Alder Reaction Research Articles

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.

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.

Novel Bicyclic P,S-Heterocycles via Stereoselective hetero-Diels–Alder Reactions of Thiochalcones with 1-Phenyl-4H-phosphinin-4-one 1-Oxide

Thiochalcones undergo cycloaddition reactions in THF solution at 60 °C with the synthetically unexplored 1-phenyl-4H-phosphinin-4-one 1-oxide in a highly regio- and stereoselective manner, yielding hitherto unknown bicyclic P,S-heterocycles containing fused thiopyran and phosphinine rings. The stereochemical structures of two of the obtained (4+2)-cycloadducts were unambiguously assigned by means of the X-ray single-crystal analysis. Based on these assignments, a concerted mechanism of the hetero-Diels–Alder reaction via the preferred endo approach of the heterodiene from the less hindered P=O side of the phosphininone molecule is postulated to explain the established rac-(4RS,8SR,9SR,10SR)-configured (4+2)-cycloadducts isolated as major products.

Asymmetric Photoenolization/Diels–Alder Reaction of 2-Methylbenzaldehydes and 2-Alkylbenzophenones with Chromones

Asymmetric Photoenolization/Diels–Alder Reaction of 2-Methylbenzaldehydes and 2-Alkylbenzophenones with Chromones

Oxidation, Halogenation and Diels–Alder Reaction Promoted by a Covalent Triazine Framework

Oxidation, Halogenation and Diels–Alder Reaction Promoted by a Covalent Triazine Framework

Correction to “Functionalization of Carbon Surfaces Using the Copper-Catalyzed Diels–Alder Reaction”

Correction to “Functionalization of Carbon Surfaces Using the Copper-Catalyzed Diels–Alder Reaction”

Next‐Generation Metabolic Glycosylation Reporters Enable Detection of Protein O−GlcNAcylation in Living Cells without S‐Glyco Modification

AbstractProtein O−GlcNAcylation is a ubiquitous posttranslational modification of cytosolic and nuclear proteins involved in numerous fundamental regulation processes. Investigation of O−GlcNAcylation by metabolic glycoengineering (MGE) has been carried out for two decades with peracetylated N‐acetylglucosamine (GlcNAc) and N‐acetylgalactosamine derivatives modified with varying reporter groups. Recently, it has been shown that these derivatives can result in non‐specific protein labeling termed S‐glyco modification. Here, we report norbornene‐modified GlcNAc derivatives with a protected phosphate at the anomeric position and their application in MGE. These derivatives overcome two limitations of previously used O−GlcNAc reporters. They do not lead to detectable S‐glyco modification, and they efficiently react in the inverse‐electron‐demand Diels–Alder (IEDDA) reaction, which can be carried out even within living cells. Using a derivative with an S‐acetyl‐2‐thioethyl‐protected phosphate, we demonstrate the protein‐specific detection of O−GlcNAcylation of several proteins and the protein‐specific imaging of O−GlcNAcylation inside living cells by Förster resonance energy transfer (FRET) visualized by confocal fluorescence lifetime imaging microscopy (FLIM).

Benign synthesis of terpene-based 1,4-p-menthane diamine

Terpenes represent a promising renewable feedstock for the substitution of fossil resources in the synthesis of renewable platform chemicals, like diamines. This work describes the synthesis and full characterization of 1,4-p-menthane diamine (1,4-PMD) obtained from α-terpinene (1). A two-step procedure using dibenzyl azodicarboxylate (DBAD) and H2 as rather benign reagents was employed under comparatively mild conditions. Both C–N bonds were formed simultaneously during a visible-light mediated Diels–Alder reaction, which was investigated in batch or flow, avoiding regioselectivity issues during the amination steps that are otherwise typical for terpene chemistry. Heterogeneously catalyzed quadruple hydrogenation of the cycloadduct (2a) yielded 1,4‑PMD (3). While the intermediate cycloadduct was shown to be distillable, the target diamine can be sublimed, offering sustainable purification methods.

Endergonic synthesis driven by chemical fuelling

AbstractSpontaneous chemical reactions proceed energetically downhill to either a local or global minimum, limiting possible transformations to those that are exergonic. Endergonic reactions do not proceed spontaneously and require an input of energy. Light has been used to drive a number of deracemizations and thermodynamically unfavourable bond-forming reactions, but is restricted to substrates that can absorb, directly or indirectly, energy provided by photons. In contrast, anabolism involves energetically uphill transformations powered by chemical fuels. Here we report on the transduction of energy from an artificial chemical fuel to drive a thermodynamically unfavourable Diels–Alder reaction. Carboxylic acid catalysed carbodiimide-to-urea formation is chemically orthogonal to the reaction of the diene and dienophile, but transiently brings the functional groups into close proximity, causing the otherwise prohibited cycloaddition to proceed in modest yield (15% after two fuelling cycles) and with high levels of regio- (>99%) and stereoselectivity (92:8 exo:endo). Kinetic asymmetry in the fuelling cycle ratchets the Diels–Alder reaction away from the equilibrium distribution of the Diels–Alder:retro-Diels–Alder products. The driving of the endergonic reaction occurs through a ratchet mechanism (an energy or information ratchet, depending on the synthetic protocol), reminiscent of how molecular machines directionally bias motion. Ratcheting synthesis has the potential to expand the synthetic chemistry toolbox in terms of reactivity, complexity and control.

Total Synthesis and Stereochemical Assignment of Talaroconvolutin A and Talarofuranone: Gram‐scale Synthesis of Ferroptosis Inducer Talaroconvolutin A

Comprehensive SummaryThe first total synthesis of talaroconvolutin A (1.1 g obtained) and talarofuranone has been achieved using accessible materials (12 steps, 7.5% and 8.2% yields, respectively). Convergent routes involved intramolecular Diels−Alder reactions in two approaches for creating the decalin moiety. Additionally, an unprecedented DMP‐mediated domino reaction resulted in the deoxy‐tetramic acid system. These syntheses not only establish the absolute configuration of talaroconvolutin A but also enable further collaborative studies of this type of ferroptosis inducers.

Asymmetric Diels–Alder reaction of chalcone and isoprene mediated by titanium-based complexes

The asymmetric Diels–Alder reaction of chalcone and isoprene has been accomplished by use of chiral titanium complexes. Notably, an enantiomeric excess as high as 61% and a regioselectivity of 95% have been achieved. The preparation of the chiral titanium complexes is simple and does not require the pre-installation of a chiral auxiliary. This study represents the first example of asymmetric Diels–Alder reaction between chalcone and isoprene.

Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET

BackgroundThe brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood–brain barrier (BBB). To overcome this physiological obstacle, we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. While these radiolabelled ligands have high affinity and specificity, their long residence time in the blood and brain, typical for large molecules, poses another challenge for PET imaging. A viable solution could be a two-step pre-targeting approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a small radiolabelled molecule with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved by using the inverse electron demand Diels–Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants. In this study, two novel 18F-labelled tetrazines were synthesized and evaluated for their potential use as pre-targeting imaging agents, i.e., for their ability to rapidly enter the brain and, if unbound, to be efficiently cleared with minimal background retention.ResultsThe two compounds, a methyl tetrazine [18F]MeTz and an H-tetrazine [18F]HTz were radiolabelled using a two-step procedure via [18F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of > 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans showed [18F]MeTz to be the more pharmacokinetically suitable agent, given its fast and homogenous distribution in the brain and rapid clearance. However, in terms of rection kinetics, H-tetrazines are advantageous, exhibiting faster reaction rates in IEDDA reactions with dienophiles like trans-cyclooctenes, making [18F]HTz potentially more beneficial for pre-targeting applications.ConclusionThis study demonstrates a significant potential of [18F]MeTz and [18F]HTz as agents for pre-targeted PET brain imaging due to their efficient brain uptake, swift clearance and appropriate chemical stability.

A molecular electron density theory study of hydrogen bond catalysed polar Diels–Alder reactions of α,β-unsaturated carbonyl compounds

The hydrogen bond (HB) catalysed Diels-Alder (DA) reactions of acrolein with cyclopentadiene have been investigated within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) computational level. The formation of HBs increases the electrophilicity of these species, suggesting an acceleration of these polar Diels-Alder (P-DA) reactions with forward electron density flux. Formation of one or two HBs with acrolein decreases the activation energies of the HB-catalysed P-DA reactions by 1.7 (methanol) and 4.0 (squaramide) kcal·mol−1, with the corresponding DA reactions exhibiting low endo stereoselectivity. These HB-catalysed DA reactions proceed through non-concerted one-step mechanisms via asynchronous transition state structures (TSs). An Interacting Quantum Atoms (IQA) energy partitioning analysis of the TSs indicates that the intra-atomic stabilization of the acrolein framework, coupled with the increase of the global electron density transfer, plays a crucial role in reducing the activation energies of these HB-catalysed DA reactions.

Comparative analysis of bio-based amino acid surfactants obtained via Diels–Alder reaction of cyclic anhydrides

Abstract Current changes in environmental legislation and customer demands set an urge for the development of more sustainable surfactants. Thus, the objective of this work was the development of novel environmentally friendly amino acid surfactants. Combining Diels–Alder cyclization of myrcene with maleic or citraconic anhydride followed by ring opening with amino acids enabled a synthesis route with a principal 100% atom economy. Variation of amino acids resulted in a large structural variety of anionic and amphoteric surfactants. Lysine gave access to either a mono-acylated product bearing a cationic side chain or a bi-acylated gemini surfactant. First, anhydride precursors were synthesized in yields of >90% in a Diels–Alder reaction under microwave radiation and subsequent amino acid coupling in aqueous environment gave fully bio-based surfactants in good yields and purity. Physicochemical characterization showed an enhanced decrease in surface tension upon addition of amino acids to the myrcene–anhydride backbone, resulting in a minimal value of 31 mN·m−1 for gemini–lysine. Foamabilitiy and foam stability were significantly increased at skin-friendly pH 5.5 by incorporation of amino acids. The carboxylic groups of surfactants with arginine were esterified with ethanol to access cationic compounds. Comparative analysis revealed moderate antimicrobial effects against yeast, Gram-positive bacteria, and Gram-negative bacteria.

Kinetic Study of the Diels-Alder Reaction between Maleimide and Furan-Containing Polystyrene Using Infrared Spectroscopy.

The Diels-Alder (D-A) reaction between furan and maleimide is a thermally reversible reaction that has become a vital chemical technique for designing polymer structures and functions. The kinetics of this reaction, particularly in polymer bulk states, have significant practical implications. In this study, we investigated the feasibility of utilizing infrared spectroscopy to measure the D-A reaction kinetics in bulk-state polymer. Specifically, we synthesized furan-functionalized polystyrene and added a maleimide small-molecule compound to form a D-A adduct. The intensity of the characteristic absorption peak of the D-A adduct was quantitatively measured by infrared spectroscopy, and the dependence of conversion of the D-A reaction on time was obtained at different temperatures. Subsequently, the D-A reaction apparent kinetic coefficient kapp and the Arrhenius activation energy Ea,D-A were calculated. These results were compared with those determined from 1H-NMR in the polymer solution states.

Organocatalytic Highly Selective Nitroso-Diels–Alder Reaction of Conjugated Trienes

Organocatalytic Highly Selective Nitroso-Diels–Alder Reaction of Conjugated Trienes

Sultines as o-Quinodimethane Precursors in an Oxa-Diels–Alder Reaction: Synthesis of Functionalized Isochromans

The development of an oxa-Diels–Alder reaction between sultines and carbonyl compounds is reported. o-Quinodimethanes, generated from sultines, undergo a [4+2]-cycloaddition with activated aldehydes and ketones in the presence of Cu(OTf)2 to provide a variety of functionalized isochromans, including spiroisochromans, in up to 99% yield. The developed protocol demonstrates broad functional group compatibility, also tolerating unprotected isatins bearing free NH-functionalities.

Visible-light-mediated Diels–Alder reactions under single-chain polymer confinement: investigating the role of the crosslinking moiety on catalyst activity

Single-chain polymer nanoparticle photoredox catalysts are designed wherein spatial proximity enables the crosslinking acene to act as a redox mediator, thus achieving up to 30-fold enhancement of catalyst activity in the model Diels–Alder reaction.

Cascade In Situ Self‐Assembly and Bioorthogonal Reaction Enable the Enrichment of Photosensitizers and Carbonic Anhydrase Inhibitors for Pretargeted Cancer Theranostics

AbstractWe report here a tumor‐pretargted theranostic approach for multimodality imaging‐guided synergistic cancer PDT by cascade alkaline phosphatase (ALP)‐mediated in situ self‐assembly and bioorthogonal inverse electron demand Diels–Alder (IEDDA) reaction. Using the enzymatic catalysis of ALP that continuously catalyses the dephosphorylation and self‐assembly of trans‐cyclooctene (TCO)‐bearing P‐FFGd‐TCO, a high density of fluorescent and magnetic TCO‐containing nanoparticles (FMNPs‐TCO) can be synthesized and retained on the membrane of tumor cells. They can act as ‘artificial antigens’ amenable to concurrently capture lately administrated tetrazine (Tz)‐decorated PS (775NP‐Tz) and carbonic anhydrase (CA) inhibitor (SA‐Tz) via the fast IEDDA reaction. This two‐step pretargeting process can further induce FMNPs‐TCO regrowth into microparticles (FMNPs‐775/SA) directly on tumor cell membranes, which is analyzed by bio‐SEM and fluorescence imaging. Thus, efficient enrichment of both SA‐Tz and 775NP‐Tz in tumors can be achieved, allowing to alleviate hypoxia by continuously inhibiting CA activity and improving PDT of tumors. Findings show that subcutaneous HeLa tumors could be completely eradicated and no tumor recurred after irradiation with an 808 nm laser (0.33 W cm−2, 10 min). This pretargeted approach may be applied to enrich other therapeutic agents in tumors to improve targeted therapy.

Synthesis of Densely Substituted Pyridines through 1,2‐Oxazine‐6‐ones Inverse Electron Demand Diels–Alder Reaction

AbstractDensely substituted pyridines are synthesized from available 1,2‐oxazin‐6‐ones and enamines through tandem hetero‐Diels–Alder and retro‐Diels–Alder reaction in 45–98 % yield.