oxa-Diels-Alder Reaction Research Articles

A Synthetic Route Towards Spiro Indanone Fused Pyrano[2,3‐c]Chromene Derivatives via Oxa–Diels–Alder Reaction: Computational Investigation, Antibacterial Evaluation and Molecular Docking Studies as Potential DNA Gyrase Inhibitors

ABSTRACTA highly efficient method for the synthesis of 2′H‐spiro[indene‐2,3′‐pyrano[2,3‐c]chromene] derivatives 20(a–s) has been developed involving oxa–Diels–Alder reaction as the key step under conventional conditions in good to excellent yields. The compounds were all characterized using 1H, 13C NMR, HRMS, and X‐ray crystallography. The present study employs DFT to validate the reaction pathway. In vitro antibacterial assay of all the synthesized derivatives was evaluated against Gram‐negative Escherichia coli and Gram‐positive Staphylococcus aureus bacterial strains. Compound 20e was found to be the most potent molecule with ZI of 19 mm and MIC of 16 μg mL−1 in E. coli and ZI of 14 mm and MIC of 32 μg mL−1 in S. aureus. Additionally, 20e demonstrated a strong inhibition of DNA gyrase in silico, with a binding affinity of −9.3 and − 9.0 kcal/mol in E. coli and S. aureus respectively. Also, significant pharmacokinetic, physicochemical, and drug‐like properties of the spirocyclic compounds were further corroborated by ADME investigations. Hence, these new series of spiro indanone fused pyrano[2,3‐c]chromene derivatives may be potent druggable antibacterial agents in future.

Chiral Phosphate-Catalyzed Enantiodivergent Oxa-Diels–Alder Reaction of Trifluoropyruvate and Simple Dienes

Chiral Phosphate-Catalyzed Enantiodivergent Oxa-Diels–Alder Reaction of Trifluoropyruvate and Simple Dienes

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

AbstractThe 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 or 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 and tolerates unprotected isatins bearing free NH-functionalities.

Catalytic asymmetric oxa-Diels–Alder reaction of acroleins with simple alkenes

The catalytic asymmetric inverse-electron-demand oxa-Diels–Alder (IODA) reaction is a highly effective synthetic method for creating enantioenriched six-membered oxygen-containing heterocycles. Despite significant effort in this area, simple α,β-unsaturated aldehydes/ketones and nonpolarized alkenes are seldom utilized as substrates due to their low reactivity and difficulties in achieving enantiocontrol. This report describes an intermolecular asymmetric IODA reaction between α-bromoacroleins and neutral alkenes that is catalyzed by oxazaborolidinium cation 1f. The resulting dihydropyrans are produced in high yields and excellent enantioselectivities over a broad range of substrates. The use of acrolein in the IODA reaction produces 3,4-dihydropyran with an unoccupied C6 position in the ring structure. This unique feature is utilized in the efficient synthesis of (+)-Centrolobine, demonstrating the practical synthetic utility of this reaction. Additionally, the study found that 2,6-trans-tetrahydropyran can undergo efficient epimerization into 2,6-cis-tetrahydropyran under Lewis acidic conditions. This structural core is widespread in natural products.

Cascade of the acylation/intramolecular oxo-Diels–Alder reaction for the diastereoselective synthesis of thienyl substituted hexahydropyrano[3,4-c]pyrrole-1,6-diones

We have developed an efficient approach toward the synthesis of functionalized hexahydropyrano[3,4-c]pyrrole-1,6-diones from readily accessible 3-thienylsubstituted allylamines and maleic anhydride. This transformation begins with the N-acylation of the allylamines with the anhydride, followed by the intramolecular oxo-Diels–Alder reaction (IMODA), which is accompanied by the tautomerization step, and ends with the formation of saturated pyrano[3,4-c]pyrroles.

Synthesis of azepane-fused pyrano[3,2-b]indoles by Lewis acid-catalysed oxa Diels-Alder reactions.

The dihydroazepino[1,2-a]indole diones 3 are tricyclic oxindole-type enones which are readily accessible by catalytic photooxygenation of cyclohepta[b]indoles 1 followed by dehydration. Lewis acid-catalysed oxa Diels-Alder reactions of enones 3 with enol ethers 4 were developed that lead to novel tetracyclic azepane-fused pyrano[3,2-b]indoles 5, with high stereoselectivity and under mild reaction conditions.

Cooperativity in Diiron(III)porphyrin Dication Diradical-Catalyzed Oxa-Diels–Alder Reactions: Spectroscopic and Mechanistic Insights

Cooperativity in Diiron(III)porphyrin Dication Diradical-Catalyzed Oxa-Diels–Alder Reactions: Spectroscopic and Mechanistic Insights

Palladium-catalysed diastereodivergent inverse-electron-demand oxa-Diels–Alder reactions of in situ formed cyclopentadienones via ligand-control

Pd(0)-Catalysed asymmetric inverse-electron-demand oxa-Diels–Alder reactions between the carbonates of 4-hydroxy-2-cyclopentenones and several kinds of α,β-unsaturated carbonyls are reported.

Organocatalytic inverse-electron-demand Diels-Alder reaction between 5-alkenyl thiazolones and β,γ-unsaturated carbonyl compounds.

An inverse-electron-demand oxa-Diels-Alder reaction of 5-alkenyl thiazolones with β,γ-unsaturated carbonyl compounds enabled by quinine thiourea was studied, which allows the enantioselective synthesis of a broad range of highly functionalized pyranthiazoles bearing three continuous stereocenters. This protocol is adaptable to a wide scope of substrates and has great potential for scale-up synthesis and facile transformation.

BF3-catalyzed oxa-Diels–Alder reaction of ethyl vinyl sulfide and β-methyl-α-phenylacrolein: a molecular electron density theory study

BF3-catalyzed oxa-Diels–Alder reaction of ethyl vinyl sulfide and β-methyl-α-phenylacrolein: a molecular electron density theory study

Multiple Activation Catalyst for Asymmetric [4+2] Cycloaddition of Aldehydes with Dienes

AbstractThe enantioselective oxa-Diels–Alder reaction of nonactivated substrates by utilizing FeCl3 and a 1,1′-bi-2-naphthol (BINOL) derived chiral phosphoric acid as a multiple activation catalyst is reported. Various oxygen-containing six-membered heterocycles were obtained in high yields and in an enantioselective manner. Density functional theory (DFT) calculations elucidate that both Lewis acidic and Brønsted acidic moieties in the catalyst system synergistically activate two lone pairs of an aldehyde to facilitate enantioselective addition reaction of dienes.

Organocatalyzed Oxa-Diels–Alder Reactions: Recent Progress

AbstractThe oxa-Diels–Alder reaction is a straightforward, atom-economical process for the construction of six-membered oxacycles, which are privileged structures due to their very common occurrence in several pharmaceuticals and natural products. As with many other asymmetric transformations, organocatalysis provides an elegant pathway to their synthesis via [4+2] annulation under mild reaction conditions. The oxa-Diels–Alder reaction utilizes either an α,β-unsaturated carbonyl as an oxa-diene with a suitable dienophile or a simple carbonyl as a dienophile with other dienes. A range of organocatalysts has been explored in the past decade to execute this strategy. The catalysts induce stereoselectivities via two basic reactivities: (1) The formation of chiral intermediates, or (2) selectively activating suitable reactants via a transition state. The present short review compiles organocatalyzed asymmetric oxa-Diels–Alder reactions published over the last ten years, along with detailed discussions on mechanistic approaches.1 Introduction2 Catalysis through Covalent Activation2.1 N-Heterocyclic Carbenes2.2 Amines2.3 Isothiourea Catalysis2.4 Phosphines3 Catalysis through Non-Covalent Activation3.1 Bifunctional Amines3.2 Brønsted Acids3.3 Guanidines4 Multicatalysis through Both Covalent and Non-Covalent Activation5 Conclusion

Isocyanide-based MCRs: Diastereoselective cascade synthesis of perfluoroalkylated pyrano[3,4-c]pyrrole derivatives

The highly diastereoselective synthesis of perfluoroalkyl-containing pyrano[3,4-c]pyrroles has been accomplished via a cascade process involving Michael addition, Passerini-type reaction, Mumm rearrangement and an oxo-Diels–Alder reaction. This domino transformation of isocyanides, methyl perfluoroalk-2-ynoates and 3-aroyl (or heteroyl) acrylic acids proceeded smoothly at room temperature and led to the formation of the highly diastereoselective target compounds with high functional-group compatibility in good to excellent yields.

The catalytic effects of a thiazolium salt in the oxa-Diels-Alder reaction between benzaldehyde and Danishefsky's diene: a molecular electron density theory study.

The oxa-Diels-Alder (ODA) reaction of benzaldehyde with Danishefsky's diene in the presence of a [thiazolium][Cl] salt, as a model of an ionic liquid, has been studied within Molecular Electron Density Theory (MEDT) at the M06-2X/6-311G(d,p) computational level. The formation of two hydrogen bonds (HBs) between the thiazolium cation and the carbonyl oxygen of benzaldehyde modifies neither the electrophilic character of benzaldehyde nor its electronic structure substantially but accelerates the reaction considerably. This ODA reaction presents an activation energy of 4.5 kcal mol-1; the formation of the only observed dihydropyranone is strongly exothermic by -28.8 kcal mol-1. The presence of the [thiazolium][Cl] salt decreases the Gibbs free energy of activation of the ODA reaction between benzaldehyde and Danishefsky's diene by 5.9 kcal mol-1. This ODA reaction presents total para regioselectivity and high endo stereoselectivity. This ODA reaction takes place through a highly asynchronous polar transition state structure (TS) associated with a non-concerted two-stage one-step mechanism. ELF analysis of para/endo TSs associated with the ODA reactions in the absence and presence of the [thiazolium][Cl] salt shows that the formation of the HBs at the TSs does not modify their electronic structure substantially. This MEDT study makes it possible to conclude that the acceleration found in the ODA reaction of benzaldehyde with Danishefsky's diene in ILs is a consequence of an increase of the global electron density transfer at TS3-pn, resulting from HB formation, and the greater strength of the HBs at the polar TS3-pn compared to that at the benzaldehyde : [thiazolium][Cl] complex, and that the strength in the HB formed is more relevant that than an increase of the electrophilic character of the interaction between reagent.

A silver-catalyzed domino inverse electron-demand oxo-Diels-Alder reaction of 3-cyclopropylideneprop-2-en-1-ones with 2,3-dioxopyrrolidines via cyclobutane-fused furan.

A silver-catalyzed diastereoselective one-pot domino cyclization-migration/inverse electron-demand oxo-Diels-Alder reaction has been disclosed in this communication through the in situ generated cyclobutane-fused furan intermediate with 4-vinyl-2,3-dioxopyrrolidine for the construction of 2-oxopyrrolidine-fused tricyclic compounds in moderate to good yields with a broad substrate scope under mild conditions. This new synthetic protocol features good efficiency and atom- and step-economy. A plausible reaction mechanism has also been proposed on the basis of previous reports, NMR tracing and control experiments.

Switching Electrophile Intermediates to Nucleophiles: Michael and Oxa-Diels-Alder Reactions to Afford Polyoxy-Functionalized Piperidine Derivatives with Tetrasubstituted Carbon.

Michael, Michael-annulation, and oxa-Diels-Alder reactions of carbohydrate derivatives that afford polyoxy-functionalized piperidine derivatives bearing tetrasubstituted carbon at the 3-position of the piperidine ring are reported. Iminium ions generated from carbohydrate derivatives with amines were converted to enamines in situ, which acted as nucleophiles. As a result, substituents were introduced at the 3-position or both 2- and 3-positions of the piperidines bearing polyoxy groups. This strategy will be useful in drug discovery efforts.

Modular Chiral Bisoxalamide–Copper-Catalyzed Asymmetric Oxo-Diels–Alder Reaction: Carbonyl Coordination for High Enantio- and Diastereocontrols

The chiral bis-oxalamides (CBOA), readily derived from optically pure 1,2-diphenylethylenediamine (DPEN), were proven to be a class of efficient C2-symmetric chiral ligands for copper(II)-catalyzed...

Inverse-Electron-Demand oxa-Diels-Alder Reactions of α-Keto-β,γ-unsaturated Esters and α,β-Unsaturated Hydrazones.

A concise synthetic method for dihydropyrans has been developed by inverse-electron-demand oxa-Diels-Alder reaction of α-keto-β,γ-unsaturated esters with α,β-unsaturated hydrazones as electron-rich olefins. This reaction is catalyzed by Eu(hfc)3 and proceeds in an endo-selective manner. This umpolung cycloaddition affords a variety of substituted dihydropyrans stereoselectively in high yields. In addition, indirect synthesis of formyl-substituted dihydropyran was achieved by dehydrazonation of the cycloadduct. This method is expected to be useful for the synthesis of dihydropyrans and tetrahydropyrans with unusual substitution patterns.

Catalytic asymmetric oxo-Diels–Alder reactions with chiral atropisomeric biphenyl diols

New chiral atropisomeric biphenyl diols 3, 4 and 6 containing additional peripheral chiral centers with different steric bulkiness and/or electronic properties were synthesized. The X-ray crystal structure of 3 shows the formation of a supramolecular structure whereas that of 6, containing additional CF3 substituents, shows the formation of a monomeric structure. Diols 1–6 were found to be active organocatalysts in oxo-Diels–Alder reactions in which 2 recorded a 72% ee with trimethylacetaldehyde as a substrate.

Remote Asymmetric Oxa-Diels-Alder Reaction of 5-Allylic Furfurals via Dearomatizative Tetraenamine Catalysis.

A previously unreported activation mode is developed through the generation of dearomatizative tetraenamine species between 5-allylic furfurals and a bifunctional amine-thiourea catalyst. The very remote ζ,η-alkenes perform as effective HOMO-raised dienophiles in inverse-electron-demand oxa-Diels-Alder cycloadditions with isatin-derived oxadiene substrates, delivering multifunctional spirocyclic oxindoles incorporating a dihydropyran skeleton in moderate to high yields with good to excellent enantio- and diastereoselectivity.