Diels-Alder Research Articles

Synthesis and Characterization of New Compounds by Enzymatically Catalysed Diels-Alder Reactions

The Diels-Alder (DA) reaction is one of the important chemical transformations to create the C–C bonds with predicted regio- and stereo-selectivity, which lead to the forming of bulk organic molecules. Despite of the significant efforts in this filed, the control of the stereoselectivity of DA reactions remain so difficult. Despite the significant efforts in this field, controlling of stereoselectivity of DA reactions remains so difficult. The design of the enzymatic DA reactions provides scientists with a huge advantage in increasing the selectivity of DA reaction products. This work aims to apply the friendly environmental method includes the application of the current approach in enzymatic DA reactions by formation the new organic compounds through the enzymatic DA reactions between anthracene derivatives as dines and pyrrole derivatives as dienophiles. All DA reactions were curried out in the inert environment using the nitrogen gas. The prepared compounds were caramelized using various techniques including mass spectroscopy, nuclear magnetic resonance, and Fourier transform infrared. The results showed that all products of DA reactions containing unnatural dienes with endo-configuration, in addition to obtain 53%–94% isolated yields. Consequently, this study provides an efficient method to control the stereochemistry of DA reactions.

A "Bottom-Up" Strategy for High-Performance Benzocyclobutene (BCB)-Subnanometer Inorganic Nanocomposites.

Developing benzocyclobutene (BCB) nanocomposites with ultra-small inorganic sizes represents a formidable challenge, although it offers great potential to produce materials with customizable structural and rich functional properties. In this study, we present a "bottom-up" design strategy for creating cross-linked benzocyclobutene (BCB) nanocomposites with highly dispersed nanodomains, such as organoalkoxysilane. This approach leverages ring-opening metathesis polymerization (ROMP) and thermally induced cycloaddition reactions to embed oligomeric silsesquioxanes, achieving a unique molecular structure with promising low-dielectric applications. The synthesis involves organoalkoxysilane and BCB as pendant groups of polynorbornenes that are covalently integrated. Additionally, the methoxyl groups of linear polymers could be further hydrolyzed under acidic conditions, and BCB groups could undergo thermal-induced ring-opening at high temperatures and Diels-Alder addition between themselves and vinyl groups, respectively. Fourier transform infrared (FTIR) spectroscopy analyses suggested the presence of ladder or network structures and high-resolution transmission electron microscopy (HRTEM) images presented the well-dispersed inorganic clusters, facilitating excellent dielectric properties with a dielectric constant (Dk) of 2.25 and a dissipation factor (Df) of 2.27 × 10-4. Compared with previously reported low-Dk materials, the cured nanocomposites also exhibited a significantly balanced enhancement of their comprehensive properties. This molecular bottom-up strategy provided a simple and universal method for constructing BCB-inorganic nanocomposites featuring a subnanometer inorganic structure, paving the way for future investigation into new classes of polymer-inorganic nanocomposites with a low Dk.

Construction of acenaphthylenes via C-H activation-based tandem penta- and hexaannulation reactions.

Acenaphthylene-containing polycyclic aromatic hydrocarbons (AN-PAHs) are noteworthy structural motifs for organic functional materials due to their non-alternant electronic structure, which increases electron affinity. However, the synthesis of AN-PAHs has traditionally required multiple sequential synthetic steps, limiting structural diversity. Herein, we present a tandem C-H penta- and hexaannulation reaction of aryl alkyl ketone with acetylenedicarboxylate. This integrated approach enhances overall efficiency and selectivity, marking a significant advancement in AN-PAH synthesis. Mechanistic studies unveil an orchestrated extension of five- and six-membered rings through C-H activation-annulation and Diels-Alder reaction. Additionally, the tandem annulation reaction can be performed stepwise, further validating the proposed mechanism and increasing the structural diversity of AN-PAHs.

Highly dispersed palladium supported on sulfuric acid-modified activated carbon for efficient dehydrogenation to produce novel aromatic monomer

Herein, a sustainable route to novel aromatic monomer, dimethyl 1,2,3,4-tetrahydro-1,4-methanonaphthalene-5,8-dicarboxylate, was developed, in which dimethyl muconate and norbornene used as the diene and dienophile undergo Diels-Alder reaction followed by dehydrogenation. The polycyclic cycloadduct, octahydro-1,4-methanonaphthalene-5,8-dicarboxylate, could be synthesized without catalyst. The activated carbon modified with sulfuric acid generated more oxygen-containing groups, stronger acidity and more acidic sites. Highly dispersed palladium metal particles with an average particle size of about 1.0 nm exhibited excellent activity in the dehydrogenation reaction and the yield of target product reached 73.8 %.

Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide

AbstractHere we report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu‐promoted dienyl enolization, intramolecular Diels–Alder reaction and enol‐ketone tautomerization to afford pedrolide, a pathway consistent with our proposal for the biogenesis of pedrolide.

Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide.

Here we report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu-promoted dienyl enolization, intramolecular Diels-Alder reaction and enol-ketone tautomerization to afford pedrolide, a pathway consistent with our proposal for the biogenesis of pedrolide.

Molecular Editing of Pyrroles to Benzenes/Naphthalenes by N2O Deletion.

A molecular editing reaction for converting pyrrole rings into benzene rings through a sequential pathway of Diels-Alder and cheletropic reactions was developed. The nitrogen atom in a N-bridged intermediate is eliminated in the form of N2O by a strain-releasing pathway, ultimately leading to the formation of substituted benzene and naphthalene derivatives.

Analysis and Formation of Polycyclic Aromatic Hydrocarbons in Canned Minced Chicken and Pork during Processing.

Polycyclic aromatic hydrocarbons (PAHs) represent important toxic compounds formed in meat products during processing. This study aims to analyze 22 PAHs by QuEChERS coupled with GC-MS/MS in canned minced chicken and pork during processing. After marinating raw minced chicken and pork separately with a standard flavoring formula used for canning meat in Taiwan, they were subjected to different processing conditions including stir-frying, degassing and sterilizing at 115 °C/60 min (low-temperature-long-time, LTLT) and 125 °C/25 min (high-temperature-short-time, HTST). The quantitation of PAHs in these meat products revealed the formation of only three PAHs including acenaphthylene (AcPy), acenaphthene (AcP) and pyrene (Pyr) in canned minced chicken and pork during processing with no significant difference in total PAHs between the meat types. Analysis of PAH precursors showed the presence of benzaldehyde at the highest level, followed by 2-cyclohexene-1-one and trans,trans-2,4-decadienal in canned minced chicken and pork, suggesting PAH formation through the reaction of benzaldehyde with linoleic acid degradation products and of 2-cyclohexene-1-one with C4 compounds through the Diels-Alder reaction, as well as the reaction of trans,trans-2,4-decadienal with 2-butene. Monounsaturated and polyunsaturated fatty acids were present in the largest proportion in LTLT-sterilized chicken/pork, followed by HTST-sterilized chicken/pork and raw chicken/pork, and their levels did not show a high impact on PAH formation, probably due to an insufficient heating temperature and length of time. A two-factorial analysis suggested that PAH formation was not significantly affected by the sterilization condition or meat type. Principal component analysis corroborated the observed results implying the formation of PAHs in canned minced chicken/pork under different processing conditions with an insignificant difference (p > 0.05) between them, with the individual PAH content following the order of Pyr > AcPy > AcP.

Physics-Informed Active Learning for Accelerating Quantum Chemical Simulations.

Quantum chemical simulations can be greatly accelerated by constructing machine learning potentials, which is often done using active learning (AL). The usefulness of the constructed potentials is often limited by the high effort required and their insufficient robustness in the simulations. Here, we introduce the end-to-end AL for constructing robust data-efficient potentials with affordable investment of time and resources and minimum human interference. Our AL protocol is based on the physics-informed sampling of training points, automatic selection of initial data, uncertainty quantification, and convergence monitoring. The versatility of this protocol is shown in our implementation of quasi-classical molecular dynamics for simulating vibrational spectra, conformer search of a key biochemical molecule, and time-resolved mechanism of the Diels-Alder reaction. These investigations took us days instead of weeks of pure quantum chemical calculations on a high-performance computing cluster.

Design and Synthesis of Out/Out, Out/In, and In/In Epoxides in Polycyclic Cage Frameworks

AbstractWe report a useful synthetic approach to assemble in/in epoxide, in/out epoxide, and out/out epoxide in cage systems using the Corey–Chaykovsky reaction and the Peterson olefination as key steps. In this regard, a variety of pentacycloundecane (PCUD) based cage compounds containing oxirane rings with diverse stereochemical disposition were synthesized via a simple synthetic sequence. Five cage diones were used for this purpose, and the starting cage diones were prepared with easily accessible starting materials such as 1,4-hydroquinone derivatives and cyclopentadiene. Here, we have used the Diels–Alder (DA) reaction, a [2+2] photocycloaddition, the Corey–Chaykovsky reaction, and the Peterson olefination as crucial steps to prepare the target molecules.

Helix-to-Disc Conversion of Thia[6]helicenes into Coronenes Facilitated by Sulfur Oxidation and Fluorination.

Helicenes, with their unique helical structures, have long captured the interest of synthetic chemists, not only as end products, but also as versatile platforms for further chemical transformations. However, transforming [6]helicene into planar coronene typically requires harsh conditions and poses significant challenges. Herein, we demonstrate that replacing the terminal benzene ring of [6]helicene with a thiophene ring enables its photochemical transformation into coronene. Sulfur oxidation of the thiophene ring enables the corresponding thermal transformation, and the terminal tetrafluorination of the opposite benzene ring further accelerates this process, yielding 1,2-difluorocoronene, as confirmed by X-ray crystallography. The transformation begins with an intramolecular Diels-Alder reaction, whose activation energy is significantly lowered by these structural changes. Our findings underscore the utility of strategic modifications such as sulfur oxidation and fluorination in promoting this "helix-to-disc" conversion and opening new avenues for synthesizing functional polycyclic aromatics.

One-pot synthesis of 5-norbornene-2,3-dicarboxylic anhydride with high exo/endo ratio in a microreactor under high temperature and appropriate pressure

5-Norbornene-exo-2,3-dicarboxylic anhydride (exo-NDA), widely used in the synthesis of medicine and pesticide, was primarily obtained through the subsequent thermal isomerization of 5-norbornene-endo-2,3-dicarboxylic anhydride (endo-NDA) synthesized from cyclopentadiene (CPD) and maleic anhydride (MAH). Herein, density functional theory (DFT) was employed to elucidate the transition states and reaction pathways of different configurations. The endo-path exhibited a lower energy barrier, and the exo-isomer demonstrates greater structural stability. It was found that both high temperature and solvent polarity influenced the generation of NDA with different configurations. Due to considering solubility of MAH, an acetone/ethylbenzene mixed solvent was chosen for the reaction instead. According to the DFT calculations, we developed continuous-flow microreactor for high-efficiency one-pot synthesis of the isomers with exo/endo ratio of up to 1.19:1 as well as almost 100 % conversion and 98 % selectivity just in 2 min at 260 °C and 4 MPa, which CPD was generated in situ to participate in a series of Diels-Alder reactions instead of dicyclopentadiene as raw material existed at room temperature. Moreover, excessive or insufficient pressure in the reaction system should elevate byproduct formation, resulting in a decrease in reaction selectivity, as could prolonged residence time.

Total Synthesis of (-)-Flueggeacosine C.

Herein we describe a total synthesis of the heterodimeric securinega alkaloid (-)-flueggeacosine C (8). The convergent synthetic strategy is based on a Liebeskind-Srogl cross-coupling reaction that combines a benzoquinolizidine fragment with a securinine-type alkaloid. An acyloxy nitroso ring-expansion was employed as the key step in accessing benzoquinolizidine 9, and a novel intramolecular Diels-Alder reaction of an allenic acid-containing pyridone expeditiously delivers the skeleton of the securinine-type fragment (16). Finally, a Cu-catalyzed hydroboration-oxidation sequence was employed to regio- and diastereoselectively introduce the secondary alcohol found in 8.

Cycloadditions of 4-Alkenyl-2-aminothiazoles with Nitroalkenes in the Formal Synthesis of Pramipexole: An Experimental and Computational Study.

4-Alkenyl-2-dialkylaminothiazoles act as in-out dienes in [4 + 2] cycloaddition reactions with nitroalkenes, furnishing 2-amino-6-nitro-4,5,6,7-tetrahydrobenzothiazoles in moderate to good yields, accompanied by a subsequent 1,3-H migration. These transformations proceed with exquisite site-, regio-, and diastereoselectivity. This strategy is further enriched by revealing a novel route for pramipexole synthesis. The examination of the potential energy surfaces associated with the four possible reaction pathways for the Diels-Alder cycloaddition (relative approach of the diene-dienophile and endo/exo approach of the nitro group) not only aligns with experimental observations but also unveils key mechanistic insights. Specifically, computational analyses uncover the favored pathway yielding 6-nitro-4,5,6,7-tetrahydrobenzothiazoles, with some instances proceeding through a two-step mechanism involving a tandem sequence of chemical processes, and the influence of various factors such as dienophile structure and the approach mode of the nitro group. Additionally, the stabilization of the exo-transition states, particularly facilitated by phenyl substitution in the dienophile, is highlighted. Asynchronicity, dipole moment, and other parameters indicative of polar character further characterize these Diels-Alder reactions. Conceptual DFT calculations underscore the pivotal role of the 1,3-thiazole ring in enhancing dienic activation and dictating regioselectivity, emphasizing interactions between the C5 of the thiazole nucleus and the Cβ atom of the nitroalkenes.

Low modulus hydrogel-like elastomer sensors with ultra-fast self-healing, underwater self-adhesion, high durability/stability and recyclability for bioelectronics

Flexible sensors simultaneously with property of hydrogel-like low modulus/room temperature ultra-fast self-healing and with elastomer-like durability /environmental stability and underwater adhesion for bioelectronics has not been reported. A low modulus hydrogel-like elastomer that achieves ultrafast self-healing through molecular chain entanglement at room temperature was prepared based on furfuryl alcohol-modified poly(sebacate glyceride) (PGS) prepolymer, furfuryl alcohol-modified poly(ionic liquid) and bismaleimide by Diels-Alder (DA) reaction. The conductive elastomer-based flexible sensors exhibit hydrogel-like properties of low modulus (6.41 kPa) and ultra-fast self-healing (98 % self-healing efficiency within 5 s). The elastomer also possesses rapid subzero and underwater self-healing properties within 5 s. Moreover, PGS-0.2DA-0.2PIL exhibits pressure sensitive adhesive properties and can be adhered/re-adhered in water. The flexible sensor shows elastomer-like high durability, high environmental stability, multiple recyclability and reusability, and it exhibits wide detection ranges, fast response time, low hysteresis, anti-freezing, anti-bacterial and good biocompatibility. The flexible sensors can accurately identify micro-expressions/eye rotation, monitor human movement/health, detect ECG/EMG signals and control robotic arm movements. In conclusion, a new strategy for design of hydrogel-like conductive elastomers via molecular structure design is proposed, and the elastomers-based flexible sensors with low modulus, rapid self-healing and durability/environmental stability show great promising for bioelectronic applications.

Large Molecular Rotation in Crystal Changes the Course of a Topochemical Diels–Alder Reaction from a Predicted Polymerization to an Unexpected Intramolecular Cyclization

AbstractA designed anthracene‐based monomer for topochemical Diels–Alder cycloaddition polymerization crystallized with head‐to‐tail arrangement of molecules, as revealed by single‐crystal X‐ray diffraction (SCXRD) analysis. The diene and dienophile units of adjacent monomer molecules are aligned at an average distance of 4.6 Å, suggesting a favorable crystalline arrangement for their intermolecular Diels–Alder cycloaddition reaction to form a linear polymer. Surprisingly, heating the monomer crystals at a temperature above 125 °C resulted in the formation of intramolecular Diels–Alder cycloadduct, which could be characterized by various spectroscopy and SCXRD analysis. Various time‐dependent studies such as NMR, PXRD, and DSC, studies established that the reaction followed topochemical pathway. Schmidt's topochemical postulates are generally used to predict the topochemical reactivity and product, by analyzing the crystal structure of the reactant. Though the crystal arrangement predicted polymerization, upon heating, the molecule avoided this pathway by undergoing a large rotation to form an intramolecular cycloadduct. Theoretical calculations supported the feasibility of the rotation, exploiting the flexibility of the molecule and voids present. These findings caution that the reliance on Schmidt's criteria for topochemical reactions may sometimes be misleading, especially in heat‐induced reactions.

Large Molecular Rotation in Crystal Changes the Course of a Topochemical Diels-Alder Reaction from a Predicted Polymerization to an Unexpected Intramolecular Cyclization.

A designed anthracene-based monomer for topochemical Diels-Alder cycloaddition polymerization crystallized with head-to-tail arrangement of molecules, as revealed by single-crystal X-ray diffraction (SCXRD) analysis. The diene and dienophile units of adjacent monomer molecules are aligned at an average distance of 4.6 Å, suggesting a favorable crystalline arrangement for their intermolecular Diels-Alder cycloaddition reaction to form a linear polymer. Surprisingly, heating the monomer crystals at a temperature above 125 °C resulted in the formation of intramolecular Diels-Alder cycloadduct, which could be characterized by various spectroscopy and SCXRD analysis. Various time-dependent studies such as NMR, PXRD, and DSC, studies established that the reaction followed topochemical pathway. Schmidt's topochemical postulates are generally used to predict the topochemical reactivity and product, by analyzing the crystal structure of the reactant. Though the crystal arrangement predicted polymerization, upon heating, the molecule avoided this pathway by undergoing a large rotation to form an intramolecular cycloadduct. Theoretical calculations supported the feasibility of the rotation, exploiting the flexibility of the molecule and voids present. These findings caution that the reliance on Schmidt's criteria for topochemical reactions may sometimes be misleading, especially in heat-induced reactions.

Divergent syntheses of complex Veratrum alkaloids

The Veratrum alkaloids are a class of highly intricate natural products renowned for their complex structural and stereochemical characteristics, which underlie a diverse array of pharmacological activities ranging from anti-hypertensive properties to antimicrobial effects. These properties have generated substantial interest among both synthetic chemists and biologists. While numerous advancements have been made in the synthesis of jervanine and veratramine subtypes over the past 50 years, the total synthesis of highly oxidized cevanine subtypes has remained relatively scarce. Building on the efficiency of our previously developed strategy for constructing the hexacyclic carbon skeleton of the Veratrum alkaloid family via a stereoselective intramolecular Diels-Alder reaction and radical cyclization, here we show the development of a unified synthetic approach to access highly oxidized Veratrum alkaloids. This includes the total synthesis of (–)-zygadenine, (–)-germine, (–)-protoverine and the alkamine of veramadine A, by capitalizing on a meticulously designed sequence of redox manipulations and a late-stage neighboring-group participation strategy.

Metathesis Mastery: Crafting Linear Triquinane Frameworks for Natural Product Synthesis

AbstractOrganic and medicinal chemists have shown great interest in developing simple approaches for creating linear triquinane structures, as they are crucial for synthesizing both natural and synthetic products. Linear triquinane shows various biological characteristics like being commonly used for antitumor, antibacterial, and antimalarial purposes, making it a popular subject of study among synthetic chemists. These come from different sources like marine organisms, plants, and fungi and make up a significant group of sesquiterpenoids. These can be classified as cis‐syn‐cis or cis‐anti‐cis based on the stereochemistry at the ring junction, with cis‐anti‐cis being the most common type and exhibiting significant biological activity. In this review, we summarized different methods using a combination of photothermal and olefin metathesis strategy to construct a triquinane framework by utilizing both traditional heat and microwave radiation. Some commonly used synthetic methods, including metathesis protocol and key reactions like Grignard reaction and Diels–Alder reaction, were utilized together with ring‐closing, ring‐opining, and ring‐rearrangement metathesis to create the linear triquinane core for use in total synthesis of natural products. Additionally, the use of photothermal olefin metathesis along with Hosomi‐Sakurai reaction conditions allows for the creation of intricate polyquinanes, which can be used to produce complex natural compounds and for designing unique molecules theoretically.

Synthesis, anti-microbial evaluation, and in silico studies of novel quinoline-isoxazole hybrids

A series of novel quinoline-isoxazole hybrids 6a–o has been synthesized via multistep synthetic approach involving hetero Diels-alder reaction strategy. The target compounds were obtained in good yield, using low-cost readily available starting materials using simple reaction conditions. The newly synthesized compounds were confirmed using 1H NMR,13C NMR, and Mass spectroscopic analysis techniques. Further, compounds 6a–o were subjected to in vitro antimicrobial screening against various bacterial and fungal strains, such as Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Salmonella typhi, Aspergillus niger, and Candida albicans. Among these, compounds 6i, 6j, and 6 l were found most active having equally potent compared to standard drug Ampicillin and Gentamycin. Moreover, in silico studies of 6a–o with E. coli DNA gyrase through molecular docking and MD simulations showed excellent binding properties of these derivatives with protein site.