219320-15-7Relevant academic research and scientific papers
Photocatalytic acyl azolium-promoted alkoxycarbonylation of trifluoroborates
Scheidt, Karl A.,Zhu, Joshua L.
, (2021/06/28)
Despite recent advancements in the selective generation and coupling of organic radical species, the alkoxycarbonyl radical remains underexplored relative to other carbon-containing radical species. Drawing inspiration from new strategies for generating acyl radical equivalents utilizing dual N-heterocyclic carbene catalysis and photocatalysis, we have prepared dimethylimidazolium esters that can function as an alkoxycarbonyl radical surrogate under photocatalytic conditions. We demonstrate the synthetic utility of these azolium-based partners through the preparation of esters arising from the coupling of this radical surrogate with an oxidatively generated alkyl radical.
Catalytic Asymmetric Fluorination of Copper Carbene Complexes: Preparative Advances and a Mechanistic Rationale
Buchsteiner, Michael,Fürstner, Alois,Jerabek, Paul,Lehmann, Christian W.,Martinez-Rodriguez, Luis,N?thling, Nils,Patzer, Michael,Pozo, Iago
supporting information, p. 2509 - 2515 (2020/02/26)
The Cu-catalyzed reaction of substituted α-diazoesters with fluoride gives α-fluoroesters with ee values of up to 95 %, provided that chiral indane-derived bis(oxazoline) ligands are used that carry bulky benzyl substituents at the bridge and moderately bulky isopropyl groups on their core. The apparently homogeneous solution of CsF in C6F6/hexafluoroisopropanol (HFIP) is the best reaction medium, but CsF in the biphasic mixture CH2Cl2/HFIP also provides good results. DFT studies suggest that fluoride initially attacks the Cu- rather than the C-atom of the transient donor/acceptor carbene intermediate. This unusual step is followed by 1,2-fluoride shift; for this migratory insertion to occur, the carbene must rotate about the Cu?C bond to ensure orbital overlap. The directionality of this rotatory movement within the C2-symmetric binding site determines the sense of induction. This model is in excellent accord with the absolute configuration of the resulting product as determined by X-ray diffraction using single crystals of this a priori wax-like material grown by capillary crystallization.
Targeting enteropeptidase with reversible covalent inhibitors to achieve metabolic benefits
Sun, Weimei,Zhang, Xuqing,Cummings, Maxwell D.,Albarazanji, Kamal,Wu, Jiejun,Wang, Mina,Alexander, Richard,Zhu, Bin,Zhang, Yuemei,Leonard, James,Lanter, James,Lenhard, James
, p. 510 - 521 (2020/12/22)
Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clinically for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clinical efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (kinact/KI) of 1.5 × 104M-1s-1. High-resolution liquid chromatography-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 hours. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 ?, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptindeficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clinically relevant efficacy. SIGNIFICANCE STATEMENT Interest in targeted covalent drugs has expanded in recent years, particularly so for kinase targets, but also more broadly. This study demonstrates that reversible covalent inhibition of the serine protease enteropeptidase is a therapeutically viable approach to the treatment of metabolic diseases and that mechanistic details of inhibition are relevant to clinical efficacy. Our mechanistic and kinetic studies outline a framework for detailed inhibitor characterization that is proving essential in guiding discovery efforts in this area.
Photoinduced Palladium-Catalyzed Negishi Cross-Couplings Enabled by the Visible-Light Absorption of Palladium–Zinc Complexes
Abdiaj, Irini,Huck, Lena,Mateo, José Miguel,de la Hoz, Antonio,Gomez, M. Victoria,Díaz-Ortiz, Angel,Alcázar, Jesús
supporting information, p. 13231 - 13236 (2018/09/25)
A visible-light-induced Negishi cross-coupling is enabled by the activation of a Pd0–Zn complex. With this photocatalytic method, the scope of deactivated aryl halides that can be employed in the Negishi coupling was significantly expanded. NMR experiments conducted in the presence and absence of light confirmed that the formation of the palladium–zinc complex is key for accelerating the oxidative addition step.
Copper-catalyzed coupling of aryl iodides and tert-butyl keto esters: Efficient access to α-aryl ketones and α-arylacetic acid tert-butyl esters
Zhao, Duo,Jiang, Yongwen,Ma, Dawei
, p. 3327 - 3332 (2014/05/06)
CuI/trans-4-hydroxy-l-proline catalyzed coupling of aryl iodides with tert-butyl keto esters proceeded smoothly at 40 °C in DMF, providing α-aryl ketones after acid-promoted deprotection and decarboxylation of tert-butyl ester group. While CuI/2-picolinic acid catalyzed coupling of aryl iodides with tert-butyl acetoacetate at 70 °C in dioxane delivered α-arylacetic acid tert-butyl esters upon spontaneous deacylation. A wide range of functional groups, such as acetyl, methoxy, nitrile, nitro, bromo, and chloro were compatible with the reaction conditions.
Palladium-catalyzed α-arylation of zinc enolates of esters: Reaction conditions and substrate scope
Hama, Takuo,Ge, Shaozhong,Hartwig, John F.
, p. 8250 - 8266 (2013/09/24)
The intermolecular α-arylation of esters by palladium-catalyzed coupling of aryl bromides with zinc enolates of esters is reported. Reactions of three different types of zinc enolates have been developed. α-Arylation of esters occurs in high yields with i
Palladium-catalyzed-arylattion of esters With chloroarenes
Hama, Takuo,Hartwig, John F.
supporting information; experimental part, p. 1549 - 1552 (2009/04/10)
Palladium-catalyzed α-arylations of esters with chloroarenes are reported. The reactions of chloroarenes with the sodium enolates of tert-butyl propionate and methyl isobutyrate occur in high yields with 0.2-1 mol % of {[P(f-Bu)3]PdBr}2/s
Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway
Desharnais, Joel,Hwang, Inkyu,Zhang, Yan,Tavassoli, Ali,Baboval, Justin,Benkovic, Stephen J.,Wilson, Ian A.,Boger, Dale L.
, p. 4511 - 4521 (2007/10/03)
The synthesis and evaluation of analogues and key derivatives of 10-CF 3CO-DDACTHF as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. Polyglutamate analogues of 1 were evaluated as inhibitors of Escherichia coli and recombinant human (rh) GAR Tfase, and AICAR Tfase. Although the pentaglutamate 6 was found to be the most active inhibitor of the series tested against rhGAR Tfase (Ki=0.004 μM), little distinction between the mono-pentaglutamate derivatives was observed (K i=0.02-0.004 μM), suggesting that the principal role of the required polyglutamation of 1 is intracellular retention. In contrast, 1 and its defined polyglutamates 3-6 were much less inactive when tested against rhAICAR Tfase (Ki=65-0.120 μM) and very selective (≥100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of 1 were examined (7 and 8) and found to be much less active (1000-fold) highlighting the exceptional characteristics of 1.
Synthesis of arylacetates by the palladium-catalyzed cross-coupling of aryl bromides and copper(II) enolates
Agnelli, Fabio,Sulikowski, Gary A.
, p. 8807 - 8810 (2007/10/03)
Palladium-catalyzed cross coupling of aryl bromides and silylketene acetals in the presence of tributyltin fluoride or copper(II) fluoride is described.
