Alder Cycloaddition Research Articles

Eudesmane-guaiane sesquiterpenoid dimers from Aucklandia costus trigger paraptosis-like cell death via ROS accumulation and MAPK hyperactivation

Three novel sesquiterpenoid heterodimers, designated as auckcostusolides A–C (1–3), were isolated from Aucklandia costus leaves. The structures of compounds 1–3 were elucidated through comprehensive spectroscopic analysis, with their absolute configurations established using a combination of X-ray single-crystal diffraction and electronic circular dichroism (ECD) calculations. Notably, compounds 1 and 2, despite sharing identical planar structures derived from two identical sesquiterpenoids, exhibited opposite configurations at C-11 and C-8′. This configurational difference can be attributed to distinct Diels−Alder cycloaddition processes between the sesquiterpenoid monomers. Additionally, the cytotoxic effects of compounds 1–3 were evaluated against colorectal cancer HCT116 cells, fibrosarcoma HT1080 cells, and hepatocellular carcinoma HepG2 cells. Compounds 1–3 induced cell death was characterized by endoplasmic reticulum (ER) swelling and cytoplasmic vacuolization, typical morphological changes associated with paraptosis. Mechanistic studies revealed that compounds 1 and 3 triggered paraptosis-like cell death through the accumulation of reactive oxygen species (ROS), activation of ER stress, and stimulation of the MAPK signaling pathway.

Diels–Alder Cycloaddition of Cyclopentadiene with α-Olefins for the Synthesis of High-Performance Sustainable Aviation Fuels

Diels–Alder Cycloaddition of Cyclopentadiene with α-Olefins for the Synthesis of High-Performance Sustainable Aviation Fuels

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.

Platinum‐Catalyzed Isomerization of Cyclopropenes to 1,3‐Dienes

AbstractHerein we report a platinum‐catalyzed isomerization of cyclopropenes to 1,3‐dienes. Diverse dienylated alcohols were obtained in 42–98 % yield. The synthetic potential of the products was demonstrated by their use in Diels–Alder cycloadditions with various dienophiles. Isotope labelling studies provide strong support for a mechanism involving pericyclic [1,5]‐σ‐bond rearrangement of a vinyl platinum carbene intermediate.

Synthesis of 2‐Aminopyridine Derivatives via a Tandem CuAAC/Ring‐Cleavage/[4+2]‐Cycloaddition/Rearrangement Reaction Sequence

Abstract2H‐Azirines are an important class of small‐ring heterocycle that have been employed as versatile synthetic building blocks. Herein, a one‐pot CuAAC/ring‐cleavage/[4+2]‐cycloaddition/rearrangement reaction sequence involving terminal ynones, sulfonyl azides and 2H‐azirines is reported that leads to 2‐aminopyridine derivatives. In the first step, highly reactive N‐sulfonyl α‐acylketenimines are generated, via a CuAAC/ring‐cleavage process, from sulfonyl azides and terminal ynones and these undergo inverse electron‐demand Diels–Alder cycloaddition reactions with 2H‐azirines to form (isolable) 1,3‐oxazines that themselves undergo base‐promoted ring‐cleavage and rearrangement reactions to afford the title compounds.

Insights into Endo/Exo Stereopreference in Diels–Alder Cycloadditions of Chitin-Derived Furans

Insights into Endo/Exo Stereopreference in Diels–Alder Cycloadditions of Chitin-Derived Furans

Molecular dynamics simulation study of post‐transition state bifurcation: A case study on the ambimodal transition state of dipolar/Diels–Alder cycloaddition

AbstractThe potential energy surfaces for the reactions of 1,3‐butadiene with 2‐hydroxythioacrolein and 2‐aminoacrolein exhibit ambimodal transition states leading to both dipolar (4 + 3) and Diels–Alder (4 + 2) cycloaddition products, thereby demonstrating a post transition state bifurcation feature. We have investigated the bifurcation dynamics of these reactions using three molecular dynamics (MD) methods: quasi‐classical trajectory, classical MD, and ring‐polymer MD simulations. The trajectory calculations were performed with the semiempirical GFN2‐xTB method with the element‐specific parameters optimized to reproduce the density‐functional theory calculations. The effect of water solvation was examined using an implicit solvation model, revealing significant differences in bifurcation dynamic between gas‐phase and solution‐phase reactions. Nuclear quantum effects were found to play a crucial role in the proton‐transfer process from the (4 + 3) intermediate to the (4 + 3) product in the case of the 2‐aminoacrolein reaction.

Rosellichalasins A–H, cytotoxic cytochalasans from the endophytic fungus Rosellinia sp. Glinf021

Eight new cytochalasans rosellichalasins A–H (1–8), as well as two new shunt metabolites rosellinins A (9) and B (10) before intramolecular Diels–Alder cycloaddition reaction in cytochalasan biosynthesis, along with nine known cytochalsans (11–19) were isolated from the endophytic fungus Rosellinia sp. Glinf021, which was derived from the medicinal plant Glycyrrhiza inflata. Their structures were characterized by extensive analysis of 1D and 2D NMR as well as HRESIMS spectra and quantum chemical ECD calculations. The cytotoxic activities of these compounds were evaluated against four human cancer cell lines including HCT116, MDA-MB-231, BGC823, and PANC-1 with IC50 values ranging from 0.5 to 58.2 μM.

Artemsieverolactones A—H, Eight Guaiane‐Type Sesquiterpenoid Trimers from Artemisia sieversiana

Comprehensive SummaryEight new guaiane‐type sesquiterpenoid trimers, artemsieverolactones A—H, possessing unprecedented scaffolds via biocatalyzed [4+2] Diels−Alder cycloaddition reactions were identified from Artemisia sieversiana. Their structures were determined by comprehensive spectroscopic data, single‐crystal X‐ray diffraction analyses, and ECD calculations. In terms of structure, artemsieverolactones A—H are first examples of sesquiterpenoid trimers from guaiane‐type sesquiterpenoid through four different [4+2] Diels−Alder cycloaddition models. Antihepatic fibrosis assay suggested that five compounds exhibited activity against HSC‐LX2 with IC50 values ranging from 37.8 to 117.1 μmol/L. The most active artemsieverolactone B (2) displayed significant inhibitory activity against HSC‐LX2 with IC50 value of 37.8 μmol/L, which was 3 times more active than the positive drug silybin (IC50, 139.7 μmol/L). Preliminary mechanism study revealed that artemsieverolactone B could inhibit the deposition of human collagen type I (Col I), human hyaluronic acid (HA), and human laminin (HL) with IC50 values of 40.4 μmol/L (Col I), 55.1 μmol/L (HL), 47.3 μmol/L (HA), which was 2 to 3‐fold more potent than silybin.

Cascade hydroarylation/Diels-Alder cycloaddition of alkynylindoles with electron-deficient alkynes and alkenes.

Herein, a novel cascade gold(I)-catalyzed hydroarylation of alkynylindoles and subsequent Diels-Alder cycloaddition with electron-deficient alkynes and alkenes is described. A variety of azepino-fused hydrocarbazoles and carbazoles were obtained in moderate to excellent yields. Key features of this methodology are low catalyst loadings, high regioselectivity, broad functional group tolerances, access to important heterocycles, and 100% atom economy.

Unveiling the role of Lewis bases in cascade furan Diels–Alder cycloadditions: asymmetric synthesis of polycyclic quinazolinones

A Lewis base catalyzed asymmetric substitution/IMDAF reaction for the synthesis of polycyclic quinazolinones has been developed. The key role of the Lewis base in the IMDAF process has been unveiled.

Photo-responsive Diels–Alder based azobenzene-functionalized main-chain liquid crystal networks

This study highlights the contribution of photothermal softening to reversibly control rheological properties of the newly developed LCNs prepared using a catalyst-free Diels–Alder cycloaddition and demonstrates the ability to tune the modulus.

Modeling mechanochemistry: pressure dependence of Diels–Alder cycloaddition reaction kinetics

We analyze the effect of pressure on the Diels–Alder (D–A) dimerization reactions using Evans–Polanyi (E–P) theory, a thermodynamic analysis of the way in which a perturbation, in this case a hydrostatic pressure, modifies a reaction rate.

Penicimides A and B, two novel diels–alder [4 + 2] cycloaddition ergosteroids from Penicillium herquei

Two novel naturally occurring [4 + 2] Diels–Alder cycloaddition ergosteroids (1 and 2), three undescribed oxidized ergosteroids (3–5), and eleven known analogs (6–16) were isolated from Penicillium herquei. Compounds 1 and 2 represent the first reported cycloadducts of a steroid with 1,4,6-trimethyl-1,6-dihydropyridine-2,5-dione or 4,6-dimethyl-1,6-dihydropyridine-2,5-dione to date. Compound 3 is the C-15 epimer of (22E,24R)-9α,11β-dihydroxyergosta-4,6,8(14),22-tetraen-3-one (14). The chemical structures of these compounds were elucidated through widespread spectroscopic analyses, mainly including HRESIMS and 1D and 2D NMR data, calculated 13C NMR-DP4+ analysis, and electronic circular dichroism (ECD) data analyses. Biological evaluations of Compounds 1–16 revealed that 3, 9–11, and 15 inhibited the production of NO in LPS-induced RAW264.7 cells with an IC50 value from 7.37 ± 0.69 to 38.9 ± 2.25 μM (the positive control dexamethasone IC50: 9.54 ± 0.71 μM). In addition, Compound 3 exhibited a potent inhibitory effect on the secretion of the proinflammatory cytokines TNF-α and IL-6, the transcription level of the proinflammatory macrophage markers TNF-α, and the expression of the iNOS protein.

Neighboring Molecular Engineering in Diels–Alder Chemistry Enabling Easily Recyclable Carbon Fiber Reinforced Composites

AbstractAlthough a variety of dynamic covalent bonds have been successfully used in the development of diverse sustainable thermosetting polymers and their composites, solving the trade‐off between recovery efficiency and comprehensive properties is still a major challenge. Herein, a “one‐stone‐two‐birds” strategy of lower rotational energy barrier (Er) phosphate‐derived Diels–Alder (DA) cycloadditions was proposed for easily recyclable carbon fiber (CF)‐reinforced epoxy resins (EPs) composites. In such a strategy, the phosphate spacer with lower Er accelerated the segmental mobility and dynamic DA exchange reaction for network rearrangement to achieve high‐efficiency repairing, reprocessing of the EPs matrix and its composites and rapid nondestructive recycling of CF; meanwhile, incorporating phosphorus‐based units especially reduced their fire hazards. The resulting materials simultaneously showed excellent thermal/mechanical properties, superb fire safety and facile recyclability, realizing the concept of recycling for high‐performance thermosetting polymers and composites. This strategy is of great significance for understanding and enriching the molecular connotation of DA chemistry, making it potentially applicable to the design and development of a wide range of dynamic covalent adaptable materials toward practical cutting‐edge‐tech applications.

Biomimetic Synthesis of an Antiviral Cinnamoylphloroglucinol Collection from Cleistocalyx operculatus: A Synthetic Strategy Based on Biogenetic Building Blocks

AbstractA synthetic strategy based on biogenetic building blocks for the collective and divergent biomimetic synthesis of cleistoperlones A−F, a cinnamoylphloroglucinol collection discovered from Cleistocalyx operculatus, has been developed. These syntheses proceeded successfully in only six to seven steps starting from commercially available 1,3,5‐benzenetriol and involving oxidative activation of stable biogenetic building blocks as a crucial step. Key features of the syntheses include a unique Michael addition/ketalization/1,6‐addition/enol‐keto tautomerism cascade reaction for the construction of the dihydropyrano[3,2‐d]xanthene tetracyclic core of cleistoperlones A and B, and a rare inverse‐electron‐demand hetero‐Diels–Alder cycloaddition for the establishment of benzopyran ring in cleistoperlones D−F. Moreover, cleistoperlone A exhibited significant antiviral activity against acyclovir‐resistant strains of herpes simplex virus type 1 (HSV‐1/Blue and HSV‐1/153).

Examination of Diels–Alder/Tsuji–Trost Route towards Kopsia Alkaloids

AbstractA reaction sequence of Diels–Alder cycloaddition and Tsuji–Trost allylation was examined in terms of its application to the synthesis of kopsinine and the related Kopsia alkaloids. Results of the studies in two synthetic directions are presented herein: 1) synthesis of the properly substituted diene, required for the Diels–Alder step; and 2) model studies and optimization of the key reaction sequence in the absence of side-chain. Details on the challenging introduction of the side-chain into tetrahydrocarboline ketone and its silylation, resulting in rare but unproductive vinylogous Claisen cyclization, and the successful Mannich/Mukaiyama aldol sequence are disclosed in the first direction. In the second direction, the endo-selective Diels–Alder reaction with allyl acrylate and Tsuji–Trost allylation providing incorrect stereochemistry are disclosed. Interaction of both dienes with an alkyne provides carbazoles via Alder–Rickert reaction.

Ab initio selection of zeolite topology for biomass conversion to para-xylene based on transition state selectivity

Recent reports have pointed out a sustainable and highly selective formation route via the Diels–Alder (DA) cycloaddition between biomass-derived 2, 5-dimethylfuran (DMF) and ethene over zeolitic catalysts to produce para-xylene (p-xylene). Here, a systematic multi-scale simulation was carried out to identify candidate zeolite frameworks with potentially better catalytic activities than previously reported catalysts, through a combination of “ab initio” synthesis, thermodynamic and kinetic analysis, and adsorption/diffusion simulations. We first screened representative zeolites based on the limiting dimensions of their voids (windows, cages, channels) for reactants and products, the extent of stabilization of the key transition states by organic structure directing agents, and the synthesis difficulty informed by literature knowledge. Subsequently, the intrinsic and apparent free energy barriers of the rate-determining step (i.e., cycloaddition) obtained from density functional theory calculations were used to predict reaction kinetics of the potentially useful zeolites. Finally, three final candidates (MOR, MOZ, and IFR) and two experimentally validated zeolites (FAU and BEA) were employed to compare the adsorption and diffusion performance of DMF and p-xylene as the final criterion by grand canonical Monte Carlo and molecular dynamics simulations. In summary, MOR shows the fastest diffusion, IFR shows the lowest apparent energy barrier, and MOZ shows the lowest intrinsic energy barrier. Altogether, this study not only predicts MOR, IFR, and MOZ zeolites to have a good catalytic performance for the DA-dehydration process of DMF and ethene to p-xylene but also illustrates the potential of ab initio selection, through combined theoretical assessments of adsorption, reaction and diffusion, for the rational selection and design of optimal catalysts for targeted catalytic transformations.

Diels–Alder cycloadditions of fullerene: Advances in mechanistic theory

AbstractFullerene exhibits a wealth of interesting characteristics owing to its unique π‐electron configuration. The structure and properties of fullerene can be manipulated by introducing chemical groups to the carbon–carbon bonds via organic reactions, extending its application field. The Diels–Alder (DA) cycloaddition reaction is commonly used to decorate the carbon cage of fullerene. Furthermore, atoms, ions, clusters, and molecules can be inserted into the hollow carbon cage of a fullerene, thereby changing the electron transfer process within the fullerene cage and thus the reactivity of the as well as the regioselectivity of the DA cycloaddition reaction. Computer‐based theoretical modeling is an essential tool for studying chemistry. Herein, we provide a brief review of theoretical investigations into the cycloaddition mechanism of two most common fullerenes (C60 and C70), especially in terms of the effects of encapsulated chemical species based on the distortion–interaction model. We hope that the current mini review will provide a useful and interesting resource for researchers working on—or simply being interested in—the in silico investigation of fullerenes and their DA‐based modification.

Machine learning‐assisted study of correlation between post‐transition‐state bifurcation and initial phase information at the ambimodal transition state

AbstractThe Diels–Alder cycloaddition of cyclopentadiene and nitroethene, the intramolecular cycloaddition between a diene and triene, and the Diels–Alder cycloaddition of 2‐hydroxyacrolein with 1,3‐butadiene involving post‐transition‐state bifurcation (PTSB) were studied. These cycloaddition reactions were investigated using quasi‐classical trajectory (QCT), classical molecular dynamics (MD), ring‐polymer molecular dynamics (RPMD) simulations, and supervised machine‐learning binary classification techniques. Room‐temperature dynamics simulations started from the ambimodal transition state (TS) using the QCT, classical MD, and RPMD methods presented similar dynamics. Binary classification revealed that the initial geometry displacement from the ambimodal TS for the Diels–Alder cycloaddition of cyclopentadiene and nitroethene contributed to the branching dynamics and that the initial momenta for the intramolecular cycloaddition between a diene and triene and the Diels–Alder cycloaddition of 2‐hydroxyacrolein with 1,3‐butadiene played a significant role in the bifurcation dynamics.