Catalytic Desymmetrizing Baeyer-Villiger Oxidation of Quaternary Carbon-Containing Cyclobutane-1,3-diones.

The first highly enantioselective Baeyer-Villiger oxidation of quaternary carbon-containing cyclobutane-1,3-diones using chiral phosphoric acid catalysis and commercially available oxidants was reported. According to the structure of the substrates, two optimized reaction conditions were developed to afford the corresponding chiral tetronic acid products in ≤93% and ≤95% ee values. This reaction offers the first catalytic asymmetric approach to chiral 5,5-disubstituted tetronic acid derivatives. The synthetic potential of this method has been demonstrated by the formal asymmetric synthesis of (-)-vertinolide and the first catalytic asymmetric total synthesis of plakinidone B.

Construction of Chiral Cyclobutanone-Fused 4-Aminoquinolines via Sequential Chiral Phosphoric Acid and Palladium Catalysis.

A one-pot catalytic asymmetric route to novel chiral quaternary-carbon-containing cyclobutanone-fused 4-aminoquinoline derivatives in good to high yields and enantioselectivities is described. This process consists of a chiral phosphoric acid-catalyzed desymmetric carbonyl-amine condensation of prochiral cyclobutane-1,3-diones with 2-halogenated anilines and a Pd-catalyzed coupling reaction of the chiral enaminone intermediates with isocyanides.

Modular synthesis of chiral 1,2-dihydropyridines via Mannich/Wittig/cycloisomerization sequence that internally reuses waste.

1,2-Dihydropyridines are valuable and reactive synthons, and particularly useful precursors to synthesize piperidines and pyridines that are among the most common structural components of pharmaceuticals. However, the catalytic enantioselective synthesis of structurally diverse 1,2-dihydropyridines is limited to enantioselective addition of nucleophiles to activated pyridines. Here, we report a modular organocatalytic Mannich/Wittig/cycloisomerization sequence as a flexible strategy to access chiral 1,2-dihydropyridines from N-Boc aldimines, aldehydes, and phosphoranes, using a chiral amine catalyst. The key step in this protocol, cycloisomerization of chiral N-Boc δ-amino α,ß-unsaturated ketones recycles the waste to improve the yield. Specifically, recycling by-product water from imine formation to gradually release the true catalyst HCl via hydrolysis of SiCl4, whilst maintaining a low concentration of HCl to suppress side reactions, and reusing waste Ph3PO from the Wittig step to modulate the acidity of HCl. This approach allows facile access to enantioenriched 2-substituted, 2,3- or 2,6-cis-disubstituted, and 2,3,6-cis-trisubstituted piperidines.

Quercetin Attenuated Myeloperoxidase-Dependent HOCl Generation and Endothelial Dysfunction in Diabetic Vasculature.

Myeloperoxidase (MPO)-dependent hypochlorous acid (HOCl) generation plays crucial roles in diabetic vascular complications. As a natural polyphenol, quercetin has antioxidant properties in various diabetic models. Herein, we investigated the therapeutic mechanism for quercetin on MPO-mediated HOCl generation and endothelial dysfunction in diabetic vasculature. In vitro, the presence of MPO could amplify high glucose-induced endothelial dysfunction which was significantly inhibited by the NADPH oxidase inhibitor, HOCl or H2O2 scavengers, revealing the contribution of MPO/H2O2/HOCl to vascular endothelial injury. Furthermore, quercetin effectively inhibited MPO/high glucose-mediated HOCl generation and cytotoxicity to vascular endothelial cells. The inhibitive effect on MPO activity was related to the fact that quercetin reduced high glucose-induced H2O2 generation in endothelial cells and directly acted as a competitive substrate for MPO, thus limiting MPO/H2O2-dependent HOCl production. Moreover, quercetin could attenuate HOCl-caused endothelial dysfunction in endothelial cells and isolated aortas. In vivo, dietary quercetin significantly inhibited aortic endothelial dysfunction in diabetic mice, while this compound simultaneously suppressed vascular MPO expression and activity. Therefore, it was demonstrated herein that quercetin inhibited endothelial injury in diabetic vasculature via suppression of MPO/high glucose-dependent HOCl formation.

Catalytic Enantioselective Desymmetrization of Cyclobutane-1,3-diones by Carbonyl-Amine Condensation.

A chiral phosphoric acid-catalyzed enantioselective condensation of 2,2-disubstituted cyclobutane-1,3-diones with a primary amine is described. This reaction offered a mild and efficient protocol for constructing quaternary carbon-containing cyclobutanes in good to high yields and enantioselectivities. This reaction is the first catalytic desymmetrizing carbonyl-amine condensation reaction and also represents the first catalytic desymmetrizing reaction of prochiral cyclobutane-1,3-dione.

Generation of a Bovine Serum Albumin-Diligand Complex for the Protection of Bioactive Quercetin and Suppression of Heme Toxicity.

As an abundant protein in milk and blood serum, bovine serum albumin (BSA) contains various sites to bind a lot of bioactive components, generating BSA-monoligand complex. Demonstration of the interaction between BSA and bioactive components (such as heme, flavonoids) is important to develop effective carrier for the protection of bioactive ligands and to reduce cytotoxicity of heme. Herein, the bindings of BSA to quercetin and/or heme were investigated by multispectroscopic and molecular docking methods. The fluorescence of protein was significantly quenched by both quercetin and heme in a static mode (i.e., generation of BSA-ligand complex). Although quercetin had lower affinity to protein than heme, the interactions of both compounds with protein did locate in site I (i.e., subdomain IIA). BSA-diligand complex was successfully generated after the coaddition of quercetin and heme. The cytotoxicity of free heme to endothelial cells was reduced in the BSA-diligand complex relative to that of heme or BSA-monoligand complex, while the stability of bioactive quercetin was promoted in the complex relative to free flavonoid. The complex provided a better inhibition on the cytotoxicity of heme than BSA-monoligand complex, in which the copresence of quercetin played a vital role.

Chiral Tertiary Amine Catalyzed Asymmetric [4 + 2] Cyclization of 3-Aroylcoumarines with 2,3-Butadienoate.

Coumarins and 2H-pyran derivatives are among the most commonly found structural units in natural products. Therefore, the introduction of 2H-pyran moiety into the coumarin structural unit, i.e., dihydrocoumarin-fused dihydropyranones, is a potentially successful route for the identification of novel bioactive structures, and the synthesis of these structures has attracted continuing research interest. Herein, a chiral tertiary amine catalyzed [4 + 2] cyclization of 3-aroylcoumarines with benzyl 2,3-butadienoate was reported. In the presence of Kumar's 6'-(4-biphenyl)-ß-iso-cinchonine, the desired dihydrocoumarin-fused dihydropyranone products could be obtained in up to 97% yield and 90% ee values.

Enantioselective Construction of Chiral Cyclopropa[c]coumarins via Lewis Base-Catalyzed Cyclopropanation.

The first highly enantioselective construction of chiral cyclopropa[c]coumarins was described. Using commercially available (bis)cinchona alkaloid (DHQ)2PYR as the chiral Lewis base catalyst, together with Cs2CO3 as the achiral base, the reaction of a series of coumarin-3-carboxylate and 3-benzoyl coumarins with tert-butyl 2-bromoacetate could give rise to the corresponding cyclopropa[c]coumarins bearing three continuous chiral stereocenters in 83-93% ee and 90-97% ee, respectively. The reaction is proposed to proceed via an in situ generated ammonium ylide intermediate.

Carbonyl-Stabilized Phosphorus Ylide as an Organocatalyst for Cyanosilylation Reactions Using TMSCN.

We report carbonyl-stabilized phosphorus ylides as general and efficient catalysts for the cyanosilylation of ketones. The N,N-diethylacetamide derived phosphorane is identified as an extremely efficient catalyst for the cyanosilylation of dialkyl ketones, alkyl aryl ketones, diaryl ketones, and α,ß-unsaturated enones with catalyst loading down to 0.005 mol %, the lowest ever known for ketone cyanosilylation. Aldehydes, aldimines, and ketimines are also viable substrates. By NMR and React IR analysis, as well as electrical conductivity experiments, it is proposed that the phosphorane acts as a Lewis base in order to mediate the reaction via the desilylative nucleophilic activation of TMSCN.

Me2(CH2Cl)SiCN: Bifunctional Cyanating Reagent for the Synthesis of Tertiary Alcohols with a Chloromethyl Ketone Moiety via Ketone Cyanosilylation.

We report a novel bifunctional cyanating reagent, Me2(CH2Cl)SiCN, which paves the way to a one-pot sequential synthesis of tertiary alcohols featuring a chloromethyl ketone moiety via enantioselective ketone cyanosilylation. This method contributes to gram-scale enantioselective total synthesis of the aggregation pheromone of the Colorado potato beetle, (S)-CPB.

Catalytic Enantioselective Desymmetrization Reactions to All-Carbon Quaternary Stereocenters.

This Review summarizes the advances in the construction of all-carbon quaternary stereocenters via catalytic enantioselective desymmetrization of prochiral and meso-compounds, highlights the power and potential of this strategy in the total synthesis of natural products and biologically active compounds, and outlines the synthetic opportunities still available.

Asymmetric sequential Au(i)/chiral tertiary amine catalysis: an enone-formation/cyanosilylation sequence to synthesize optically active 3-alkenyloxindoles from diazooxindoles.

An unprecedented sequential gold-catalyzed enone-formation and bifunctional tertiary amine mediated asymmetric cyanosilylation reaction is developed, allowing the highly enantioselective synthesis of 3-alkenyloxindoles from diazooxindoles, furans and trimethylsilyl cyanide (TMSCN).

Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly Enantioselective Cyanosilylation of Ketones and Enones.

Phosphoranes 2 are identified as a class of effective Lewis bases to activate chiral (salen)AlCl complex 1 to enhance its electrophilicity. Accordingly, a three-component catalyst system consisting of complex 1, phosphorane 2e, and Ph3PO is developed as a powerful tool for asymmetric ketone cyanosilylation. In particular, an unprecedented highly enantioselective cyanosilylation of linear aliphatic ketones is achieved. A tandem Wittig-cyanosilylation sequence starting from phosphorane 2a and enals 10 is further achieved, which internally utilizes the Ph3PO byproduct and remaining phosphorane 2a as cocatalysts for cyanosilylation of α,ß,γ,δ-unsaturated enones, providing atom-efficient access to valuable chiral conjugated dienes and enynes. The high efficiency of the cyanosilylation originates from orthogonal activation of both (salen)AlCl complex 1 and cyanotrimethylsilane by the phosphorane and Ph3PO, respectively. This mechanistic insight is supported by NMR, MS, and ReactIR analyses and DFT calculations. Furthermore, the formation of charged complexes through the activation of chiral complex 1 by phosphorane 2a is confirmed by electrical conductivity experiments.

Successively recycle waste as catalyst: a one-pot Wittig/1,4-reduction/Paal-Knorr sequence for modular synthesis of substituted furans.

A one-pot tandem Wittig/conjugate reduction/Paal-Knorr reaction is reported for the synthesis of di- or trisubstituted furans. This novel sequence first demonstrates the possibility of successively recycling waste from upstream steps to catalyze downstream reactions.

Asymmetric triple relay catalysis: enantioselective synthesis of spirocyclic indolines through a one-pot process featuring an asymmetric 6π electrocyclization.

A rare example of a one-pot process that involves asymmetric triple relay catalysis is reported. The key step is an asymmetric [1,5] electrocyclic reaction of functionalized ketimines. The substrates for this process were obtained in situ in a two-step process that involved the hydrogenation of nitroarenes with a Pd/C catalyst to yield aryl amines and their subsequent coupling with isatin derivatives in a Brønsted acid catalyzed ketimine formation reaction. The electrocyclization was catalyzed by a bifunctional chiral Brønsted base/hydrogen bond donor catalyst. The one-pot process gave the desired products in good yields and with excellent enantioselectivity.

Palladium/norbornene-mediated tandem C-H amination/C-I alkenylation reaction of aryl iodides with secondary cyclic O-benzoyl hydroxylamines and activated terminal olefins.

A novel palladium-catalyzed norbornene-mediated three-component reaction for the construction of ortho-alkenyl aromatic tertiary amines has been achieved, which represents a useful extension of the Catellani-type tandem ortho-selective CH amination transformations.

One-pot tandem approach to spirocyclic oxindoles featuring adjacent spiro-stereocenters.

All in a sequence: An organocatalyzed Morita-Baylis-Hillman (MBH)/bromination/[3+2] annulation sequence for highly stereoselective syntheses of bis(spirooxindole)s featuring adjacent spiro-stereocenters is described. The key step is an unprecedented catalytic asymmetric [3+2] annulation of isatin-derived MBH adducts, containing a tetrasubstituted alkene moiety, with isatins.

Organocatalytic asymmetric synthesis of 3,3-disubstituted oxindoles featuring two heteroatoms at the C3 position.

We report the first organocatalytic asymmetric synthesis of 3,3-disubstituted oxindoles featuring two heteroatoms at the C3 position. Importantly, 3-thiooxindoles and 3-alkoxyoxindoles are demonstrated to be reactive nucleophiles for the development of catalytic asymmetric reactions for the first time.