Diels-Alder Research Articles

Approach to the Core Structure of Signermycin B.

Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis-decalin. In this paper, we demonstrate that the cis-decalin section of signermycin B can be accessed by an anionic oxy-Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels-Alder reaction of a masked ortho-benzoquinone, generated by oxidation of an α-methoxyphenol in presence of cis-2-hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy-Cope rearrangement to a cis-decalinone. While we could show, that introduction of the 4-ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4-epi-isomer was formed.

Nickel(II)-Catalyzed Asymmetric Inverse-Electron-Demand Diels–Alder Reaction of 2-Pyrones with Styrenes and Indenes

Nickel(II)-Catalyzed Asymmetric Inverse-Electron-Demand Diels–Alder Reaction of 2-Pyrones with Styrenes and Indenes

Cobalt(II)‐Nitromethane Complex As An Efficient Catalyst Of Demanding Diels‐Alder Reactions On The Example Of An Anthracene‐Chalcone System

Diels‐Alder (DA) cycloaddition of chalcones to anthracene and its 9‐substituted derivatives is an example of a demanding reaction that is not effective even under increased pressure. In this article we show good catalytic activity of an easily accessible complex cation [Co(CH3NO2)6]2+ stabilized by weakly coordinating anion [Al(OC(CF3)3)4]−. Our screening covering chalcone and anthracene derivatives with either activating or deactivating effects on reactivity in DA cycloadditions show that the catalyst allows to obtain [4+2] cycloadducts with yields up to 99% under mild conditions, even for 9‐bromoanthracene – a very poor diene in DA reactions. The reaction proceeds best in liquid SO2, which is an unusual solvent for this type of reaction. 9‐methylanthracene ‐ the most reactive diene among those tested in the study ‐ gives two regioisomeric cycloadducts and their ratio depends on the solvent used. Modelling of the reaction with DFT methods shows that Co(II) significantly lowers the activation energy of the cycloaddition. In the case of 9‐bromoanthracene the effect is much more pronounced than with e.g. recently reported redox‐activation of the diene, which is in agreement with much better yields obtained with the use of the cobalt catalyst.

A novel flame retardant epoxy thermoset based on renewable honokiol and furfuryl alcohol

In this study, honokiol epoxy resin was directly functionalized by bio-based material honokiol, which was combined with furfuryl alcohol-derived flame retardant by Diels-Alder reaction to prepare bio-based epoxy cross-linking system. After curing with 4,4′-diaminodiphenyl methane, HE1/FP0.5/DDM (121.37 °C) offered higher glass transition temperature than EP/DDM (91.75 °C). Meanwhile, the HE1/FP0.5/DDM exhibited excellent thermal stability and flame retardancy compared to EP/DDM. The char residue of HE1/FP0.5/DDM was obviously increased from 12.8% (EP/DDM) to 35.6% at 700 °C. Notably, the HE1/FP0.5/DDM achieved a limiting oxygen index value of 37.4% and UL-94 V-0 rating. Cone calorimeter demonstrated that the peak heat release rate, total heat release and fire growth rate of HE1/FP0.5/DDM were 400.29 kW/m2, 33.45 MJ/m2 and 4.40 kW/m2·s, reduced by 57.47%, 63.39% and 41.1% compared with EP/DDM, respectively. The satisfactory flame retardancy and smoke suppression were attributed to the flame-retardant function of FP in the condensed and gas phases. Thus, this work not only provided a simple but also eco-friendly approach to achieve flame retardant thermosets from honokiol to replace bisphenol A epoxy.

Promotion and Detection of Cell-Cell Interactions through a Bioorthogonal Approach.

Manipulation of cell-cell interactions via cell surface modification is crucial in tissue engineering and cell-based therapy. To be able to monitor intercellular interactions, it can also provide useful information for understanding how the cells interact and communicate. We report herein a facile bioorthogonal strategy to promote and monitor cell-cell interactions. It involves the use of a maleimide-appended tetrazine-caged boron dipyrromethene (BODIPY)-based fluorescent probe and a maleimide-substituted bicyclo[6.1.0]non-4-yne (BCN) to modify the membrane of macrophage (RAW 264.7) and cancer (HT29, HeLa, and A431) cells, respectively, via maleimide-thiol conjugation. After modification, the two kinds of cells interact strongly through inverse electron-demand Diels-Alder reaction of the surface tetrazine and BCN moieties. The coupling also disrupts the tetrazine quenching unit, restoring the fluorescence emission of the BODIPY core on the cell-cell interface, and promotes phagocytosis. Hence, this approach can promote and facilitate the detection of intercellular interactions, rendering it potentially useful for macrophage-based immunotherapy.

Structural diversity of decalin forming Diels-Alderase.

The Diels-Alder (DA) reaction, specifically referring to the [4+2] cycloaddition reaction in pericyclic reactions, is a process that forms two carbon-carbon covalent bonds in a single step via an electron ring transition state. Among the secondary metabolites produced by microorganisms, numerous compounds are biosynthesized through DA reactions, most of which are enzymatic. Our research group has discovered an enzyme named Diels-Alderase (DAase) that catalyzes the DA reaction in filamentous fungi, and we have been investigating its catalytic mechanism. This review describes the reported microbial DAase enzymes, with a particular focus on those involved in the construction of the decalin ring.

Rapid access to divergent fused polycycles via one-pot A3 coupling and intramolecular Diels-Alder reaction.

Divergent nitrogen-containing fused polycyclic ring systems are constructed from simple starting materials via a one-pot aldehyde-alkyne-amine (A3) coupling and intramolecular Diels-Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa-bridged fused 5/5 bicycle and a 1,6-enyne substructure. One-step derivation of the oxa-bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back-to-back to pyrroline or a 6/5 bicycle with the hexahydro-1H-isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5-membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one-pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity-oriented synthetic approach thus allows rapid access to an under-explored structural space for discovery of new biological or non-biological activities or functions.

Dynamic covalent polymer network enabled bio‐based vitrimers with excellent substrate bonding

AbstractIn this article, we report the synthesis of dynamic covalent polymer network (DCPN)‐enabled vitrimers derived from gum rosin—a pine tree extract. The concept of Diels Alder (DA) thermo‐reversibility has been used to introduce self‐healing/dynamic covalent ability into the polymer systems. For this purpose, the diene moieties were incorporated in the gum rosin‐based polymer network, and the bismaleimides served as the dienophiles. The thermo‐reversible crosslinks formed between the diene and dienophile moieties can enhance the service life of the materials by improving the durability, mechanical as well as chemical properties of the materials. Upon damage, the thermo‐reversible DA bonds de‐crosslink resulting in smaller chain segments, enabling the material to flow to the site of damage and seal the fractured edges. The formation of DA crosslinks has been confirmed by using Fourier transform‐infrared spectroscopic technique. Scanning electron microscopy analysis was used to verify the self‐healing ability of the resin matrix. The healing process was studied after manual scratches were made. The polymers' ability to heal multiple times is investigated using differential scanning calorimetry. The adhesion strength of the self‐healing material has been examined on variety of substrates such as glass, steel, and concrete. The materials exhibited superior adhesion strength on glass substrate.

Bioorthogonal Cycloadditions of C3-Trifluoromethylated 1,2,4-Triazines with trans-Cyclooctenes.

1,2,4-triazines are a valuable class of heterodienes that can be employed in inverse electron-demand Diels-Alder reactions. However, their broader application in bioorthogonal chemistry is limited due to their low reactivity. This article focuses on 3-(trifluoromethyl)-1,2,4-triazines, which can be efficiently prepared in a one-pot reaction from NH-1,2,3-triazoles. These triazines are highly reactive in reactions with strained cyclooctenes, giving second-order rate constants as high as 230 M-1 s-1. Despite their high reactivity, the compounds remain sufficiently stable under biologically relevant conditions. We show that some of the compounds are fluorogenic, a property of potential use in bioimaging. In addition, we demonstrate the successful application of the triazines in labeling model biomolecules. Our work shows that the reactivity of 1,2,4-triazines can be enhanced by the 3-CF3-substitution, which we consider an important step toward the wider use of this promising class of reagents.

Chiral twisted molecular carbons: Synthesis, properties, and applications

AbstractIn recent years, the precisely controlled synthesis of chiral twisted molecular carbons has emerged as a forefront topic in the research of carbon materials. Molecular carbons refer to carbon nanomaterials synthesized with precision at the atomic level. Through rational design, rigid and stable chiral twisted structures can be synthesized. The exploration in the field of chiral twisted molecular carbons is key to fully understanding the various twisted configurations of carbon materials and delving into the relationship between structure design and functionality. This review explores chiral twisted configurations of carbon nanomaterials such as nanographene, carbon nanobelts, carbon nanosheets, graphdiyne, etc. It emphasizes the role of photocyclization, Scholl reaction, and Diels–Alder reactions in achieving precise chiral control and discusses a range of innovative design strategies. These strategies have led to the development of various twisted structures, such as helical, propeller, and Möbius strip configurations. The introduction of chirality, combined with the inherent exceptional optical properties of nanocarbon materials, has facilitated the creation of materials with superior chiroptical performances. This advancement is driving applications in fields such as optoelectronics and chiral optics.

Coherence mapping to identify the intermediates of multi-channel dissociative ionization

Identifying the short-lived intermediates and reaction mechanisms of multi-channel radical cation fragmentation processes remains a current and important challenge to understanding and predicting mass spectra. We find that coherent oscillations in the femtosecond time-dependent yields of several product ions following ultrafast strong-field ionization represent spectroscopic signatures that elucidate their mechanism of formation and identify the intermediate(s) they originate from. Experiments on endo-dicyclopentadiene show that vibrational frequencies from various intermediates are mapped onto their resulting products. Aided by ab initio methods, we identify the vibrational modes of both the cleaved and intact molecular ion intermediates. These results confirm stepwise and concerted fragmentation pathways of the dicyclopentadiene ion. This study highlights the power of tracking the femtosecond dynamics of all product ions simultaneously and sheds further light onto one of the fundamental reaction mechanisms in mass spectrometry, the retro-Diels Alder reaction.

Confinement as a Tool in Chemistry: Accelerated Intracapsular Dimerization of Cyclopentadiene in Water

AbstractIn this study, the occurrence of Diels–Alder reaction of cyclopentadiene yielding dicyclopentadiene within a confined closed space provided by octa acid (OA) in water at room temperature is established. The Diels–Alder reaction within the OA capsule occurs at least 2000 times faster than in water. Catalysis of Diels–Alder reaction by hosts such as cyclodextrin, cucurbituril, and Fujita's Pd nano–host occurs in water. Despite their similarity, these three hosts provide an open environment where the reactant molecules are exposed to aqueous environment. The only fully closed host known to catalyze the Diels–Alder reaction in water is OA. Although Rebek's host is established to catalyze Diels–Alder reaction it occurs in an organic solvent. The closed environment explored in this presentation provides an opportunity to better understand the origin of non–covalent catalysis in a restricted space and in water. Because the product binds stronger than the reactant, disappointingly, the capsule can't be recycled. We recognize that this aspect needs to be addressed for the OA capsule to become synthetically useful. We are in the process of understanding the origin of catalysis and finding ways to make reaction recyclable.

Weak Interaction Activates Esters: Reconciling Catalytic Activity and Turnover Contradiction by Tailored Chalcogen Bonding.

The activation of esters by strong Lewis acids via the formation of covalent adducts is a classic strategy to give reactivity; however, this approach frequently incurs limited turnover due to the low efficiency in the dissociation of catalyst from a stable catalyst-product complex. While the use of some weak interaction catalysts that can easily dissociate from any bonding complexes in the reaction system would solve this catalyst turnover problem, the poor catalytic activity in the ester activation that can be provided by these noncovalent forces in turn sets up a formidable challenge. Herein, we describe the activation and catalytic transformation of esters by weak interactions, which provides a promising platform to reconcile the catalytic activity and turnover problems. Several tailored chalcogen-bonding catalysts were developed for the activation of esters, enabling achieving several inherently low reactive Diels-Alder reactions as well as the ring-opening polymerization of lactones through weak chalcogen bonding interactions. This supramolecular catalysis approach is particularly highlighted by its capability to promote some uncommon Diels-Alder reactions involving using dienes bearing electron-withdrawing groups coupled by α,β-unsaturated ester as dienophiles and substrate incorporating competitive Lewis basic sites, in which typical strong Lewis acids showed low catalytic efficiency, while representative hydrogen and halogen bonding catalysts were inactive.

Controlled In Situ Self-Assembly of Biotinylated Trans-Cyclooctene Nanoparticles for Orthogonal Dual-Pretargeted Near-Infrared Fluorescence and Magnetic Resonance Imaging.

A pretargeted strategy that decouples targeting vectors from radionuclides has shown promise for nuclear imaging and/or therapy in vivo. However, the current pretargeted approach relies on the use of antibodies or nanoparticles as the targeting vectors, which may be compromised by poor tissue penetration and limited accumulation of targeting vectors in the tumor tissues. Herein, we present an orthogonal dual-pretargeted approach by combining stimuli-triggered in situ self-assembly strategy with fast inverse electron demand Diels-Alder (IEDDA) reaction and strong biotin-streptavidin (SA) interaction for near-infrared fluorescence (NIR FL) and magnetic resonance (MR) imaging of tumors. This approach uses a small-molecule probe (P-Cy-TCO&Bio) containing both biotin and trans-cyclooctene (TCO) as a tumor-targeting vector. P-Cy-TCO&Bio can efficiently penetrate subcutaneous HeLa tumors through biotin-assisted targeted delivery and undergo in situ self-assembly to form biotinylated TCO-bearing nanoparticles (Cy-TCO&Bio NPs) on tumor cell membranes. Cy-TCO&Bio NPs exhibited an "off-on" NIR FL and retained in the tumors, offering a high density of TCO and biotin groups for the concurrent capture of Gd-chelate-labeled tetrazine (Tz-Gd) and IR780-labeled SA (SA-780) via the orthogonal IEDDA reaction and SA-biotin interaction. Moreover, Cy-TCO&Bio NPs offered multiple-valent binding modes toward SA, which additionally regulated the cross-linking of Cy-Gd&Bio NPs into microparticles (Cy-Gd&Bio/SA MPs). This process could significantly (1) increase r1 relaxivity and (2) enhance the accumulation of Tz-Gd and SA-780 in the tumors, resulting in strong NIR FL, bright MR contrast, and an extended time window for the clear and precise imaging of HeLa tumors.

Green synthesis of functionalized graphene-based material with dimethyl but-2-ynedioate for electrochemical energy storage devices

Functionalization of graphene with dimethyl acetylenedicarboxylate is achieved through a microwave-assisted Diels-Alder reaction. The physical, chemical, and electrochemical properties of the modified sheets are thoroughly investigated by complementary characterization techniques. Density Functional Theory calculations are employed to examine the functionalization mechanism and to highlight the role of defects such as epoxide bridges introduced in graphene during exfoliation. Our findings provide valuable insights into the development of efficient and cost-effective methods for large-scale production of high-quality graphene-based materials. Specifically, the electrochemical properties of anode materials containing functionalized graphene are evaluated for Li-ion electrochemical energy storage devices, demonstrating excellent electrochemical reversibility and rate capability. The cyclic voltammetry analysis reveals material stabilization after a few cycles, resulting in a coulombic efficiency of up to 95 % and a discharge capacity of 162.3 mA·h·g−1. The galvanostatic cycling test indicates that the material electrode retains 57 % of its initial capacity at a C-rate of 10C, indicating high-power capability. These promising results position organic modified graphene as a potential material for Li-ion capacitors, with a specific capacity that aligns with the last intercalation stage capacity at a lower potential. Overall, the study's findings offer significant contributions to the advancement of graphene-based materials in energy storage applications.

Enhancing weatherability and mechanical properties of tung oil wood finishes through natural rubber modification via the Diels-Alder reaction

Tung oil is commonly utilized for coating protection in wooden products, often attracting attention for its appearance, antimicrobial capabilities, and insect-resistant coatings. However, its poor mechanical properties and poor weather resistance stem from excessive self-crosslinking of surplus conjugated double bonds and molecular chains, resulting in poor film wrinkling. Therefore, this study introduces natural rubber via the Diels-Alder reaction to consume the residual double bonds in tung oil, resulting in tung oil/natural rubber composite coatings (NRTO) with excellent mechanical properties and weather resistance. The results indicate that NRTO exhibits excellent mechanical properties, including high elongation (32 %) and strong adhesion (4.55 MPa). Furthermore, NRTO demonstrates outstanding acid resistance and UV aging resistance. Given its many benefits, NRTO film emerges as a promising candidate for substantially protecting wood surfaces in demanding environments.

A Novel tetrahydrocannabinol (THC) analog, 3,10,10-Trimethyl-1,2,3,4,4a,6,7,8,10,10a-decahydro-9-oxa-5-phenanthrenone (TDP), mitigates the decrease in cell viability in oxidatively-stressed osteosarcoma bone-like cell cultures, UMR 106-01 BSP (UMR cells)

Cannabinoids have been extensively studied in the field of cancer research. Tetrahydrocannabinol (THC) has shown promising results in influencing cellular proliferation and viability when used in association with other cannabinoids. However, not many studies have been done to explore the effect of THC analogs on osteosarcoma cells when used in concert with oxidative stressors like camptothecin (CPT). In this study, it was hypothesized that TDP would mitigate the oxidative effect of CPT on UMR cells. Briefly, synthesis of the novel THC analog, TDP, was attempted via a Knoevenagel condensation and a Diels-Alder reaction, using 1,3-cyclohexanediol dissolved in methanol and citronellal with ethylenediamine diacetic acid (EDDA) at a temperature of 60°C. UMR cells were routinely passaged, counted, plated in six-well culture plates at 480,000 cells/mL, then treated with 10-fold dilutions of TDP. The plates were incubated for 72 hours in a humidified incubator at 37 degrees Celsius with 5% carbon dioxide infusion. At the end of the experiment, the cells were routinely washed with HANKS buffered saline solution (HBSS), then counted using the Luna II Automated Cell Counter. In another experiment, designated cells were treated with different concentrations of CPT alone, while others were co-treated with different concentrations of TDP+CPT, following the protocol above. F test ANOVA was used to compare variances and all values in the results were expressed as means ± SD. The results from the attempted cannabinoid analog synthesis yielded an active novel THC analog, TDP. Serial dilutions treatment of the UMR cells with TDP alone showed its ability to decrease cell viability in a concentration-dependent manner. The treatment of the UMR cells with different concentrations of CPT alone resulted in a decrease in cell viability in a concentration-dependent manner. Co-treatment of the UMR cells with different concentrations of CPT+TDP showed that TDP was able to mitigate the effect of the oxidative stressor (CPT) on the UMR cell cultures. Moreover, the F Test ANOVA showed robust statistical significance (p values <0.05) regarding TDP’s ability to decrease the oxidative effect of CPT on UMR cells. Overall, the outcomes of this study suggest that active forms of THC analogs can be synthesized and tested in concert with oxidative stressors like CPT. This study opens the door to explore the mechanisms by which TDP exerts its effect on oxidatively-stressed cells and how it can possibly be used to prevent or mitigate the effect of oxidative stress on a variety of cells in culture. Moreover, the hopes of suggesting therapeutic uses of THC analogs, upon future mechanistic experimentations, is a goal. La Sierra University Title V Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Competing Domino Knoevenagel-Cyclization Sequences with N-Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of N-arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the N-vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC50 values was identified for some of the novel scaffolds.

Castor oil-based polyurethane Vitrimer modified asphalts regulated by dual dynamic reversible reactions and crosslinking density: Preparation, basic assessment and self-healing behavior

Thermosetting polymers, commonly used to improve asphalt properties, bring excellent pavement performance, but also pose significant challenges to the healing and recyclability of their modified asphalts after long-term service. An effective approach involves introducing dynamic bonds into the crosslinking networks to synthesize Vitrimer-modified asphalts with self-healing response. Due to the splendid mechanical properties, high elasticity, flexibility and easily controllable cross-linked structure of polyurethane, a novel castor oil-based polyurethane Vitrimer modified asphalt with disulfide bonds and Diels-Alder reactions was developed. Based on the prepared castor oil-based polyurethane Vitrimer (C-PUV, composed of components A and B) and its modified asphalts (C-PUVAs), a comprehensive study was conducted on the crosslinking density, mechanical properties, thermal stability, viscosity, compatibility, rheological properties, and self-healing behavior. The results indicated that C-PUVAs (C-PUVA1/C-PUVA2/C-PUVA3/C-PUVA4) exhibited sufficient retention times for viscosity, uniform phase distribution, and good high-temperature performance. The damaged C-PUVAs achieved a mechanical strength recovery rate more than 75 % after the first cycle of self-healing at 80 ℃ and 0.3 MPa. Furthermore, the crosslinking density of C-PUV was regulated by the segment length of component B. As the crosslinking density increased, C-PUV and C-PUVAs obtained higher mechanical strength while sacrificing part of self-healing efficiency. The mechanism is that increased crosslinking density altered the gel point distributions of the reversible crosslinked networks, resulting in a longer relaxation time and higher activation energy. In conclusion, the above findings provided valuable insights for developing bio-based polyurethane Vitrimer modified asphalts, and endosing thermosetting polymer modified asphalts with self-healing and recyclable properties.

Synthesis of chlorophyll–quinone conjugates by Diels–Alder reaction and their fluorescence quenching by intramolecular electron transfer

Methyl pyropheophorbides-a possessing a 1,4-naphthoquinon-5-yl or 9,10-anthraquinon-1-yl group at the 3-position were prepared by the Diels–Alder reaction of 3-(1,3-butadienyl)chlorin with benzoquinone or naphthoquinone and successive dehydrogenative oxidation. The synthetic chlorophyll-a derivatives directly bonded with the quinone were atropisomers around the C3–C31 bond, which were readily separated by HPLC. Since the quinone moiety was nearly perpendicular to the chlorin π-system, the distance and orientation between the chlorin and quinone chromophores were fixed in a molecule. The visible absorption spectra of the synthetic chlorin–quinone conjugates were independent of the quinone part and the axial chirality. Their fluorescence emissions were almost completely quenched by intramolecular electron transfer from the photoexcited chlorin to the quinone, which resembled the charge-separating process in photosynthetic reaction centers.