Ester-amide Exchange Reaction Research Articles

Total Synthesis and Functional Analysis of Complex Peptidic Natural Products and Their Artificial Analogues

This review focuses on a new solid-phase synthetic strategy for an anticancer natural product yaku'amide B (1) and its target identification and structure-function relationship study using synthetic analogues and probes. To realize the Fmoc-based solid-phase synthesis of 1, we developed new synthetic methods for enamide formation. Namely, modified traceless Staudinger ligation using alkenyl azides and newly designed phosphinophenol esters enabled stereoselective construction of the (E)- and (Z)-ΔIle moieties. Furthermore, resin-cleavage and C-terminus modification were simultaneously achieved with an ester-amide exchange reaction using C-terminal amine and AlMe3, which successfully afforded 1 via a full solid-phase route. The developed strategy was applied to the construction of seven E/Z isomers of 1. In the target identification of 1, fluorescent imaging study and affinity pull-down assay using the synthetic probes revealed that 1 exerts potent cytostatic activity by binding to subunits α and β of mitochondrial FoF1-ATP synthase. On the basis of the mode of action of 1, we conducted biological evaluation of the seven E/Z-isomers of 1. Assessment of growth inhibition activity and the effect on FoF1-ATP synthase indicates that the E/Z-stereochemistry of the three ΔIle residues controls the magnitude of biological functions of 1.

The effect of temperature on the kinetics of enhanced amide bond formation from lactic acid and valine driven by deep eutectic solvents.

Deep eutectic solvents have been found to facilitate the copolymerization of hydroxy acids and amino acids through an ester-amide exchange reaction, and to drive the formation of amino acid-enriched oligomers with peptide backbones. The complexity of oligomer distribution is significantly reduced in deep eutectic solvents and amide-linked oligomers can be selectively produced. In the present study, we investigated the kinetics of amide bond formation in deep eutectic solvents to understand how the solvents regulate the pathways of complex copolymerization. A mathematical model successfully simulated the reaction of a lactic acid/valine mixture in deep eutectic solvents at different temperatures and provided insight into the activation energy of each step. Our findings indicated that the esterification and the evaporation of hydroxy acids were greatly suppressed in deep eutectic solvents because of the strong interaction between the quaternary ammonium salts and the hydroxy acids. In contrast, the ester-amide exchange reaction in deep eutectic solvents was significantly enhanced by lowering the activation entropies. The synergic effect of reduced esterification and increased exchange leads to amino acid-enriched oligomers with high yield and high selectivity. Furthermore, the reduced evaporation of hydroxy acids in deep eutectic solvents may preserve limited reactants in the prebiotic scenario. These results reveal deep eutectic solvents as sustainable media for the simple synthesis of amide bonds.

Kinetic Resolution of α-Nitrolactones by Catalytic Asymmetric Hydrolysis or Ester–Amide Exchange Reaction

Abstract C 1-Symmetric chiral ammonium salt catalysts induced a kinetic resolution of racemic α-nitrolactones through an asymmetric ester–amide exchange reaction. The corresponding amides were obtained with high enantioselectivities and high S (= k fast/k slow) values. This reaction system is a useful approach for obtaining carbocyclic quaternary α-nitroamides as chiral building blocks.

Solid‐Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

AbstractWe report a solid‐phase strategy for total synthesis of the peptidic natural product yaku'amide B (1), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β‐dialkylated α,β‐dehydroamino acid residues and is capped with an N‐terminal acyl group (NTA) and a C‐terminal amine (CTA). To realize the Fmoc‐based solid‐phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C‐terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)3 led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin‐cleavage and C‐terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe3 to deliver 1 in 9.1 % overall yield (24 steps from the resin).

Solid-Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation.

We report a solid-phase strategy for total synthesis of the peptidic natural product yaku'amide B (1), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β-dialkylated α,β-dehydroamino acid residues and is capped with an N-terminal acyl group (NTA) and a C-terminal amine (CTA). To realize the Fmoc-based solid-phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C-terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)3 led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin-cleavage and C-terminus modification were simultaneously achieved with an ester-amide exchange reaction using CTA and AlMe3 to deliver 1 in 9.1 % overall yield (24 steps from the resin).

Facile and Efficient Modification of Polystyrene-block-poly(methyl methacrylate) for Achieving Sub-10 nm Feature Size

Nanofabrication based on block copolymer self-assembly is one of the most promising methods for producing nanopatterns with a sub-10 nm feature size. Although polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) has been widely studied as a suitable template for nanofabrication, the insufficient incompatibility between the PS and PMMA blocks makes it difficult to achieve a microphase separation with the domain spacing of less than ca. 20 nm. We now present a simple and efficient method for the postpolymerization modification of PS-b-PMMA for effectively increasing the incompatibility between the two blocks, so that microphase separation can be achieved even at a low degree of polymerization. The ester–amide exchange reactions of PS-b-PMMA with primary and secondary amines were performed to introduce a small number of methacrylamides into the PMMA block to increase its hydrophilicity. The results of small-angle X-ray scattering measurements performed on bulk samples showed that the modified PS-b-PMMA se...

Unprecedented Ester–Amide Exchange Reaction Using Highly Versatile Two-Dimensional Graphene Oxide Supported Base Metal Nanocatalyst

The present study is the first report of an atom economical and environmentally benign amidation of unactivated esters wherein a novel and highly versatile graphene oxide based cobalt nanocatalytic system has been effectively exploited for the synthesis of pharmaceutically significant amide derivatives under neutral reaction conditions. Experimental results revealed that the developed catalyst not only possesses immense potential to accelerate ester amide exchange reaction in the absence of any additives but also exhibits several remarkable attributes like wide functional group tolerance, durability, high turnover numbers, improved yield, and recycling and reusability for subsequent runs without any discernible loss in the catalytic activity. The enhanced catalytic performance may be attributed to the structure of 2-D graphene oxide based material which provides space between graphitic overlayers and metal surfaces making it work like a nanoreactor to expedite ester amide exchange reaction.

Kinetics of prebiotic depsipeptide formation from the ester-amide exchange reaction.

In this work, we introduce a kinetic model to study the effectiveness of ester-mediated amide bond formation under prebiotic conditions. In our previous work, we found that a simple system composed of α-hydroxy acids and α-amino acids is capable of forming peptide bonds via esterification followed by the ester-amide exchange reaction. To further understand the kinetic behavior of this copolymerization, we first tracked the growth of initial species from a valine/lactic acid mixture in a closed system reactor. A mathematical model was developed to simulate the reactions and evaluate the rate constants at different temperatures. We found these reactions can be described by the empirical Arrhenius equation even when reaction occurred in the solid (dry) state. Further calculations for activation parameters showed that the ester-mediated pathway facilitates amide bond formation by lowering activation entropies. These results provide a theoretical framework that illustrates why the ester-mediated pathway for peptide bond formation is efficient and why it would have been more favorable on the early Earth, compared to peptide bond formation without the aid of hydroxy acids.

Graphene oxide as a covalent-crosslinking agent for EVM-g-PA6 thermoplastic elastomeric nanocomposites

A novel polyamide 6 grafted ethylene-vinyl acetate rubber copolymer (EVM-g-PA6) was synthesized in the presence of graphene oxide (GO),viaa sequential ring-opening polymerisation and ester–amide exchange reaction.

Macroscopic chirality of supramolecular gels formed from achiral tris(ethyl cinnamate) benzene-1,3,5-tricarboxamides.

A C3 -symmetric benzene-1,3,5-tricarboxamide substituted with ethyl cinnamate was found to self-assemble into supramolecular gels with macroscopic chirality in a DMF/H2 O mixture. The achiral compound simultaneously formed left- and right-handed twists in an unequal number, thus resulting in the macroscopic chirality of the gels without any chiral additives. Furthermore, ester-amide exchange reactions with chiral amines enabled the control of both the handedness of the twists and the macroscopic chirality of the gels, depending on the structures of the chiral amines. These results provide new prospects for understanding and regulating symmetry breaking in assemblies of supramolecular gels formed from achiral molecular building blocks.

Macroscopic Chirality of Supramolecular Gels Formed from Achiral Tris(ethyl cinnamate) Benzene‐1,3,5‐tricarboxamides

AbstractA C3‐symmetric benzene‐1,3,5‐tricarboxamide substituted with ethyl cinnamate was found to self‐assemble into supramolecular gels with macroscopic chirality in a DMF/H2O mixture. The achiral compound simultaneously formed left‐ and right‐handed twists in an unequal number, thus resulting in the macroscopic chirality of the gels without any chiral additives. Furthermore, ester–amide exchange reactions with chiral amines enabled the control of both the handedness of the twists and the macroscopic chirality of the gels, depending on the structures of the chiral amines. These results provide new prospects for understanding and regulating symmetry breaking in assemblies of supramolecular gels formed from achiral molecular building blocks.

Study on ester-amide exchange reactions between Nylon 1010 and Ethylene-vinyl acetate rubber with different metal derivatives

Ester-exchange reaction was a useful method to improve the compatibility of polymer blends. In this article, ester-amide exchange reaction between Nylon 1010 and Ethylene-vinyl acetate rubber (EVM) was studied in the presence of different Ti and Zn derivatives as catalysts. The chemical reactions were studied by 1H NMR. Catalytic activities of Ti(OBu)4, TiO(OOCCH3)2, ZnO and Zn(OOCCH3)2 were compared and Ti(OBu)4 showed the highest catalytic reactivity. Melt flow index (MFI) of Nylon 1010/EVM blends indicated that crosslinking and degradation took place in the reactive blends. Gel permeation chromatography (GPC) provided the evidence for the degradation behavior during melt blending. SEM images showed that the compatibility of the blends was improved at the presence of catalyst. SAXS results showed that the long period of Nylon 1010/EVM decreased after adding Ti(OBu)4, implying the formation of imperfect crystallites in Nylon 1010/EVM/Ti(OBu)4 blend.

In situ ester–amide exchange reaction between polyamide 6 and ethylene‐vinyl acetate rubber during melt blending

AbstractThe ester–amide exchange reaction between polyamide 6 (PA6) and ethylene‐vinyl acetate rubber (EVM) with dibutyltin oxide (DBTO) as a catalyst took place during melt blending, leading to the formation of PA6‐grafted EVM copolymer (EVM‐g‐PA6) and acetamide‐terminated PA6. The exchange reaction extent, expressed by the percentage content of the acetate groups taking part in the exchange reaction, was 5.9 mol %, and the yield of EVM‐g‐PA6 copolymer was 6.8 wt % for PA6/EVM/DBTO (60/40/1) blend at 230°C for 60 min. The number‐average molecular weight of PA6 branches in EVM‐g‐PA6 was ∼278 g/mol as evaluated from nuclear magnetic resonance spectra. The reaction kinetic parameters were calculated according to a second‐order reversible reaction mechanism. The rate constant was dependent on the catalyst concentration, PA6/EVM ratio, and shearing conditions. In this article, the characterized ester–amide exchange reaction between PA6 and EVM will guide the fabrication of novel EVM‐based graft copolymers and high‐performance PA6/EVM thermoplastic elastomers for engineering applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40272.

Study on ester–amide exchange reactions between Nylon 1010 and Ethylene‐vinyl acetate rubber

AbstractReactive processing is a useful method to improve the compatibility of immiscible polymer blends. Nylon 1010/Ethylene‐vinyl acetate rubber (EVM) blends were prepared via melt blending at 240°C and tetrabutyl titanate (Ti(OBu)4) was used as a catalyst. Ester–amide exchange reactions were proven to take place between Nylon and EVM during the shear processing. Melt flow index, Fourier transform infrared spectroscopy, and proton nuclear magnetic resonance spectra were used to study the reactions. It was demonstrated that tuning the shear rate could control the properties and reaction extent of Nylon 1010/EVM/Ti(OBu)4 blends. The results revealed that the reactions were promoted by high shear rate. Tensile strength of the blends increased from 4.5 to 11.4 MPa when the shear rate increased from 20 to 80 rpm. Meanwhile, scanning electron microscopy was adopted to study the morphology of the reactive blends. It was found that the morphology of the blends was changed from sea‐island structures to co‐continuous structures while increasing the shear rate from 20 to 100 rpm. Dynamic mechanical analysis confirmed that high‐shear processing was found to promote the compatibility of the blends. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40064.

Synthesis of imidazole-terminated hyperbranched polymers with POSS-branching points and their pH responsive and coordination properties

An imidazole-terminated hyperbranched polymer with octafunctional POSS branching units denoted as POSS-HYPAM-Im was prepared by the polymerization of excess amounts of tris(2-aminoethyl)amine with the first-generation methyl ester-terminated POSS-core poly(amidoamine)-typed dendrimer, reacting with methyl acrylate, and ester-amide exchange reaction with 3-aminopropylimidazole. The imidazole-terminated hyperbranched poly(amidoamine) denoted as HYPAM-Im was also synthesized with 1-(3-aminopropyl)imidazole from a methyl ester-terminated hyperbranched poly(amidoamine) by the ester-amide exchange reaction. The transmittance of the POSS-HYPAM-Im solution drastically decreased when the solution pH was greater than 8.2. On the other hand, the transmittance of the HYPAM-Im solution gradually decreased when the solution pH at 8.5 and was greater than 9. Spectrophotometric titrations of the hyperbranched polymer aqueous solutions with Cu2+ ions indicated the variation of the coordination modes of POSS-HYPAM-Im from the Cu2+–N4 complex to the Cu2+–N2O2 complex and the existence of the only one complexation mode of Cu2+–N4 between Cu2+ ion and HYPAM-Im with increasing the concentrations. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2695–2701

Construction and Characterization of Molecular Nonwoven Fabrics Consisting of Cross-Linked Poly(γ-methyl-l-glutamate)

Molecular nonwoven fabrics in the form of ultrathin layer-by-layer (LbL) helical polymer films with covalent cross-linking were assembled on substrates by an alternate ester-amide exchange reaction between poly(γ-methyl L-glutamate) (PMLG) and cross-linking agent ethylene diamine or 4,4'-diamino azobenzene. The regular growth of helical monolayers without excessive adsorption and the formation of amide bonds were confirmed by ultraviolet-visible (UV-vis) spectrophotometry, quartz crystal microbalance (QCM), ellipsometry, and infrared reflection-absorption spectroscopy (IR-RAS) measurements. Nanostructures with high uniformity and ultrathin films with few defects formed by helical rod segments of PMLG were characterized by atomic force microscopy (AFM) and Kelvin probe force microscopy (KFM).

Synthesis of first- and second-generation imidazole-terminated POSS-core dendrimers and their pH responsive and coordination properties

Imidazole-terminated first- and second-generation poly(amidoamine)-type oligomeric silsesquioxanes (POSS)-core dendrimers (denoted as POSS-Im16 and POSS-Im32, respectively) were synthesized by the ester–amide exchange reaction from first- and second-generation methyl ester-terminated POSS-core dendrimers, respectively. Transmittances of the aqueous POSS-Im32 solution drastically decreased at pH>7.2, but the change was reversible without hysteresis. The results of pH titrations for POSS-Im16 and POSS-Im32 showed well-defined one-step titration curves identical to those of monomeric imidazole compounds, such as 1-methylimidazole. Such simple acid–base behavior caused phase transition in the aqueous dendrimer solution to be highly sensitive to pH changes. The pKa values of 1-methylimidazole, POSS-Im16 and POSS-Im32 were 7.3, 7.0 and 6.7, respectively. Spectrophotometric titrations of the aqueous dendrimer solutions with Cu2+ ions indicated that coordination modes of POSS-Im16 changed from the Cu2+–N2O2 complex to the Cu2+–N4 complex as the concentration of the dendrimers increased; however, only one complexation mode (Cu2+–N4) existed between Cu2+ ions and POSS-Im32.

Study on Ester–Amide Exchange Reaction between PBS and PA6IcoT

To improve the thermal properties and mechanical properties of synthetic biodegradable polymers, poly(butylene succinate) (PBS) and poly(hexamethylene isophthalamide-co-terephthalamide) (PA6IcoT) are reactively blended in a LIST corotating processor under melting conditions. The products are fractionated into insoluble and soluble parts using chloroform as the solvent. The Fourier transform infrared spectra of these two fractions confirm that the exchange reaction between PA6IcoT and PBS occurs when p-toluenesulfonic acid is used as the catalyst. On the basis of the 13C NMR analysis, the pathway of the exchange reaction is described. The extent of exchange reaction, average length of the various sequences, and degree of randomness in the reactive blends are calculated. It has been found that the randomness of copolymers is increased with the increase in reaction extent. Scanning electron microscopy (SEM) is employed to investigate morphology development of the reactive blends. It shows that the copolymers generated by the exchange reaction act as the compatibilizer to improve the compatibility of PBS and PA6IcoT. The fraction of PA6IcoT- and PBS-rich phases is significantly reduced with increasing reaction extent.

An ATP-independent strategy for amide bond formation in antibiotic biosynthesis

A-503083 B, a capuramycin-type antibiotic, contains an L-aminocaprolactam and an unsaturated hexuronic acid that are linked via an amide bond. A putative class C beta-lactamase (CapW) was identified within the biosynthetic gene cluster that-in contrast to the expected beta-lactamase activity-catalyzed an amide-ester exchange reaction to eliminate the L-aminocaprolactam with concomitant generation of a small but significant amount of the glyceryl ester derivative of A-503083 B, suggesting a potential role for an ester intermediate in the biosynthesis of capuramycins. A carboxyl methyltransferase, CapS, was subsequently demonstrated to function as an S-adenosylmethionine-dependent carboxyl methyltransferase to form the methyl ester derivative of A-503083 B. In the presence of free L-aminocaprolactam, CapW efficiently converts the methyl ester to A-503083 B, thereby generating a new amide bond. This ATP-independent amide bond formation using methyl esterification followed by an ester-amide exchange reaction represents an alternative to known strategies of amide bond formation.

EFFECT OF ESTER-AMIDE EXCHANGE REACTION ON THERMAL BEHAVIOUR AND MORPHOLOGY OF NYLON 6/THERMOTROPIC LIQUID CRYSTALLINE POLYMER BLENDS

Binary blends of two grades of nylon 6 and three kinds of commercialized thermotropic liquid crystal polymers (LCPs) (Vectra A950,Vectra B950 and Rodrun LC5000) were prepared by melting blending process,respectively.The ester-amide exchange reaction between nylon 6 and LCPs was analyzed by using diffuse reflectance FTIR spectroscopy (DRIFT) and differential scanning calorimetry (DSC).The blending time,composition and the type of LCPs exerted dramatic influence on the exchange reaction,resulting in the decrease of melting point and crystallinity of nylon 6 in the blends.The increase of blending time promoted the contact and the entanglement of macromolecular chains of the two phases,and therefore,promoted the exchange reaction.The increase of LCP content was another favorable parameter for the exchange reaction.When the content of Rodrun LC5000 was 80 wt%,the melting temperature of nylon 6 in the blend decreased from 219.1℃ to 185.5℃,and the crystallinity was decreased from 37.9% to 20.0%.Compared with Vectra A950 and Vectra B950,Rodrun LC5000 tends to react with nylon 6 more extensively,due to its more flexible molecular chain.The morphology of blends was characterized by using scanning electron microscopy (SEM).It is shown that,unlike other completely incompatible blending systems,the morphology of nylon 6/LCP blends was controlled by blending time as well as the exchange reaction.With the increase of blending time,the morphology of dispersed LCP was developed from droplets to deformed short bars,and finally,fine fibrils with diameter of about 1 μm.