Enone Functionality Research Articles

Total Synthesis of Penicyclone A Using a Double Grignard Reaction.

We describe the first total synthesis of penicyclone A, a novel deep-sea fungus-derived polyketide, and a reevaluation of its antimicrobial activity. The synthesis of this unique spirolactone was achieved in 10 steps starting from a known d-ribose derivative. The key steps include a double Grignard reaction for the diastereoselective construction of the chiral tertiary alcohol intermediate, tandem oxidation/cyclization, and photooxygenation, followed by an oxidative rearrangement to introduce the enone functionality.

Bottom-Up De Novo Synthesis of Porous Organic Polymers with Enone Functionalities as Supports for Pd and Cu Nanoparticles for Catalytic Tandem Synthesis

Bottom-Up De Novo Synthesis of Porous Organic Polymers with Enone Functionalities as Supports for Pd and Cu Nanoparticles for Catalytic Tandem Synthesis

Unified Total Synthesis of Tetracyclic Diquinane Lycopodium Alkaloids (+)-Paniculatine, (-)-Magellanine, and (+)-Magellaninone.

A unified route for the total synthesis of three tetracyclic diquinane Lycopodium alkaloids (+)-paniculatine, (-)-magellanine, and (+)-magellaninone has been accomplished in 13-14 overall steps based on late-stage diverse transformations from an advanced tetracyclic common intermediate. In the established synthesis, quick formation of the two five-membered rings was efficiently achieved by an intramolecular reductive coupling of ketone-carbonyl and ester-carbonyl and an organocatalytic intramolecular Michael addition of aldehyde-derived enamine to an internal enone functionality with satisfactory redox and step economies and excellent stereoselectivities, providing the requisite tricyclic carbo-framework possessing multiple dense stereogenic centers, and an intramolecular reductive amination finally furnished the essential piperidine ring.

Palladium(0)-Catalyzed Remote Decarboxylative Allylation and Base-Mediated 1,3-Migration.

Herein we have reported the palladium(0)-catalyzed decarboxylative oxa-Michael addition/remote α-allylation/1,3- migration of prochiral allyl carbonate-tethered cyclohexadienones in good yields. This unconventional intramolecular rearrangement is triggered by the base-mediated retro-Michael ring-opening reaction (β-elimination) and subsequent syn-selective oxa-Michael addition on the less substituted enone functionality. The generality of tandem decarboxylative allylation was examined with various substrates and in the gram-scale reaction.

Synthesis of pleiogenone A and 2,3-dihydropleiogenone A: Identification of the pleiogenone pharmacophore

Pleiogenone A was identified in 2015 from organic extracts of the bark of Pleiogynium timoriense and shown to exhibit sub-micromolar antiproliferative activity against the A2780 ovarian tumor cell line. A central structural feature of pleiogenone A is a hydroxylated cyclohexenone. As a potential electrophilic site this group may represent the pharmacophore of pleiogenone A. To evaluate the relevance of the enone functionality to the antitumor activity of pleiogenone A, the saturated analog (2,3-dihydropleiogenone A) was prepared by chemical synthesis and compared to pleiogenone A in a cell proliferation assay. As 2,3-dihydropleiogenone A was inactive in the proliferation assay we conclude the cyclohexenone core represents the pharmacophore of pleiogenones A-C and a likely site of protein adduction.

Total Synthesis of Stemarene and Betaerene Diterpenoids: Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

A unified protecting group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first t...

Rapid Synthesis of Functionalized Hydrocarbazolones via Indole C2−H Activation Using Enone Functionality as a Directing Group/Electrophilic Species

AbstractHydrocarbazolones are a key structural unit in many natural bioactive compounds and are thus a valuable synthetic target. A rhodium‐catalyzed C−H functionalization reaction with acceptor/acceptor diazo compounds was developed for synthesizing 2,3‐fused indole variants. An α,β‐unsaturated enone was utilized as a directing group for site‐selective C−H activation and as an electrophile for the subsequent cyclization. Overall, the developed annulation enabled the rapid assembly of synthetically valuable hydrocarbazolones from readily available indoles. Additionally, computational investigations were conducted to elucidate the reaction pathway and rationalize the experimentally observed site‐selectivity.magnified image

Rh-Catalyzed cyclization of 2,3-allenoic acids in the presence of 2,3-allenols.

Herein we report a [Cp*RhCl2]2-catalyzed coupling cyclization of two different classes of allenes with 2,3-allenoic acids affording 2(5H)-furanone skeletons of products and 2,3-allenols forming a conjugated (E)-enal or enone functionality to the β-position of the 2(5H)-furanones. These products are important building blocks for the syntheses of potentially bioactive compounds. The reaction proceeded via the nucleometalation, insertion, and stereodefined 1,4-H delivery carried by rhodium.

Silver(I)-Catalyzed Enyne Cyclization/Aromatization of Alkyne-Tethered Cyclohexadienones to Access Meta-Substituted Phenols.

Herein we report a highly regioselective silver(I)-catalyzed intramolecular annulation of alkyne-tethered cyclohexadienones to access meta-substituted phenols with enone functionality, which are difficult to synthesize from conventional methods. The reaction proceeds via intramolecular 1,6-enyne cyclization followed by aromatization and subsequent oxetene ring rearrangement. This strategy has also been compatible with a wide range of C-tethered cyclohexadienones to afford indanes in high yields. The unique functionality of products allows further transformations to expand the diversity.

Trioxolone Methyl, a Novel Cyano Enone-Bearing 18βH-Glycyrrhetinic Acid Derivative, Ameliorates Dextran Sulphate Sodium-Induced Colitis in Mice.

Semi-synthetic triterpenoids, bearing cyano enone functionality in ring A, are considered to be novel promising therapeutic agents with complex inhibitory effects on tissue damage, inflammation and tumor growth. Previously, we showed that the cyano enone-containing 18βH-glycyrrhetinic acid derivative soloxolone methyl (SM) effectively suppressed the inflammatory response of macrophages in vitro and the development of influenza A-induced pneumonia and phlogogen-stimulated paw edema in vivo. In this work, we reported the synthesis of a novel 18βH-glycyrrhetinic acid derivative trioxolone methyl (TM), bearing a 2-cyano-3-oxo-1(2)-en moiety in ring A and a 12,19-dioxo-9(11),13(18)-dien moiety in rings C, D, and E. TM exhibited a high inhibitory effect on nitric oxide (II) production by lipopolysaccharide-stimulated J774 macrophages in vitro and dextran sulfate sodium (DSS)-induced colitis in mice, displaying higher anti-inflammatory activity in comparison with SM. TM effectively suppressed the DSS-induced epithelial damage and inflammatory infiltration of colon tissue, the hyperproduction of colonic neutral mucin and TNFα and increased glutathione synthesis. Our in silico analysis showed that Akt1, STAT3 and dopamine receptor D2 can be considered as mediators of the anti-colitic activity of TM. Our findings provided valuable information for a better understanding of the anti-inflammatory activity of cyano enone-bearing triterpenoids and revealed TM as a promising anti-inflammatory candidate.

Multifunctional porous organic polymers (POPs): Inverse adsorption of hydrogen over nitrogen, stabilization of Pd(0) nanoparticles, and catalytic cross-coupling reactions and reductions

In spite of the fact that a variety of reactions have been exploited for creation of innumerable porous organic polymers (POPs), aldol condensation reactions between aldehydes and ketones leading to enones remain unutilized quite inexplicably. We surmised that the enone functionality can be exploited for stabilization of Pd akin to the manner of Pd(0) in Pd2(dba)3 by developing POPs based on aldol condensation reactions of polycarbonyl compounds with dialdehydes, and that such materials can be employed for catalytic transformations. By subjecting rationally designed tri-/tetraacetyl-functionalized aryl amines to aldol condensations with terephthalaldehyde, three different POPs, i.e., TPAPOPs 1–3, that feature enone functionalities have been synthesized and shown to exhibit palpable gas sorption properties. Remarkably, inverse uptake for sorption of H2 over N2 was observed for all POPs. As surmised, the representative POP, i.e., TPAPOP-1, was found to stabilize in situ-generated Pd(0) nanoparticles to enable application of the resultant material, i.e., Pd@TPAPOP-1, as a recyclable heterogeneous catalyst for a number of organic transformations. It is shown that coupling reactions such as Suzuki and Heck, and reductions such as nitro-to-amine and hydrogenation of olefins can be accomplished in a facile manner by employing Pd@TPAPOP-1 as a heterogeneous recyclable catalyst; the aforementioned transformations have been demonstrated on a broad set of substrates for each type.

Deep insights into the response of human cervical carcinoma cells to a new cyano enone-bearing triterpenoid soloxolone methyl: a transcriptome analysis.

Semisynthetic triterpenoids, bearing cyano enone functionality in ring A, are considered now as novel promising anti-tumor agents. However, despite the large-scale studies, their effects on cervical carcinoma cells and, moreover, mechanisms underlying cell death activation by such compounds in this cell type have not been fully elucidated. In this work, we attempted to reconstitute the key pathways and master regulators involved in the response of human cervical carcinoma KB-3-1 cells to the novel glycyrrhetinic acid derivative soloxolone methyl (SM) by a transcriptomic approach. Functional annotation of differentially expressed genes, analysis of their cis-regulatory sequences and protein-protein interaction network clearly indicated that stress of endoplasmic reticulum (ER) is the central event triggered by SM in the cells. A range of key ER stress sensors and transcription factor AP-1 were identified as upstream transcriptional regulators, controlling the response of the cells to SM. Additionally, by using Gene Expression Omnibus data, we showed the ability of SM to modulate the expression of key genes involved in regulation of the high proliferative rate of cervical carcinoma cells. Further Connectivity Map analysis revealed similarity of SM's effects with known ER stress inducers thapsigargin and geldanamycin, targeting SERCA and Grp94, respectively. According to the molecular docking study, SM could snugly fit into the active sites of these proteins in the positions very close to that of both inhibitors. Taken together, our findings provide a basis for the better understanding of the intracellular processes in tumor cells switched on in response to cyano enone-bearing triterpenoids.

Molecular Networking-Based Analysis of Cytotoxic Saponins from Sea Cucumber Holothuria atra.

The saponin composition of a specimen of black sea cucumber, Holothuria atra collected in the Persian Gulf was studied by a combined approach including LC-MS/MS, Molecular Networking, pure compound isolation, and NMR spectroscopy. The saponin composition of Holothuria atra turned out to be more complex than previously reported. The most abundant saponins in the extract (1–4) were isolated and characterized by 1D- and 2D-NMR experiments. Compound 1 was identified as a new triterpene glycoside saponin, holothurin A5. The side chain of the new saponin 1, unprecedented among triterpene glycosides, is characterized by an electrophilic enone function, which can undergo slow water or methanol addition under neutral conditions. The cytotoxic activity of compounds 1–4, evaluated on the human cervix carcinoma HeLa cell line, was remarkable, with IC50 values ranging from 1.2 to 2.5 µg/mL.

ChemInform Abstract: Alternative Routes to the Acylphloroglucinol Rhodomyrtone.

Two novel routes to the acylphloroglucinol rhodomyrtone (1) which has antibiotic properties are presented. In the first route an ortho-quinone methide, generated from dioxaborinine 23, is reacted with syncarpic acid (10) leading to xanthenedione 25. Cleavage of the methyl ether functions led to the known rhodomyrtone precursor 16. In the second route the bis-ester derivative 28 of trihydroxybenzaldehyde 26 is condensed with syncarpic acid (10) to give tricyclic hemiacetal 29. Acetalization and cuprate addition to the enone function led to bis-ester 32 which gave rhodomyrtone (1) by TiCl4-induced regioselective Fries rearrangement.

Alternative routes to the acylphloroglucinol rhodomyrtone

Two novel routes to the acylphloroglucinol rhodomyrtone (1) which has antibiotic properties are presented. In the first route an ortho-quinone methide, generated from dioxaborinine 23, is reacted with syncarpic acid (10) leading to xanthenedione 25. Cleavage of the methyl ether functions led to the known rhodomyrtone precursor 16. In the second route the bis-ester derivative 28 of trihydroxybenzaldehyde 26 is condensed with syncarpic acid (10) to give tricyclic hemiacetal 29. Acetalization and cuprate addition to the enone function led to bis-ester 32 which gave rhodomyrtone (1) by TiCl4-induced regioselective Fries rearrangement.

ChemInform Abstract: Gold‐Catalyzed Oxidation of Propargylic Ethers with Internal C—C Triple Bonds: Impressive Regioselectivity Enabled by Inductive Effect.

Abstract Inductive perturbations of C–C triple bonds are shown to dictate the regiochemistry of gold-catalyzed oxidation of internal C–C triple bonds in the cases of propargylic ethers, resulting in highly regioselective formation of β-alkoxy-α,β-unsaturated ketones (up to >50/1 selectivity) via α-oxo gold carbene intermediates. Ethers derived from primary propargylic alcohols can be reliably transformed in good yields, and various functional groups are tolerated. With substrates derived from secondary propargylic alcohols, the development of a new P,N-bidentate ligand enables the minimization of competing alkyl group migration to the gold carbene center over the desired hydride migration; the preferred migration of a phenyl group, however, results in efficient formation of a α-phenyl-β-alkoxy-α,β-unsaturated ketone. These results further advance the surrogacy of a propargyl moiety to synthetically versatile enone function with reliable and readily predictable regioselectivity.

ChemInform Abstract: Synthesis of 3‐Carbonyl Pyrazole‐5‐phosphonates via 1,3‐Dipolar Cycloaddition of Bestmann—Ohira Reagent with Ynones.

Abstract The present work explores the hitherto unexplored reactivity of ynones as dipolarophiles with Bestmann–Ohira reagent. The reaction offers a convenient route for the synthesis of regioisomerically pure 3,5-disubstituted or 3,4,5-trisubstituted pyrazoles in excellent yields. However, di-ynones and molecules possessing both ynone and enone functionalities provide only monocycloaddition products, whereas another multiple bond undergoes Michael addition with the methoxide anion.

Gold-catalyzed oxidation of propargylic ethers with internal C–C triple bonds: Impressive regioselectivity enabled by inductive effect

Inductive perturbations of C–C triple bonds are shown to dictate the regiochemistry of gold-catalyzed oxidation of internal C–C triple bonds in the cases of propargylic ethers, resulting in highly regioselective formation of β-alkoxy-α,β-unsaturated ketones (up to >50/1 selectivity) via α-oxo gold carbene intermediates. Ethers derived from primary propargylic alcohols can be reliably transformed in good yields, and various functional groups are tolerated. With substrates derived from secondary propargylic alcohols, the development of a new P,N-bidentate ligand enables the minimization of competing alkyl group migration to the gold carbene center over the desired hydride migration; the preferred migration of a phenyl group, however, results in efficient formation of a α-phenyl-β-alkoxy-α,β-unsaturated ketone. These results further advance the surrogacy of a propargyl moiety to synthetically versatile enone function with reliable and readily predictable regioselectivity.

Synthesis of 3-carbonyl pyrazole-5-phosphonates via 1,3-dipolar cycloaddition of Bestmann–Ohira reagent with ynones

The present work explores the hitherto unexplored reactivity of ynones as dipolarophiles with Bestmann–Ohira reagent. The reaction offers a convenient route for the synthesis of regioisomerically pure 3,5-disubstituted or 3,4,5-trisubstituted pyrazoles in excellent yields. However, di-ynones and molecules possessing both ynone and enone functionalities provide only monocycloaddition products, whereas another multiple bond undergoes Michael addition with the methoxide anion.

Synthesis, molecular modeling and NAD(P)H:quinone oxidoreductase 1 inducer activity of novel cyanoenone and enone benzenesulfonamides

In biological systems, the Keap1/Nrf2/antioxidant response element pathway determines the ability of mammalian cells to adapt and survive conditions of oxidative, electrophilic and inflammatory stress by regulating the production of cytoprotective enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1, EC 1.6.99.2) being one of them. Novel biologically active benzenesulfonamides 2, 3, 5–7, penta-2,4-dienamide 4 and chromene-2-carboxamide 8 structurally augmented with an electron-deficient Michael acceptor enone or cyanoenone functionalities were prepared. A new biological activity was conferred to these molecules, that of induction of NQO1. The potency of induction was increased by incorporation of a nitrile group adjacent to the enone and the dinitrophenyl derivative 3 was the most promising inducer. Also, molecular docking of the new compounds in the Nrf2-binding site of Keap1 was performed to assess their ability to inhibit Keap1 which biologically leads to a consequent Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed considerable interactions between the new molecules and essential binding site amino acids.