Α-amino Acid N-carboxyanhydrides Research Articles

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

Molecular Bottlebrushes with Polypeptide Backbone Prepared via Ring‐Opening Polymerization of NCA and ATRP

A new type of molecular bottlebrush with poly-L-lysine (PLL) as backbone was synthesized via ROP followed by ATRP. A Nϵ-bromoisobutyryl functionalized Nα-CBZ-L-lysine was firstly synthesized and converted in polymerizable α-amino acid N-carboxyanhydride (NCA), which was then polymerized using Ni(0) transition metal complex to give well-defined bromo-functionalized homopolypeptide (PBrLL), from which we prepared two types of polypeptide bottlebrushes with polystyrene and poly(oligoethylene glycol methacrylate) as side-chains. PBrLL macroinitiator was demonstrated to have high initiation efficiency for ATRP, which allowed good control over side-chain length. CD and FTIR characterization revealed that both PBrLL macroinitiator and PLL backbone of bottlebrushes adopted α-helical conformation in appropriate solvents.

Thermoresponsive Polypeptides from Pegylated Poly-l-glutamates

The synthesis and characterization of new thermoresponsive pegylated poly-L-glutamate (poly-L-EG(x)Glu) are described. The obtained polypeptides display low critical solution temperature (LCST) behaviors in water, and the LCST can be tuned via copolymerization of different amino acid monomers at varied molar ratio. This is the first example of thermoresponsive polypeptide made from ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs). Circular dichroism characterizations reveal that the secondary structure of poly-L-EG(x)Glu depended on the chain length of the side chain.

Synthesis of thiol-clickable and block copolypeptide brushes via nickel-mediated surface initiated polymerization of α-amino acid N-carboxyanhydrides (NCAs)

We describe the synthesis of homo-, block, and clickable copolypeptide brushes from low surface area substrates using nickel-mediated surface-initiated polymerization of α-amino N-carboxyanhydrides.

Surface characteristics of poly(γ-alkyl α l-glutamate)s with different alkyl groups

A series of poly(γ-alkyl α L-glutamate)s with different alkyl groups were synthesized by the ring opening polymerization of corresponding α-amino acid N-carboxyanhydrides. The characteristics of these polyglutamate surfaces were evaluated by attenuated total reflectance Fourier transform infrared spectroscopy spectra, water contact angle, water absorption, protein adsorption, and platelet adhesion measurements. Changing the length of the alkyl side chain provides a unique opportunity to study the influence of carbon number in the alkyl group on the surface properties of the polyglutamates. Water contact angle and water absorption data show that the hydrophilicity of these polyglutamate surfaces decreases with the increasing of methylene in the alkyl group. Protein adsorption on these polyglutamate surfaces increases with the enhancing of surface hydrophobicity. However, the changes in platelets adhesion could be attributed to the hydrophilicity/hydrophobicity of the polyglutamates and the specific effect of alkyl group. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Revolutionary phosgene‐free synthesis of α‐amino acid N‐carboxyanhydrides using diphenyl carbonate based on activation of α‐amino acids by converting into imidazolium salts

α-Amino acids imidazolium salt smoothly reacted with diphenylcarbonate to afford the corresponding urethanes. The urethanes were activated by adding carboxylic acid to undergo selective cyclization, leading to successful development of a new phosgene-free process for synthesizing α-amino acid N-carboxyanhydrides (NCAs). Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

ChemInform Abstract: Practical Synthesis of α-Amino Acid N-Carboxy Anhydrides of Polyhydroxylated α-Amino Acids from β-Lactam Frameworks. Model Studies Toward the Synthesis of Directly Linked Peptidyl Nucleoside Antibiotics.

A straightforward method for the synthesis of polyhydroxylated α-amino acid N-carboxy anhydrides (NCAs) is described as the means by which short peptide segments comprised of a polyhydroxylated chain are easily affordable. The entire sequence lies in the preparation of nonracemic 3-hydroxy β-lactams through the highly diastereoselective Staudinger reaction of hydroxyketene equivalents with chiral α-oxyaldehyde-derived imines, followed by TEMPO radical assisted cycloexpansion to the corresponding NCA and subsequent peptide coupling with α-amino acid esters. The method has been applied to the synthesis of short peptide segments derived from carbamoylpolyoxamic acid, some glycoglycines, as well as C2 symmetric hydroxy amino acids.

ChemInform Abstract: A Strategy for the Asymmetric Aminohomologation of α,β-Dihydroxy Aldehydes: Application to the Synthesis of the Southwest Tripeptide Segment of Echinocandin B.

The synthesis of the (2S,3S,4S)-3,4-dihydroxyhomotyrosine amino acid segment, present in echinocandin B, in its activated form ready for peptide coupling is described. The key steps of the approach are the enantioselective AD reaction of 4-methoxycinnamic acid methyl ester, a completely diastereoselective [2 + 2] hydroxyketene−imine cycloaddition, and the TEMPO-assisted cycloexpansion of the resulting 3-hydroxy β-lactam to the corresponding α-amino acid N-carboxy anhydride (NCA). The smooth opening of the latter upon treatment with l-Thr(OSitBuPh2)OMe and further acylation with the N-Cbz protected l-4-tert-butyldiphenylsilyloxy proline rendered the southwest portion of echinocandin B.

Peptide Synthesis in Aqueous Environments: The Role of Extreme Conditions on Peptide Bond Formation and Peptide Hydrolysis

The mechanisms and free energetics underlying the formation of peptides from alpha-amino acids and alpha-amino acid N-carboxyanhydrides (NCAs) in bulk water at both ambient and extreme temperature and pressure conditions were investigated using accelerated ab initio molecular dynamics. In particular, peptide bond formation using an activated amino acid in form of its NCA, subsequent decarboxylation, as well as hydrolysis of the formed peptide were studied using glycine. It is shown to what extent thermodynamic conditions affect the reaction mechanisms qualitatively and the energetics quantitatively in solution. In particular, the zwitterionic intermediate in the peptidization step found in ambient water degenerates into a transient species in hot-pressurized water, whereas the hydrolysis reaction is found to follow qualitatively different pathways at ambient and extreme conditions. The work also quantifies the impact of extreme solvent conditions on both peptide bond formation and peptide hydrolysis in aqueous media. Beyond the specific case, the results provide important insights into how elevated temperatures and increased pressures affect organic reactions in aqueous solutions.

Synthesis of well-defined poly( N-isopropylacrylamide)- b-poly(L-glutamic acid) by a versatile approach and micellization

A novel Fmoc-protected chain transfer agent (CTA) was synthesized and applied in the reversible addition–fragmentation chain transfer (RAFT) polymerization of N-isopropylacrylamide (NIPAAm), resulting in well-defined Fmoc-protected PNIPAAm and the amino-end capped PNIPAAm by the subsequent hydrolysis. Poly( N-isopropylacrylamide)- b-poly( l-glutamic acid) (PNIPAAm- b-PLGA) with controlled molecular weight and narrow molecular weight distribution was synthesized successfully via ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs) by using PNIPAAm-NH 2 as the macroinitiator. Both pH- and thermo-responsive micellization behaviors of the block copolymer PNIPAAm 55- b-PLGA 35 in dilute aqueous solution were investigated by means of the pyrene fluorescence, circular dichroism, 1H NMR, transmission electron microscopy and dynamic and static light scattering. Spherical PLGA-core and rod-like PNIPAAm-core micelles are formed in response to pH and temperature. The reversible transition between the PLGA-core and PNIPAAm-core micelles was observed. This work provides a versatile approach for synthesizing well-defined stimuli-responsive polypeptide-based double hydrophilic diblock copolymers (DHBCs), and is of great potential for generating useful stimuli-responsive materials in biomedical applications.

Polypeptide Synthesis via Living Polymerization

The authors report a controlled polymerization, mediated by hexamethyldisilazane (HMDS), of α-amino acid N-carboxyanhydrides (NCAs) to synthesize polypeptides and block co-polypeptides. The polymerization is living, yielding polypeptides with molecular weights (Mn) closely matching predicted values. With polypeptides playing an increasingly larger role as functional materials employed in a wide range of applications, the establishment of a highly efficient method of their syntheses is a notable accomplishment.

Hexamethyldisilazane-Mediated Controlled Polymerization of α-Amino AcidN-Carboxyanhydrides

Ring-opening polymerizations of α-amino acid N-carboxyanhydrides (NCAs) initiated with amines typically form polypeptides with uncontrolled molecular weights and broad molecular weight distributions. However, we found that hexamethyldisilazane (HMDS)-mediated controlled NCA polymerizations gave polypeptides with predictable molecular weights and narrow molecular weight distributions. Using MS, NMR, and FT-IR, we demonstrated that the initiation step involved the cleavage of the N−Si bond of HMDS and the formation of a trimethylsilyl carbamate (TMS-CBM) terminal group. Polypeptide chains were propagated through the migration of TMS of the TMS-CBM end group to the incoming monomer and formed a new TMS-CBM terminal group. This organosilicon reagent mediated NCA polymerization offers a metal-free strategy for the convenient synthesis of homo- or block polypeptides with predictable molecular weights and narrow molecular weight distributions.

Ring-opening polymerization of γ-benzyl-l-glutamate-N-carboxyanhydride in ionic liquids

This work deals with ring-opening polymerization of a representative N-carboxy-α-amino acid anhydride (NCA) in ionic liquids. The polymerization of γ-benzyl-l-glutamate-N-carboxyanhydride (BLG-NCA) with n-butylamine as an initiator in an ionic liquid ([BMI][PF6]) proceeded as a milky white dispersion with no evidence of macroscopic precipitation. The polymerization with the primary amine under suitable conditions afforded poly(amino acid) having narrow polydispersity, molecular weights close to the theoretical values, and helical secondary structure. The polymerization rate was slightly affected by the nature of the anion and hydrophobicity of the ionic liquids, while poly(BLG)s having low polydispersities were obtained regardless of the kind of the ionic liquids. Several parameters, such as the existence of organic solvent as a co-solvent and monomer concentration, had also clear effects on the polymerization rate and/or the polydispersity of the resulting poly(BLG)s. The possible interactions between the ionic liquid and NCA monomer or the ionic liquid and the initiator were characterized using FT-IR, 1H and 13C NMR measurements. The character of this polymerization process was also studied by performing kinetic investigations. We believe that this represents the first report on amine-initiated ring-opening polymerization of NCA in ionic liquid.

Practical Syntheses of Chiral α-Amino Acids and Chiral Half-Esters by Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Desymmetrization of Cyclic meso-Anhydrides with New Modified Cinchona Alkaloid Catalysts

The large-scale applications of the kinetic resolution of urethane-protected α-amino acid N-carboxyanhydrides (UNCAs) and the desymmetrization of cyclic meso-anhydrides using modified cinchona alkaloids are described. These asymmetric reactions are effective organocatalytic methods for the synthesis of chiral α-amino acids 6 and chiral half-esters 2 on an industrial scale, because the organocatalyst recovery and product purification can be carried out by a simple extractive procedure obviating a chromatographic purification step. The modified cinchona alkaloid catalysts (DHQD)2AQN and (DHQ)2AQN, as reported by Deng and co-workers, are not readily available and therefore not suitable for industrial-scale synthesis. Various O-alkylated quinidine and quinine derivatives were prepared and screened as catalysts for the kinetic resolution of phenylalanine UNCA with alcohol. The readily prepared O-propargylquinidine (OPQD) and O-propargylquinine (OPQ) were discovered to be highly enantioselective and practical catalysts. These new catalysts were applied to the synthesis of chiral propargylglycine 24 and the key intermediate of BAY10-8888/PLD-118, 26, on an industrial scale, by the kinetic resolution of UNCA 22 and the desymmetrization of cyclic meso-anhydride 25, respectively.

Polyphenylene Dendrimers as Scaffolds for Shape-Persistent Multiple Peptide Conjugates

The present work describes synthetic concepts for the coupling of peptides to polyphenylene dendrimers (PPDs). Novel functionalized cyclopentadienones have been synthesized whose Diels-Alder cycloaddition with various core molecules leads to polyphenylene dendrimers possessing (protected) amino or carboxyl groups. In addition, the resulting functionalized molecules exhibit the characteristic shape-persistence and monodispersity of PPDs. Their functions have been used for the attachment of polylysine to the dendritic scaffold. Three different methods for the decoration of dendrimers with polypeptides are presented. First, polylysine segments are grafted from the surface of the dendrimers employing alpha-amino acid N-carboxyanhydride (NCA) polymerization. Second, the C-terminal carboxyl groups of protected polypeptides are activated and then coupled to the amino groups on the surface of the PPD. Finally, cysteine terminated, unprotected peptide sequences are attached to polyphenylene dendrimers utilizing the addition of the sulfhydryl group of a cysteine to the maleimide functions on the dendrimer surface. Moreover, Diels-Alder cycloaddition of suitably functionalized cyclopentadienons to a desymmetized core molecule allows the design of a dendritic scaffold with a specific number of different anchor groups on its periphery. These approaches are important for the tailoring of new, shape-persistent, polyfunctional multiple antigen conjugates.

Graft Polymerization of Cyclic Compounds on Cellulose Dissolved in Tetrabutylammonium Fluoride / Dimethyl Sulfoxide.

Cyclic compounds such as lactones and N-carboxy α-amino acid anhydrides (NCAs) were graft-polymerized on cellulose dissolved in tetrabutylammonium fluoride ⁄ dimethyl sulfoxide (TBAF ⁄ DMSO). e-Caprolactone was grafted on cellulose with grafting of 64% in this solvent system. NCAs were also grafted with grafting of over 100%. It is thought that an increase in the nucleophilicity of hydroxyl groups of cellulose by the interaction with TBAF was related to this polymerization.

Kinetic study of the polymerization of α-amino acid N-carboxyanhydrides in aqueous solution using capillary electrophoresis

N-Carboxyanhydrides of amino acids (NCAs) are very reactive monomers able to polymerize into oligopeptides. They are assumed to be prebiotic precursors of the first polypeptides. Few reports have been published on the study of NCA polymerization in aqueous solution. In this work, a kinetic study focused on the hydrolysis of NCA and its coupling with amino acids and homopeptides (up to tripeptide) was carried out, taking l-valine derivatives as model compounds. For that purpose, capillary electrophoresis appeared to be an effective and reliable technique for the measurement of the kinetic constants. The electrophoretic separation conditions, the procedure for stopping NCA reactivity, as well as the conditions of reaction are discussed in detail. We report the variation of the kinetic constant of the coupling reaction of the NCA of valine with an oligovaline as a function of its degree of polymerization. Finally, a temperature study also allowed us to estimate the activation energies associated with the NCA of valine hydrolysis and its coupling reaction with valine.

A β-lactam route to short peptide segments related to angiotensin-converting enzyme (ACE) inhibitors

The stereocontrolled synthesis of the Angiotensin Converting Enzyme (ACE) inhibitor enalapril is reported. The key transformation of the synthesis is a formal carboxylation of imines, which lies in the sequence: imine-ketene (2+2) cycloaddition reaction, ring expansion of the resulting 3- hydroxy β-lactam to a N-carboxy α-amino acid anhydride (NCA), and final opening of the NCA with alcohols.

A concise synthesis of α-amino acid N-carboxy anhydrides of (2 S,3 S)-β-substituted serines

A general access to 3-hydroxy-4-(1-hydroxyalkyl)-β-lactams with a C 4–C 1′ relative configuration unlike is provided. The subsequent oxidative ring expansion of the corresponding 3-hydroxy β-lactam smoothly affords an α-amino acid N-carboxy anhydride (NCA) formally derived from (2 S,3 S)-β-substituted serine, which upon sequential peptide coupling furnishes the tripeptide segment 2 , present in lysobactin.

Versatility of β-lactams in synthesis. Studies directed toward the synthesis of complex nucleoside antibiotics and some macrocyclic peptides

Abstract The diastereoselective [2+2] cycloaddition of α-hydroxyketene equivalents with chiral α,ω-oxyaldehyde-derived imines followed by the 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO)-promoted ring expansion of the resulting α-hydroxy β-lactam adducts provides an unconventional and short route to α-amino acid N-carboxy anhydrides (NCAs). The required enantiopure α,ω-oxyaldehydes were obtained either from the chiral pool or through the Sharpless AD methodology. Following the present strategy, several nonproteinogenic NCAs were synthesized, which were further coupled with α-amino acid esters giving rise to key fragments of some nucleoside antibiotics and macrocyclic peptides.