67671-05-0Relevant articles and documents
Method for preparing single-configuration C-2-position-monosubstituted norbornene derivative
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Paragraph 0041-0042, (2021/07/01)
The invention discloses a method for preparing a single-configuration C-2-position-monosubstituted norbornene derivative. The method comprises the following steps of: firstly, preparing exo-isomer enriched exo-isomer mixed 5-norbornene-2-carboxylic ester by taking commercial exo-isomer/endoisomer mixed 5-norbornene-2-carboxylic acid and large-steric-hindrance monohydric alcohol as raw materials; separating 5-norbornene-2-carboxylate with a single configuration through common column chromatography separation or fractionation; and finally, preparing the C-2-position-monosubstituted norbornene derivative with the single configuration from the separated 5-norbornene-2-carboxylate with the single configuration. The raw materials used in the invention are easy to obtain, the preparation process is simple, and the C-2-position-monosubstituted norbornene derivative with high purity (greater than 98%) and single configuration can be obtained.
Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity
Hansen, Bettina Borreschmidt,Jepsen, Tue Heesgaard,Larsen, Mogens,Sindet, Rikke,Vifian, Thomas,Burhardt, Mia N?rreskov,Larsen, Jens,Seitzberg, Jimmi Gerner,Carnerup, Martin A.,Jerre, Anders,M?lck, Christina,Lovato, Paola,Rai, Sanjay,Nasipireddy, Venkatarathnam Reddy,Ritzén, Andreas
, p. 7008 - 7032 (2020/07/28)
Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.
Amphiphilic Bottlebrush Block Copolymers: Analysis of Aqueous Self-Assembly by Small-Angle Neutron Scattering and Surface Tension Measurements
Alaboalirat, Mohammed,Qi, Luqing,Arrington, Kyle J.,Qian, Shuo,Keum, Jong K.,Mei, Hao,Littrell, Kenneth C.,Sumpter, Bobby G.,Carrillo, Jan-Michael Y.,Verduzco, Rafael,Matson, John B.
, p. 465 - 476 (2019/01/14)
A systematic series of 16 amphiphilic bottlebrush block copolymers (BCPs) containing polystyrene and poly(N-acryloylmorpholine) (PACMO) side chains were prepared by a combination of atom-transfer radical polymerization (ATRP), photoiniferter polymerization, and ring-opening metathesis polymerization (ROMP). The grafting-through method used to prepare the polymers enabled a high degree of control over backbone and side-chain molar masses for each block. Surface tension measurements on the self-assembled amphiphilic bottlebrush BCPs in water revealed an ultralow critical micelle concentration (cmc), 1-2 orders of magnitude lower than linear BCP analogues on a molar basis, even for micelles with >90% PACMO content. Combined with coarse-grained molecular dynamics simulations, fitting of small-angle neutron scattering traces (SANS) allowed us to evaluate solution conformations for individual bottlebrush BCPs and micellar nanostructures for self-assembled macromolecules. Bottlebrush BCPs showed an increase in anisotropy with increasing PACMO content in toluene-d8, which is a good solvent for both blocks, reflecting an extended conformation for the PACMO block. SANS traces of bottlebrush BCPs assembled into micelles in D2O, a selective solvent for PACMO, were fitted to a core-shell-shell model, suggesting the presence of a partially hydrated inner shell. Results showed an average micelle diameter of 40 nm with combined shell diameters ranging from 16 to 18 nm. A general trend of increased stability of micelles (i.e., resistance to precipitation) was observed with increases in PACMO content. These results demonstrate the stability of bottlebrush polymer micelles, which self-assemble to form spherical micelles with ultralow (70 nmol/L) cmc's across a broad range of compositions.
Approach Matters: The Kinetics of Interfacial Inverse-Electron Demand Diels–Alder Reactions
Sen, Rickdeb,Gahtory, Digvijay,Escorihuela, Jorge,Firet, Judith,Pujari, Sidharam P.,Zuilhof, Han
supporting information, p. 13015 - 13022 (2017/09/06)
Rapid and quantitative click functionalization of surfaces remains an interesting challenge in surface chemistry. In this regard, inverse electron demand Diels–Alder (IEDDA) reactions represent a promising metal-free candidate. Herein, we reveal quantitative surface functionalization within 15 min. Furthermore, we report the comprehensive effects of substrate stereochemistry, surrounding microenvironment and substrate order on the reaction kinetics as obtained by surface-bound mass spectrometry (DART-HRMS).
Exploring the Potential of Norbornene-Modified Mannosamine Derivatives for Metabolic Glycoengineering
Sp?te, Anne-Katrin,Dold, Jeremias E. G. A.,Batroff, Ellen,Schart, Verena F.,Wieland, Daniel E.,Baudendistel, Oliver R.,Wittmann, Valentin
, p. 1374 - 1383 (2017/02/14)
Metabolic glycoengineering (MGE) allows the introduction of unnaturally modified carbohydrates into cellular glycans and their visualization through bioorthogonal ligation. Alkenes, for example, have been used as reporters that can react through inverse-electron-demand Diels–Alder cycloaddition with tetrazines. Earlier, norbornenes were shown to be suitable dienophiles; however, they had not previously been applied for MGE. We synthesized two norbornene-modified mannosamine derivatives that differ in the stereochemistry at the norbornene (exo/endo linkage). Kinetic investigations revealed that the exo derivative reacts more than twice as rapidly as the endo derivative. Through derivatization with 1,2-diamino-4,5-methylenedioxybenzene (DMB) we confirmed that both derivatives are accepted by cells and incorporated after conversion to a sialic acid. In further MGE experiments the incorporated sugars were ligated to a fluorophore and visualized through confocal fluorescence microscopy and flow cytometry.
Dual responsive polymeric nanoparticles prepared by direct functionalization of polylactic acid-based polymers via graft-from ring opening metathesis polymerization
Veccharelli, Kate M.,Tong, Venus K.,Young, Jennifer L.,Yang, Jerry,Gianneschi, Nathan C.
supporting information, p. 567 - 570 (2016/01/12)
Polylactic acid (PLA) has found widespread use in plastics and in biomedical applications due to its biodegradability into natural benign products. However, PLA-based materials remain limited in usefulness due to difficulty of incorporating functional groups into the polymer backbone. In this paper, we report a strategy for PLA functionalization that establishes the preparation of highly derivatized materials in which ring opening metathesis polymerization (ROMP) is employed as a graft-from polymerization technique utilizing a norbornene-modified handle incorporated into the PLA backbone. As a demonstration of this new synthetic methodology, a PLA-derived nanoparticle bearing imidazole units protected with a photolabile group was prepared. The morphology of this material could be controllably altered in response to exposure of UV light or acidic pH as a stimulus. We anticipate that this graft-from approach to derivatization of PLA could find broad use in the development of modified, biodegradable PLA-based materials.
Structure-Based Design of β5c Selective Inhibitors of Human Constitutive Proteasomes
Xin, Bo-Tao,De Bruin, Gerjan,Huber, Eva M.,Besse, Andrej,Florea, Bogdan I.,Filippov, Dmitri V.,Van Der Marel, Gijsbert A.,Kisselev, Alexei F.,Van Der Stelt, Mario,Driessen, Christoph,Groll, Michael,Overkleeft, Herman S.
supporting information, p. 7177 - 7187 (2016/08/24)
This work reports the development of highly potent and selective inhibitors of the β5c catalytic activity of human constitutive proteasomes. The work describes the design principles, large hydrophobic P3 residue and small hydrophobic P1 residue, that led to the synthesis of a panel of peptide epoxyketones; their evaluation and the selection of the most promising compounds for further analyses. Structure-activity relationships detail how in a logical order the β1c/i, β2c/i, and β5i activities became resistant to inhibition as compounds were diversified stepwise. The most effective compounds were obtained as a mixture of cis- and trans-biscyclohexyl isomers, and enantioselective synthesis resolved this issue. Studies on yeast proteasome structures complexed with some of the compounds provide a rationale for the potency and specificity. Substitution of the N-terminus in the most potent compound for a more soluble equivalent led to a cell-permeable molecule that selectively and efficiently blocks β5c in cells expressing both constitutive proteasomes and immunoproteasomes.
High Tg sulfonated insertion polynorbornene ionomers prepared by catalytic insertion polymerization
Pierre, Florian,Commarieu, Basile,Tavares, Ana C.,Claverie, Jerome
, p. 91 - 97 (2016/02/10)
A simple method to synthesize high Tg sulfonated ionomers based on catalytic insertion polynorbornene is reported. Copolymers of norbornene and 5-methyl alcohol norbornene (endo:exo = 82:18) or 5-methyl bromide norbornene (endo:exo = 86:14) as well as terpolymers of norbornene, 5-methyl alcohol norbornene and 5-hexyl norbornene are prepared using a cationic Pd catalyst. These copolymers are then thioacetylated. Using hydrogen peroxide as oxidant, a sulfonated polynorbornene is obtained. Ionomers containing as much as 30 mol% SO3H and with Tgs above 200 °C are obtained in a four-step procedure of overall 40-75% yield.
Heterogenization of ferrocene palladacycle catalysts on ROMP-derived monolithic supports and application to a Michael addition
Sudheendran, Mavila,Eitel, Simon H.,Naumann, Stefan,Buchmeiser, Michael R.,Peters, Ren
supporting information, p. 5597 - 5607 (2014/12/11)
The anchoring of well-defined molecular catalysts on a surface is an attractive strategy to develop sustainable catalytic processes. This article describes the first syntheses of monolith-supported ferrocene palladacycle catalysts. Monolithic supports were prepared via ring-opening metathesis polymerization (ROMP) using the 1st generation Grubbs catalyst . Fluorinated carboxylates were surface-grafted utilizing living Ru-termini. The immobilization of the palladacycles onto the monolithic support was accomplished by ligand substitution on the fluorinated carboxylates of the graft polymer. An investigation of these supported catalysts on the efficiency and reusability under different reaction conditions in a direct Michael addition generating a quaternary C-atom is reported. Whereas stereoselectivity was found to be significantly lower than in a comparable homogeneous system, Pd-leaching was not detected in all analyzed samples indicating a permanently immobilized catalyst system. This journal is
Lewis acid mediated asymmetric Diels-Alder reactions of chiral 2-phosphonoacrylates
Zhu, Jia-Liang,Chen, Po-Erh,Huang, Hue-Wen
, p. 23 - 36 (2013/02/23)
2-Phosphonoacrylates containing four chiral alcohol auxiliaries were efficiently prepared and evaluated in Lewis acid mediated Diels-Alder reactions. Under the activation of SnCl4, all reactions performed in CH 2Cl2 at -65 °C exclusively afforded the endo (endo-to-carboxylate) cycloadducts with dr's ranging from 50:50 to >99:1. The best facial selectivity was obtained from the substrate bearing a (-)-phenylmenthyl group, to give adducts as (dr >99:1) or almost as (dr = 99:1) single diastereomers. Detailed strategies for the structural elucidation of the cycloadducts as well as a rationalization of the observed stereoselectivity are described.
