- Application of Dually Activated Michael Acceptor to the Rational Design of Reversible Covalent Inhibitor for Enterovirus 71 3C Protease
-
Targeted covalent inhibitors (TCIs) have attracted growing attention from the pharmaceutical industry in recent decades because they have potential advantages in terms of efficacy, selectivity, and safety. TCIs have recently evolved into a new version with reversibility that can be systematically modulated. This feature may diminish the risk of haptenization and help optimize the drug-target residence time as needed. The enteroviral 3C protease (3Cpro) is a valuable therapeutic target, but the development of 3Cpro inhibitors is far from satisfactory. Therefore, we aimed to apply a reversible TCI approach to the design of novel 3Cpro inhibitors. The introduction of various substituents onto the α-carbon of classical Michael acceptors yielded inhibitors bearing several classes of warheads. Using steady-state kinetics and biomolecular mass spectrometry, we confirmed the mode of reversible covalent inhibition and elucidated the mechanism by which the potency and reversibility were affected by electronic and steric factors. This research produced several potent inhibitors with good selectivity and suitable reversibility; moreover, it validated the reversible TCI approach in the field of viral infection, suggesting broader applications in the design of reversible covalent inhibitors for other proteases.
- Ma, Yuying,Li, Linfeng,He, Shuai,Shang, Chengyou,Sun, Yang,Liu, Ning,Meek, Thomas D.,Wang, Yaxin,Shang, Luqing
-
-
Read Online
- Visible-Light Organophotoredox-Catalyzed Synthesis of Precursors for Horner-Type Olefinations
-
A metal-free photoredox-catalyzed α-heteroarylation of 2-bromophosphonoacetic esters allows the synthesis of precursors for Horner-olefinations from indoles in a single step. Numerous functional groups are tolerated in this photoinduced radical coupling u
- Nebe, Marco M.,Loeper, Daniel,Fürmeyer, Fabian,Opatz, Till
-
-
Read Online
- Enantioselective organocatalytic synthesis of α- cyclopropylphosphonates through a domino michael addition/intramolecular alkylation reaction
-
An organocatalytic domino reaction consisting of Michael addition/intramolecular alkylation between α,β-unsaturated aldehydes and bromophosphonoacetates was developed. Highly functionalised cyclopropylphosphonates containing three chiral centres, one of them quaternary, were obtained with good diastereoselectivities of up to 83:17 and very high enantioselectivities of up to 99 %. α-Cyclopropylphosphonates with three stereogenic centres were obtained in good yields and high enantio-and diastereocontrol through a "one-pot" domino process catalysed by a chiral pyrrolidine. The highly functionalised cyclopropanes should be versatile starting materials for biologically important compounds. Copyright
- Faisca Phillips, Ana Maria,Barros, Maria Teresa
-
-
Read Online
- Synthesis of 3-alkoxycarbonyl-1β-methylcarbapenem by using the palladium-catalyzed C-N bond-forming reaction between vinyl halide and β-lactam nitrogen
-
3-Alkoxycarbonyl-1β-methylcarbapenem could be synthesized by using a palladium-catalyzed C-N bond-forming reaction between vinyl halide and β-lactam nitrogen. In this reaction, the use of Pd-(OAc)2 and DPEphos gave a good result, and the generation of Pd(0) from Pd(OAc)2 in the absence of a base is necessary to increase the yield.
- Kozawa, Yuji,Mori, Miwako
-
-
Read Online
- Multisubstituted Cyclohexene Construction through Telescoped Radical-Addition Induced Remote Functional Group Migration and Horner–Wadsworth–Emmons (HWE) Olefination
-
An efficient telescoped method for the rapid assembly of multisubstituted cyclohexenes is presented herein. The whole process nicely merges photoredox-promoted alkene difunctionalization via remote functional group migration with concomitant intramolecular Horner–Wadsworth–Emmons (HWE) olefination. The characteristic feature of this protocol resides in the fact that the follow-up requiring ketone functionality for ring-closing olefination is in situ unveiled from the otherwise inert tertiary alcohol by the preceding alkene difunctionalization.
- Zhang, Xing-Gui,Li, Xin,Zhang, Chi,Feng, Chao
-
supporting information
p. 9611 - 9615
(2021/12/17)
-
- Visible-Light-Promoted Generation of α-Ketoradicals from Vinyl-bromides and Molecular Oxygen: Synthesis of Indenones and Dihydroindeno[1,2-c]chromenes
-
Ortho-alkynylated α-bromocinnamates can be converted by a visible-light-mediated photocascade reaction with molecular oxygen into either indenones or dihydroindeno[1,2-c]chromenes. The one-step process features key photochemical steps, that is, the initial activation of vinyl bromides through energy transfer to give α-ketoradicals in a reaction with molecular oxygen, followed by α-oxidation of an arene moiety by 6-π electrocyclization, and subsequent hydroxylation by an electron-transfer process from the same photocatalyst leads to the dihydroindeno[1,2-c]chromenes.
- Pagire, Santosh K.,Kreitmeier, Peter,Reiser, Oliver
-
supporting information
p. 10928 - 10932
(2017/08/30)
-
- Palladium-Catalyzed Long-Range Deconjugative Isomerization of Highly Substituted α,β-Unsaturated Carbonyl Compounds
-
The long-range deconjugative isomerization of a broad range of α,β-unsaturated amides, esters, and ketones by an in situ generated palladium hydride catalyst is described. This redox-economical process is triggered by a hydrometalation event and is thermodynamically driven by the refunctionalization of a primary or a secondary alcohol into an aldehyde or a ketone. Di-, tri-, and tetrasubstituted carbon-carbon double bonds react with similar efficiency; the system is tolerant toward a variety of functional groups, and olefin migration can be sustained over 30 carbon atoms. The refunctionalized products are usually isolated in good to excellent yield. Mechanistic investigations are in support of a chain-walking process consisting of repeated migratory insertions and β-H eliminations. The bidirectionality of the isomerization reaction was established by isotopic labeling experiments using a substrate with a double bond isolated from both terminal functions. The palladium hydride was also found to be directly involved in the product-forming tautomerization step. The ambiphilic character of the in situ generated [Pd-H] was demonstrated using isomeric trisubstituted α,β-unsaturated esters. Finally, the high levels of enantioselectivity obtained in the isomerization of a small set of α-substituted α,β-unsaturated ketones augur well for the successful development of an enantioselective version of this unconventional isomerization.
- Lin, Luqing,Romano, Ciro,Mazet, Clément
-
supporting information
p. 10344 - 10350
(2016/08/31)
-
- Synthesis of the ABC ring system of jiadifenin via pd-catalyzed cyclizations
-
An efficient route toward the central ABC system of jiadifenin has been developed using two key Pd-catalyzed cyclizations. A protic solvent-activated Mizoroki-Heck reaction was used to construct the C9 quaternary carbon and the A ring. A cascad
- Harada, Kenichi,Imai, Akiko,Uto, Kazuharu,Carter, Rich G.,Kubo, Miwa,Hioki, Hideaki,Fukuyama, Yoshiyasu
-
supporting information; experimental part
p. 988 - 991
(2011/05/08)
-
- A new general approach to 4-substituted-3-halo-2-quinolones
-
A general procedure for the preparation of 4-substituted-3-halo-2-quinolones (halo = F, Cl, Br) utilizing 2-halo diethylphosphonoacetic acids (halo = F, Cl, Br) and o-aminophenylketones as the starting materials is described. The title compounds are obtained by an intramolecular Horner-Wadsworth-Emmons olefination of halogen-containing N-acyl-o-aminophenylketones. The transformation process is generally applicable under mild conditions.
- Zhao, Shuai,He, Yan-hong,Wu, Di,Guan, Zhi
-
experimental part
p. 597 - 605
(2010/06/21)
-
- Facile access to 2-arylindolines and 2-arylindoles by microwave-assisted tandem radical cyclization
-
A new route providing access to 2-arylindoles has been developed. The synthesis consists of a tin-mediated tandem radical cyclization of appropriate precursors to form 2,3-disubstituted dihydroindoles, which in turn are oxidized to yield the corresponding 2-arylindoles. The reactions proceed smoothly under microwave irradiation, furnishing the desired products in good yields. Georg Thieme Verlag Stuttgart.
- Prediger, Inga,Weiss, Torsten,Reiser, Oliver
-
experimental part
p. 2191 - 2198
(2009/04/06)
-
- A highly regio- and stereoselective formation of bicyclo[4.2.0]oct-5-ene derivatives through thermal intramolecular [2 + 2] cycloaddition of allenes
-
(Chemical Equation Presented) Thermal [2 + 2] cycloaddition of allenes with an additional multiple bond is described. By simply heating the allenenes or allenynes having a three-atom tether in an appropriate solvent such as dioxane or DMF, the distal doub
- Ohno, Hiroaki,Mizutani, Tsuyoshi,Kadoh, Yoichi,Aso, Akimasa,Miyamura, Kumiko,Fujii, Nobutaka,Tanaka, Tetsuaki
-
p. 4378 - 4389
(2008/02/05)
-
- Stereoselective preparation of (E)-α-bromoacrylates from mixtures of brominated ando phosphonates
-
We prepared 69:31-11:89 mixtures of phosphonates 6b and 7b containing two phenoxy substituents, a CO2Et group, and 1 or 2 bromine atoms, respectively, at the interspersed methylene group. Deprotonating 64:36 mixtures of these reagents with NaH
- Olpp, Thomas,Brueckner, Reinhard
-
p. 2135 - 2152
(2007/10/03)
-
- Asymmetric photodeconjugation: Highly stereoselective synthesis of α-fluorocarboxylic derivatives
-
Irradiations of α-fiuoro-α,β-unsaturated esters lead to the corresponding α-fluoro-β,γ-unsaturated isomers in good yields. The reaction required the use of an achiral base (typically an amine) to promote the protonation of the photodienolic intermediate. By replacing the ethyl group with a diacetone-D-glucose moiety, the reaction can be carried out in a diastereoselective manner to furnish the deconjugated esters with similar yields and selectivities up to 95%. The adducts were submitted to osmylation conditions to deliver α-fluoro-β-hydroxy-butyrolactones in one single step.
- Bargiggia, Frédéric,Dos Santos, Sylvia,Piva, Olivier
-
p. 427 - 437
(2007/10/03)
-
- Horner-Emmons reaction in the synthesis of esters of unsaturated acids from aclamantane series and related carcass compounds
-
In reaction with triethyl phosphonoacetate in the presence of sodium hydride at 100-120°C ketones related to adamantane, 1,3-diazaadamantane, and bicyclo[3.3.1]nonane with a carbonyl group either in the ring or in the side chain, and also aldehydes from adamantane series transform into acryl acid derivatives. The reaction of triethyl iodophosphonoacetate with 1-adamantanecarboxaldehyde yields a derivative of propargylic acid. Phosphonate reagents prepared from 4-azahomoadamantane give the corresponding unsaturated esters already on reacting with acetaldehyde at 30°C.
- Miryan,Isaev,Kovaleva,Petukh,Dvornikova,Kardakova,Yurchenko
-
p. 857 - 861
(2007/10/03)
-
- Cascade Reactions with Chiral Michael Acceptors; Synthesis of Enantiomerically Pure Tricyclo2,7>- and Bicyclooctanes
-
Starting from the easily accesible chiral aldehyde 2, we obtained enantiomerically pure (Z)- and (E)-α-chloro-α,β-unsaturated esters 4c in good yields by olefination reactions. (Z)- and (E)-4c were allowed to react with the kinetically controlled generate
- Braun, Norbert A.,Klein, Iris,Spitzner, Dietrich,Vogler, Bernhard,Braun, Siegmar,et al.
-
p. 2165 - 2170
(2007/10/03)
-