Ketone Functionality Research Articles

Synthesis and pharmacological evaluation of nature-inspired phenacyl glycosides

Phenylethanoid glycosides are a well-studied class of bioactive compounds found throughout the plant kingdom. In contrast, research on the synthesis and pharmacological activity of phenacyl glycosides, a specific subgroup of phenylethanoid glycosides with a ketone functionality at the alpha position of the phenol ring, has been limited. In this study, we report the synthesis, cytotoxic, antiviral, and anti-inflammatory evaluation of a series of 18 4′-hydroxyphenacyl glycosides. These compounds consist of six different sugar residues (β-d-glucose, β-d-galactose, α-l-arabinose, β-d-xylose, α-l-rhamnose, and β-d-glucuronic acid) and display three distinct methoxylation patterns at the phenacyl ring, similar to the substitution motifs of anthocyanins. We obtained the target phenacyl glycosides in high yield and stereoselectivity through the coupling of benzoyl-protected trichloroacetimidate glycosyl donors and corresponding acetophenones. Our work represents the first total synthesis of the natural products 4′-hydroxyphenacyl-β-d-glucopyranoside (1) and 4′-hydroxy-3′-methoxyphenacyl-β-d-glucopyranoside (2). None of the phenacyl glycosides showed cytotoxicity against the tested cell lines. Notably, several of the synthesized compounds exhibited antiviral activity, with natural product 2 being the most active against herpes simplex virus type 1, while phenacyl arabinoside 9 and natural product 2 were the most active against human coronavirus OC43. Natural product 2 significantly inhibited the production of interleukin-6 in lipopolysaccharide-stimulated microglia cells. Overall, our findings highlight the importance of the sugar residue and phenacyl ring substitution pattern in modulating the antiviral activity of phenacyl glycosides. Natural product 2 and phenacyl arabinoside 9 emerge as promising leads for the development of antiviral agents.

BioLindlar Catalyst: Ene‐Reductase‐Promoted Selective Bioreduction of Cyanoalkynes to Give (Z)‐Cyanoalkenes

AbstractThe direct synthesis of alkenes from alkynes usually requires the use of transition‐metal catalysts. Unfortunately, efficient biocatalytic alternatives for this transformation have yet to be discovered. Herein, the selective bioreduction of electron‐deficient alkynes to alkenes catalysed by ene‐reductases (EREDs) is described. Alkynes bearing ketone, aldehyde, ester, and nitrile moieties have been effectively reduced with excellent conversions and stereoselectivities, observing clear trends for the E/Z ratios depending on the nature of the electron‐withdrawing group. In the case of cyanoalkynes, (Z)‐alkenes were obtained as the major product, and the reaction scope was expanded to a wide variety of aromatic substrates (up to >99 % conversion, and Z/E stereoselectivities of up to >99/1). Other alkynes containing aldehyde, ketone, or ester functionalities also proved to be excellent substrates, and interestingly gave the corresponding (E)‐alkenes. Preparative biotransformations were performed on a 0.4 mmol scale, producing the desired (Z)‐cyanoalkenes with good to excellent isolated yields (63–97 %). This novel reactivity has been rationalised through molecular docking by predicting the binding poses of key molecules in the ERED‐pu‐0006 active site.

BioLindlar Catalyst: Ene-Reductase-Promoted Selective Bioreduction of Cyanoalkynes to Give (Z)-Cyanoalkenes.

The direct synthesis of alkenes from alkynes usually requires the use of transition-metal catalysts. Unfortunately, efficient biocatalytic alternatives for this transformation have yet to be discovered. Herein, the selective bioreduction of electron-deficient alkynes to alkenes catalysed by ene-reductases (EREDs) is described. Alkynes bearing ketone, aldehyde, ester, and nitrile moieties have been effectively reduced with excellent conversions and stereoselectivities, observing clear trends for the E/Z ratios depending on the nature of the electron-withdrawing group. In the case of cyanoalkynes, (Z)-alkenes were obtained as the major product, and the reaction scope was expanded to a wide variety of aromatic substrates (up to >99 % conversion, and Z/E stereoselectivities of up to >99/1). Other alkynes containing aldehyde, ketone, or ester functionalities also proved to be excellent substrates, and interestingly gave the corresponding (E)-alkenes. Preparative biotransformations were performed on a 0.4 mmol scale, producing the desired (Z)-cyanoalkenes with good to excellent isolated yields (63-97 %). This novel reactivity has been rationalised through molecular docking by predicting the binding poses of key molecules in the ERED-pu-0006 active site.

An all-in-one cytosine fused dihydroisoquinoline reaction center with ultralow Pt loading for excellent solar-to-hydrogen production

Rationally designed carbon nitride materials for solar-to-hydrogen transformation is a promising alternative to fossil fuels. A cytosine-fused dihydroisoquinoline reaction center is constructed through copolymerization of urea with tyrosine, in which the amine of tyrosine promotes the incorporation of a ketone functionality via a ring-closing reaction, playing an important role in boosting HER activity. This construct represents a unique “all-in-one” reaction center that synergistically enhances visible light responsiveness through π-conjugation, improves charge-carrier spatial separation by forming a donor(melon)―bridge(dihydroisoquinoline)―acceptor(cytosine) architecture, and promotes the formation of Pt―O configuration as a highly efficient reaction center by directly loading Pt onto the photoelectron harvesting cytosine. The assembled construct with ultra-low Pt loading (0.37 %) exhibits a H2 production rate of 35200 μmol/g/h and 44.5 % AQY at 420 nm, which are superior to all reported values in HER photocatalysis and fulfills the demand of environmental friendliness, attesting to the success of an unprecedented “all-in-one” design.

Ultrasound-Mediated Green Synthesis of Imidazo[1,2-a]pyridines and Imidazo[2,1-b]thiazoles through C(sp3)–H Functionalization

AbstractAn ultrasound-assisted expedient protocol has been developed for the synthesis of imidazo[1,2-a]pyridines and imidazo[2,1-b]thiazoles by the C–H functionalization of ketones using a KI/tert-butyl hydroperoxide catalytic system. The reaction takes place in water, a green solvent, and does not require a metal catalyst; it also gives good yields of the products. The method offers numerous noteworthy characteristics, including mild reaction conditions, the absence of a base, broad functional-group compatibility, and excellent reaction yields. Moreover, it avoids the use of costly and air-sensitive chemicals, and can be conducted under ambient reaction conditions.

Regioselective Hydroxylation of Unsymmetrical Ketones Using Cu, H2O2, and Imine Directing Groups via Formation of an Electrophilic Cupric Hydroperoxide Core.

Herein, we describe the regioselective functionalization of unsymmetrical ketones using imine directing groups, Cu, and H2O2. The C-H hydroxylation of the substrate-ligands derived from 2-substituted benzophenones occurred exclusively at the γ-position of the unsubstituted ring due to the formation of only one imine stereoisomer. Conversely, the imines derived from 4-substituted benzophenones produced E/Z mixtures that upon reacting with Cu and H2O2 led to two γ-C-H hydroxylation products. Contrary to our initial hypothesis, the ratio of the hydroxylation products did not depend on the ratio of the E/Z isomers but on the electrophilicity of the reactive [LCuOOH]1+. A detailed mechanistic analysis suggests a fast isomerization of the imine substrate-ligand binding the CuOOH core before the rate-determining electrophilic aromatic hydroxylation. Varying the benzophenone substituents and/or introducing electron-donating and electron-withdrawing groups on the 4-position of pyridine of the directing group allowed for fine-tuning of the electrophilicity of the mononuclear [LCuOOH]1+ to reach remarkable regioselectivities (up to 91:9 favoring the hydroxylation of the electron-rich arene ring). Lastly, we performed the C-H hydroxylation of alkyl aryl ketones, and like in the unsymmetrical benzophenones, the regioselectivity of the transformations (sp3 vs sp2) could be controlled by varying the electronics of the substrate and/or the directing group.

DMAP-promoted oxidative functionalization of α-amino ketones via oxygen delivery from water/alcohols.

This paper shows a novel oxidative functionalization of α-amino ketones to yield the corresponding α-ketoamides and α-acylimidates. The reaction proceeds via oxygen delivery from water/alcohols in conjunction with an electron acceptor and 4-dimethylaminopyridine (DMAP). Mechanistic study indicates that DMAP exhibits a dual function of nucleophilic catalysis and proton abstraction.

Recent Progress in Environmentally-Friendly Methods for Chalcone Synthesis

Abstract: Chalcones are important scaffolds in the field of medicinal chemistry due to the presence of α,β-unsaturated ketone functionality. They are usually synthesized by reacting an aldehyde with acetophenone in the presence of acid or base using the Claisen-Schmidt condensation reaction. Numerous chalcone derivatives have been developed due to the simplicity of their synthesis, and they have intriguing biological activity that has clinical implications for a range of disorders. The review article discusses the advancements made since 2005 for the synthesis of chalcones derivatives using environmentally friendly methods such as the use of green catalysts and solvents, ultrasonic radiation, microwave energy, and methodologies involving grinding in the absence of solvents.

Azide-based in situ preparation of fused heterocyclic imines and their multicomponent reactions.

Structurally diverse pyrroles, indoles and imidazoles bearing an N-ω-azidoalkyl moiety and an aldehyde or ketone function were prepared and successfully introduced into in situ imine generation via the intramolecular Staudinger/aza-Wittig tandem reaction. Reduction of the generated imines led to medicinally relevant nitrogen-containing fused heterocycles such as tetrahydropyrrolo[1,2-a]pyrazines and diazepines. Rare 8-membered hexahydropyrrolo[1,2-a][1,4]diazocine and 9-membered dihydro-4,8-(metheno)pyrrolo[1,2-a][1,4]diazacycloundecine were also synthesized. In addition, several one-pot transformations involving cyclic anhydrides or isocyanides (Castagnoli-Cushman, Ugi and azido-Ugi reactions) were added to the Staudinger/aza-Wittig sequence to afford novel fused polyheterocyclic delta-lactams, cyclic bisamides and tetrazoles in a multicomponent fashion. The synthesized compounds were profiled against human Trace Amine-Associated Receptor 1 (hTAAR1), and the best performing compound showed low nanomolar agonistic activity with an EC50 of 0.025 μM.

Redox-enabled cooperative catalysis by activating secondary alcohols using low-valent Zn complexes.

Inspired by nature's redox management in bioinorganic systems, we developed various Zn-complexes to catalyze a radical-mediated borrowing hydrogen process for producing β-disubstituted ketones. A diverse range of secondary alcohols, including fatty alcohols, terpenoids and steroid analogs, were successfully utilized for the chemoselective functionalization of ketones. Several organometallic and control studies suggest that coordinatively unsaturated radical species operate as active catalysts to promote alcohol activation and initiate the HAT process.

Fungal polyketides produced by an endophytic fungus Phoma sp. associated with Gastrodia elata

Two novel fungal polyketides, phometides A (1) and B (2), together with four known compounds (3–6), were isolated from the endophytic fungus Phoma sp. YUD17001 obtained from Gastrodia elata Blume. The structures were elucidated based on spectroscopic analyses, X-ray crystal diffraction, and time-dependent density functional theory/electronic circular dichroism (TDDFT/ECD) calculations. Structurally, phometide A (1) represented the first example of C12 polyketide characterized by an unusual tetrahydrobenzofuran-3(2H)-one core with an α,β-unsaturated ketone functionality, while phometide B (2) was an unprecedented molecule containing a 2-pentylcycloheptan-1-one scaffold. In an antimicrobial activity assay, phometide A (1) exhibited significant inhibitory activity against Staphylococcus aureus with MIC value of 4 μg/mL. Phometide B (2) showed moderate antifungal activity against Candida albicans with an MIC value of 16 μg/mL. Furthermore, compounds 1 and 2 were evaluated for their acetylcholinesterase inhibitory and cytotoxic activities.

(Invited) Electrocatalytic Syntheses with Interfacial Control

Synthesis driven by renewable electricity offers a sustainable, scalable, decentralized, and energy-efficient route to furnish value-added products. As all electrocatalytic reactions occur at the phase boundary between conductive solids and liquid electrolytes, the discovery, design, and manipulation of selective electricity-driven reactivity demands new methods to probe and tune this interface and predict how interfacial structural changes influence reaction selectivity.The functionalization of aldehydes and ketones with organic halide electrophiles remains a privileged reaction class to construct C(sp3)‒C(sp3) bonds. Translation to molecular catalytic strategies remains challenging due to competitive side reactivity imposed by radical intermediates following sp3 organic halide activation. Our group has uncovered an alternative paradigm that deploys catalytic electrode surfaces to develop reductive fragment-based electrophile coupling reactions. Using in-situ spectroscopy and electrochemical analyses, we reveal the “black box” of the catalytic interface. The addition of Lewis acids pre-organizes the surface, enabling a carbon-centered radical (obtained via electrocatalytic activation) to efficiently add to the carbonyl. Our studies lay a foundation to develop sustainable synthetic methodologies by tuning the interfacial structure at catalytic, reusable electrodes at the molecular level.

β-Ketoallylic methylsulfones synthesis via inert C(sp3)–H bond activation by magnetic Ag–Cu MOF

Herein, the one-pot tandem synthesis of β-ketoallylic methylsulfones has been achieved from readily available dimethyl sulfoxide and acetophenones as coupling partners in one step. In this procedure, dimethyl sulfoxide serves as a triple role including solvent, dual synthon and as an oxidant agent. The use of magnetic Ag–Cu MOF as a bimetallic catalyst is the key to the progress of the reaction due to its accessible active sites. It provides facile access to various β-ketoallylic methylsulfone derivatives from direct C(sp3)–H bond activation and functionalization of aromatic methyl ketones especially acetophenones with electron-rich and electron-poor groups. Moreover, the present work offers a synthetically powerful strategy to form products in good to excellent yields (74–96%) with the atom, step, and pot economics. It has also delivered a new chromane-4-one derivative from 2-hydroxy acetophenone with intramolecular Michael-addition of related β-ketoallyl methylsulfone product. In the final step, the electronic properties of some products have been predicted with the theoretical studies.

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.

Exploration of ketone derivatives of succinimide for their antidiabetic potential: In vitro and in vivo approaches

Abstract Diabetes mellitus (DM) is one of the most challenging diseases among all the other diseases in the recent era, and it is a life-threatening disorder. The best enzymes to target for treating DM are α-glucosidase and α-amylase. For this purpose, we explored numerous succinimides with ketone functionalities. First, we explored these compounds for their in vitro analysis. Compounds 1 and 4 exhibited excellent inhibition of both enzymes in in vitro studies. These compounds displayed excellent activity with IC50 values of 3.69 and 1.526 µg·mL−1 against the α-glucosidase enzyme. In the α-amylase inhibitory assay, compound 1 has shown excellent potential with an IC50 value of 1.07 µg·mL−1 and compound 4 with an IC50 value of 0.115 µg·mL−1. Based on the in vitro analysis, the potent compounds were further subjected to their in vivo analysis. Before the in vivo analysis, the toxicity profile was checked, and it was confirmed that the compounds were safe at 1,500 µg·kg−1. Then, these compounds were subjected for their in vivo anti-diabetic potential in a mouse model of diabetes. Various concentrations of compounds 1 and 4 were explored by in vivo analysis using glibenclamide as a standard drug. The blood glucose level of the tested and control groups was measured at 0 to 15 days accordingly. Similarly, we also explored compounds 1 and 4 for the oral glucose tolerance test at 0–120 min using glibenclamide as the standard drug. Hence, the succinimide having ketone moiety displayed excellent potential against diabetes.

Oxidative Cross-Coupling of α-Amino Ketones with Alcohols Enabled by I2-Catalyzed C-H Hydroxylation.

An I2-catalyzed oxidative cross-coupling of α-amino ketones with a wide range of alcohols is described. Using a combination of air and dimethyl sulfoxide (DMSO) as oxidants, the protocol allows an efficient synthesis of α-carbonyl N,O-acetals with high functional group tolerance and enables the late-stage introduction of α-amino ketones into biorelevant alcohols. Moreover, the present method can be used in the coupling of α-amino ketones with other kinds of nucleophiles, which demonstrates great generality for the functionalization of α-amino ketones. A preliminary mechanistic investigation suggests that C-H hydroxylation of α-amino ketones has been recognized as the key step followed by subsequent dehydration coupling.

Electrochemical construction of 2,5-diaryloxazoles via N–H and C(sp3)-H functionalization

An efficient NH and C(sp3)-H functionalization of aryl ketones with benzylamines/amino acids was developed under mild conditions by virtue of anodic oxidation. A variety of functionalized 2,5-diaryloxazoles were obtained with good to excellent yields. Moreover, some important natural products can be prepared by this method. The reaction features a broad substrate scope, scalability, metal-free and chemical oxidant-free.

Photocatalytic Alkylation/Arylative Cyclization of N-Acrylamides of N-Heteroarenes and Arylamines with Dihydroquinazolinones from Unactivated Ketones.

We describe a visible-light photoredox-catalyzed alkylation/arylative cyclization of N-acrylamides─from 2-arylindoles, 2-arylbenzimidazoles, or N-substituted anilines─with ketone-derived dihydroquinazolinones, accessing indolo- and benzimidazolo[2,1-a]isoquinolines or 2-oxindoles. The consecutive incorporation of alkyl- and aryl-carbogenic motifs across a C=C bond via formal cleavage of ketone α-C-C and arene C-H bonds leads to the formation of five- and six-membered rings, with an all-carbon quaternary stereocenter. This dicarbofunctionalization elaborates aromatization-driven radical C-C functionalization of unactivated aliphatic ketones to construct diverse cyclic structures with functionality tolerance.

C−H Functionalization of Aldehydes and Ketones with Transient Directing Groups: Recent Developments

AbstractIn order to directly functionalize C−H bonds of complex molecules and, in particular, to control the regioselectivity of the reaction, a wide range of directing groups has been used. However, these directing groups need to be installed and removed for further applications, which may limit the use of C−H activation in synthesis. Concerning aldehydes and ketones, a transient directing group strategy has recently emerged to overcome this drawback. The addition of an additive, in general an amine, allowed the in situ formation of the real directing group to achieve C−H activation. This review presents the latest developments in the field over the period 2020–2023.

Formal γ-C(sp3)-H Activation of Ketones via Microwave-Promoted and Iminyl-Radical-Mediated 1,5-Hydrogen Atom Transfer.

Microwave irradiation of O-phenyloximes triggers N-O homolysis and 1,5-hydrogen atom transfer (HAT), resulting in formal γ-C-H functionalization of ketones after trapping of the radical intermediate and in situ imine hydrolysis. The Lewis acid InCl3·H2O facilitated HAT, enabling functionalization of benzylic and nonbenzylic secondary carbon atoms. Functionalization of primary carbons was feasible but afforded low yields, requiring ClCH2CO2H instead of InCl3·H2O as an additive. C-O and C-C bond formation could both be accomplished by this method.