Peptide Coupling Agent Research Articles

ChemInform Abstract: Selective Synthesis of 5,6‐Dihydrophenanthridines, 5,6‐Dihydrobenzo[c][1,8]naphthyridines and Their Fully Aromatized Analogues via the Pictet—Spengler Reaction Mediated by Peptide Coupling Agent Propylphosphonic Anhydride (T3P).

Abstract A new method has been developed for the selective synthesis of 5,6-dihydrophenanthridines, 5,6-dihydrobenzo[c][1,8]naphthyridines and their fully aromatized analogues via the Pictet–Spengler reaction mediated by propylphosphonic anhydride (T3P). The method, which uses less toxic and readily available T3P, generally seems to be more flexible, efficient in the preparation of 5,6-dihydrophenanthridine derivatives and complementary to conventional routes in the preparation of fused pyridines.

Selective synthesis of 5,6-dihydrophenanthridines, 5,6-dihydrobenzo[c][1,8]naphthyridines and their fully aromatized analogues via the Pictet–Spengler reaction mediated by peptide coupling agent propylphosphonic anhydride (T3P)

A new method has been developed for the selective synthesis of 5,6-dihydrophenanthridines, 5,6-dihydrobenzo[c][1,8]naphthyridines and their fully aromatized analogues via the Pictet–Spengler reaction mediated by propylphosphonic anhydride (T3P). The method, which uses less toxic and readily available T3P, generally seems to be more flexible, efficient in the preparation of 5,6-dihydrophenanthridine derivatives and complementary to conventional routes in the preparation of fused pyridines.

Highly efficient and chemoselective acetalization and thioacetalization of aldehydes catalyzed by propylphosphonic anhydride (®T3P) at room temperature

Propylphosphonic anhydride (®T3P), a low toxic peptide coupling agent, has been demonstrated to be an efficient catalyst for the chemoselective acetalization and thioacetalization of aldehydes in the presence of ketones. Cyclic and acyclic acetals of diverse aldehydes were obtained in good to excellent yields at room temperature in the presence of a catalytic amount of T3P.

An efficient one-pot synthesis of coumarins mediated by propylphosphonic anhydride (T3P) via the Perkin condensation

An efficient one-pot synthesis of coumarins mediated by T3P, a mild and low toxic peptide coupling agent, via the Perkin condensation has been demonstrated.

Epimerization Free Synthesis of O-Acyl Isodipeptides Employing COMU

O-Acyl isodipeptides are prepared by coupling Boc-Ser/Thr-OBzl with Fmoc-Xaa-OH employing COMU, well known third generation peptide coupling agent. The reaction proceeds with high yield and the chemical homogeneity of the synthesized molecules were established via chiral HPLC analyses. The O-acyl isodipeptide units play crucial role in the success of ' click peptide' protocol employed for assembling ' difficult sequence' peptides.

ChemInform Abstract: An Efficient Catalytic Method for the Friedlaender Annulation Mediated by Peptide Coupling Agent Propylphosphonic Anhydride (T3P®).

AbstractT3P is utilized as efficient water‐scavenging agent to access carbocyclic and heterocyclic fused quinolines.

An efficient catalytic method for the Friedländer annulation mediated by peptide coupling agent propylphosphonic anhydride (T3P®)

We have demonstrated the utilization of T3P, a mild and low toxic peptide coupling agent, as a promoter and water scavenger in the Friedländer annulation, and thus introduced a highly efficient catalytic process to access carbocyclic and heterocyclic fused quinolines under microwave irradiation or a conventional heating technique. The reaction conditions are sufficiently mild to tolerate the acid and base sensitive functional groups that can serve as levers for further extension of the quinoline products.

Solid Phase Synthesis of Aromatic Oligoamides: Application to Helical Water-Soluble Foldamers

Synthetic helical aromatic amide foldamers and in particular those based on quinolines have recently attracted much interest due to their capacity to adopt bioinspired folded conformations that are highly stable and predictable. Additionally, the introduction of water-solubilizing side chains has allowed to evidence promising biological activities. It has also created the need for methods that may allow the parallel synthesis and screening of oligomers. Here, we describe the application of solid phase synthesis to speed up oligomer preparation and allow the introduction of various side chains. The synthesis of quinoline-based monomers bearing protected side chains is described along with conditions for activation, coupling, and deprotection on solid phase, followed by resin cleavage, side-chain deprotection, and HPLC purification. Oligomers having up to 8 units were thus synthesized. We found that solid phase synthesis is notably improved upon reducing resin loading and by applying microwave irradiation. We also demonstrate that the introduction of monomers bearing benzylic amines such as 6-aminomethyl-2-pyridinecarboxylic acid within the sequences of oligoquinolines make it possible to achieve couplings using a standard peptide coupling agent and constitute an interesting alternative to the use of acid chloride activation required by quinoline residues. The synthesis of a tetradecameric sequence was thus smoothly carried out. NMR solution structural studies show that these alternate aminomethyl-pyridine residues do not perturb the canonical helix folding of quinoline monomers in protic solvents, contrary to what was previously observed in nonprotic solvents.

ChemInform Abstract: Facile One‐Step Synthesis of Acyl Azides and Nα‐Fmoc/Boc/Z Protected Amino Acid Azides Employing Benzotriazole‐1‐yl‐oxy‐tris(dimethylamino)‐phosphonium Hexafluorophosphate (BOP).

A simple route for the preparation of acyl azides from the corresponding carboxylic acids employing the peptide-coupling agent BOP is described. The procedure is simplc, clean and high yielding, The chemistry is also extended to the preparation of several urethane protcctcd amino acid azidcs (eight examples) as well.

Chiral Phosphanylferrocenecarboxamides with Amino Acid Pendant Groups as Ligands for Cu‐Mediated Asymmetric Conjugate Additions of Diethylzinc to Chalcones – Structural Characterisation of Precursors to the Cu Catalyst

AbstractA series of chiral phosphanylferrocenecarboxamides was prepared by treatment of either 1′‐(diphenylphosphanyl)ferrocene‐1‐carboxylic acid (Hdpf) or its planar‐chiral 1,2‐isomers with amino acid methyl esters in the presence of peptide coupling agents. The compounds were characterised by spectroscopic methods, and the crystal structure of one representative was determined by X‐ray diffraction. Catalytic testing of these donors in Cu‐catalysed asymmetric conjugate additions of diethylzinc to chalcones revealed that the reaction outcomes were highly sensitive to the ligand structure and the reaction conditions (copper source and solvent), whereas the chalcone substituents (Me, MeO, or Cl in positions 4 or 4′) had a less pronounced influence. Compounds based on Hdpf proved to be better ligands than their planar‐chiral analogues. Under optimised conditions, the reactionwith L‐valine–Hdpf conjugate, (S)‐Ph2PfcCONHCH(CHMe2)CO2Me (fc = ferrocene‐1,1′‐diyl) and unsubstituted chalcone gave the alkylation product with complete conversion (20 °C/4 h) and in 87 % ee. The catalytic behaviour of the amidophosphane ligands was correlated to the results of amodel coordination study and the crystal structure of [Cu(Ph2PfcCONHCH2CO2Me)2](CF3SO3)·2CHCl3.

New and simple synthesis of acid azides, ureas and carbamates from carboxylic acids: application of peptide coupling agents EDC and HBTU

Conversion of carboxylic acids into acid azides using peptide coupling agents, EDC and HBTU is described. The procedure is efficient, practical and applicable to a diverse range of carboxylic acids including N-protected amino acids. Using the same reagents, one-pot synthesis of ureas, dipeptidyl urea esters and carbamates from acids has also been achieved.

Phosphinoferrocenyl Carboxamides Bearing Glycine Pendant Groups: Synthesis, Palladium(II) Complexes, and Catalytic Use in Polar and Aqueous Reaction Media

The reaction of 1′-(diphenylphosphino)-1-ferrocenecarboxylic acid (Hdpf) with H2NCH2CO2CR3 mediated by peptide coupling agents (EDC/HOBt) afforded novel glycine phosphino-carboxamides Ph2PfcCONHCH2CO2CR3 (fc = ferrocene-1,1′-diyl; R = H (1) and Me (2*)). Compound 1 was converted to its corresponding phosphine oxide (3*) and sulfide (4*), to N-acyl glycine Ph2PfcCONHCH2CO2H (5), and to bis-amide Ph2PfcCONHCH2CONH2 (6*). Compounds 1 and 6 reacted with [PdCl2(cod)] (cod = η2:η2-cycloocta-1,5-diene) and 5 reacted with Na2[PdCl4] to afford the respective, mostly solvated bis-phosphine complexes trans-[PdCl2(L-κP)2] (7: L = 1; 8: L = 5, 9: L = 6). Two different solvatomorphs of 9 were isolated in crystalline form and structurally characterized (9* and 9a*). Furthermore, bridge cleavage reaction of [{Pd(μ-Cl)(LNC)}2] (LNC = 2-[(dimethylamino-κN)methyl]phenyl-κC1) with 1 gave [(LNC)Pd(Cl)(1-κP)] (10*), which was further reacted with AgClO4 or KOt-Bu to afford bis-chelate complexes [(LNC)Pd(1-κ2O,P)]ClO4 (11*) and [(LNC)Pd(L-κ2N,P)] (12*; L = 1 deprotonated at the NH group), respectively. All compounds were characterized by spectroscopic methods (multinuclear NMR, MS, and IR) and by elemental analyses; the asterisk indicates that the crystal structure has been determined. Compounds 1, 3−6, and 10−12 were studied by electrochemical methods, while phosphines 1, 5, and 6 in combination with palladium(II) acetate were shown to be highly active catalysts for the Suzuki−Miyaura cross-coupling of aryl bromides with phenylboronic acid in polar solvents (ethanol and dioxane), in their aqueous mixtures, and in pure water.

Preparation and characterization of d 6 tungsten compounds with amino acid derivatized diimine ligands and preparation of dipeptide derivatives using peptide coupling agents

Attempts to prepare dipeptide compounds from organometallic N-substituted amino acids are reported. Condensation of pyridine-2-carboxaldehyde, α-amino acids (H- l-Ala-OH or H- l-Asp-OH) and W(CO) 4(pip) 2 leads to formation of W(CO) 4(pyca-Et) ( 1) (pyca refers to the α-diimine fragment, C 5H 4NCH N) following decarboxylation of one or two equivalents of CO 2. This decarboxylation does not occur for β-alanine or GABA (γ-aminobutyric acid). Coupling of [Hpip][W(CO) 4(pyca-β-Ala-O)] ( 2) or [Hpip][W(CO) 4(pyca-GABA-O)] ( 3) to amino acid esters, H- l-Ala-OEt, or H- l-Val-OMe, using the standard 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) procedure produced four new dipeptide compounds, 4– 7. The reactions proceed in good yield and compounds were characterized spectroscopically. The dipeptide complex, W(CO) 4(pyca-Ala-Ala-OMe) ( 8), was prepared by reaction of W(CO) 4(pip) 2 with H- l-Ala- l-Ala-OMe and pyridine-2-carboxaldehyde. In addition the molecular structure of W(CO) 4(pyca-β-Ala-Val-OMe) ( 5) is reported.

Determination of the Source of the N-Methyl Impurity in the Synthesis of Pemetrexed Disodium Heptahydrate

The synthesis of Pemetrexed Disodium Heptahydrate has consistently resulted in a very low level (ca. 0.02%) unknown impurity. To ensure long-term control, the identity and source of the impurity were desired. Isolation and characterization identified the impurity as the N-methyl derivative. The source was identified as the methyl groups on the peptide coupling agent, 2,6-Dimethoxy-1,3,5-triazine (CDMT). Further work assured the current conditions provide adequate control.

Immobilization of horseradish peroxidase on chitosan for use in nonaqueous media

AbstractChitosan, a natural polysaccharide, was used for the covalent immobilization of horseradish peroxidase, an enzyme of high synthetic utility, with the carbodiimide method. Of the enzyme, 62% was immobilized on chitosan when 1‐ethyl‐3‐(3‐dimethylaminopropyl carbodiimide) was used as the peptide coupling agent. The influence of different parameters, such as the enzyme concentration, carbodiimide concentration, and incubation period, on the activity retention of the immobilized enzyme was investigated. Kinetic studies using horseradish peroxidase immobilized on chitosan revealed the effects of several parameters, such as the substrate hydrophilicity and hydrophobicity, the solubility of substrates in the medium, the solvent hydrophobicity, and the support aquaphilicity, on the catalytic activity of the immobilized enzyme in nonaqueous media. General rules for the optimization of solvents for nonaqueous enzymology based on the partitioning of the solvent were not applicable for the immobilized horseradish peroxidase. The catalytic efficiency was greatest when o‐phenylene diamine was used as the substrate and least when guaiacol was used. The aquaphilicity of the support played an important role in the kinetics of the immobilized horseradish peroxidase in water‐miscible solvents. The results were promising for the future development of chitosan‐immobilized enzymes for use in organic media. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 1456–1464, 2003

PENTAFLUOROPHENYL 4-NITROBENZENESULFONATE AS A PEPTIDE COUPLING REAGENT

Protected dipeptides were obtained in good yield by coupling Boc- or Fmoc-protected amino acids with amino acid esters in the presence of pentafluorophenyl 4-nitrobenzenesulfonate (PFNB) as peptide coupling agent and 1-hydroxybenzotriazole as catalyst.

Synthesis and characterisation of poly ( l-lactic acid) galactosyl derivatives; access to functionalised microspheres

A new series of galactosyl-derived polymers has been used for the preparation of microspheres. The strategy is based on the modification of the terminal carboxylic group l-PLA (73.000) by coupling to a galactosyl antenna in the presence of the peptide coupling agents: DCC/HOBT. The degree of functionalisation varies between 60 and 70%, and antenna density between 1.74 and 2.78. The characterisations of the new products were carried out using 1H NMR, gel permeation chromatography, and acid base titration; the size of the functionalised microspheres was determined to be 210–270 μm by DLS.

The effects of the peptide-coupling agent, EEDQ, on 5-HT 2A receptor binding and function in rat frontal cortex

This ex vivo study in rat frontal cortex determined the influence of 5-HT receptor agonists and antagonists on EEDQ-induced depletion of 5-HT 2A binding sites and reduction in their functional coupling to phospholipid hydrolysis. Twenty-four hours after EEDQ (6 mg/kg) administration a marked reduction (66%) of cortical 5-HT 2A binding sites with no change in binding affinity was observed. The 5HT 2A antagonists ritanserin (1 mg/kg), ketanserin (1 and 5 mg/kg), metergoline (3 mg/kg) or the 5HT 2A agonist, DOI (3 and 10 mg/kg) also significantly reduced (by 15–44%) these binding sites 24 h after injection. Thirty minute pretreatment with ritanserin, ketanserin, metergoline or DOI (at the doses above) afforded 49–65% protection against the loss of 5-HT 2A binding sites induced by EEDQ (6 mg/kg). DOI (10 mg/kg) pretreatment (−24 h) decreased by 26% the accumulation of [ 3H]inositol phosphates (IPs) evoked by 5-HT (100 μM), but did not affect that produced by DOI (100 μM). Ketanserin (5 mg/kg, −24h) decreased 5-HT- and DOI-induced IP formation by 65% and 53%, respectively. The EEDQ (6 mg/kg, −24h)-evoked reductions (−50%) of 5-HT- and DOI-induced IP formation were not altered by DOI (10 mg/kg) or ketanserin (5 mg/kg) given 30 min before EEDQ. G-protein-stimulated IP accumulation was unaffected by EEDQ (6 mg/kg). Overall, EEDQ reduces 5-HT 2A binding sites and function in rat frontal cortex, whereas its effects on binding were attenuated by various 5-HT receptor antagonists and agonists, its effects on function was unaltered by these drugs.

The effects of chronic imidazoline drug treatment on glial fibrillary acidic protein concentrations in rat brain.

1. The concentration of the astrocytic marker, glial fibrillary acidic protein (GFAP) was quantitated by immunoblotting (western blotting) in the rat brain after treatment with various imidazoline drugs and other agents. 2. Chronic (7 days) but not acute (1 day) treatment with the imidazoline drugs, cirazoline (1 mg kg-1, i.p.) and idazoxan (10 mg kg-1, i.p.), but not with the structurally related alpha 2-adrenoceptor antagonists, RX821002 (2-methoxy idazoxan) (10 mg kg-1, i.p.) and efaroxan (10 mg kg-1, i.p.), markedly increased (45%) GFAP immunoreactivity in the rat cerebral cortex. Chronic treatment (7 days) with yohimbine (10 mg kg-1, i.p.), a non-imidazoline alpha 2-adrenoceptor antagonist, did not significantly modify GFAP immunoreactivity in the cerebral cortex. 3. Chronic treatment (7 days) with cirazoline and idazoxan did not alter the density of brain monoamine oxidase (MAO)-B sites labelled by [3H]-Ro 19-6327 (lazabemide), another relevant astroglial marker. Moreover, these imidazoline drug treatments did not modify the levels of alpha-tubulin in the cerebral cortex. These negative results reinforced the specificity of the effects of imidazoline drugs on GFAP. 4. Irreversible inactivation of brain alpha 2-adrenoceptors (and other neurotransmitters receptors) after treatment with an optimal dose of the peptide-coupling agent EEDQ (1.6 mg kg-1, i.p., for 6-24 h) did not alter GFAP immunoreactivity in the cerebral cortex. These results further disproved the involvement of these receptors on astroglial cells in the tonic control of GFAP levels.5. The binding of [3H]-idazoxan in the presence of 10-6 M (-)-adrenaline was used to quantitate in parallel 12-imidazoline preferring sites in the rat brain after the same treatments. Chronic treatment (7 days) with cirazoline and idazoxan, but not with RX821002, efaroxan or yohimbine, significantly increased (25%) the density of I2-sites in the cerebral cortex. The up-regulation of I2-sites induced by cirazoline was not observed in the liver, a tissue that also expresses 12-sites but lacks glial cells.6. A strong correlation (r = 0.97) was found when the mean percentage changes in GFAP immuno reactivity were related to the mean percentage changes in 12 imidazoline sites after the various drug treatments.7. Together the results suggest a direct physiological function of glial I2-imidazoline preferring sites in the regulation of GFAP levels.

Differential Effects of the Alkylating Agent N‐Ethoxycarbonyl‐2‐Ethoxy‐1,2‐Dihydroquinoline on Brain α2‐Adrenoceptors and I2‐Imidazoline Sites In Vitro and In Vivo

The alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is a peptide-coupling agent that is being used to inactivate irreversibly alpha 2-adrenoceptors and other receptors. The aim of the present study was to assess the in vitro and in vivo effects of EEDQ on the newly discovered brain I2-imidazoline sites, located mainly in mitochondria. Preincubation of rat cortical membranes with EEDQ (10(-8)-10(-5) M) markedly decreased (20-90%) the specific binding of the selective antagonist [3H]RX821002 to alpha 2-adrenoceptors without affecting that of [3H]idazoxan (in the presence of adrenaline) to I2-imidazoline sites. In EEDQ-pretreated membranes (10(-5) M, 30 min at 25 degrees C), the density of I2-imidazoline sites (Bmax = 80 +/- 4 fmol/mg of protein) was not different from that determined in untreated membranes in the presence of (10(-6) M (-)-adrenaline (Bmax = 83 +/- 4 fmol/mg of protein), and both densities were lower (24%, p < 0.05) than the total native density of [3H]idazoxan binding sites (Bmax = 107 +/- 6 fmol/mg of protein) (I2-imidazoline sites plus alpha 2-adrenoceptors). Treatment of rats with an optimal dose of EEDQ (1.6 mg/kg, i.p., for 2 h to 30 days) reduced maximally at 6 h (by 95 +/- 1%) the specific binding of [3H]-RX821002 to alpha 2-adrenoceptors, but also the binding of [3H]idazoxan to I2-imidazoline sites (by 44 +/- 5%). Pretreatment with yohimbine (10 mg/kg, i.p.) fully protected against EEDQ-induced alpha 2-adrenoceptor inactivation.(ABSTRACT TRUNCATED AT 250 WORDS)