- Conditional Copper-Catalyzed Azide–Alkyne Cycloaddition by Catalyst Encapsulation
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Supramolecular encapsulation is known to alter chemical properties of guest molecules. We have applied this strategy of molecular encapsulation to temporally control the catalytic activity of a stable copper(I)–carbene catalyst. Encapsulation of the copper(I)–carbene catalyst by the supramolecular host cucurbit[7]uril (CB[7]) resulted in the complete inactivation of a copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction. The addition of a chemical signal achieved the near instantaneous activation of the catalyst, by releasing the catalyst from the inhibited CB[7] catalyst complex. To broaden the scope of our on-demand CuAAC reaction, we demonstrated the protein labeling of vinculin with the copper(I)–carbene catalyst, to inhibit its activity by encapsulation with CB[7] and to initiate labeling at any moment by adding a specific signal molecule. Ultimately, this strategy allows for temporal control over copper-catalyzed click chemistry, on small molecules as well as protein targets.
- Araman, Can,Brevé, Tobias G.,Eelkema, Rienk,Filius, Mike,Hagedoorn, Peter-Leon,Joo, Chirlmin,van Kasteren, Sander I.,van der Helm, Michelle P.
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Read Online
- A new route to furanoeremophilane sesquiterpenoids. Synthesis of (±)-6β-hydroxyeuryopsin
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The naturally occurring furanoeremophilane 6β-hydroxyeuryopsin was synthesized by a novel route which involved Stille coupling of a 2-furylstannane with a cyclohexylmethyl bromide, followed by intramolecular formylation of the furan to complete the tricyclic nucleus of the sesquiterpenoid.
- Shanmugham, M. Sundaram,White, James D.
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Read Online
- New Natural Products from Asphodelus albus MILL. Essential Oil
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A detailed chemical analysis of the essential oil of Asphodelus albus roots performed in this work, in combination with a chemical synthesis approach – the synthesis of selected compounds and their detailed spectral analysis – has led to the identification of a series of new natural products, the esters of furan-3-ylmethanol: furan-3-ylmethyl 2-methylpropanoate, furan-3-ylmethyl butanoate, furan-3-ylmethyl 2-methylbutanoate, furan-3-ylmethyl 3-methylbutanoate, furan-3-ylmethyl pentanoate, furan-3-ylmethyl 4-methylpentanoate, and furan-3-ylmethyl hexanoate.
- Deki?, Milan S.,Selimovi?, Enisa S.
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Read Online
- Efficient Electrocatalytic Reduction of Furfural to Furfuryl Alcohol in a Microchannel Flow Reactor
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Furfural is considered to be an essential biobased platform molecule. Recently, its electrocatalytic hydrogenation is regarded as a more environmentally friendly process compared to traditional catalytic hydrogenation. In this study, a new, continuous-flow approach enabling furfural electrocatalytic reduction was developed. In an undivided multichannel electrochemical flow reactor at ambient temperature and pressure in basic reaction conditions, the yield of furfuryl alcohol reached up to 90% in only 10 min residence time. Interestingly, the faradaic efficiency was 90%, showing a good effectiveness of the consumed electrons in the generation of the targeted compound. Furthermore, the innovation lies in the direct electrolysis using the green solvent ethanol without the need for membrane separation or catalyst modification, which offers further proof for continuous and sustainable production in industry.
- Cao, Yiran,No?l, Timothy
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Read Online
- Disproportionation of aliphatic and aromatic aldehydes through Cannizzaro, Tishchenko, and Meerwein–Ponndorf–Verley reactions
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Disproportionation of aldehydes through Cannizzaro, Tishchenko, and Meerwein–Ponndorf–Verley reactions often requires the application of high temperatures, equimolar or excess quantities of strong bases, and is mostly limited to the aldehydes with no CH2 or CH3 adjacent to the carbonyl group. Herein, we developed an efficient, mild, and multifunctional catalytic system consisting AlCl3/Et3N in CH2Cl2, that can selectively convert a wide range of not only aliphatic, but also aromatic aldehydes to the corresponding alcohols, acids, and dimerized esters at room temperature, and in high yields, without formation of the side products that are generally observed. We have also shown that higher AlCl3 content favors the reaction towards Cannizzaro reaction, yet lower content favors Tishchenko reaction. Moreover, the presence of hydride donor alcohols in the reaction mixture completely directs the reaction towards the Meerwein–Ponndorf–Verley reaction. Graphic abstract: [Figure not available: see fulltext.].
- Sharifi, Sina,Sharifi, Hannah,Koza, Darrell,Aminkhani, Ali
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p. 803 - 808
(2021/07/20)
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- Selective Inhibition of DNA Polymerase β by a Covalent Inhibitor
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DNA polymerase β (Pol β) plays a vital role in DNA repair and has been closely linked to cancer. Selective inhibitors of this enzyme are lacking. Inspired by DNA lesions produced by antitumor agents that inactivate Pol β, we have undertaken the development of covalent small-molecule inhibitors of this enzyme. Using a two-stage process involving chemically synthesized libraries, we identified a potent irreversible inhibitor (14) of Pol β (KI = 1.8 ± 0.45 μM, kinact = (7.0 ± 1.0) × 10-3 s-1). Inhibitor 14 selectively inactivates Pol β over other DNA polymerases. LC-MS/MS analysis of trypsin digests of Pol β treated with 14 identified two lysines within the polymerase binding site that are covalently modified, one of which was previously determined to play a role in DNA binding. Fluorescence anisotropy experiments show that pretreatment of Pol β with 14 prevents DNA binding. Experiments using a pro-inhibitor (pro-14) in wild type mouse embryonic fibroblasts (MEFs) indicate that the inhibitor (5 μM) is itself not cytotoxic but works synergistically with the DNA alkylating agent, methylmethanesulfonate (MMS), to kill cells. Moreover, experiments in Pol β null MEFs indicate that pro-14 is selective for the target enzyme. Finally, pro-14 also works synergistically with MMS and bleomycin to kill HeLa cells. The results suggest that pro-14 is a potentially useful tool in studies of the role of Pol β in disease.
- Yuhas, Shelby C.,Laverty, Daniel J.,Lee, Huijin,Majumdar, Ananya,Greenberg, Marc M.
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supporting information
p. 8099 - 8107
(2021/06/21)
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- Reaction of Diisobutylaluminum Borohydride, a Binary Hydride, with Selected Organic Compounds Containing Representative Functional Groups
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The binary hydride, diisobutylaluminum borohydride [(iBu)2AlBH4], synthesized from diisobutylaluminum hydride (DIBAL) and borane dimethyl sulfide (BMS) has shown great potential in reducing a variety of organic functional groups. This unique binary hydride, (iBu)2AlBH4, is readily synthesized, versatile, and simple to use. Aldehydes, ketones, esters, and epoxides are reduced very fast to the corresponding alcohols in essentially quantitative yields. This binary hydride can reduce tertiary amides rapidly to the corresponding amines at 25 °C in an efficient manner. Furthermore, nitriles are converted into the corresponding amines in essentially quantitative yields. These reactions occur under ambient conditions and are completed in an hour or less. The reduction products are isolated through a simple acid-base extraction and without the use of column chromatography. Further investigation showed that (iBu)2AlBH4 has the potential to be a selective hydride donor as shown through a series of competitive reactions. Similarities and differences between (iBu)2AlBH4, DIBAL, and BMS are discussed.
- Amberchan, Gabriella,Snelling, Rachel A.,Moya, Enrique,Landi, Madison,Lutz, Kyle,Gatihi, Roxanne,Singaram, Bakthan
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supporting information
p. 6207 - 6227
(2021/05/06)
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- SUBSTITUTED CYCLOALKYLS AS MODULATORS OF THE INTEGRATED STRESS PATHWAY
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Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.
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Page/Page column 236
(2020/11/12)
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- SUBSTITUTED CYCLOLAKYLS AS MODULATORS OF THE INTEGRATED STRESS PATHWAY
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Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.
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Page/Page column 327-328
(2020/11/12)
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- NOVEL THYROMIMETICS
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Compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, X1, X2, Q, R1, R2 and n are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.
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Page/Page column 155-156
(2020/09/19)
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- Peptidylarginine deiminase inhibitor and application thereof
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The invention belongs to the technical field of medicine, and particularly relates to a peptidylarginine deiminase PAD4 inhibitor compound shown in a formula (I) or pharmaceutically acceptable salts,stereoisomers and tautomers thereof, as well as pharmaceutical compositions, pharmaceutical preparations and application thereof. X, Y, R1, R2, R3, R4, R5, R7, R8, R9, ring B and m are as defined in the specification. The compound has inhibitory effect on peptidylarginine deiminase PAD4, and can be used for treating various diseases, such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, multiple sclerosis, cystic fibrosis, cancer, cutaneous lupus erythematosus, asthma and psoriasis.
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Paragraph 0834; 0836; 0837; 0838
(2019/09/10)
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- Regio- A nd chemoselective deprotection of primary acetates by zirconium hydrides
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A combination of DIBAL-H and Cp2ZrCl2 is shown to promote the regioselective cleavage of primary acetates on a broad scope of substrates, ranging from carbohydrates to terpene derivatives, with a high tolerance toward protecting groups and numerous functionalities found in natural products and bioactive compounds. Apart from providing highly valuable building blocks in only two steps from biosourced raw materials, this selective de-O-acetylation should also be strongly helpful to solve selectivity issues in organic synthesis.
- Gavel, Marine,Courant, Thibaut,Joosten, Antoine Yvan Philippe,Lecourt, Thomas
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supporting information
p. 1948 - 1952
(2019/04/10)
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- Polypyridyl iridium(III) based catalysts for highly chemoselective hydrogenation of aldehydes
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Iridium-catalyzed transfer hydrogenation (TH) of carbonyl compounds using HCOOR (R = H, Na, NH4) as a hydrogen source is a pivotal process as it provides the clean process and is easy to execute. However, the existing highly efficient iridium catalysts work at a narrow pH; thus, does not apply to a wide variety of substrates. Therefore, the development of a new catalyst which works at a broad pH range is essential as it can gain a broader scope of utilization. Here we report highly efficient polypyridyl iridium(III) catalysts, [Ir(tpy)(L)Cl](PF6)2 {where tpy = 2,2′:6′,2′'-Terpyridine, L = phen (1,10-Phenanthroline), Me2phen (4,7-Dimethyl-1,10-phenanthroline), Me4phen (3,4,7,8-Tetramethyl-1,10-phenanthroline), Me2bpy (4,4′-Dimethyl-2–2′-dipyridyl)} for the chemoselective reduction of aldehydes to alcohols in aqueous ethanol and sodium formate as the hydride source. The reaction can be carried out efficiently in broad pH ranges, from pH 6 to 11. These catalysts are air stable, easy to prepare using commercially available starting materials, and are highly applicable for a wide range of substrates, such as electron-rich or deficient (hetero)arenes, halogens, phenols, alkoxy, ketones, esters, carboxylic acids, cyano, and nitro groups. Particularly, acid and hydroxy groups containing aldehydes were reduced successfully in basic and acidic reaction conditions, demonstrating the efficiency of the catalyst in a broad pH range with high conversion rates under microwave irradiation.
- Pandrala, Mallesh,Resendez, Angel,Malhotra, Sanjay V.
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p. 283 - 288
(2019/09/30)
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- IMIDAZO-PYRIDINE COMPOUNDS AS PAD INHIBITORS
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Heterocyclic compounds of Formula (I), (II), and (III) are described herein along with their polymorphs, stereoisomers, prodrugs, solvates, co-crystals, intermediates, pharmaceutically acceptable salts, and metabolites thereof. The compounds described herein, their polymorphs, stereoisomers, prodrugs, solvates, co-crystals, intermediates, pharmaceutically acceptable salts, and metabolites thereof are PAD4 inhibitors and may be useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosis, cutaneous lupus erythematosis, ulcerative colitis, cancer, cystic fibrosis, asthma, multiple sclerosis and psoriasis. The process of preparation of the compounds of Formula (I), (II), and (III), their polymorphs, stereoisomers, prodrugs, solvates, co-crystals, intermediates, pharmaceutically acceptable salts, and metabolites thereof, along with a pharmaceutical composition comprising a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof have also been described.
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Paragraph 000133; 000318
(2019/05/10)
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- Domino Direct Arylation and Cross-Aldol for Rapid Construction of Extended Polycyclic π-Scaffolds
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Five-membered aromatic heterocycles are a ubiquitous skeleton of π-conjugated organic compounds, and their incorporation requires synthetic protocols that are not easily industrially sustainable or scalable. Improved methodologies for their insertion into π-scaffolds are therefore necessary. We report an efficient and scalable protocol involving a one-pot cross-Aldol direct arylation reaction protocol for the rapid construction of thiophene- and furan-based π-extended organic materials.
- Nitti, Andrea,Bianchi, Gabriele,Po, Riccardo,Swager, Timothy M.,Pasini, Dario
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supporting information
p. 8788 - 8791
(2017/07/12)
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- A camptothecin and its derivatives for quick synthesis of
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The invention relates to camptothecin and a rapid synthesis method of a derivative of the camptothecin. According to the invention, the synthetic route convergence is simple and short, the condition is gentle and the operation is simple. The rapid synthesis method comprises the following steps: one-pot reaction of oxidation-oxa-Diels-Alder; (2) convergence aminolysis of quinoline pyrrolin and intermediate of pyran lactone; (3) cascade reaction of forming camptothecin D/E ring in one step. The invention further discloses another similar method namely the preparation method of the intermediate of pyran carboxylic acid containing camptothecin E ring. The rapid synthesis method has the following benefits: the route convergence is simple and short, the operation is simple and the reaction is gentle.
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Paragraph 0066-0068
(2016/10/10)
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- Selective hydrogenation of furanic aldehydes using Ni nanoparticle catalysts capped with organic molecules
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Ni nanoparticles were synthesized by a colloidal method in the presence of organic surface-capping agents and used to catalyze the selective hydrogenation of unsaturated furanic aldehydes to furanic alcohols. The effects of the Ni nanoparticle size and surface organic layer were evaluated. Of the 3.7, 5.1, 6.8, and 10.4 nm Ni nanoparticles tested in selective furfural (FFR) hydrogenation to furfuryl alcohol (FFA), the 6.8 nm Ni nanoparticles exhibited the highest yield because access to the surface sites on the smaller and larger nanoparticles was blocked by the densely packed organic layer and by their agglomeration due to magnetic attraction, respectively. The capped Ni nanoparticles exhibited a high FFA yield of 96%, whereas significant over-hydrogenation was observed when uncapped calcined Ni/SiO2 catalysts with similarly sized Ni nanoparticles were employed. Steric hindrance of the Ni surface induced by the organic surface layer led to selective FFR hydrogenation to FFA. The capped Ni nanoparticles could be reused repeatedly without a significant loss in the FFA yield. They also exhibited high selectivity (>90%) in the hydrogenation of other unsaturated furanic aldehydes to their corresponding alcohols.
- Jeong, Hojin,Kim, Chanyeon,Yang, Sungeun,Lee, Hyunjoo
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p. 609 - 615
(2016/11/25)
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- Short protecting group-free syntheses of camptothecin and 10-hydroxycamptothecin using cascade methodologies
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A convergent protecting group-free total synthesis route of camptothecin and 10-hydroxycamptothecin has been developed in this work. Cascade oxidation of 3-(hydroxymethyl)furan-2(5 H)-one and in situ intermolecular oxa Diels-Alder reaction with vinyl ether was developed and applied to construct the E-ring, and TMSCl-promoted cascade closure of the D-ring delivered the whole skeleton of the alkaloids in the total synthesis. The new short syntheses were advantageous with regard to step economy, low cost, easily available starting materials and reagents, and convenient operations.
- Xu, Peng,Chen, Dong-Sheng,Xi, Jie,Yao, Zhu-Jun
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supporting information
p. 976 - 981
(2015/04/14)
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- New platelet aggregation inhibitors based on pyridazinone moiety
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New series of pyridazinone derivatives (4, 5 and 6) were synthesized in good yields following a synthetic strategy based on singlet oxygen oxidation of alkyl furans, in which a suitable β(α)-substituted γ ghydroxybutenolide (10 or 11) or a bicyclic lactone (12 or 13) was the key intermediate. The synthesized compounds were tested in vitro as antiplatelet agents and some of them (compounds 4b, 4d and 5b) exhibited potent inhibitory effects on collagen-induced platelet aggregation with IC50 values in the low μM range. Studies performed with the most active compound of these series (4b) demonstrated its lack of activity as inhibitor of platelet aggregation induced by other agonists as thrombin, ionomycin or U- 46619 suggesting a selective action on the biochemical mechanisms triggered by collagen in the platelets.
- Costas, Tamara,Costas-Lago, María Carmen,Vila, Noemí,Besada, Pedro,Cano, Ernesto,Terán, Carmen
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p. 113 - 122
(2015/03/14)
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- Synthesis of C3-substituted enantiopure 2-(p-tolylsulfinyl)-furans: The sulfoxide group as a chiral inductor for furan dienes as precursors of a wide variety of chiral intermediates
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(-)-(1R,2S,5R)-Menthyl (SS)-p-toluenesulfinate and its enantiomer are a common source for a chiral sulfoxide group in organic synthesis, by means of nucleophilic substitution. The replacement of the menthyloxy group, with complete inversion of configuration at the sulfur center of the chiral sulfoxide, allows the inclusion of this organic function into numerous substrates, with defined stereochemistry and high enantiomeric purity. Nine C3-substituted, enantiomerically pure, 2-sulfinylfurans were prepared by this synthetic methodology with moderate to high yields. These enantiopure C3-substituted 2-sulfinylfurans can be used as chiral dienes for [4+3] cycloaddition reactions and in other chemical transformations, in which π-facial selectivity should be induced in order to obtain enantioselective reactions.
- Montana, Angel M.,Grima, Pedro M.,Batalla, Consuelo,Kociok-Koehn, Gabriele
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p. 677 - 689
(2014/05/20)
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- Constituents of Vigna angularis and their in vitro anti-inflammatory activity
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Nine non-phenolic compounds, including four furanylmethyl glycosides, angularides A-D, one ent-kaurane diterpene glycoside, angularin A, and four triterpenoid saponins, angulasaponins A-D, were isolated from seeds of Vigna angularis, together with eight known compounds. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic analysis as well as chemical methods. Angularin A, angulasaponins A-C, and azukisaponins III and VI showed inhibition of nitric oxide production in LPS-activated RAW264.7 macrophages, with IC50 values ranging from 13 μM to 24 μM.
- Jiang, Yong,Zeng, Ke-Wu,David, Bruno,Massiot, Georges
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p. 111 - 118
(2015/02/19)
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- Construction of polyaromatics via photocyclization of 2-(fur-3-yl) ethenylarenes, using a 3-furyl group as an isopropenyl equivalent synthon
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The construction of different types of substituted arenes was demonstrated through the photocyclization of 2-(fur-3-yl)ethenylarenes using a 3-furyl group as an isopropenyl equivalent synthon in the photocyclization reaction. The furan portion of the photocyclization intermediate could be fragmented via a base-induced elimination reaction to yield a series of substituted polyaromatics, including naphthalene, benzofuran, benzothiophene, phenanthrene, phenalene, acenaphthene, and triphenylene. Using different reagents, this method made it possible to introduce methyl or 2-hydroxyethyl groups as substituents at specific positions in these arenes.
- Chen, Ying-Zhe,Ni, Ching-Wen,Teng, Fu-Lin,Ding, Yi-Shun,Lee, Tunng-Hsien,Ho, Jinn-Hsuan
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p. 1748 - 1762
(2014/03/21)
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- Electrophilicity and nucleophilicity of commonly used aldehydes
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The present approach for determining the electrophilicity (E) and nucleophilicity (N) of aldehydes includes a kinetic study of KMNO4 oxidation and NaBH4 reduction of aldehydes. A transition state analysis of the KMNO4 promoted aldehyde oxidation reaction has been performed, which shows a very good correlation with experimental results. The validity of the experimental method has been tested using the experimental activation parameters of the two reactions. The utility of the present approach is further demonstrated by the theoretical versus experimental relationship, which provides easy access to E and N values for various aldehydes and offers an at-a-glance assessment of the chemical reactivity of aldehydes in various reactions. the Partner Organisations 2014.
- Pratihar, Sanjay
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p. 5781 - 5788
(2014/07/22)
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- Synthesis and determination of the absolute configuration of (-)-(5R,6Z)-dendrolasin-5-acetate from the nudibranch Hypselodoris jacksoni
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A small sample of (-)-(5R,6Z)-dendrolasin-5-acetate, which was fully characterized by 2D NMR studies, was isolated from the nudibranch Hypselodoris jacksoni, along with the sesquiterpenes (+)-agassizin, (-)-furodysinin, (-)-euryfuran, (-)-dehydroherbadysidolide and (+)-pallescensone. A synthetic sample ([α]D -8.7) of the new metabolite was prepared by [1,2]-Wittig rearrangement of a geranylfuryl ether followed by acetylation of purified alcohol isomers. The absolute configuration at C-5 was established as R by the analysis of MPA ester derivatives of (Z)-5-hydroxydendrolasin obtained by preparative enantioselective HPLC.
- Mudianta, I. Wayan,Challinor, Victoria L.,Winters, Anne E.,Cheney, Karen L.,De Voss, James J.,Garson, Mary J.
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p. 2925 - 2933
(2014/01/23)
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- A molecularly defined iron-catalyst for the selective hydrogenation of α,β-unsaturated aldehydes
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A selective iron-based catalyst system for the hydrogenation of α,β-unsaturated aldehydes to allylic alcohols is presented. Applying the defined iron-tetraphos complex [FeF(L)][BF4] (L=P(PhPPh 2)3) in the presence of trifluoroacetic acid a broad range of aldehydes are reduced in high yields using low catalyst loadings (0.05-1 mol %). Excellent chemoselectivity for the reduction of aldehydes in the presence of other reducible moieties, for example, ketones, olefins, esters, etc. is achieved. Based on the in situ detected hydride species [FeH(H 2)(L)]+ a catalytic cycle is proposed that is supported by computational calculations. Copyright
- Wienh?fer, Gerrit,Westerhaus, Felix A.,Junge, Kathrin,Ludwig, Ralf,Beller, Matthias
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supporting information
p. 7701 - 7707
(2013/07/11)
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- Cycloaddition of C-3 substituted furans. Stereoselectivity induced by coordination effects
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Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone in the presence of a reducing metal, resulting in the formation of [4+3]-cycloadducts with complete cis-trans and endo-exo diastereoselectivity and in excellent yield. A certain variability of the conversion and reaction yield could be observed, when changing the reaction conditions, but in all cases the stereoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also, a general method of assignment of stereochemistry of cycloadducts has been established by NMR, considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on the stereochemistry of diastereomeric cycloadducts.
- Montana, Angel M.,Castellvi, Maria,Batalla, Consuelo,Grima, Pedro M.,Font-Bardia, Merce
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p. 9982 - 9998,17
(2012/12/12)
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- Cycloaddition of C-3 substituted furans. Stereoselectivity induced by coordination effects
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Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone in the presence of a reducing metal, resulting in the formation of [4+3]-cycloadducts with complete cis-trans and endo-exo diastereoselectivity and in excellent yield. A certain variability of the conversion and reaction yield could be observed, when changing the reaction conditions, but in all cases the stereoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also, a general method of assignment of stereochemistry of cycloadducts has been established by NMR, considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on the stereochemistry of diastereomeric cycloadducts.
- Monta?a, ángel M.,Grima, Pedro M.,Castellví, María,Batalla, Consuelo,Font-Bardia, Mercè
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p. 9982 - 9998
(2013/01/14)
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- Synthesis of a functionalized oxabicyclo[2.2.1]-heptene-based chemical library
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The 7-oxabicyclo[2.2.1]heptene ring system is a common structural motif in many pharmacologically interesting molecules. We recognized the potential to employ this highly oxygenated and conformationally-restricted scaffold in diversity-oriented synthesis to generate a library of non-chiral but topologically complex compounds. Herein, we report the synthesis and biological evaluation of two 96-member tricyclic libraries containing the oxabicyclo[2.2.1]heptene framework using acetal formation as the key step.
- Luesse, Sarah B.,Wells, Gregg,Miller, Jeanne,Bolstad, Erin,Bergmeier, Stephen C.,McMills, Mark C.,Priestley, Nigel D.,Wright, Dennis L.
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scheme or table
p. 81 - 89
(2012/06/01)
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- Semisynthetic neoclerodanes as kappa opioid receptor probes
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Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors.
- Lovell, Kimberly M.,Vasiljevik, Tamara,Araya, Juan J.,Lozama, Anthony,Prevatt-Smith, Katherine M.,Day, Victor W.,Dersch, Christina M.,Rothman, Richard B.,Butelman, Eduardo R.,Kreek, Mary Jeanne,Prisinzano, Thomas E.
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scheme or table
p. 3100 - 3110
(2012/06/18)
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- A convenient and general iron-catalyzed hydrosilylation of aldehydes
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A general and highly chemoselective hydrosilylation of aldehydes using iron catalysts is reported. Fe(OAc)2 in the presence of tricyclohexylphosphine as ligand and polymethylhydrosiloxane (PMHS) as an economical hydride source forms an efficient catalyst system for the hydrosilylation of a variety of aldehydes. Aryl, heteroaryl, alkyl and α,β-unsaturated aldehydes are successfully reduced to the corresponding primary alcohols. Broad substrate scope and high tolerance against several functional groups make the process synthetically useful.
- Shaikh, Nadim S.,Junge, Kathrin,Beller, Matthias
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p. 5429 - 5432
(2008/09/19)
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- Acid-promoted cyclization reactions of tetrahydroindolinones. Model studies for possible application in a synthesis of selaginoidine
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The synthesis of various substituted bicyclic lactams by an acid-induced Pictet-Spengler reaction of tetrahydroindolinones bearing tethered heteroaromatic rings is presented. The outcome of the cyclization depends on the position of the furan tether, tether length, nature of the tethered heteroaromatic ring, and the substituent group present on the 5-position of the tethered heteroaryl group. A one-pot procedure was developed to efficiently prepare tetrahydroindolinones containing tethered furan rings. In a typical example, the reaction of furanyl azide 26 with n-Bu3P delivered iminophosphorane 27, which was allowed to react with a 1-alkyl-(2-oxocyclohexyl) acetic acid to provide the desired furanyl-substituted tetrahydroindolinone system 29. Treatment of 29 with trifluoroacetic acid afforded the tetracyclic lactam skeleton 30 found in the alkaloid (±)-selaginoidine.
- Rose, Mickea D.,Cassidy, Michael P.,Rashatasakhon, Paitoon,Padwa, Albert
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p. 538 - 549
(2007/10/03)
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- A new route to furanoeremophilane sesquiterpenoids. Synthesis of Senecio metabolites (±)-6-hydroxyeuryopsin, (±)-1,10-epoxy-6- hydroxyeuryopsin, (±)-toluccanolide A and (±)-toluccanolide C
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A new strategy for the synthesis of sesquiterpenoids of the furanoeremophilane family was developed in which the tricyclic nucleus was assembled in an A + C → A-C → A-B-C sequence. The A-C connection was made via coupling of a cyclohexenylmethyl bromide with a stannylfuran under "ligandless" Stille conditions, and the key cyclization which closed ring B was accomplished with complete stereocontrol by intramolecular formylation of a 2-silylfuran in the presence of trimethylsilyl triflate. This route was used to complete the first total syntheses of the furanoeremophilane 6-hydroxyeuryopsin and the eremophilenolides toluccanolide A and toluccanolide C, as well as a formal synthesis of 1,10-epoxy-6-hydroxyeuryopsin. The Royal Society of Chemistry 2006.
- Mace, Laura H.,Shanmugham, M. Sundaram,White, James D.,Drew, Michael G. B.
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p. 1020 - 1031
(2007/10/03)
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- The interaction of heteroaryl-acrylates and alanines with phenylalanine ammonia-lyase from parsley
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Acrylic acids and alanines substituted with heteroaryl groups at the β-position were synthesized and spectroscopically characterized (UV, HRMS, 1H NMR, and 13C NMR spectroscopy). The heteroaryl groups were furanyl, thiophenyl, benzofuranyl, and benzothiophenyl and contained the alanyl side chains either at the 2- or 3-positions. While the former are good substrates for phenylalanine ammonia lyase (PAL), the latter compounds are inhibitors. Exceptions are thiophen-3-yl-alanine, a moderate substrate and furan-3-yl-alanine, which is inert. Possible reasons for these exceptions are discussed. Starting from racemic het eroaryl-2-alanines their D-enantiomers were prepared by using a stereodestructive procedure. From the heteroaryl-2- acrylates, the L-enantiomers of the heteroaryl-2-alanines were prepared at high ammonia concentration. These results can be best explained by a Friedel - Crafts-type electrophilic attack at the aromatic part of the substrates as the initial step of the PAL reaction.
- Paizs, Csaba,Katona, Adrian,Retey, Janos
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p. 2739 - 2744
(2008/02/03)
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- Process for producing cyclopropanecarboxylates
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There is disclosed a process process for producing a cyclopropanecarboxylate of formula (1): 1which process comprises reacting cyclopropanecarboxylic acid of formula (2): 2with a monohydroxy compound of formula (3): R6OH??(3),in the presence of a catalyst compound comprising an element of to Group 4 of the Periodic Table of Elements.
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- Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy
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The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 μM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
- Kempf, Dale J.,Sham, Hing L.,Marsh, Kennan C.,Flentge, Charles A.,Betebenner, David,Green, Brian E.,McDonald, Edith,Vasavanonda, Sudthida,Saldivar, Ayda,Wideburg, Norman E.,Kati, Warren M.,Ruiz, Lisa,Zhao, Chen,Fino, Lynnmarie,Patterson, Jean,Molla, Akhteruzzaman,Plattner, Jacob J.,Norbeck, Daniel W.
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p. 602 - 617
(2007/10/03)
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- Regioselective Preparation of 2,4-, 3,4-, and 2,3,4-Substituted Furan Rings. 1. [1,4] O → C and [1,4] C → O Silyl Migrations of Silyl Ethers and Esters Attached to Furan and Thiophene Rings
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[1,4] O → C and [1,4] C → O rearrangements are described for a variety of furans and thiophenes. Treatment of 3-((silyloxy)methyl)furans and -thiophenes with n-BuLi in HMPA provided 2-silylated-3-(hydroxymethyl)furans and -thiophenes in good to excellent yields. The reaction was shown by crossover studies to proceed via an intramolecular [1,4] O → C silyl migration. Silyl esters of 3-furoic acids also underwent an intramolecular [1,4] O → C silyl migration to provide 2-silylated-3-furoic acids in moderate to good yield when treated with a mixture of LDA and HMPA. Finally, the above silyl migrations were shown to be reversible. Treatment of 2-silylated-3-(hydroxymethyl)-furans and -thiophenes with NaH in DMF provided 3-((silyloxy)methyl)furans and -thiophenes in excellent yields via a [1,4] C → O silyl migration. The [1,4] C → O silyl migration was also shown to be an intramolecular process by a crossover study.
- Bures, Edward,Spinazze, Patrick G.,Beese, Giovanna,Hunt, Ian R.,Rogers, Christine,Keay, Brian A.
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p. 8741 - 8749
(2007/10/03)
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- Synthetic studies on prehispanolone and 14,15-dihydroprehispanolone
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Employing an intramolecular Michael addition as a pivotal step, butenolide 5, furans 6 and 7 have been converted to dioxaspiro compounds 8, 9, 10 and 11, whose heterocyclic frameworks constitute important structural units of prehispanolone (2) as well as 14,15-dihydroprehispanolones (3) and (4), respectively. Hispanolone (1) was converted to 2, 3 and 4 by utilizing a similar strategy.
- Wang, En Si,Choy, Yuen Min,Wong, Henry N. C.
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p. 12137 - 12158
(2007/10/03)
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- Model study and partial synthesis of prehispanolone and 14,15-dihydroprehispanolone from hispanolone
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Employing an intramolecular Michael addition as a pivotal step, furan 4 has been converted to dioxaspiro compounds 5 and 6, whose heterocyclic frameworks constitute important structural units of 14,15-dihydroprehispanolone 3 and prehispanolone 1, respectively. Hispanolone 2 was converted to 3 as well as 1 by utilizing a similar strategy.
- Wang, En Si,Luo, Bao Sheng,Mak, Thomas C. W.,Choy, Yuen Min,Wong, Henry N. C.
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p. 7401 - 7404
(2007/10/02)
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- THE 1,4 CO SILYL MIGRATIONS OF VARIOUS FURAN AND THIOPHENE SYSTEMS
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2-Trialkylsilyl-3-hydroxymethyl-furans and -thiophenes undergo a 1,4 CO silyl migration when treated with bases containing either potassium or sodium counterions to produce 3furans and -thiophenes in excellent yields.
- Spinazze, Patrick G.,Keay, Brian A.
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p. 1765 - 1768
(2007/10/02)
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- Intramolecular rhodium carbenoid insertions into aromatic C-H bonds. Preparation of 1,3-dihydrothiophene 2,2-dioxides fused onto aromatic rings
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The preparation of 1-carboalkoxy-1,3-dihydrobenzenothiophene 2,2-dioxides via rhodium acetate or rhodium trifluoro-acetate catalyzed decomposition of α-diazo-β-arylmethanesulfonyl esters is described.The reaction has been extended to yield 1,3-dihydrothiophene 2,2-dioxides fused to the 2,3 position of thiophene and indole, but not of furans.In the latter case products derived from the opening of the furan ring were obtained.Key words: synthesis, 1-carboalkoxy-1,3-dihydrobenzothiophene 2,2-dioxides, intramolecular carbenoid insertions, rhodium acetate catalysis.
- Babu, Suresh D.,Hrytsak, Michael D.,Durst, Tony
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p. 1071 - 1076
(2007/10/02)
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- A Study of the Terpenoids of the Sponge Euryspongia sp.
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The metabolites of the sponge Euryspongia sp. (Dysideidae) were investigated.The sponge was shown to contain the previously unknown sesquiterpene epoxides (15) and (16), and three known compounds, dehydrodendrolasin (1), thiofurodysinin acetate (13) and thiofurodysin acetate (14).Based on the spectral data of (1) and the synthetic compounds (1'E)- and (1'Z)-3-(4',8'-dimethylnon-1-enyl)furan (5) and (6), the structures of 'the cis isomer of dehydrodendrolasin' (2), tetradehydrofurospongian-1 (3) and the related C21 furanoterpene (4) should be reevaluated.
- Altena, Ian A. van,Miller, Darren A.
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p. 2181 - 2190
(2007/10/02)
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- Tobacco smoke chemistry 3. Aromatic acids of cigarette smoke condensate.
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A fraction containing mainly aromatic acids has been isolated from cigarette smoke condensate. Gas chromatographic and mass spectral analysis of the corresponding methyl esters and comparison with reference compounds, many of which were synthesized for this purpose, made possible the identification of 27 constituents (Table 1). Eighteen of these have not been detected in tobacco smoke condensate before.
- Arnarp,Dahlin,Enzell,Pettersson
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p. 381 - 385
(2007/10/02)
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- THE 1,4 O->C SILYL MIGRATIONS OF VARIOUS 3--FURANS AND -THIOPHENES
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Numerous 3--furans and -thiophenes undergo a 1,4 O->C silyl migration when treated with n-BuLi/HMPA in THF or DME to produce 2-(trialkylsilyl)-3-(hydroxymethyl)-furans and -thiophenes in good yields.
- Bures, Edward J.,Keay, Brian A.
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p. 5965 - 5968
(2007/10/02)
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- A SIMPLE, EFFICIENT SYNTHESIS OF 3-SUBSTITUTED FURANS
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3-Substituted furan can be readily prepared in a single step via a tandem Diels-Alder/retro Diels-Alder reaction between 4-phenyloxazole and simple alkylacetylenes.
- Liotta, Dennis,Saindane, Manohar,Ott, Walter
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p. 2473 - 2476
(2007/10/02)
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- 3. 2. 1.
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8-Oxabicyclo left bracket 3. 2. 1 right bracket octan-3-one derivatives serve as excellent models that elucidate factors controlling the reactivities and selectivities in the Baeyer-Villiger oxidation. The regioselectivity of the oxidation with trifluoroperacetic acid is markedly affected by the electronic properties of substituents at position alpha or beta to the carbonyl function. Remote effects of the gamma -substituents are also of significance. This study has disclosed yet unrecognized through-bond electronic influence and regioselection based on chiral orientation of hydroxyl group in the transient tetrahedral intermediate.
- Noyori,Sato,Kobayashi
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p. 2661 - 2679
(2007/10/02)
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- A SIMPLE SYNTHESIS OF 3-SUBSTITUTED FURANS. THE PREPARATIONS OF DENDROLASIN, PERILLENE AND CONGENERS
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The Grignard reagent 7, derived from 3-chloromethyl furan, reacts with various alkyl- and allylic halides, in the presence of Li2CuCl4, to provide high yields of 3-substituted furans.
- Tanis, Steven P.
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p. 3115 - 3118
(2007/10/02)
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- Selenium--Stabilized Anions. Preparation of α,β-Unsaturated Carbonyl Compounds Using Propargyl Selenides. Synthesis of (+/-)-7-Hydroxymyoporone
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The reaction of alkyl halides, carbonyl compounds, and trimethylsilyl chloride with the mono- and dianion (1) prepared by deprotonation of phenyl propargyl selenide with lithium diisopropylamide gives 1- or 3-monosubstituted or 1,3-disubstituted propargyl selenides (3a).Oxidation to selenoxides (3b) results in rearrangement to 2-(phenylseleno)-1,3-disubstituted propenones.The rate of rearrangement of propargyl selenoxides increases dramatically when the phenyl group is replaced by a 2-nitrophenyl group, and an intermediate allenyl selenate ester (7c) can be observed by low-temperature NMR.By appropriate modification of oxidation conditions, modest yields of 2-iodopropenes (e.g., 10) or the selenium-free enones or enals can be obtained.A synthesis of (+/-)-7-hydroxymyoporone (15) and its epimer has been carried out by using the dianion 1 to assemble the carbon skeleton.The preparation of α-lithioallenyl phenyl selenide (26) has been accomplished, and its reaction with electrophiles has been studied.
- Reich, Hans J.,Shah, Shrenik K.,Gold Paul M.,Olson Richard E.
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p. 3112 - 3120
(2007/10/02)
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