Imide Formation Research Articles

Genesis and regulation of C-terminal cyclic imides from protein damage.

C-Terminal cyclic imides are post-translational modifications (PTMs) that can arise from spontaneous intramolecular cleavage of asparagine or glutamine residues resulting in a form of irreversible protein damage. These protein damage events are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN), indicating that these aging-related modifications may require cellular quality control mechanisms to prevent deleterious effects. However, the factors that determine protein or peptide susceptibility to C-terminal cyclic imide formation or their effect on protein stability have not been explored in detail. Here, we characterize the primary and secondary structures of peptides and proteins that promote intrinsic formation of C-terminal cyclic imides in comparison to deamidation, a related form of protein damage. Extrinsic effects from solution properties and stressors on the cellular proteome additionally promote C-terminal cyclic imide formation on proteins like glutathione synthetase (GSS) that are susceptible to aggregation if the protein damage products are not removed by CRBN. This systematic investigation provides insight to the regions of the proteome that are prone to these unexpectedly frequent modifications, the effects of this form of protein damage on protein stability, and the biological role of CRBN.

Mining the Biosynthetic Landscape of Lactic Acid Bacteria Unearths a New Family of RiPPs Assembled by a Novel Type of ThiF-like Adenylyltransferases.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are chemically diverse natural products of ribosomal origin. These peptides, which frequently act as signals or antimicrobials, are biosynthesized by conserved enzymatic machinery, making genome mining a powerful strategy for unearthing previously uncharacterized members of their class. Herein, we investigate the untapped biosynthetic potential of Lactobacillales (i.e., lactic acid bacteria), an order of Gram-positive bacteria closely associated with human life, including pathogenic species and industrially relevant fermenters of dairy products. Through genome mining methods, we systematically explored the distribution and diversity of ThiF-like adenylyltransferase-utilizing RiPP systems in lactic acid bacteria and identified a number of unprecedented biosynthetic gene clusters. In one of these clusters, we found a previously undescribed group of macrocyclic imide biosynthetic pathways containing multiple transporters that may be involved in a potential quorum sensing (QS) system. Through in vitro assays, we determined that one such adenylyltransferase specifically catalyzes the intracyclization of its precursor peptide through macrocyclic imide formation. Incubating the enzyme with various primary amines revealed that it could effectively amidate the C-terminus of the precursor peptide. This new transformation adds to the growing list of Nature's peptide macrocyclization strategies and expands the impressive catalytic repertoire of the adenylyltransferase family. The diverse RiPP systems identified herein represent a vast, unexploited landscape for the discovery of a novel class of natural products and QS systems.

Chemical separation of polyurethane via acidolysis – combining acidolysis with hydrolysis for valorisation of aromatic amines

Neat acidolysis of flexible PU foam with succinic acid is demonstrated to give quantitative imide formation and high-quality polyols. The easily separable imides are further converted to anilines which may re-enter the PU-value chain.

Divergent Cascade Ring-Expansion Reactions of Acryloyl Imides.

Macrocyclic and medium-sized ring ketones, lactones and lactams can all be made from common acryloyl imide starting materials through divergent, one-pot cascade ring-expansion reactions. Following either conjugate addition with an amine or nitromethane, or osmium(VIII)-catalysed dihydoxylation, rearrangement through a four-atom ring expansion takes place spontaneously to form the ring expanded products. A second ring expansion can also be performed following a second iteration of imide formation and alkene functionalisation/ring expansion. In the dihydroxylation series, three- or four-atom ring expansion can be performed selectively, depending on whether the reaction is under kinetic or thermodynamic control.

Atmospheric Oxidation of Hydroperoxy Amides.

Recently, hydroperoxy amides were identified as major products of OH-initiated autoxidation of tertiary amines in the atmosphere. The formation mechanism is analogous to that found for ethers and sulfides but substantially faster. However, the atmospheric fate of the hydroperoxy amides remains unknown. Using high-level theoretical methods, we study the most likely OH-initiated oxidation pathways of the hydroperoxy and dihydroperoxy amides derived from trimethylamine autoxidation. Overall, we find that the OH-initiated oxidation of the hydroperoxy amides predominantly leads to the formation of imides under NO-dominated conditions and more highly oxidized hydroperoxy amides under HO2-dominated conditions. Unimolecular reactions are found to be surprisingly slow, likely due to the restricting, planar structure of the amide moiety.

Towards high-performance polyurethanes: a mechanism of amine catalyzed aromatic imide formation from the reaction of isocyanates with anhydrides

The mechanism of aromatic imide formation from reaction between isocyanate and anhydride using secondary amine as a pre-catalyst is driven by deprotonated urea, which is obtained from the reaction of isocyanate and amine with the help of bases.

Preparation of β-hydroxyketones (aldols) from the alkylation of O-silyl aryl cyanohydrins with epoxides

β-Hydroxyketones (aldols) are prepared from the alkylation-deprotection of O-silylated aryl cyanohydrins with epoxides. Key to the success of the method was the suppression of an in situ cyclic imidate formation that occurs upon initial opening of the epoxide ring.

Saving the Energy Loss in Lithium-Mediated Nitrogen Fixation by Using a Highly Reactive Li3 N Intermediate for C-N Coupling Reactions.

Direct synthesis of N‐containing organic compounds from dinitrogen (N2) can make synthetic chemistry more sustainable. Previous bottlenecks in lithium‐mediated N2 fixation were resolved by loading Li‐metal anodes covered with the typical Li+ ion‐conducting solid electrolyte interface, which are subsequently allowed to react with N2. The developed strategy allowed us to reach high Faradaic efficiencies toward Li3N. These reactive Li3N were then contacted with acylchlorides. Surface nitride ions are more nucleophilic than amines which direct the two C−N coupling reactions toward formation of imides rather than amides, and an integrated current efficiency of 57–77 % could be realized. This study thereby not only provides a feasible electrochemical Li3N synthesis, but also delineates an economical and green synthesis of highly valuable N‐containing compounds from N2 under mild conditions, just using commercial spare parts and processes from the omnipresent Li battery technology.

Saving the Energy Loss in Lithium‐Mediated Nitrogen Fixation by Using a Highly Reactive Li3N Intermediate for C−N Coupling Reactions

AbstractDirect synthesis of N‐containing organic compounds from dinitrogen (N2) can make synthetic chemistry more sustainable. Previous bottlenecks in lithium‐mediated N2fixation were resolved by loading Li‐metal anodes covered with the typical Li+ion‐conducting solid electrolyte interface, which are subsequently allowed to react with N2. The developed strategy allowed us to reach high Faradaic efficiencies toward Li3N. These reactive Li3N were then contacted with acylchlorides. Surface nitride ions are more nucleophilic than amines which direct the two C−N coupling reactions toward formation of imides rather than amides, and an integrated current efficiency of 57–77 % could be realized. This study thereby not only provides a feasible electrochemical Li3N synthesis, but also delineates an economical and green synthesis of highly valuable N‐containing compounds from N2under mild conditions, just using commercial spare parts and processes from the omnipresent Li battery technology.

Sterically shielded primary anilides of the alkaline-earth metals of the type (thf)nAe(NH-Ar*)2 (Ae = Mg, Ca, Sr, and Ba; Ar* = bulky aryl)

Metalation of bulky primary amines with alkaline-earth metal reagents in THF leads to primary amides, and imide formation does not occur. Coordination of THF bases competes with π-interactions with phenyl groups.

Trichloroacetimidate-Triggered Expeditious and Novel Synthesis of N-Acylbenzotriazoles

AbstractA facile route for the synthesis of a diverse range of N-acylbenzotriazole derivatives from the corresponding carboxylic acids has been established through a carbonyl activation pathway. In this method, trichloroacetonitrile is performed as an effective reagent for an easy access of N-acylbenzotriazoles which was simply proceeded through the activation of carboxylic acids via in situ imidate formation in anhydrous 1,2-dichloroethane followed by addition of 1H-benzotriazole at 80 °C for 3–4 h. Easy handling, one-pot, and metal-free conditions demonstrate the notable merits of the devised protocol.

Reprocessing of Covalent Adaptable Polyamide Networks through Internal Catalysis and Ring-Size Effects.

Here, we report the introduction of internally catalyzed amide bonds to obtain covalent adaptable polyamide networks that rely on the dissociation equilibrium between dicarboxamides and imides. While amide bonds are usually considered to be robust and thermally stable, the present study shows that their dynamic character can be activated by a smart choice of available building blocks without the addition of any external catalyst or other additives. Hence, a range of polyamide-based dynamic networks with variable mechanical and viscoelastic properties have been obtained in a systematic study, using a straightforward curing process of dibasic ester and amine compounds. Since the dissociation process involves a cyclic imide formation, the correlation between ring size and the thermomechanical viscosity profile was studied for five- to seven-membered ring intermediates, depending on the chosen dibasic ester monomer. This resulted in a marked temperature response with activation energies in the range of 116-197 kJ mol-1, yielding a sharp transition between elastic and viscous behavior. Moreover, the ease and versatility of this chemistry platform were demonstrated by selecting a variety of amines, resulting in densely cross-linked dynamic networks with Tg values ranging from -20 to 110 °C. With this approach, it is possible to design amorphous polyamide networks with an acute temperature response, allowing for good reprocessability and, simultaneously, high resistance to irreversible deformation at elevated temperatures.

Formation of phosphine imide (HNPH3) and its phosphinous amide (H2N–PH2) isomer

We present the first formation of the previously elusive phosphine imide (HN[double bond, length as m-dash]PH3) along with its phosphinous amide (H2N-PH2) isomer via exposure of phosphine (PH3) and ammonia (NH3) ices to ionizing radiation. Our approach may be extended to prepare, separate, and detect highly reactive compounds such as intermediates of Wittig reactions.

One-pot synthesis of 1,3,5-triazine-2,4-dithione derivatives via three-component reactions.

A catalyst-free one-pot synthetic methodology was developed for the preparation of 1,3,5-triazine-2,4-dithione derivatives through three-component reactions of arylaldehydes, thiourea, and orthoformates. The procedure tolerated a diverse range of arylaldehydes and orthoformates and provided a rapid entry to a variety of 4-aryl-6-(alkylthio)-3,4-dihydro-1,3,5-triazine-2(1H)-thiones (29 examples). The synthetic strategy relies on the dual role of thiourea in the cyclization with the aldehydes and the alkylation via an intermediate imidate formation. The structures of 1,3,5-triazine-2,4-dithione derivatives were characterized by spectroscopic techniques as well as by single crystal X-ray diffraction.

A molecular fluorophore in citric acid/ethylenediamine carbon dots identified and quantified by multinuclear solid-state nuclear magnetic resonance.

The composition of fluorescent polymer nanoparticles, commonly referred to as carbon dots, synthesized by microwave-assisted reaction of citric acid and ethylenediamine was investigated by 13 C, 13 C{1 H}, 1 H─13 C, 13 C{14 N}, and 15 N solid-state nuclear magnetic resonance (NMR) experiments. 13 C NMR with spectral editing provided no evidence for significant condensed aromatic or diamondoid carbon phases. 15 N NMR showed that the nanoparticle matrix has been polymerized by amide and some imide formation. Five small, resolved 13 C NMR peaks, including an unusual ═CH signal at 84 ppm (1 H chemical shift of 5.8 ppm) and ═CN2 at 155 ppm, and two distinctive 15 N NMR resonances near 80 and 160 ppm proved the presence of 5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid (IPCA) or its derivatives. This molecular fluorophore with conjugated double bonds, formed by a double cyclization reaction of citric acid and ethylenediamine as first shown by Y. Song, B. Yang, and coworkers in 2015, accounts for the fluorescence of the carbon dots. Cross-peaks in a 1 H─13 C HETCOR spectrum with brief 1 H spin diffusion proved that IPCA is finely dispersed in the polyamide matrix. From quantitative 13 C and 15 N NMR spectra, a high concentration (18 ± 2 wt%) of IPCA in the carbon dots was determined. A pronounced gradient in 13 C chemical-shift perturbations and peak widths, with the broadest lines near the COO group of IPCA, indicated at least partial transformation of the carboxylic acid of IPCA by amide or ester formation.

Electrospinning of Aqueous Solutions of a Triethylammonium Salt of Polyamic Acid and Properties of the Nonwoven Polyimide Materials

The electrospinning conditions of aqueous and aqueous-alcoholic solutions of the triethylammonium salt of a polyamic acid derived from pyromellitic dianhydride and 4,4′-diaminodiphenyl ether in the concentration interval 8–15 wt % were studied comprehensively. The best operation characteristics of the nonwoven materials are reached when forming the fibers from a 10% solution of the prepolymer in a 70/30 wt % alcohol/water mixture at the reaction mixture viscosity in the interval 0.27–0.96 Pa s and the surface tension of 26 mN m−1. The dynamics of thermal imidization of the nonwoven material based on the triethylammonium salt polyamic acid was monitored by IR spectroscopy; it was found that the imide ring formation was complete at 200°C. Samples of the nonwoven polyimide material were obtained, and their deformation, strength, and thermal properties were determined.

Sustainable Manganese-Catalyzed Solvent-Free Synthesis of Pyrroles from 1,4-Diols and Primary Amines.

A general and selective metal-catalyzed conversion of biomass-derived primary diols and amines to the highly valuable 2,5-unsubstituted pyrroles has been developed. The reaction is catalyzed by a stable nonprecious manganese complex (1 mol %) in the absence of organic solvents whereby water and molecular hydrogen are the only side products. The manganese catalyst shows unprecedented selectivity, avoiding the formation of pyrrolidines, cyclic imides, and lactones.

Computational studies on cyclic imide formation mechanism of glutamic acid residues catalyzed by two water molecules

Aspartic acid (Asp) residues in peptides and proteins are prone to nonenzymatic stereoinversion and/or isomerization to form three types of isomerized Asp residues (L-β-Asp, D-α-Asp, and D-β-Asp) via a five-membered ring succinimide intermediate. These isomerized Asp residues are detected more frequently in aged tissues. However, stereoinversion and/or isomerization of glutamic acid (Glu) residues having a chemical structure similar to Asp residues are hardly detected in proteins. In this study, we investigate computationally the formation mechanism of the cyclic imide, i.e., amino-glutarimidyl (Agl) from Glu residues, with water molecules as catalyst. We study the reaction mechanism by using quantum chemical B3LYP/6-31+G(d,p) density functional theory calculations. All calculations are performed by using model compounds in which a Glu residue is capped with acetyl and methylamino groups on the N- and C-termini, respectively. Agl formation consists of the three steps of iminolization, cyclization, and dehydration, and two water molecules acting as proton-relay mediators catalyze all three steps. The calculated activation energy for Agl formation from Glu residues is 30.3 kcal mol−1, which is somewhat greater than found experimentally for Asp-residue stereoinversion. This calculation suggests that in vivo Glu-residue stereoinversion is unlikely to occur because of the high activation barrier.

DBU-Catalyzed Alkyne-Imidate Cyclization toward 1-Alkoxypyrazino[1,2- a]indole Synthesis.

1-(Propargyl)indol-2-carbonitriles react with alcohols to afford 1-alkoxypyrazino[1,2- a]indoles under DBU-catalyzed microwave-assisted conditions. The reaction scope includes a wide range of indoles, primary and secondary alcohols, and a thiol. The initial mechanistic study shows that the domino process presumably proceeds through an alkyne-allene rearrangement, imidate formation, and nucleophilic cyclization reaction sequence.

Iron-catalyzed C(sp3)-H functionalization of N,N-dimethylanilines with isocyanides.

An efficient ligand-free Fe-catalyzed oxidative Ugi-type reaction toward the assembly of α-amino amides and short peptides is described. The reaction proceeds through the α-C(sp3)-H oxidation of N,N-dimethylanilines and further nucleophilic attack of the resulting iminium species by isocyanides. Additive screening showed that judicious choice of the carboxylic acid could lead to the formation of α-amino imides via a 3-component reaction. The process occurs with operational simplicity and is compatible with a variety of sensitive functional groups.