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Vsevolod A Peshkov, Olga P Pereshivko, Anton A Nechaev, Anatoly A Peshkov, Erik V Van der Eycken
This focused review aims to summarize recent developments in the processes involving additions of secondary propargylamines to various heteroallenes and subsequent transition metal-catalyzed or electrophile-mediated cyclizations. The utility of this convenient and tunable strategy spans from the carbon dioxide fixation and target-oriented synthesis of complex natural and biologically active products to the generation of extended synthetic libraries of diverse oxygen-, nitrogen- and sulfur-containing heterocycles...
March 16, 2018: Chemical Society Reviews
Barry M Trost, Chris Kalnmals
Herein, we report a valuable umpolung strategy that highlights the ambiphilic nature of the bis(phenylsulfonyl)methyl synthon and demonstrates its utility as a synthetic linchpin. While the bis(phenylsulfonyl)methyl group is typically introduced as an sp3 carbon nucleophile, we demonstrate that it can also function as an effective sp2 carbon electrophile in the presence of organolithium nucleophiles. Akyl- and aryllithiums couple with the central carbon of the bis(phenylsulfonyl)methyl unit to ultimately generate trisubstituted alkenes, comprising a formal sp3-sp2 and sp2-sp2 cross-coupling between organolithiums and bis(sulfones)...
March 15, 2018: Chemistry: a European Journal
Sindhu Kancherla, Marianne Lorentzen, Victor Snieckus, Kåre Bredeli Jørgensen
A general method for the regioselective synthesis of a series of ortho-substituted chrysenyl N,N-diethyl-O-carbamates by the directed ortho metalation (DoM) strategy is reported. The starting O-carbamates were prepared from corresponding chrysenols, available by oxidative photochemical cyclization or directed remote metalation tactics. Chrysen-1-yl and chrysene-3-yl ring site selectivity of directed ortho metalation (DoM) and anionic ortho Fries rearrangement (AoF) protocols, with s-BuLi/TMEDA, followed by electrophilic quench using a selection of electrophiles, were observed leading to new chrysenyl derivatives...
March 15, 2018: Journal of Organic Chemistry
Victor Laurent, Ekaterina Darii, Angelina Aujon, Marine Debacker, Jean-Louis Petit, Virgil Hélaine, Tibor Liptaj, Martin Breza, Aline Mariage, Lionel Nauton, Mounir Traikia, Marielle Lemaire, Marcel Salanoubat, Christine Guérard-Hélaine, Véronique De Berardinis
Dihydroxyacetone phosphate (DHAP)-dependent rhamnulose aldolases display an unprecedented versatility for ketones as electrophile substrates. We selected and characterized a rhamnulose aldolase from Bacteroides thetaiotaomicron (RhuABthet) to provide a proof of concept. DHAP was added as a nucleophile to several alpha-hydroxylated ketones used as electrophiles. This aldol addition was stereoselective and produced branched-chain monosaccharide adducts with a tertiary alcohol moiety. Several aldols were thus readily obtained in good to excellent yields (from 76 to 95%)...
March 15, 2018: Angewandte Chemie
Trevor A Hamlin, Marcel Swart, F Matthias Bickelhaupt
The reaction potential energy surface (PES) and, thus, the mechanism of bimolecular nucleophilic substitution (SN2) depend profoundly on the nature of the nucleophile and leaving group, but also on the central, electrophilic atom, its substituents, as well as on the medium in which the reaction takes place. Here, we provide an overview of recent studies and demonstrate how changes in any one of the aforementioned factors affect the SN2 mechanism. One of the most striking effects is the transition from a double-well to a single-well PES when the central atom is changed from a second-period (e...
March 15, 2018: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
Eiki Yoshida, Takafumi Suzuki, Masanobu Morita, Keiko Taguchi, Kohei Tsuchida, Hozumi Motohashi, Minoru Doita, Masayuki Yamamoto
Keap1 is a negative regulator of Nrf2, a master transcription factor that regulates cytoprotection against oxidative and electrophilic stresses. Although several studies have suggested that the Keap1-Nrf2 system contributes to bone formation besides the maintenance of redox homeostasis, how Nrf2 hyperactivation by Keap1 deficiency affects the bone formation remains to be explored, as the Keap1-null mice are juvenile lethal. To overcome this problem, we used viable Keap1-deficient mice that we have generated by deleting the esophageal Nrf2 in Keap1-null mice (NEKO mice)...
March 15, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Thomas Knoepfel, Pascal Furet, Robert Mah, Nicole Buschmann, Catherine Leblanc, Sebastien Ripoche, Diana Graus-Porta, Markus Wartmann, Inga Galuba, Robin A Fairhurst
As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities below 30 nM have been identified. Consistent with the hypothesized reversible-covalent mechanism of inhibition, the 2-FPUs exhibited slow binding kinetics, and the aldehyde, as the putative electrophile, could be demonstrated to be a key structural element for activity...
March 8, 2018: ACS Medicinal Chemistry Letters
Jun Zheng, Bernhard Breit
A palladium-catalyzed intermolecular direct C-H allylation of polyfluoroarenes with alkynes is reported. Unlike classic hydroarylation reactions, alkynes are used as allylic electrophile surrogates in this direct aromatic C-H allylation. As an atom-economic and efficient method, various linear allylated fluoroarenes were synthesized from two simple and easy-to-access feedstocks in good to excellent yields, as well as regio- and stereoselectivity.
March 14, 2018: Organic Letters
Shobhana Krishnaswamy, Mysore Srikantiah Shashidhar
Intermolecular acyl transfer reactivity in several molecular crystals was studied and the outcome of the reactivity was analysed in the light of structural information obtained from the crystals of the reactants. Minor changes in the molecular structure resulted in significant variations in the non-covalent interactions and packing of molecules in the crystal lattice, which drastically affected the facility of the intermolecular acyl transfer reactivity in these crystals. Analysis of the reactivity Vs. crystal structure data revealed dependence of the reactivity on electrophile...
March 14, 2018: Journal of Organic Chemistry
Marc A van Bochove, Goedele Roos, Célia Fonseca Guerra, Trevor A Hamlin, F Matthias Bickelhaupt
Our quantum chemical activation strain analyses demonstrate how Mg2+ lowers the barrier of the enzymatic triphosphate hydrolysis through two distinct mechanisms: (a) weakening of the leaving-group bond, thereby decreasing activation strain; and (b) transition state (TS) stabilization through enhanced electrophilicity of the triphosphate PPP substrate, thereby strengthening the interaction with the nucleophile.
March 14, 2018: Chemical Communications: Chem Comm
Sreenivas Katukojvala, Vinaykumar Kanchupalli
Described herein is a dirhodium carboxylate catalyzed [1+1+3] annulation reaction of diazoenals and vinyl azides which gives synthetically important enal-functionalized 1-pyrroline derivatives. The reaction involves a novel rhodium-catalyzed olefination of diazoenals with vinyl azides via electrophilic enalcarbenoid, resulting in the new class of enal-acrylates. The annulation reaction was used for the direct synthesis of valuable deuterated 1-pyrrolines. Structural diversification of the enal-functionalized 1-pyrrolines resulted in the biologically important pyrrolidine fused oxaziridine, amino acid derivatives, and a 6-azabicyclo[3...
March 14, 2018: Angewandte Chemie
Wei Sun, Lu Wang, Chungu Xia, Chao Liu
Dual functionalization of 1,1-diborylalkanes via a deoxygenative enolization with carboxylic acids strategy has been developed for the first time. 1,1-Diborylalkanes were activated by MeLi to generate α-monoboryl carbanion. In-situ IR spectroscopy exhibited the interaction between carboxylic acid and 1,1-diborylalkane before adding activation reagent. The release of active α-monoboryl carbanion from its masked form was necessary for its reaction with carboxylate to afford enolate species. Electrophilic trapping of enolate species with various electrophiles achieved dual functionalization of 1,1-diborylalkanes to afford a variety of α-mono, di- and tri-substituted ketones...
March 13, 2018: Angewandte Chemie
Tian-Ren Li, Mary L Maliszewski, Wen-Jing Xiao, Jon A Tunge
A palladium-catalyzed decarboxylative coupling of enol carbonates with diarylmethyl electrophiles that are derived from secondary benzylic alcohols has been developed. This method allows the generation of a variety of β-diaryl ketones through an efficient and highly stereospecific coupling. In addition, detailed mechanistic insight into the coupling suggests that the reaction is a rare example of an intramolecular decarboxylative coupling that proceeds without crossover between reactants.
March 13, 2018: Organic Letters
Anna Kowalkowska, Andrzej Jończyk, Jan K Maurin
A novel domino reaction featuring a Michael addition/[1,2]-Stevens rearrangement reaction of pyrrolidinium ylides with electrophilic alkenes is described. Ylides generated under mild conditions from 2-aryl- N-cyanomethyl- N-methylpyrrolidinium salts entered the Michael addition, followed by a [1,3]-hydrogen shift and finally the [1,2]-Stevens rearrangement to give 3-aryl-2-cyano-2-(2-EWG-ethyl)-1-methylpiperidines.
March 13, 2018: Journal of Organic Chemistry
Yi Zhao, Marcus J C Long, Yiran Wang, Sheng Zhang, Yimon Aye
Posttranslational modifications (PTMs) are the lingua franca of cellular communication. Most PTMs are enzyme-orchestrated. However, the reemergence of electrophilic drugs has ushered mining of unconventional/non-enzyme-catalyzed electrophile-signaling pathways. Despite the latest impetus toward harnessing kinetically and functionally privileged cysteines for electrophilic drug design, identifying these sensors remains challenging. Herein, we designed "G-REX"-a technique that allows controlled release of reactive electrophiles in vivo...
February 28, 2018: ACS Central Science
Sean A Newmister, Shasha Li, Marc Garcia-Borràs, Jacob N Sanders, Song Yang, Andrew N Lowell, Fengan Yu, Janet L Smith, Robert M Williams, K N Houk, David H Sherman
Hapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These complex metabolites are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps: a rare Cope rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution. Here we report the structure of HpiC1, a Stig cyclase that catalyzes the formation of 12-epi-hapalindole U in vitro. The 1...
March 12, 2018: Nature Chemical Biology
Shinya Tanaka, Yuki Saito, Takaya Yamamoto, Tetsutaro Hattori
A variety of terminal alkenes, as well as heteroaromatic compounds, are borylated by the combined use of BBr3 /2,6-dichloropyridine (B3) or BBr3 /2,6-lutidine (B5). α,α-Diarylalkenes prefer the former reagent combination, while other alkenes prefer the latter. Mechanistic considerations strongly suggest that the former and latter reactions proceed through electrophilic substitution reactions with BBr3 and [BBr2 ·B5]+ BBr4 - , respectively.
March 12, 2018: Organic Letters
Jiliang Zhou, Liu Leo Liu, Levy L Cao, Douglas W Stephan
A cyclic (amino)(aryl)nitrenium cation 2 has been achieved by treatment of spiro[fluorene-9,3'-indazole] (1) with Ph2 CHCl and AgBF4 . This cation 2 is Lewis acidic at nitrenium N1, reacting with PMe3 affording a Lewis acid/base adduct 3. In contrast, deprotonation of 2 with other bases provides a neutral compound 4 which is Lewis basic at N1, reacting with electrophiles including GaCl3 , MeOTf and PhNCO.
March 12, 2018: Chemical Communications: Chem Comm
Stefan E Payer, Hannah Pollak, Silvia M Glueck, Kurt Faber
The promiscuous regio- and stereoselective hydration of 4-hydroxystyrenes catalyzed by ferulic acid decarboxylase from Enterobacter sp. (FDC_ Es ) depends on bicarbonate bound in the active site, which serves as a proton relay activating a water molecule for nucleophilic attack on a quinone methide electrophile. This "cofactor" is crucial for achieving improved conversions and high stereoselectivities for ( S )-configured benzylic alcohol products. Similar effects were observed with simple aliphatic carboxylic acids as additives...
March 2, 2018: ACS Catalysis
Eric Tan, Ophélie Quinonero, M Elena de Orbe, Antonio M Echavarren
We report the alkynylation of C(sp2 )-H bonds with bromoalkynes (inverse-Sonogashira reaction) directed by synthetically useful ester, ketone, and ether groups under rhodium catalysis. Other less common directing groups such as amine, thioether, sulfoxide, sulfone, phenol ester, and carbamate are also suitable directing groups. Mechanistic studies indicate that the reaction proceeds by a turnover-limiting C-H activation step via an electrophilic-type substitution.
March 2, 2018: ACS Catalysis
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