhydrides with α-amino esters

A new one step synthesis of α,α-disubstituted α-amino acid N-carboxy anhydrides from α-hydroxy β-lactams and their coupling with α-aminoesters promoted by KCN is described.

New Synthesis of .alpha.-Amino Acid N-Carboxy Anhydrides through Baeyer-Villiger Oxidation of .alpha.-Keto .beta.-Lactams

A conceptually new route for the generation of optically active α-aminoacid N-carboxy anhydrides (NCAs) and hence α-amino acid derivatives is described. The strategy developed is simple and consists of the oxidation of α-hydroxy β-lactams to the corresponding α-keto β-lactams followed by a Baeyer-Villiger rearrangement. By that means, a wide variety of functionalized α-aminoacid N-carboxy anhydrides can be obtained, i.e., α,β-diamino acid and β-amino β-hydroxy acid-derived NCAs. The starting α-hydroxy(alkoxy) β-lactams required for the study are easily prepared in large quantities either by the cycloaddition reaction of achiral alkoxyketenes with chiral aldehyde-derived imines or by the addition of Grignard reagents to a 3-(benzyloxy)-4-formylazetidin-2-one. The construction of a wide variety of NCA's from non-amino acid precursors becomes the most remarkable point of the reaction methodology developed

Esterification of 9-fluorenylmethyloxycarbonyl α-amino acid N-carboxyanhydrides to hydroxyl-functionalized resins

Two hydroxyl-containing resins (Wang and Rink resins) were esterified using 9-fluorenylmethyloxycarbonyl α-amino acid N-carboxyanhydrides (Fmoc-NCAs) efficiently with high levels of substitution. The solvent of choice for this procedure was toluene. With varying amounts of N-methylmorpholine (NMM) as the base and reaction time, the level of racemization was remarkably low. For maximum substitution efficiency and low racemization, the following conditions gave the best results: toluene 15 min and NMM (1.0 equiv.) for the Wang resin and toluene 1.5 h and NMM (1.0 equiv.) for the Rink resin.

New routes to 1,4- benzodiazepin-2,5-diones

1,4-benzodiazepin-2,5-diones have been synthesized in good overall yields by two routes, the first one by cyclisation of dipeptides prepared from Boc anthranilic acid and α-amino acid methyl esters, the second one by reaction of N-carboxy α-amino acid anhydrides with Boc anthranilic acid.

A β-lactam framework as a β-alanyl dication equivalent: new synthesis of α-amino acid N-carboxy anhydrides (NCAs) derived from β-substituted alanines

Optically pure 4-formyl-3-hydroxy β-lactams are transformed into 4-methylaryl and 4-(2-ethylaryl) derivatives and converted into β-substituted alanine-derived NCAs through oxidation and Baeyer–Villiger rearrangement of the resulting α-keto β-lactams.

生体分解性ポリマーの合成とドラッグデリバリシステムへの応用

Study of biodegradable polymers for application in drug delivery systems is reviewed. Such biodegradable polymers as poly (a-amino acid), poly (α-hydroxy acids), and copolymers consisting of α-amino acids and α-hydroxy acids were synthesized by means of N-carboxy α-amino acid anhydride (NCA), direct polycondensation without the use of catalysts, and O-nitrophenylsulfenyl-N-carboxy α-amino acid anhydride (Nps-NCA), respectively.The biodegradation profiles of these polymers can be roughly classified into three patterns, parabolic-type, linear-type, and S-type, according to kind of polymer, molecular weight, crystallinity, and morphology. The drugs incorporated into matrices by a melt-pressing technique newly developed are applied to animal experiments and clinical cases.