Benzylic Oxidation Research Articles

A Class of Valuable (Pro-)Activity-Based Protein Profiling Probes: Application to the Redox-Active Antiplasmodial Agent, Plasmodione.

Plasmodione (PD) is a potent antimalarial redox-active drug acting at low nM range concentrations on different malaria parasite stages. In this study, in order to determine the precise PD protein interactome in parasites, we developed a class of (pro-)activity-based protein profiling probes (ABPP) as precursors of photoreactive benzophenone-like probes based on the skeleton of PD metabolites (PDO) generated in a cascade of redox reactions. Under UV-photoirradiation, we clearly demonstrate that benzylic oxidation of 3-benzylmenadione 11 produces the 3-benzoylmenadione probe 7, allowing investigation of the proof-of-concept of the ABPP strategy with 3-benzoylmenadiones 7–10. The synthesized 3-benzoylmenadiones, probe 7 with an alkyne group or probe 9 with -NO2 in para position of the benzoyl chain, were found to be the most efficient photoreactive and clickable probes. In the presence of various H-donor partners, the UV-irradiation of the photoreactive ABPP probes generates different adducts, the expected “benzophenone-like” adducts (pathway 1) in addition to “benzoxanthone” adducts (via two other pathways, 2 and 3). Using both human and Plasmodium falciparum glutathione reductases, three protein ligand binding sites were identified following photolabeling with probes 7 or 9. The photoreduction of 3-benzoylmenadiones (PDO and probe 9) promoting the formation of both the corresponding benzoxanthone and the derived enone could be replaced by the glutathione reductase-catalyzed reduction step. In particular, the electrophilic character of the benzoxanthone was evidenced by its ability to alkylate heme, as a relevant event supporting the antimalarial mode of action of PD. This work provides a proof-of-principle that (pro-)ABPP probes can generate benzophenone-like metabolites enabling optimized activity-based protein profiling conditions that will be instrumental to analyze the interactome of early lead antiplasmodial 3-benzylmenadiones displaying an original and innovative mode of action.

Break‐and‐Build Strategy for the Synthesis of 2‐Benzoylbenzoxazoles from o‐Aminophenols and Acetophenones

AbstractAlthough compounds with a 2‐benzoylbenzoxazole motif are biologically relevant, there are only a few methods for synthesizing them, most of which relied on multistep process or required substrates bearing activating groups. Herein, we report an efficient method for the synthesis of such compounds by direct reactions of o‐aminophenols with acetophenones promoted by sulfur in DMSO. The reaction was found to proceed via a Willgerodt rearrangement‐type benzoxazolation of acetophenones followed by a benzylic oxidation to reinstall the carbonyl function. This method has a broad substrate scope and good tolerance for sensitive functional groups.magnified image

Recent advances in the copper-catalyzed aerobic Csp3-H oxidation strategy.

The interplay between copper catalysts and molecular oxygen provides the opportunity to control the promiscuous catalytic behaviors in aerobic Csp3-H bond oxidations without using stoichiometric amounts of oxidants. This mini-review aims to cover the Cu-catalyzed aerobic benzylic and α-carbonyl Csp3-H oxidations and that of the carbon next to an amine group in the past five years. The development of tandem multicomponent reactions employing aerobic Csp3-H bond oxidations will be discussed to highlight the controlled catalyst behaviors and the catalyst interactions between multiple reaction components.

An efficient and practical aerobic oxidation of benzylic methylenes by recyclable N-hydroxyimide.

An efficient and practical benzylic aerobic oxidation catalyzed by cheap and simple N-hydroxyimide organocatalyst has been achieved with high yields and broad substrate scope. The organocatalyst used can be recycled and reused by simple workup and only minute amount (1 mol% in most cases) of simple iron salt is used as promoter. Phenyl substrates with mild and strong electron-withdrawing group could also be oxygenated in high yields as well as other benzylic methylenes. Influence of substituents, gram-scale application, catalysts decay and general mechanism of this methodology has also been discussed.

Benzylic Oxidation Catalyzed by Cobalt(II)-Terpyridine Coordination Polymers

Benzylic Oxidation Catalyzed by Cobalt(II)-Terpyridine Coordination Polymers

Exploration of highly electron-rich manganese complexes in enantioselective oxidation catalysis; a focus on enantioselective benzylic oxidation

The development of highly electron-rich manganese complexes for enantioselective benzylic oxidation (and asymmetric epoxidation) is described, to provide chiral benzylic alcohols and epoxides in good yields and enantioselectivites.

Solvent-free benzylic oxidation of aromatics over Cu(II)-containing propylsalicylaldimine anchored on the surface of mesoporous silica catalysts.

A sustainable method was used to produce aromatic ketones by the solvent-free benzylic oxidation of aromatics over mesoporous Cu(II)-containing propylsalicylaldimine anchored on the surface of Santa Barbara Amorphous type material-15 (CPSA-SBA-15) catalysts. For comparison, mesoporous Cu(II)-containing propylsalicylaldimine anchored with Mobil Composition of Matter-41 (CPSA-MCM-41) was assessed for these reactions under similar reaction conditions. The washed CPSA-SBA-15(0.2) (W-CPSA-SBA-15(0.2)) catalyst was prepared using an easy chemical method for the complete removal of non-framework CuO nanoparticle species on the surface of pristine CPSA-SBA-15(0.2) (p-CPSA-SBA-15(0.2) prepared with 0.2 wt% of Cu, and its catalytic activity was evaluated with different reaction parameters, oxidants and solvents. In order to confirm the catalytic stability, the recyclability was assessed, and the performance of hot-filtration experiments was also evaluated. All the catalysts used for these catalytic reactions were characterized using many instrumental techniques to pinpoint the mesoporous nature and active sites of the catalysts. The proposed reaction mechanism has been well documented on the basis of catalytic results obtained for solvent-free oxidation of aromatics. Based on the catalytic results, we found that W-CPSA-SBA-15(0.2) is a very ecofriendly catalyst with exceptional catalytic activity.

Surface oxygen vacancies of Pd/Bi2MoO6-x acts as “Electron Bridge” to promote photocatalytic selective oxidation of alcohol

The recombination of photogenerated carriers seriously restricts their utilization efficiency in photocatalysis. Herein, surface oxygen vacancies (SOVs) were constructed in Pd-Bi2MoO6 interface to bridge ultra-low loading Pd cluster and Bi2MoO6 semiconductor (Pd/BMO-SOVs). It was found SOVs in Pd/Bi2MoO6-x serve as “Electron Bridge” to bridge ultra-low loading Pd cluster and Bi2MoO6-x, thus tremendously enhance utilization efficiency of photoexcited carriers and ultra-low loading Pd active sites for blue LED driven selective oxidation reaction. The Pd(0.05)/Bi2MoO6-SOVs exhibited 57.8 % conversion for selection oxidation of benzyl which are 6.5, 3.3 and 2.1 times higher than pristine Bi2MoO6, Bi2MoO6-x and Pd(0.05)/Bi2MoO6. Combined with theoretical calculations, SOVs was proposed as “Electron Bridge” to transfer photogenerated electrons from Bi2MoO6-x to ultra-low loading Pd clusters, thus greatly boosting separation and utilization efficiency of photogenerated electron-hole pairs.

Effect of Metal Ions on Oxidation of Micropollutants by Ferrate(VI): Enhancing Role of FeIV Species.

This paper investigated the oxidation of recalcitrant micropollutants [i.e., atenolol (ATL), flumequine, aspartame, and diatrizoic acid] by combining ferrate(VI) (FeVIO42-, FeVI) with a series of metal ions [i.e., Fe(III), Ca(II), Al(III), Sc(III), Co(II), and Ni(II)]. An addition of Fe(III) to FeVI enhanced the oxidation of micropollutants compared solely to FeVI. The enhanced oxidation of studied micropollutants increased with increasing [Fe(III)]/[FeVI] to 2.0. The complete conversion of phenyl methyl sulfoxide (PMSO), as a probe agent, to phenyl methyl sulfone (PMSO2) by the FeVI-Fe(III) system suggested that the highly reactive intermediate FeIV/FeV species causes the increased oxidation of all four micropollutants. A kinetic modeling of the oxidation of ATL demonstrated that the major species causing the increase in ATL removal was FeIV, which had an estimated rate constant as (6.3 ± 0.2) × 104 M-1 s-1, much higher than that of FeVI [(5.0 ± 0.4) × 10-1 M-1 s-1]. Mechanisms of the formed oxidation products of ATL by FeIV, which included aromatic and/or benzylic oxidation, are delineated. The presence of natural organic matter significantly inhibited the removal of four pollutants by the FeVI-Fe(III) system. The enhanced effect of the FeVI-Fe(III) system was also seen in the oxidation of the micropollutants in river water and lake water.

Chemoselective Oxidation ofp-Methoxybenzyl Ethers by an Electronically Tuned Nitroxyl Radical Catalyst

The oxidation of p-methoxy benzyl (PMB) ethers was achieved using nitroxyl radical catalyst 1, which contains electron-withdrawing ester groups adjacent to the nitroxyl group. The oxidative deprotection of the PMB moieties on the hydroxy groups was observed upon treatment of 1 with 1 equiv of the co-oxidant phenyl iodonium bis(trifluoroacetate) (PIFA). The corresponding carbonyl compounds were obtained by treating the PMB-protected alcohols with 1 and an excess of PIFA.

Activity-Based Sensing of Ascorbate by Using Copper-Mediated Oxidative Bond Cleavage.

Ascorbate is an important biological reductant and enzyme cofactor. Although direct detection through ascorbate-mediated reduction is possible, this approach suffers from poor selectivity due to the wide range of cellular reducing agents. To overcome this limitation, we leverage reduction potential of ascorbate to mediate a copper-mediated oxidative bond cleavage of ether-caged fluorophores. The copper(II) complexes supported by a {bis(2-pyridylmethyl)}benzylamine or a {bis(2-pyridylmethyl)}(2-methoxybenzyl)amine ligand were identified as an ascorbate responsive unit and their reaction with ascorbate yields a copper-based oxidant that enables rapid benzylic oxidation and the release of an ether-caged dye (coumarin or fluorescein). The copper-mediated bond cleavage is specific to ascorbate and the trigger can be readily derivatized for tuning photophysical properties of the probes. The probes were successfully applied for the fluorometric detection of ascorbate in commercial food samples, human plasma, and serum, and within live cells by using confocal microscopy and flow cytometry.

Asymmetric one-pot transformation of isoflavones to pterocarpans and its application in phytoalexin synthesis

Phytoalexins have attracted much attention due to their health-promoting effects and their vital role in plant health during the last years. Especially the 6a-hydroxypterocarpans glyceollin I and glyceollin II, which may be isolated from stressed soy plants, possess a broad spectrum of bioactivities such as anticancer activity and beneficial contributions against western diseases by anti-oxidative and anti-cholesterolemic effects. Aiming for a catalytic asymmetric access to these natural products, we establish the asymmetric syntheses of the natural isoflavonoids (−)-variabilin, (−)-homopterocarpin, (−)-medicarpin, (−)-3,9-dihydroxypterocarpan, and (−)-vestitol by means of an asymmetric transfer hydrogenation (ATH) reaction. We successfully adapt this pathway to the first catalytic asymmetric total synthesis of (−)-glyceollin I and (−)-glyceollin II. This eight-step synthesis features an efficient one-pot transformation of a 2′-hydroxyl-substituted isoflavone to a virtually enantiopure pterocarpan by means of an ATH and a regioselective benzylic oxidation under aerobic conditions to afford the susceptible 6a-hydroxypterocarpan skeleton.

Total Synthesis of the Plant Growth Promoter Auxofuran Featuring a Gold(I) Catalyzed Furan Formation.

A concise synthesis of auxofuran (1) was developed. Starting with a Sonogashira cross-coupling reaction, enynol (10) was prepared. A gold(I) catalyzed cycloisomerization led to disubstituted furan 12. Via an intramolecular Friedel-Crafts cyclization, a dihydrobenzofuranone was obtained. Functional group manipulations, including benzylic oxidation, led to the target molecule.

Electrochemical Total Synthesis of Pyrrolophenanthridone Alkaloids: Controlling the Anodically Initiated Electron Transfer Process.

Electrochemical intramolecular C(sp2)-H cross-coupling and dehydrogenative indole synthesis were developed. Both reactions were initiated by anodic oxidation of the same electron-rich indoline moiety, but the product selectivity was controlled by different electron-transfer processes. Intramolecular cross-coupling was achieved by the generation of a strong electrophilic radical cation intermediate in the MeNO2-HFIP-LiClO4 system. Indole formation was accomplished through benzylic oxidation and continuous deprotonation. We applied these reactions to the total synthesis of natural pyrrolophenanthridone alkaloids.

Comparison study of ε‐caprolactone, L‐lactide, and ε‐decalactone polymerizations using aluminum complexes bearing pyrazole derivatives, and synthesis of polylactide‐gradual‐poly‐ε‐caprolactone copolymer

AbstractThis study compared ε‐caprolactone (CL), L‐lactide (LA), and ε‐decalactone (DL) polymerizations, where aluminum complexes bridged by two pyrazole ligands was used as catalysts. The reactivites of these Al complexes between CL, LA, and DL polymerization were different that L Bu 2Al 2Me 4, with the distort boat form, exhibits the greatest catalytic activity for LA and DL polymerization at 60°C but the lowest catalytic activity for CL polymerization at room temperature. This may be because dinuclear L Bu 2Al 2Me 4 cannot react with BnOH to form aluminum benzyl oxide at room temperature, making it unable to reduce catalytic activity. Because these aluminum complexes had different reactivities for LA and CL polymerizations, the selectivity of polylactide‐gradual‐poly‐ε‐caprolactones (PLA(10–80%)‐gradual‐PCL(59–79%)) (PLA‐g‐PCLs) was observed.

An unexpected benzylic oxidation in the multicomponent synthesis of simplified analogs of anchinopeptolides and eusynstyelamides

The combination of a photoinduced multicomponemt reaction with dimerization of the resulting intermediate can generate complex heterocyclic compounds in a stereodefined manner, with six new bonds and two quaternary carbons formed in just two steps. Remarkably, final heterocycles share the same core with two families of natural products, namely anchinopeptolides and eusynstyelamides. During the synthesis of simplified analogs of these compounds, we came across an unexpected oxidation and decided to study this process, trying to understand the factors able to influence it. We report here preliminary results showing that the structure of the substrates is a key factor in determining the oxidative or nonoxidative outcome of the dimerization reaction.

Formal synthesis of cochlearol A, a meroterpenoid with renoprotective activity

Cochlearol A, a renoprotective meroterpenoid isolated from Ganoderma cochlear, was formally synthesized by intramolecular acetal formation. Its characteristic perhydro-3,9a-epoxybenzo[c]oxepine skeleton was stereoselectively constructed by intramolecular acetal formation employing spiroepoxide as a key intermediate, which was prepared via benzylic oxidation under Nicolaou’s conditions employing photochemically activated Pb(OAc)4 and introduction of epoxide under Concellón’s conditions using diiodomethane and methyllithium.

Iodine(III)-catalyzed benzylic oxidation by using the (PhIO)n/Al(NO3)3 system

The first iodine(III)-based procedure for the benzylic oxidation of different arenes is described by using the (PhIO)n/Al(NO3)3 system under catalytic conditions leading to the formation of the corresponding carbonyl derivatives. The method proceeds under mild, operationally simple, room temperature, short reaction times, and open flask conditions. In light of the organocatalysis relevance and the novelty of our protocol, we wish to communicate our initial results of this novel oxidation.

Benzylic Oxidation and Functionalizations of Xanthenes by Ligand Trasfer Reactions of Hypervalent Iodine Reagents

Benzylic Oxidation and Functionalizations of Xanthenes by Ligand Trasfer Reactions of Hypervalent Iodine Reagents

Highly selective electrocatalytic oxidation of benzyl C–H using water as safe and sustainable oxygen source

H2O serves as a safe oxygen source in the electrocatalytic oxidation of benzyl C–H, with significantly improved overpotential and faradaic efficiency on layered MnO2 catalysts.