Cyclic Enones Research Articles

Ring Expansion via One-Pot Conversion of Lactone Acetals to Cyclic Enones. Synthesis of (±)-1-epi-Xerantholide.

Baeyer-Villiger oxidation of α-alkoxy ketones 1 provides lactone acetals 2, which react with the lithium salts of dimethyl(alkyl) phosphonates in the presence of LaCl3·2LiCl to provide cyclic enones 3 in good to excellent yields after treatment with dilute aqueous potassium carbonate. Thus, five-, six-, and seven-membered lactones are converted to five-, six-, and seven-membered cyclic enones. The utility of this two-step ring expansion method is demonstrated in the synthesis of (±)-1-epi-xerantholide from 5-methyl-2-cyclohexen-1-one.

H2-driven biocatalysis for flavin-dependent ene-reduction in a continuous closed-loop flow system utilizing H2 from water electrolysis

Despite the increasing demand for efficient and sustainable chemical processes, the development of scalable systems using biocatalysis for fine chemical production remains a significant challenge. We have developed a scalable flow system using immobilized enzymes to facilitate flavin-dependent biocatalysis, targeting as a proof-of-concept asymmetric alkene reduction. The system integrates a flavin-dependent Old Yellow Enzyme (OYE) and a soluble hydrogenase to enable H2-driven regeneration of the OYE cofactor FMNH2. Molecular hydrogen was produced by water electrolysis using a proton exchange membrane (PEM) electrolyzer and introduced into the flow system via a designed gas membrane addition module at a high diffusion rate. The flow system shows remarkable stability and reusability, consistently achieving >99% conversion of ketoisophorone to levodione. It also demonstrates versatility and selectivity in reducing various cyclic enones and can be extended to further flavin-based biocatalytic approaches and gas-dependent reactions. This electro-driven continuous flow system, therefore, has significant potential for advancing sustainable processes in fine chemical synthesis.

Asymmetric Organocatalytic 1,3-Dipolar Cycloaddition of Azomethine Ylides with β-Substituted Cyclic Enones.

The enantioselective and diastereoselective control of 1,3-dipolar cycloaddition reactions to β-substituted cyclic enones has been developed. The 1,3-dipolar cycloaddition of phthalazinium dicyanomethanides with cyclic dienones affords chiral tetrahydropyrrolo[2,1-a]phthalazine derivatives 3 through vinylogous iminium ion activation by combining a cinchona-based primary amine C3 and a chiral camphorsulfonic acid additive. Conversely, with a weaker 3,5-bis(trifluoromethyl)benzoic acid additive, the 1,3-dipolar cycloaddition of phthalazinium dicyanomethanides with β-substituted cyclic enones leads to chiral hexahydroisoindolo[1,2-a]phthalazin-10(8H)-one derivatives 4 with excellent stereocontrol via endo-dienamine activation.

Pd(II)/N,N'-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Synthesis of Cyclic Quaternary Centers and Mechanistic Investigations.

A Pd(II)/N,N'-disulfonyl bisimidazoline-catalyzed asymmetric 1,4-conjugate addition reaction of low-cost arylboronic acids with readily available β-substituted cyclic enones is described, providing a straightforward way of constructing cyclic all-carbon quaternary stereocenters with high enantioselectivity, in which ≥96% ee was obtained in most cases. The reaction proceeded without the protection of inert gas, making the operation process simple. Theoretical calculations have been applied to understand the origins of enantioselectivity.

Understanding and Controlling the Mizoroki–Heck Reaction of Cyclic Enones

Understanding and Controlling the Mizoroki–Heck Reaction of Cyclic Enones

Photoredox-Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols.

Dearomative photocycloaddition of monocyclic arenes is an appealing strategy for comprehending the concept of "escape from flatland". This brings the replacement of readily available planar aromatic hydrocarbon units with a 3D fused bicyclic core with sp3-enriched carbon units. Herein, we outline an intermolecular approach for the dearomative photocycloaddition of phenols. In order to circumvent the ground-state aromaticity and to construct conformationally restrained building blocks, bicyclo[1.1.0]butanes were chosen as coupling partners. This dearomative approach renders straightforward access to a bicyclo[2.1.1]hexane unit fused to a cyclic enone moiety, which further contributed as a synthetic linchpin for postmodifications. Mechanistic experiment advocates for a plausible onset from both the reactants, depending on the redox potential.

Structural and functional characterization of a new thermophilic-like OYE from Aspergillus flavus

Old yellow enzymes (OYEs) have been proven as powerful biocatalysts for the asymmetric reduction of activated alkenes. Fungi appear to be valuable sources of OYEs, but most of the fungal OYEs are unexplored. To expand the OYEs toolbox, a new thermophilic-like OYE (AfOYE1) was identified from Aspergillus flavus strain NRRL3357. The thermal stability analysis showed that the T1/2 of AfOYE1 was 60 °C, and it had the optimal temperature at 45 °C. Moreover, AfOYE1 exhibited high reduction activity in a wide pH range (pH 5.5–8.0). AfOYE1 could accept cyclic enones, acrylamide, nitroalkenes, and α, β-unsaturated aldehydes as substrates and had excellent enantioselectivity toward prochiral alkenes (> 99% ee). Interestingly, an unexpected (S)-stereoselectivity bioreduction toward 2-methylcyclohexenone was observed. The further crystal structure of AfOYE1 revealed that the “cap” region from Ala132 to Thr182, the loop of Ser316 to Gly325, α short helix of Arg371 to Gln375, and the C-terminal “finger” structure endow the catalytic cavity of AfOYE1 quite deep and narrow, and flavin mononucleotide (FMN) heavily buried at the bottom of the active site tunnel. Furthermore, the catalytic mechanism of AfOYE1 was also investigated, and the results confirmed that the residues His211, His214, and Tyr216 compose its catalytic triad. This newly identified thermophilic-like OYE would thus be valuable for asymmetric alkene hydrogenation in industrial processes.Key pointsA new thermophilic-like OYE AfOYE1 was identified from Aspergillus flavus, and the T1/2of AfOYE1 was 60 °CAfOYE1 catalyzed the reduction of 2-methylcyclohexenone with (S)-stereoselectivityThe crystal structure of AfOYE1 was revealedv

Diastereodivergent α-Homoallylation of Cyclic Enones.

α,β-Unsaturated carbonyls are essential structural motifs for nucleophiles of disease-related proteins. Methods for stereoselective functionalizations at the α-position include the Morita-Baylis-Hillman, Negishi, Sonogashira, Stille, and Rauhut-Currier reactions. Described here is a method for the diastereodivergent α-homoallylation of cyclic enones via a sequence of conjugate addition, aldol condensation, and diastereoselective [3,3]-sigmatropic rearrangement. Mechanistic investigations revealed that the [3,3]-sigmatropic rearrangement proceeds with transfer of chirality. These inspire a photocatalyzed olefin isomerization of the aldol condensation product leading to a highly diastereoselective [3,3]-sigmatropic rearrangement to furnish the α-homoallylation of cyclic enones. Importantly, this photocatalyzed olefin isomerization/diastereoselective [3,3]-sigmatropic rearrangement reaction sequence permits a full stereocontrol of the exo-β-position featuring an allyl group as a synthetic functional handle.

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines.

The study presents a novel approach utilizing iminium salt activation and mild enolization of thioesters, offering an efficient and rapid synthesis of Michael adducts with promising stereoselectivity and marking a significant advancement in mechanocatalysis. The stereoselective addition of bisthiomalonates 1-4 to cyclic enones and 4-chlorobenzylideneacetone proceeds stereoselectively under iminium activation conditions secured by chiral primary amines, in contrast to oxo-esters as observed in dibenzyl malonate addition. Mild enolization of thioesters allows for the generation of Michael adducts with good yields and stereoselectivities. Reactions in a ball mill afford product formation with similar efficacy to solution-phase reactions but with slightly reduced enantioselectivity, yet they yield products in just one hour compared to 24 or even 168 hours in solution-based reactions. It is noteworthy that this represents one of the early reports on the application of iminium catalysis using first-generation chiral amines under mechanochemical conditions, along with the utilization of easily enolizable thioesters as nucleophiles in this transformation.

Visible-Light-Induced Three-Component Radical Coupling of Selenocarbamates, Enones, and Allylstannanes with Diphenyl (2,4,6-trimethylbenzoyl)phosphine Oxide

AbstractA blue LED-induced three-component coupling of a carbamoyl radical, cyclic enone, and allylstannane was developed. The use of blue LEDs and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO) as a radical initiator permitted the three-component radical coupling to proceed with a high chemoselectivity. An elucidation of the mechanism revealed a pathway for the formation of a tributyltin radical from TPO and allylstannane. This tandem radical reaction is expected to be applicable in natural-product synthesis.

Photoinduced 1,3‐Dipolar Cycloadditions of Cyclic Enones and 2,5‐Disubstituted Tetrazoles: An Unprecedented Pathway to Polysubstituted Pyrazolines and Pyrazoles

AbstractWe report herein the syntheses of original pyrazolines and pyrazoles through 1,3‐dipolar cycloaddition of cyclic enones with 2,5‐disubstituted nitrile imines achieved via photochemical activation of 2,5‐diaryl substituted tetrazoles. Monitoring of the reactions, similar to nitrile imine‐mediated tetrazole‐ene cycloadditions (NITEC), could be performed by means of UV‐vis absorption and emission measurements. The presence or absence of substituents in the alpha position of the ketone function makes it possible to direct these reactions towards the selective formation of pyrazoles or pyrazolines. The choice of the cyclic enones and 2,5‐disubstituted tetrazoles proved crucial for the fluorescence properties of the polycyclic derivatives obtained.

Acetic acid mediated Michael-addition/cyclization cascade sequence of cyclic diones and enones; A convenient, proficient, and eco-friendly access to the fused dihydropyrans

An acetic acid-mediated Michael addition-cyclization cascade sequence of cyclic diones and enones is developed to afford fused dihydropyrans. A broad range of structurally diverse aliphatic, aromatic, and functionalized enones are successfully employed under the optimized reaction conditions. The current strategy takes advantage of using easily accessible and environmentally benign conditions to access the synthetically challenging 3,4-dihydropyran in high yields (up to 90%) and selectivity (up to 20:1). The applicability of these reaction conditions is underscored by successfully isolating the desired dihydropyrans from the Michael adduct, for the first time. Moreover, Density Functional Theory (DFT) provided a comprehensive analysis involving Frontier Molecular Orbital (FMO), Mulliken population, and Molecular Electrostatic Potential (MEP) investigations to gain deeper insights into the underlying reaction sequence.

ω-(3-Trifluoromethylpyrazol-4-yl)alkanoic acids via (3 + 2)-cycloaddition of nitrile imines with cyclic enones and deacylative aromatization

A series of ω-substituted alkanoic acids functionalized with 1-aryl-3-trifluoromethylpyrazol-4-yl group was synthesized via two-step protocol using in situ generated CF3-nitrile imines and cyclic enones as key building blocks. The first 1,3-dipolar cycloaddition step proceeded in a fully selective manner either in solutions or under solvent-free mechanochemical activation. Treatment of the first formed cycloadducts derived from 2-cyclopentenone or 2-cyclohexenone with DDQ afforded corresponding bicyclic pyrazoles formed via dehydrogenative oxidation pathway, whereas MnO2-mediated deacylative aromatization led to desired propionic or butyric acid derivatives, respectively. In contrast, oxidation of model 2-cycloheptenone-derived (3 + 2)-cycloadduct yielded bicyclic analogue irrespectively to the applied conditions.

Synthesis of 4H‐Indazol‐4‐ones and Fused Pyrazoles via Copper‐Catalyzed Annulation of Hydrazones with Cyclic Enones

AbstractHerein, we report the synthesis of cyclic ketone‐fused pyrazoles via [3+2] annulation reaction between hydrazones and cyclic enones (five‐, six‐ and seven‐membered) catalyzed by Cu(II) under aerobic conditions. These compounds were further functionalized by reactions such as Suzuki‐Miyaura cross‐coupling, Heck coupling, and Aldol reaction to afford diverse molecular scaffolds in good yield, selectivity and functional group tolerance.

Selective Vinylogous Aldol Reactions of β‐Methyl‐Substituted Cyclic Enones with Isatins Catalyzed by DBU and Pyrrolidine to Afford 3‐Substituted 3‐Hydroxyoxindoles

AbstractThe development of regioselective aldol reactions of β‐methyl‐substituted cyclic enone derivatives with isatins to afford the aldol products with the bond formation at the methyl group of the β‐methyl‐substituted cyclic enone derivatives is described. Catalyst systems composed of DBU and pyrrolidine with DMSO were identified that resulted in the aldol reactions with almost perfect regioselectivities. DBU, pyrrolidine, and DMSO were all required to selectively afford the γ‐position‐reacted aldol products. With the use of this method, the scope of the 3‐substituted 3‐hydroxyoxindole derivatives that can be concisely synthesized was expanded.

Functionalized Cyclopentenones with Low Electrophilic Character as Anticancer Agents.

In this study were synthesized non-Michael acceptor cyclopentenones (CP) from biomass derivative furfural as anticancer agents. Cyclic enones, both from natural sources and synthetic analogues, have been described as cytotoxic agents. Most of these agents were unsuccessful in becoming valuable therapeutic agents due to toxicity problems derived from unselective critical biomacromolecule alkylation. This may be caused by Michael addition to the enone system. Ab initio studies revealed that 2,4-substituted CPs are less prone to Michael additions, and as such were tested three families of those derivatives. We prepare the new CPs from furfural through a tandem furan ring opening/Nazarov electrocyclization and further functionalization. Experimentally the 2,4-substituted CPs exhibited no reactivity towards sulphur nucleophiles, while maintaining cytotoxicity against HT-29, MCF-7, NCI-H460, HCT-116 and MDA-MB 231 cells lines. Moreover, the selected CP are non-toxic against healthy HEK 293T cell lines and present proper calculated drug-like properties.

Asymmetric Aminative Dearomatization of 2-Naphthols via Non-covalent N-Heterocyclic Carbene Catalysis

Herein, successful utilization of non-covalent N-heterocyclic carbene (NHC) catalysis toward asymmetric aminative dearomatization of naphthols is presented. The NHC-catalyzed process offers enantioselective synthesis of cyclic enones possessing a nitrogen-containing α-quaternary stereocenter. The reaction applies to various functionalized substrates including acid-labile groups and is shown to be scalable. Substrate activation via an O-H···NHC hydrogen-bonding interaction is suggested based on the results obtained in mechanistic studies.

Cationic cascade cyclizations terminated by MOM ether derivatives of β-keto esters

It has been known for some time that cationic cascade cyclizations initiated by Lewis acid mediated opening of an epoxide can be trapped by reaction with a β-keto ester. The studies reported here show that the efficiency of these cyclizations can be improved through preparation of a MOM enol ether from the β-keto ester. Furthermore, in both geranyl and farnesyl derivatives the stereochemistry of the enol ether controls formation of the major product. In both series, the E-enol ether leads to a cyclic vinylogous carbonate incorporating the oxygen originating in the ketone in the ring system, while the Z-enol ether leads to a cyclic enone incorporating the oxygen originating in the ester carbonyl group. Upon treatment with catalytic HCl, a facile rearrangement converts the enone product to the vinylogous carbonate. Because these cyclizations faithfully extend the stereochemistry of the original epoxide into multiple stereocenters, they have the potential to afford significantly more complex structures from relatively simple starting materials.

Synthesis of γ-Aryl Medium-Sized Cyclic Enones by a Domino 4π-Electrocyclic Reaction/Heck–Matsuda Arylation Sequence at Ambient Temperature

AbstractBicyclo[n.2.0]cyclobutenes were transformed into medium-sized cyclic γ-aryl enones by using a cationic aryl palladium(II) species generated from a diazonium salt. The reaction proceeded at ambient temperature by capturing the cis,trans-cycloalkadiene intermediate generated through a conrotatory 4π-electrocyclic ring-opening reaction, followed by a Heck–Matsuda arylation sequence. Optically pure γ-aryl enones were also synthesized by using a point-to-planar-to-point chirality-transfer process.

Thia-Michael Reaction under Heterogeneous Catalysis

Thia-Michael reactions between aliphatic and aromatic thiols and various Michael acceptors were performed under environmentally-friendly solvent-free conditions using Amberlyst® A21 as a recyclable heterogeneous catalyst to efficiently obtain the corresponding adducts in high yields. Ethyl acrylate was the main acceptor used, although others such as acrylamide, linear, and cyclic enones were also utilized successfully. Bifunctional Michael donor, 3-mercaptopropanoic acid, positively furnished the product, albeit in a lower yield and after leaving the reaction to take place for a longer time. The catalyst was easy and safe to handle and successfully recycled for five consecutive cycles.