Showing papers on "Enone published in 2014"

Access to Oxoquinoline Heterocycles by N‐Heterocyclic Carbene Catalyzed Ester Activation for Selective Reaction with an Enone

Abstract: Organocatalytic ester activation is developed for a highly selective cascade reaction between saturated esters and amino enones. The reaction involves activation of the β-carbon atom of the ester as a key step. This method allows a single-step access to multicyclic oxoquinoline-type heterocycles with high enantiomeric ratios.

Cross-Dehydrogenative Couplings between Indoles and β-Keto Esters : Ligand-Assisted Ligand Tautomerization and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II)

Abstract: Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by (1)H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (ωB97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the β-keto ester ligand from an O,O'-chelate to an α-C-bound Pd enolate. This ligand tautomerization event is assisted by the π-bound indole ligand. Subsequent scission of the β'-C-H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step.

A computational study: reactivity difference between phosphine- and amine-catalyzed cycloadditions of allenoates and enones.

Abstract: Allenoates and enones form cyclopentenes via a phosphine-catalyzed [3 + 2] cycloaddition while the amine-catalyzed [2 + 4] cycloaddition yields dihydropyrans or pyrans. The difference between these catalysts is studied with M06-2X/6-31+G* calculations. The addition of the catalyst to the allenoate is the first step in both pathways followed by the reaction with the enone. The formation of the [3 + 2] phosphorus-ylide is exergonic, and hence, the [3 + 2] cycloaddition is kinetically favored over the [2 + 4] addition. Amines do not stabilize [3 + 2] ammonium-ylides. However, electron-withdrawing groups on the enone enable [2 + 4] cycloadditions. The strength of the electron-withdrawing group further controls the α/γ regioselectivity of the [2 + 4] cycloaddition, and the analysis of the HOMO-LUMO interactions explains why only E-dihydropyrans from the direct γ-[2 + 4] cycloaddition have been observed in experiments. The quantum calculations further reveal a new path to the α-[2 + 4] product starting with an intermediate Rauhut-Currier reaction. This new path is kinetically favored over the direct amine-catalyzed α-[2 + 4] cycloaddition.

Stereodivergent organocatalytic intramolecular michael addition/ lactonization for the asymmetric synthesis of substituted dihydrobenzofurans and tetrahydrofurans

Abstract: A stereodivergent asymmetric Lewis base cata- lyzed Michael addition/lactonization of enone acids into sub- stituted dihydrobenzofuran and tetrahydrofuran derivatives is reported. Commercially available (S)-()-tetramisole hydro- chloride gives products with high syn diastereoselectivity in excellent enantioselectivity (up to 99:1 d.r.syn/anti ,9 9 % ee syn), whereas using a cinchona alkaloid derived catalyst gives the corresponding anti-diastereoisomers as the major product (up to 10:90 d.r.syn/anti ,9 9 % ee anti).

Palladium-catalyzed, copper-mediated construction of benzene rings from the reactions of indoles with in situ generated enones

Abstract: Construction of the benzene ring in carbazoles was efficiently realized through a domino dehydrochlorination/alkenylation/cycloaddition–oxidation sequence by means of palladium(II)-catalyzed, copper(II)-mediated reactions of N-protected 2,3-unsubstituted indoles with 3-chloropropiophenones in the presence of a base. 3-Alkenylated indole was confirmed to be formed as the reaction intermediate which then underwent Diels–Alder cycloaddition to the initially in situ generated enone from a 3-chloropropiophenones substrate, and the subsequent dehydrogenative aromatization yielded the carbazole product. The strategy to employ in situ generated enones as the reactive species avoided the use of a large excess of labile substrates and lessened the side reactions.

ent-Kaurane-based regio- and stereoselective inverse electron demand hetero-Diels-Alder reactions: synthesis of dihydropyran-fused diterpenoids.

Abstract: A mild and concise approach for the construction of a 3,4-dihydro-2H-pyran ring integrated into the A-ring of the natural product oridonin using an optimized inverse electron demand hetero-Diels–Alder (IED HDA) reaction is reported herein. A self-dimerization of the exocyclic enone installed in the A-ring through a homo-HDA reaction was identified to exclusively give a dimeric ent-kaurane diterpenoid with the spirochroman core. Moreover, efficient cross-HDA cycloadditions of this enone with various vinyl ethers or vinyl sulfides, instead of its own homo-HDA dimerization, were achieved in a regio- and stereoselective manner, thus providing access to novel dihydropyran-fused diterpenoids as potential anticancer agents to overcome chemoresistance.

Microwave‐Assisted, Rhodium(III)‐Catalyzed N‐Annulation Reactions of Aryl and α,β‐Unsaturated Ketones with Alkynes

Abstract: New Rh(III)-catalyzed, one-pot N-annulation reactions of aryl and α,β-unsaturated ketones with alkynes in the presence of ammonium acetate have been developed. Under microwave irradiation conditions, the processes lead to rapid formation of the respective isoquinoline and pyridine derivatives with efficiencies that are strongly dependent on the steric nature of the aryl ring and enone substituents. By employing this protocol, a variety of isoquinoline and pyridine derivatives were prepared in high yields. In addition, a new one-pot approach to the synthesis of pyridines, involving four-component reactions of ketones, formaldehyde, NH(4)OAc, and alkynes, has been uncovered. This process takes place through a route involving initial aldol condensation of the ketone with formaldehyde to generate a branched α,β-unsaturated ketone that then undergoes Rh(III)-catalyzed N-annulation with NH(4)OAc and the alkyne

Iron catalyzed enantioselective sulfa-Michael addition: a four-step synthesis of the anti-asthma agent Montelukast

Abstract: A salen ligand based on a chiral cis-2,5-diaminobicyclo[222]octane scaffold forms an iron(III) complex with ferric chloride which catalyzes asymmetric addition of thiols to α,β-unsaturated ketones under mild conditions The reaction (sulfa-Michael addition) produces β-thioketones in excellent yield and high enantiomeric excess from a wide range of aliphatic and aromatic thiols using chalcones and other conjugated enones as Michael acceptors With α-substituted α,β-unsaturated ketones as acceptors, the addition shows strong preference (typically >50:1) for the syn diastereomer over the anti product An asymmetric synthesis of (R)-Montelukast, the sodium salt of which is the commercial anti-asthma drug Singulair®, was devised using conjugate addition of a thiol catalyzed by our iron(III)–salen complex to an α,β-unsaturated ketone synthesized in a four-component, one-pot tandem Michael-aldol condensation The reaction sequence to (R)-Montelukast proceeded in 72% overall yield over four steps from commercially available materials A mechanism for our catalyzed asymmetric sulfa-Michael addition is advanced which coordinates the enone acceptor to the metal centre of the iron–salen complex in an open lower quadrant under the bicyclic scaffold, thereby exposing only the si face of the double bond to attack by the external nucleophilic thiol Prior internal coordination of the thiol to the metal centre of the complex is proposed based on spectroscopic and chemical evidence and leads to activation of the catalyst through a trans ligand effect

Gold(I)‐Catalyzed Furan‐yne Cyclizations Involving 1,2‐Rearrangement: Efficient Synthesis of Functionalized 1‐Naphthols and Its Application to the Synthesis of Wailupemycin G

Abstract: Gold-catalyzed cascade cyclization/1,2-rearrangement of 1-(2-furanyl)phenyl propargyl alcohols has been developed, which provides a rapid and efficient access to multisubstituted 1-naphthols bearing an enal or enone moiety with high stereoselectivity. The (Z)- or (E)-stereochemistry can be easily controlled by choosing protected- or non-protected substrates. The utility of the methodology has been illustrated in the first total synthesis of wailupemycin G.

The photo-Nazarov reaction: scope and application.

Abstract: The reaction conditions and scope of the photo-Nazarov reaction of aryl vinyl ketones were investigated. In contrast to the conventional acid-catalyzed methods, this photolytic electrocyclization proceeds in the neutral or basic conditions. Irradiating substrates bearing various aromatic rings, acid-sensitive groups, cyclohexenyl, cycloheptenyl, and unsaturated pyran with UV-light (254 nm) smoothly yielded hexahydrofluorenones and related structures. This photo-Nazarov reaction could also be applicable to the substrates carrying β-alkyl groups on the enone, which gave corresponding polycyclic rings containing quaternary centers. These photo-electrocyclized products may prove useful for synthesizing a variety of natural products and their derivatives. Further application of this mild photo-Nazarov reaction in the synthesis of taiwaniaquinol B was achieved.

Copper-catalyzed asymmetric conjugate addition of alkylzirconium reagents to cyclic enones to form quaternary centers

Abstract: This protocol describes the catalytic asymmetric formation of all-carbon quaternary centers--a distinctive feature of many natural products and pharmaceuticals--via conjugate addition of alkylzirconium reagents to a tertiary enone. This methodology uses alkenes as starting materials and enables the incorporation of functional groups. The alkylzirconium reagent is generated in situ by mixing the alkene with the Schwartz reagent. The alkylzirconium is added to a solution containing a copper-ligand complex, and then the enone is added to the mixture. The addition of pent-4-en-1-ylbenzene to 3-methyl-2-cyclohexenone is detailed herein as a generic example. This procedure works at room temperature (∼25 °C), and it is scalable to at least 1.5 g. The setup of the reaction takes 3-5 h and the reaction goes to completion within 4-20 h.

Ni(NHC)]-catalyzed cycloaddition of diynes and tropone: apparent enone cycloaddition involving an 8π insertion.

Abstract: A Ni/N-heterocyclic carbene catalyst couples diynes to the C(α)-C(β) double bond of tropone, a type of reaction that is unprecedented for metal-catalyzed cycloadditions with aromatic tropone. Many different diynes were efficiently coupled to afford [5-6-7] fused tricyclic products, while [5-7-6] fused tricyclic compounds were obtained as minor byproducts in a few cases. The reaction has broad substrate scope and tolerates a wide range of functional groups, and excellent regioselectivity is found with unsymmetrical diynes. Theoretical calculations show that the apparent enone cycloaddition occurs through a distinctive 8π insertion of tropone. The initial intramolecular oxidative cyclization of diyne produces the nickelacyclopentadiene intermediate. This intermediate undergoes an 8π insertion of tropone, and subsequent reductive elimination generates the [5-6-7] fused tricyclic product. This initial product undergoes two competing isomerizations, leading to the observed [5-6-7] and [5-7-6] fused tricyclic products.

Palladium-Catalyzed Oxidative Heck-Type Allylation of β,β-Disubstituted Enones with Allyl Carbonates

Abstract: The palladium-catalyzed oxidative heck-type allylation of beta,beta-disubstitutedenones, i.e., alpha-oxoketene dithioacetals, was efficiently realized with allyl carbonates, providing a concise route to highly functionalized dienes. the present synthetic methodology utilizes the substrate activation strategy to activate the c-h bond of beta,beta-disubstituted enones by introduction of a 1,2-dithiolane functionality to make the enone substrate highly polarized and thus increase its reactivity, demonstrating rare examples for transition metal-catalyzed allylic substitution of beta,beta-disubstituted enones through a heck-type allylation process.

Total Synthesis of (R,R,R)-γ-Tocopherol through Cu-Catalyzed Asymmetric 1,2-Addition

Abstract: Based on the asymmetric copper-catalyzed 1,2-addition of Grignard reagents to ketones, (R,R,R)-γ-tocopherol has been synthesized in 36 % yield over 12 steps (longest linear sequence). The chiral center in the chroman ring was constructed with 73 % ee by the 1,2-addition of a phytol-derived Grignard reagent to an α-bromo enone prepared from 2,3-dimethylquinone.

Ruthenium(II)‐Catalyzed Protocol for Preparation of Diverse α,β‐ and β,β‐Dihaloenones from Diazodicarbonyls

Abstract: Efficient one-step syntheses of a,b- and b,b-dihaloenones were achieved by ruthenium(II)- catalyzed reactions between cyclic or acyclic diazodi- carbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodolo- gy offers several significant advantages, which in- clude ease of handling, mild reaction conditions, one-step reaction, and the use of an effective and non-toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.

Enantioselective Synthesis and Profiling of Two Novel Diazabicyclooctanone β-Lactamase Inhibitors

Abstract: The enantioselective synthesis of two novel cyclopropane-fused diazabicyclooctanones is reported here. Starting from butadiene monoxide, the key enone intermediate 7 was prepared in six steps. Subsequent stereoselective introduction of the cyclopropane group and further transformation led to compounds 1a and 1b as their corresponding sodium salt. The great disparity regarding their hydrolytic stability was rationalized by the steric interaction between the cyclopropyl methylene and urea carbonyl. These two novel β-lactamase inhibitors were active against class A, C, and D enzymes.

Tertiary amine-promoted enone aziridination: investigations into factors influencing enantioselective induction

Abstract: trans-N- Unsubstituted aziridines were synthesised (up to 77% ee) via a chiral tertiary amine-promoted nucleophilic aziridination of α,β-unsaturated ketones utilising in situ generated N – N ylides (aminimines). A wide range of chiral tertiary amines were synthesised and evaluated, allowing structure–activity relationships to be drawn. The most efficient promoter for asymmetric aziridination, quinine, was assessed with several enones to ascertain the effect of substrate structure on product ee, while the intermediate hydrazinium salt was characterised by X-ray crystallography.

New route for synthesis, spectroscopy, and X-ray studies of 2-[aryl-(6′-hydroxy-4′,4′-dimethyl-2′-oxocyclohex-6′-enyl)methyl]-3-hydroxy-5,5-dimethylcyclohex-2-enone and 1,8-dioxo-octahydroxanthenes and antitumor evaluation

Abstract: Treatment of 1-(benzothiazol-2-yl-thio)-acetonitrile 1 with 5,5-dimethyl-1,3-cyclohexanedione-(dimedone) 2 and aromatic aldehyde 3a, b in refluxing ethanol containing a catalytic amount of piperidine lead to bisdimedone derivatives 5a and b in short periods of times with excellent yields and not 4H-chromen-5(6H)-one derivatives 8. The compound 5a was then cyclized to 1,8-dioxo-octahydroxanthene derivative 6. The structures of the synthesized compounds were elucidated by elemental analysis 1H NMR and 13C NMR spectra, COSY, HSQC, HMBC, MS, and X-ray crystallographic investigations. The cytotoxicity of the synthesized compounds 5a, b, and 6 were studied and evaluated. Three human tumor and three normal cell lines, namely as breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268), human fibroblast (WI-38), normal prostate epithelial cells, and normal colon mucosal, NCM 460 cells, respectively. The tested compounds were found to exhibit higher inhibitory effects toward the tumor and normal cell lines than the reference drug, doxorubicin.

Stereoselective syntheses of galanthamine and its stereoisomers by complementary Luche and L-selectride reductions

Abstract: A diastereodivergent approach for the stereoselective syntheses of all four stereoisomers of galanthamine, (−)-galanthamine 1 , (+)-galanthamine 2 , (−)-epigalanthamine 3 , and (+)-epigalanthamine 4 , from (±)-narwedine 5 is reported. Thus (±)-narwedine 5 was resolved by dynamic kinetic resolution to obtain enantiomerically pure (−)-narwedine 6 and (+)-narwedine 7 . Each enantiomerically pure isomer of narwedine was subjected to Luche and L-selectride reactions to obtain all four isomers of galanthamine. In these reactions, the (−)-galanthamine 1 and (+)-galanthamine 2 isomers were obtained with an enantiomeric purity of >99.5%, whereas (−)-epigalanthamine 3 and (+)-epigalanthamine 4 are obtained with a chiral purity of >97%. The axial hydride attack by the Luche reduction and the equatorial hydride attack by the L-selectride reduction on the cyclic enone system are explored in the stereoselective synthesis of the galanthamine isomers and thus it was demonstrated that the stereoselective synthesis involving the Luche and L-selectride reductions are complementary in yielding enantiomeric stereogenic centers from a prochiral carbonyl group on the cyclic enone system.

Synthesis of the C10–C24-Bis-Spiroacetal Core of 13-Desmethyl Spirolide C Based on a Sila-Stetter-Acetalization Process

Abstract: Synthesis of the bis-spiroacetal core of 13-des- methyl spirolide C has been completed based on a sila-Stet- ter-acetalization process. The acylsilane and enone partners in the Stetter reaction were prepared in seven and 11 steps, respectively, from (S) and (R)-aspartic acid. The quaternary center at C19 in the enone moiety was controlled by relying on the Seebach's chiral self-reproduction method by using an enantiopure (S)-lactic acid based dioxolanone. The final acid-catalyzed spiroacetalization provided the desired spiroa- cetal as a mixture of diastereoisomers in 13 linear steps. Whatever the conditions used, the non-natural transoid isomer was formed preferentially. However, both cisoid and transoid isomers were isolated pure and their structure as- signed unambiguously through NMR spectroscopic studies.

Access to Oxoquinoline Heterocycles by N-Heterocyclic Carbene Catalyzed Ester Activation for Selective Reaction with an Enone.

Abstract: Organocatalytic ester activation is developed for a highly selective cascade reaction between saturated esters and amino enones. The reaction involves activation of the β-carbon atom of the ester as a key step. This method allows a single-step access to multicyclic oxoquinoline-type heterocycles with high enantiomeric ratios.