Enol Esters Research Articles

Asymmetric Synthesis of Dialkyl Carbinols by Ni-Catalyzed Reductive-Oxidative Relay of Distinct Alkenes.

Enantioenriched unsymmetric dialkyl carbinol derivatives are of importance in natural products, bioactive molecules, and functional organic materials. However, the catalytic asymmetric synthesis of dialkyl carbinol derivatives remains challenging due to the similar steric and electronic properties of two alkyl substituents. Herein, an unprecedented synthesis of chiral dialkyl carbinol ester derivatives from Ni-catalyzed reductive-oxidative relay cross-coupling of two alkenes is developed for the first time. The reaction features the use of enol esters and unactivated alkenes as two different alkyl equivalents to undergo head-to-tail and enantioselective alkyl-alkyl cross-coupling. The reaction undergoes two-electron reduction and single electron oxidation in the presence of both reductants and oxidants. The use of an allyl bromide as single electron acceptor is crucial for the success of this non-trivial asymmetric cross-coupling, providing a new reaction mode for asymmetric alkyl-alkyl bond-forming event in the absence of stoichiometric alkyl electrophiles.

Synergistic Homogeneous Asymmetric Cu Catalysis with Pd Nanoparticle Catalysis in Stereoselective Coupling of Alkynes with Aldimine Esters.

Understanding the nature of a transition-metal-catalyzed process, including catalyst evolution and the real active species, is rather challenging yet of great importance for the rational design and development of novel catalysts, and this is even more difficult for a bimetallic catalytic system. Pd(0)/carboxylic acid combined system-catalyzed allylic alkylation reaction of alkynes has been used as an atom-economical protocol for the synthesis of allylic products. However, the asymmetric version of this reaction is still rather limited, and the in-depth understanding of the nature of active Pd species is still elusive. Herein we report an enantioselective coupling between readily available aldimine esters and alkynes using a synergistic Cu/Pd catalyst system, affording a diverse set of α-quaternary allyl amino ester derivatives in good yields with excellent enantioselectivities. Mechanistic studies indicated that it is most likely a synergistic asymmetric molecular Cu catalysis with Pd nanoparticle catalysis. The Pd catalyst precursor is transformed to soluble Pd nanoparticles in situ, which are responsible for activating the alkyne to an electrophilic allylic Pd intermediate, while the chiral Cu complex of the aldimine ester enolate provides chiral induction and works in synergy with the Pd nanoparticles.

Z-ligustilide provides a neuroprotective effect by regulating the phenotypic polarization of microglia via activating Nrf2-TrxR axis in the Parkinson's disease mouse model

The polarization phenotype of microglia is critical in the progression of Parkinson's disease (PD). Molecules that can polarize microglia toward the M2 phenotype represent a promising class of compounds for anti-PD medications. Z-ligustilide (ZLG) is a naturally occurring enol ester with diverse pharmacological properties, especially in neuroprotection. For the first time, we investigated the effect of ZLG on anti-PD and elucidated its underlying mechanism. The results primarily showed that ZLG attenuated motor deficits in mice and prevented the loss of dopaminergic neurons in the substantia nigra. Mechanistically, ZLG alleviates oxidative stress-induced apoptosis of microglia by triggering the endogenous antioxidant system. Besides, ZLG modulated phenotypic polarization of the microglia through the activation of the Nrf2-TrxR axis, leading to microglia polarization towards the M2 phenotype. Taken together, our research showed that ZLG is a prospective therapy candidate for PD by altering microglia polarization and restoring redox equilibrium through the Nrf2-TrxR axis.

Construction of Vicinal Quaternary Centers via Ru-Catalyzed Enantiospecific Allylic Substitution with Lithium Ester Enolates.

The installation of vicinal quaternary centers with absolute stereocontrol constitutes a considerable challenge in organic synthesis. Herein, we introduce a novel [Cp*Ru(MeCN)3]PF6/phenoxythiazoline catalyst system that achieves enantiospecific allylic substitution of tertiary carbonates with α,α-disubstituted lithium ester enolates to give products containing vicinal quaternary centers. Noteworthy features include the direct use of nonstabilized ester enolates, a class of nucleophiles which has rarely been used in transition metal-catalyzed allylic substitution reactions. The approach is demonstrated for a broad scope of tertiary electrophiles as well as ester enolates and accomplishes stereoretentive substitution with excellent conservation of ee (89-99%) and branched/linear regioselectivities (up to 40:1).

A Three-Step Catalytic Asymmetric Sequence from Alkynes to α-Silyloxyaldehydes and Its Application to a C22-C41 Fragment of Bastimolide A.

1,5-Polyol structures present challenges in stereocontrol, configurational assignment, and diastereomer separation; these are all compromised by remote stereochemical relationships. A configuration-encoded approach with alcohol configurations previously established within enantiopure building blocks offers a versatile solution to these issues. The iterative construction begins with α-silyloxyaldehydes; here, we introduce an enantioselective and step-economical route from alkynes to α-silyloxyaldehydes via silyl cation-induced ring opening of enol ester epoxides. This development enables an efficient configuration-encoded synthesis of the C22-C41 fragment of the bastimolides.

Gold‐Zinc Co‐Catalyzed Alkynoate Hydrocarboxylation with N‐Protected Amino Acids for Preparation of Storable Acylating Reagents and Racemization‐Free Peptide Synthesis

AbstractHydrocarboxylation of methyl 2‐octynoate, a chemical commercially available at a low cost, with N‐protected amino acids was developed with a gold‐zinc cooperative catalyst constructed with a 5‐[(2,2′‐bipyridin)‐5‐yl]imidazo[1,5‐a]pyridin‐3‐ylidene to prepare α‐methoxycarbonyl enol esters as acylating reagents. The α‐methoxycarbonyl enol esters were isolable through silica‐gel column chromatography and storable without precautions regarding moisture. Acylation of free amines with the α‐methoxycarbonyl enol esters proceeded without epimerization of the stereogenic center derived from the enol esters, affording analytically pure dipeptide compounds through filtration and hexane‐washing.

Selective O-Acylation of Enol Silyl Ethers with Acyl Fluorides Catalyzed by Fluoride Ions Derived from Potassium Fluoride and 18-Crown-6.

The fluoride ion-catalyzed selective O-acylation of enol silyl ethers with acyl fluorides using KF and 18-Crown-6 is described herein. This catalytic system facilitated the practical and facile reaction of a variety of enol silyl ethers derived from aromatic/aliphatic ketones and aldehydes with acyl fluorides to afford useful and valuable enol esters.

A formal vinylic substitution reaction for the synthesis of α,β-unsaturated enol esters and their anticancer potential.

Arylsulfonyl group-bearing α,β-unsaturated enol esters were readily assembled via the Cs2CO3-mediated union of 2-bromoallyl sulfones and cinnamic acids. The overall transformation is equivalent to an sp2 carbon-oxygen coupling reaction, and therefore constitutes a formal vinylic substitution. Several of the products display promising levels of antiproliferative activities higher than that of the anticancer drug carboplatin. Thiophenol reacted with 2-bromoallyl sulfones under identical conditions to afford α-thiophenyl-α'-tosyl acetone via an apparent aerial oxidation.

Blue light-mediated carbene transfer reaction of thioesters with diazoesters: efficient synthesis of tetrasubstituted Z-enol esters

An efficient metal-free, blue light-mediated carbene transfer reaction of thioesters with diazoesters has been achieved. This protocol produced tetrasubstituted Z-enol esters containing arylsulfur groups in good yields under mild conditions.

Cooperative catalysis of carbenes and Lewis acids for the highly enantioselective synthesis of dihydroquinolones via in situ generation of aza-ortho-quinone methide and enolate intermediates

An efficient protocol for the highly enantioselective synthesis of dihydroquinolones was developed via NHC-catalyzed [4 + 2] annulation between in situ generated aza-ortho-quinone methide and enolate intermediates.

Carbene-Catalyzed Direct O-Functionalization of Ketone: Atroposelective Access to Non-C2-Symmetric Binaphthyls.

Disclosed here is NHC-catalyzed direct intermolecular trapping of the ketone oxygen atom with the acyl azolium intermediate. The overall reaction is a dynamic kinetic resolution process that converts ketone to the corresponding enol ester with well-controlled axial chirality. Our reaction eventually affords non-C2-symmetric binaphthyl derivatives with important applications, such as in the area of asymmetric catalysis.

Catalyst-Free Trans-Selective Oxyiodination and Oxychlorination of Alkynes Employing N-X (Halogen) Reagents.

β-halogenated enol esters and ethers are versatile building blocks in organic synthesis, which has attracted increasing attention. In this study, we report the facile trans-oxyiodination and oxychlorination of alkynes, leading to the direct construction of versatile halogenated enol esters and ethers. This transformation features an easy operation, optimal atomic economy, a strong functional group tolerance, broad substrate scope, and excellent trans-selectivity. Employing highly electrophilic bifunctional N-X (halogen) reagents was the key to achieving broad reaction generality. To our knowledge, this transformation represents the first oxyhalogenation system employing N-X (halogen) reagents as both oxylation and halogenation sources.

Catalysts Originating from Tailor‐made Metal Ethylene Glycol Carboxylates

AbstractEthylene glycol metal carboxylates are suited as low‐temperature precursors for M and MxOy nanoparticle formation, which are applicable in catalytic heterogeneous reactions including hydrogenations, hydrometalations or C,C cross‐couplings. For the synthesis of β‐oxo‐propyl and enol esters [Ru(CO)2(PPh3)2(O2CR)2] complexes are excellent homogeneous catalysts with high regioselectivities. Additionally, applications of the title complexes beyond catalysis are presented.

Gold-Catalyzed Asymmetric Transformation of Hydroxylated Propargylic Esters.

By combining tandem asymmetric gold catalysis and subsequent stereoconvergent hydrolysis of enol ester in a one-pot process, hydroxylated propargylic esters are converted into chiral β-oxygenated ketones with mostly good enantiomeric ratios and in largely good to excellent yields. The product chiral center is formed via stereoselective cyclization of a hydroxylated allenyl ester intermediate, which is enabled by asymmetric gold-ligand cooperation.

Photocatalyzed Direct α-Alkylation of Esters Using Styrenes.

A mild photocatalyzed approach to achieve the α-alkylation of esters via formation of an α -radical is disclosed here. Cesium enolates of esters were generated in situ using Cs2CO3 as a base. A subsequent photocatalyzed oxidation at the α-carbon of these enolates produced an α-radical that was added into activated alkenes. This is the first example accessing the α-carbon radical of esters in photoredox catalyed transformations.

Catalytic Asymmetric Hydrogen Atom Transfer: Enantioselective Hydroamination of Alkenes.

We report a highly enantioselective radical-based hydroamination of enol esters with sulfonamides jointly catalyzed by an Ir photocatalyst, Brønsted base, and tetrapeptide thiol. This method is demonstrated for the formation of 23 protected β-amino-alcohol products, achieving selectivities up to 97:3 er. The stereochemistry of the product is set through selective hydrogen atom transfer from the chiral thiol catalyst to a prochiral C-centered radical. Structure-selectivity relationships derived from structural variation of both the peptide catalyst and olefin substrate provide key insights into the development of an optimal catalyst. Experimental and computational mechanistic studies indicate that hydrogen-bonding, π-π stacking, and London dispersion interactions are contributing factors for substrate recognition and enantioinduction. These findings further the development of radical-based asymmetric catalysis and contribute to the understanding of the noncovalent interactions relevant to such transformations.

GC-MS profile and antimicrobial activities of extracts from root of Senna occidentalis Linn.

Abstract We considered the extraction of plant materials from Senna occidentalis root, and its fractionation monitored by bioassay towards isolating its bioactive principles. Pulverized root sample of Senna occidentalis (fam. leguminaceae) was extracted with methanol using a maceration method. The crude methanol extract (MSo) 6.06 g was partitioned into petroleum ether and ethyl acetate to yield their respective fractions viz: petroleum ether fraction (1.20 g), ethyl acetate fraction (1.86 g) and methanol fraction (2.92 g). The crude methanol extract was analyzed using phytochemical screening, infrared spectroscopy, and gas chromatography/mass spectrometry while the fractions were examined for antimicrobial properties. Phytochemical screening indicated the presence of tannins, phenolics, alkaloids, flavonoids, saponins, cardiac glycosides, phlobatannin, and absence of steroids. The infrared spectrum revealed a broad absorption band at 3437.26 cm-1 due to O-H symmetric stretch in polymeric alcohols, and absorption frequency of 1640.51cm-1 of moderate intensity due to C=O stretch. Enols are easily identified by the broad H-bonded O-H stretch absorption and low C=O stretch frequency as in β-keto enolic esters and phenol acetates, -CO-O-C=C-, (1690-1650 cm-1). Gas chromatography/mass spectrometry identified the presence of ten compounds including n-hexadecanoic acid (23.76%), linoleic acid (1.64%), E-9-tetradecenoic acid (4.88%), octadecanoic acid, 2-(2 hydroxyethoxy) ethyl ester (6.24%) and E-2-octadecadecen-1-ol (13.74%). Similar broad spectrum antimicrobial activities were manifested by methanol and ethyl acetate fractions. Escherichia coli and Bacillus cereus were the most susceptible with the highest zone of inhibition of 30 mm and 28 mm respectively at minimum inhibition concentration of 1.35 x103 μg/ml. The methanol fraction has the highest potency against the tested pathogens whereas the petroleum ether fraction exhibited activity only on gram negative pathogens. The antimicrobial activities observed in these fractions suggest the presence of active chemical components in the crude methanol root extract of Senna occidentalis thus provides a potential source of novel antimicrobial agents. Further work is however, required to isolate and characterize these bioactive principles.

Overcoming Energy Transfer for the Metallophotoredox Catalyzed Decarboxylative Alkenylation between Alkylcarboxylic Acids and Enol Triflates.

Herein we report on the decarboxylative alkenylation between alkyl carboxylic acids and enol triflates. The reaction is mediated by a dual catalytic nickel and iridium system, operating under visible light irradiation. Two competing catalytic pathways, from the excited state iridium photocatalyst, are identified. One is energy transfer from the excited state, resulting in formation of an undesired enol ester. The desired pathway involves electron transfer, resulting in decarboxylation to ultimately give the target product. The use of a highly oxidizing iridium photocatalyst is essential to control the reactivity. A diverse array of enol triflates and alkyl carboxylic acids are investigated, providing both scope and limitations of the presented methodology.

Application of alkane-diyl based chiral phosphine-aminophosphine (P-NP) and thioether-aminophosphine (S-NP) ligands in Rh-catalyzed asymmetric hydrogenation

Rhodium(I)-complexes of five new alkane-diyl based phosphine-aminophosphine (P,NP) type chiral ligands (Ph2PCH(CH3)(CH2)nCH(CH3)N(R1)PR22 (n = 0-2, R1 = Me, Et, iPr, R2 = Ph, Cy)) and a thioether-aminophosphine type compound ((S,S)-PhSCH(CH3)(CH2)CH(CH3)N(iPr)PPh2) have been synthesized. The investigation of the coordination chemistry of structurally analogous systems by NMR and IR spectroscopy and in one case by X-ray crystallography enabled the comparison of the effect of (i) the ligand backbone length, (ii) the N-substituent, (iii) the type of the coordinating functionality and (iv) the P-substituent in aminophosphine moiety on the stereo-electronic properties of the complexes. The novel Rh-compounds were tested in the asymmetric hydrogenation of a broad range of prochiral substrates including dimethyl itaconate, dehydroaminoacid derivatives and α,β-unsaturated enol ester phosphonates. Catalysts modified by the pentane-2,4-diyl based phosphine-aminophosphine ligands provided superior catalytic performance compared to the analogous butane- and hexane-diyl based systems and thioether containing compound. Most importantly, by the proper choice of the N-substituent outstanding enantioselectivities could be obtained in the asymmetric hydrogenation of acetamidocinnamic acid derivatives (up to 98% ee) and enol ester phosphonates (up to 97% ee).

A Distinct Mode of Strain-Driven Cyclic Allene Reactivity: Group Migration to the Central Allene Carbon Atom.

Strained cyclic allenes are reactive species that can be trapped in a variety of complementary fashions that capitalize on their inherent high potential energy. 1,2,4-Cyclohexatrienes represent a subclass of allenes that, notably, can be conveniently generated by a net [4 + 2] cycloaddition within a 1,3-enyne bearing a tethered alkyne via a tetradehydro-Diels-Alder reaction. A limitation to the use of this type of thermally generated cyclic allene as a construct for the introduction of molecular complexity is their propensity to isomerize to benzenoids via a simple net 1,5-hydrogen atom migration. We have discovered that when the enyne component of the substrate is modified as an enol silyl ether (or an enol ester), migration of the silyl (or acyl) group can become the predominant event. Specifically, an appropriately electrophilic group can migrate from the O atom to the central allene carbon adjacent to the 1-siloxy(acyloxy) substituent. This process leads to highly substituted phenolic products (e.g., o-silyl phenols) following tautomerization of the intermediate cyclohexa-2,4-dienone. Experimental studies show that this novel mode of reactivity is general; DFT studies reveal the unimolecular nature of the group migration.