- Mechanistic Insight on the Mode of Action of Colletoic Acid
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The natural product colletoic acid (CA) is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which primarily converts cortisone to the active glucocorticoid (GC) cortisol. Here, CA's mode of action and its potential as a chemical tool to study intracellular GC signaling in adipogenesis are disclosed. 11β-HSD1 biochemical studies of CA indicated that its functional groups at C-1, C-4, and C-9 were important for enzymatic activity; an X-ray crystal structure of 11β-HSD1 bound to CA at 2.6 ? resolution revealed the nature of those interactions, namely, a close-fitting and favorable interactions between the constrained CA spirocycle and the catalytic triad of 11β-HSD1. Structure-activity relationship studies culminated in the development of a superior CA analogue with improved target engagement. Furthermore, we demonstrate that CA selectively inhibits preadipocyte differentiation through 11β-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e., PPARγ, PGC-1α), presumably by negatively modulating the glucocorticoid signaling pathway. The combined findings provide an in-depth evaluation of the mode of action of CA and its potential as a tool compound to study adipose tissue and its implications in metabolic syndrome.
- Ling, Taotao,Miller, Darcie J.,Lang, Walter H.,Griffith, Elizabeth,Rodriguez-Cortes, Adaris,El Ayachi, Ikbale,Palacios, Gustavo,Min, Jaeki,Miranda-Carboni, Gustavo,Lee, Richard E.,Rivas, Fatima
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supporting information
p. 6925 - 6940
(2019/08/20)
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- Neutral Organic Super Electron Donors Made Catalytic
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Neutral organic super electron donors (SEDs) display impressive reducing power but, until now, it has not been possible to use them catalytically in radical chain reactions. This is because, following electron transfer, these donors form persistent radical cations that trap substrate-derived radicals. This paper unlocks a conceptually new approach to super electron donors that overcomes this issue, leading to the first catalytic neutral organic super electron donor.
- Rohrbach, Simon,Shah, Rushabh S.,Tuttle, Tell,Murphy, John A.
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supporting information
p. 11454 - 11458
(2019/07/18)
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- Iron-Catalyzed Coupling of Propargyl Bromides and Alkyl Grignard Reagents
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An iron-catalyzed Kumada-type cross-coupling reaction of propargyl halides with alkylmagnesium reagents is described. The reaction is fast, takes place in smooth conditions, tolerates several functional groups that would be able to react with the Grignard reagent, and may afford either allene or propargyl coupling derivatives. Factors involved in the observed regioselectivity have been studied.
- Domingo-Legarda, Pablo,Soler-Yanes, Rita,Quirós-López, M. Teresa,Bu?uel, Elena,Cárdenas, Diego J.
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supporting information
p. 4900 - 4904
(2018/09/10)
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- Nickel(II)-Catalyzed Asymmetric Propargyl [2,3] Wittig Rearrangement of Oxindole Derivatives: A Chiral Amplification Effect
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A highly enantioselective [2,3] Wittig rearrangement of oxindole derivatives was realized by using a chiral N,N′-dioxide/NiII complex as the catalyst under mild reaction conditions. A strong chiral amplification effect was observed, and allowed access to chiral 3-hydroxy 3-substituted oxindoles bearing allenyl groups in high yields and enantioselectivities (up to 92 % ee) by using a ligand with only 15 % ee. A reasonable explanation was given based on the experimental investigations and X-ray crystal structures of enantiomerically pure and racemic catalysts. Moreover, the first catalytic kinetic resolution of racemic oxindole derivatives by a [2,3] Wittig rearrangement was realized with high efficiency and stereoselectivity.
- Xu, Xi,Zhang, Jianlin,Dong, Shunxi,Lin, Lili,Lin, Xiaobin,Liu, Xiaohua,Feng, Xiaoming
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supporting information
p. 8734 - 8738
(2018/07/14)
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- Chemoproteomics-Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT
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We present a novel chemical scaffold for cysteine-reactive covalent inhibitors. Chloromethyl triazoles (CMTs) are readily accessed in only two chemical steps, thus enabling the rapid optimization of the pharmacological properties of these inhibitors. We d
- Wang, Chao,Abegg, Daniel,Hoch, Dominic G.,Adibekian, Alexander
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supporting information
p. 2911 - 2915
(2016/02/27)
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- Gold(I)-Catalyzed Angle Strain Controlled Strategy to Furopyran Derivatives from Propargyl Vinyl Ethers: Insight into the Regioselectivity of Cycloisomerization
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A unique strategy for the regiospecific synthesis of bicyclic furopyran derivatives has been developed via a gold(I)-catalyzed propargyl-Claisen rearrangement/6-endo-trig cyclization of propargyl vinyl ethers. The introduction of angle strain into the substrates significantly altered the reaction's regioselectivity. Insight into the regioselectivity of the cycloisomerization was obtained with density functional theory calculations. (Chemical Equation).
- Jin, Shengfei,Jiang, Chongguo,Peng, Xiaoshi,Shan, Chunhui,Cui, Shanshan,Niu, Yuanyuan,Liu, Yang,Lan, Yu,Liu, Yongxiang,Cheng, Maosheng
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supporting information
p. 680 - 683
(2016/03/01)
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- Benzannulation of triynes to generate functionalized arenes by spontaneous incorporation of nucleophiles
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The thermal reaction of ester-tethered 1,3,8-triynes provides novel benzannulation products with concomitant incorporation of a nucleophile. Evidence suggests that this reaction proceeds via an allene-enyne intermediate generated by an Alder-ene reaction in the first step. Depending on the substituent of the alkyne moiety on the allene-enyne intermediate, the subsequent transformation can take one of two different paths, each leading to discrete aromatization products. The benzannulation of a silane-substituted 1,3,8-triynes provides arene products with a nucleophile incorporated onto the newly formed benzene core, whereas an aryl substituent leads to nucleophile trapping at the benzylic carbon atom connected to the aryl substituent. The formation of these two different products results from the involvement of two regioisomeric allene-enyne intermediates.
- Karmakar, Rajdip,Yun, Sang Young,Chen, Jiajia,Xia, Yuanzhi,Lee, Daesung
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p. 6582 - 6586
(2015/06/02)
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- Copper(i) iodide catalyzed synthesis of primary propargylic alcohols from terminal alkyne
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A highly efficient and practical method for the synthesis of primary propargylic alcohols has been developed using CuI as catalyst and paraformaldehyde as the formaldehyde source. The reaction was performed under mild reaction conditions offering the desired products in good to excellent yields with a variety of terminal alkynes.
- Kundu, Shrishnu Kumar,Mitra, Kanchan,Majee, Adinath
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p. 13220 - 13223
(2015/02/19)
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- Copper-catalyzed enantioselective allylic substitution with alkylboranes
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The first catalytic enantioselective allylic substitution reaction with alkylboron compounds has been achieved. The reaction between alkyl-9-BBN reagents and primary allylic chlorides proceeded with excellent γ-selectivities and high enantioselectivities under catalysis of a Cu(I)-DTBM-SEGPHOS system. The protocol produces terminal alkenes with an allylic stereogenic center branched with functionalized sp3-alkyl groups. The reaction with a γ-silicon-substituted allyl chloride affords an efficient strategy for the enantioselective synthesis of functionalized α-stereogenic chiral allylsilanes.
- Shido, Yoshinori,Yoshida, Mika,Tanabe, Masahito,Ohmiya, Hirohisa,Sawamura, Masaya
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supporting information
p. 18573 - 18576
(2013/01/15)
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- A highly reusable rhodium catalyst-organic framework for the intramolecular cycloisomerization of 1,6-enynes
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The intramolecular cycloisomerization of 1,6-enynes in 95-99% ee is reported using an immobilized Rh catalyst-organic framework synthesized from alternating ring-opening metathesis polymerization (altROMP) assembly. The framework was reused up to seven times, and it was used in high turnover number (TON) batch reactions. The catalyst provided the highest TONs to date (up to 890) for the cycloisomerizations, with catalyst loadings ranging from 0.2 to 0.06 mol %.
- Corkum, Elizabeth G.,Hass, Michael J.,Sullivan, Andrew D.,Bergens, Steven H.
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supporting information; experimental part
p. 3522 - 3525
(2011/09/16)
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- Application of a chiral scaffolding ligand in catalytic enantioselective hydroformylation
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The synthesis of β-amino-aldehydes has been achieved through enantioselective hydroformylation of PMP-protected allylic amines. The reaction is accomplished by using a scalemic scaffolding ligand that covalently and reversibly binds to the substrate. These ligands behave like chiral auxiliaries because they are covalently attached to the substrate during hydroformylation; however, similar to traditional asymmetric ligands, they can be used in catalytic quantities. The directed hydroformylation of disubstituted olefins occurs under mild conditions (35 °C and 50 psi CO/H2), and Z-olefins afford excellent enantioselectivities (up to 93% ee).
- Worthy, Amanda D.,Joe, Candice L.,Lightburn, Thomas E.,Tan, Kian L.
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supporting information; experimental part
p. 14757 - 14759
(2010/12/19)
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- Gold(I)-catalyzed enantioselective ring expansion of allenylcyclopropanols
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(Chemical Equation Presented) The asymmetric gold(I)-catalyzed ring expansion of 1-allenylcyclopropanols is described. The method provides synthetically valuable cyclobutanones with a vinyl-substituted quaternary stereogenic center in high enantioselectivities and yields. The method shows a broad substrate scope, tolerating protected alcohols and amines, alkenes, unsaturated esters, and acetals. The reaction is easily adjustable to large-scale synthesis, leading to product formation without significant loss of selectivity or yield with only 0.5 mol% catalyst loading.
- Kleinbeck, Florian,Toste, F. Dean
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supporting information; experimental part
p. 9178 - 9179
(2009/12/06)
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- An atom-economic and selective ruthenium-catalyzed redox isomerization of propargylic alcohols. An efficient strategy for the synthesis of leukotrienes
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Catalytic ruthenium complexes in conjunction with an indium cocatalyst and Broensted acid isomerize primary and secondary propargylic alcohols in good yields to provide trans enals and enones exclusively. Readily available indenylbis(triphenylphosphine)ruthenium chloride, in the presence of indium triflate and camphorsulfonic acid, gives the best turnover numbers and reactivity with the broadest range of substrates. Deuterium labeling experiments suggest that the process occurs through propargylic hydride migration followed by protic cleavage of the resultant vinylruthenium intermediate. Application of this method to the synthesis of leukotriene B4 demonstrates its utility and extraordinary selectivity.
- Trost, Barry M.,Livingston, Robert C.
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supporting information; experimental part
p. 11970 - 11978
(2009/02/05)
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- Catalytic intermolecular linear allylic C-H amination via heterobimetallic catalysis
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A novel heterobimetallic Pd(II)sulfoxide/(salen)Cr(III)Cl-catalyzed intermolecular linear allylic C-H amination (LAA) is reported. This reaction directly converts densely functionalized α-olefin substrates (1 equiv) to linear (E)-allylic carbamates with good yields and outstanding regio- and stereoselectivities (>20:1). Chiral bis-homoallylic and homoallylic oxygen, nitrogen, and carbon substituted α-olefins undergo allylic C-H amination with good yields, excellent selectivities, and no erosion in enantiomeric purity. Streamlined routes to (E)-allylic carbamates that can be further elaborated to medicinally and biologically relevant allylic amines are also demonstrated. Valuable 15N-labeled allylic amines may be generated directly from allyl moieties at late stages of synthetic routes by using the readily available 15N-(methoxycarbonyl)-p-toluenesulfonamide nucleophile. Evidence is provided that this reaction proceeds via a heterobimetallic mechanism where Pd/sulfoxide mediates allylic C-H cleavage to form a π-allylPd intermediate, and (salen)Cr(III)Cl/BQ work together to promote functionalization with the nitrogen nucleophile. Copyright
- Reed, Sean A.,White, M. Christina
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p. 3316 - 3318
(2008/10/09)
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- Au-catalyzed synthesis of 5,6-dihydro-8H-indolizin-7-ones from N-(pent-2-en-4-ynyl)-β-lactams
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(Chemical Equation Presented) Au-catalyzed synthesis of 5,6-dihydro-8H-indolizin-7-ones from readily available N-(pent-2-en-4-ynyl)- β-lactams is developed. In this reaction, a 5-exo-dig cyclization of the β-lactam nitrogen to the Au-activated C-C triple bond is followed by heterolytic fragmentation of the amide bond, forming a highly nucleophilic acyl cation. An expedient formal synthesis of indolizidine 167B was easily achieved using this new method.
- Peng, Yu,Yu, Meng,Zhang, Liming
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supporting information; experimental part
p. 5187 - 5190
(2009/06/06)
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- Dihydropyridazinones, pyridazinones and related compounds as fungicides
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This invention relates to substituted dihydropyridazinones, pyridazinones and related compounds, of the formula STR1 wherein A, Q, D and R1 are as defined within, compositions containing these compounds and methods of controlling agricultural and mammalian fungal diseases.
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