Organic & Biomolecular Chemistry (v.15, #36)
Front cover (7479-7480).
Contents list (7481-7489).
Transition metal mediated carbonylative benzannulations by Wangze Song; Stephanie A. Blaszczyk; Jitian Liu; Shuojin Wang; Weiping Tang (7490-7504).
In carbonylative benzannulations, feedstock carbon monoxide is converted to a benzene ring, which is one of the most fundamentally important and common rings in natural products and pharmaceutical compounds. Carbon monoxide, however, is rather inert in the absence of transition metals. Historically, carbonylative benzannulations have been mediated by stoichiometric chromium and iron in the form of Fischer carbenes. Recently, a number of transition metal-catalyzed carbonylative benzannulations have been developed, and almost all of them involve rhodium catalysts. This review will briefly discuss the mechanism and applications of carbonylative benzannulations involving Fischer carbenes and compare them with the more recent transition metal-catalyzed processes, including [3 + 2 + 1] cycloadditions, [5 + 1] cycloadditions, and other less common cycloadditions.
Organocatalytic condensation–ring opening–annulation cascade reactions between N-Bocindolin-2-ones/benzofuran-2(3H)-ones and salicylaldehydes for synthesis of 3-arylcoumarins by Yuyu Cheng; Pengfei Zhang; Yanwen Jia; Zhiqiang Fang; Pengfei Li (7505-7508).
An organocatalytic cascade synthesis of 3-arylcoumarins has been developed. Mediated by 1,8-diazabicyclo[5,4,0]-undec-7-ene or tetramethylguanidine, a number of 3-arylcoumarins were obtained in good to excellent yields via condensation–ring opening–annulation between N-Bocindolin-2-ones/benzofuran-2(3H)-ones and salicylaldehydes. This method was featured by a broad scope of reactants, mild conditions, and simple operation.
Synthesis of 4-benzylpyridines via Pd-catalyzed CH3-arylation of 4-picoline by Jing Wu; Dadian Wang; Xiang Chen; Qingwen Gui; Hua Li; Ze Tan; Genping Huang; Guangwei Wang (7509-7512).
A highly efficient synthesis of 4-benzylpyridines was developed via Pd-catalyzed C(sp3)–H arylation between 4-picoline and aryl halides. It was found that the best yields were achieved with a simple Pd(PPh3)4 catalyst and Cs2CO3 as the base. Compared with the known methods, our reaction does not require the use of a strong organometallic reagent as the base.
Base-mediated diastereoselective [4 + 3] annulation of in situ generated ortho-quinone methides with C,N-cyclic azomethine imines by Jianfeng Xu; Shiru Yuan; Jingyi Peng; Maozhong Miao; Zhengkai Chen; Hongjun Ren (7513-7517).
An efficient [4 + 3] annulation of 2-(1-tosylalkyl)phenols with C,N-cyclic azomethine imines via in situ generation of ortho-quinone methides (o-QMs) under mild basic reaction conditions is disclosed, furnishing biologically interesting seven-membered heterocyclic compounds with moderate to good yields and excellent diastereoselectivities. A gram-scale reaction is performed to demonstrate the potential in industrial application and two transition states are proposed to rationalize the outstanding diastereoselectivity.
Modular total syntheses of mycolactone A/B and its [2H]-isotopologue by Sarah Saint-Auret; Hajer Abdelkafi; Didier Le Nouen; Laure Guenin-Macé; Caroline Demangel; Philippe Bisseret; Nicolas Blanchard (7518-7522).
A modular total synthesis of mycolactone A/B, the exotoxin produced by Mycobacterium ulcerans, has been achieved through the orchestration of several Pd-catalyzed key steps. While this route leads to a mixture of the natural product and its C12 epimer (4 : 1 ratio), this was inconsequential from the biological activity standpoint. Compared to the previously reported routes, this synthetic blueprint allows the late-stage modification of the toxin, as exemplified by the preparation of [22,22,22-2H3]-mycolactone A/B.
Phosphine-catalyzed [3 + 2] annulation reaction: highly regio- and diastereoselective synthesis of 2-azaspiro[4.4]nonene-1,3-diones by Wenjun Luo; Haiwen Hu; Sanfei Nian; Liang Qi; Fei Ling; Weihui Zhong (7523-7526).
A novel phosphine-catalyzed [3 + 2] annulation of γ-substituted allenoates with succinimides was developed, which was successfully applied to the synthesis of 2-azaspiro[4.4]nonene-1,3-dione derivatives. The reaction afforded the desired products in moderate to high yields (up to 96%) with excellent regioselectivities and diastereoselectivities (up to >99 : 1 dr). A plausible reaction mechanism has also been proposed based on previous literature.
Selective synthesis of three product classes from imine and carboxylic acid precursors via direct imine acylation by James A. Rossi-Ashton; Richard J. K. Taylor; William P. Unsworth (7527-7532).
Three divergent Direct Imine Acylation (DIA) procedures are reported that allow the selective generation of δ-lactams, β-lactams and tetrahydropyrimidinones (via a novel three-component coupling) from imine and carboxylic acid precursors. All operate via initial N-acyliminium ion formation and diverge depending on the reaction conditions and nature of the substrates.
Highly efficient one-pot assembly of peptides by double chemoselective coupling by Ivo E. Sampaio-Dias; Carlos A. D. Sousa; Sara C. Silva-Reis; Sara Ribeiro; Xerardo García-Mera; José E. Rodríguez-Borges (7533-7542).
This study describes a methodological advancement in solution-phase peptide synthesis via the development of a convenient and operational protocol to synthesize oligopeptides in a one-pot three-step cascade method, in which two peptide bonds are introduced chemoselectively. Tri- to hexapeptides were obtained in high global yields (80–95%) with virtually no epimerization as determined via HPLC. The methodology described herein represents a faster, easier and milder approach to the synthesis of peptides, and it operates at equimolar amounts. This protocol comprises the formation of secondary and tertiary amides and is compatible with Z, Boc and Fmoc N-protecting groups as well as the use of d/l and non-proteinogenic amino acids.
Formation of hydrazones and stabilized boron–nitrogen heterocycles in aqueous solution from carbohydrazides and ortho-formylphenylboronic acids by Han Gu; Tak Ian Chio; Zhen Lei; Richard J. Staples; Jennifer S. Hirschi; Susan Bane (7543-7548).
A recent addition to the suite of fast bioorthogonal reactions combines hydrazines and hydroxylamines with ortho-carbonyl substituted phenylboronic acids. Carbohydrazides are easily incorporated into biomolecules, making them appealing substrates in these reactions. Here we show that simple alkyl carbohydrazides form a single product with ortho-formylphenylboronic acid in an organic solvent and in the solid state. The solution structures of the products formed from the carbohydrazides in buffered aqueous solution, however, are markedly different from those identified in the organic solvent and solid state. The reactants form a mixture of hydrazone and heterocyclic products, the relative composition of which varies with pH. The observed reversibility of bioconjugates using carbohydrazide can thus be explained by the reversibility of the boron–nitrogen bond in the heterocycle. In contrast, the inclusion of an α-amine into the carbohydrazide substrate yields a single product in which both nitrogens are bonded to boron. These tricyclic structures are the same in organic solvent, solid state and aqueous solution from pH 4 to pH 9. Bioconjugates formed with α-amino carbohydrazides are stable to SDS-PAGE, while those formed with simple alkyl carbohydrazides are not. We propose that the inclusion of an intramolecular stabilizing ligand into a carbohydrazide substrate is a generally applicable principle that may be exploited to form boronic acid-based bioconjugates with a defined structure and resistance to hydrolysis.
Novel pyrrolobenzodiazepine and pyrroloquinazoline scaffolds synthesized by a simple and highly selective Ugi/cyclization sequence by Pablo Pertejo; Pablo Peña-Calleja; Israel Carreira-Barral; Roberto Quesada; Nicolás Alejandro Cordero; Francisco Javier Rodríguez; María García-Valverde (7549-7557).
Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) and other benzo-fused N-heterocycles constitute privileged structures found in numerous bioactive compounds. Thus, developing simple and selective syntheses to furnish these derivatives from easily accessible starting materials is an important and challenging goal. In this work, novel pyrrolobenzodiazepine and pyrroloquinazoline derivatives have been synthesized following a common two step synthetic strategy. This strategy involves a one-pot Ugi/cyclization sequence followed by a reduction with spontaneous thermocontrolled cyclization. The control of the temperature in this second step allows fully selective access to either pyrrolo[2,1-c][1,4]benzodiazepine-3-ones 6 or pyrrolo[2,1-b]quinazolines 7. Density functional theory (DFT) calculations have been carried out to rationalize this reactivity, identifying the kinetic and thermodynamic reaction products and offering insights into the cyclization pathways. These synthetic methodologies show the versatility of the Ugi reaction as a tool in the synthesis of heterocyclic compounds with a pseudopeptidic skeleton.
Dye-conjugated complementary lipophilic nucleosides as useful probes to study association processes by fluorescence resonance energy transfer by M. J. Mayoral; J. Camacho-García; E. Magdalena-Estirado; M. Blanco-Lomas; E. Fadaei; C. Montoro-García; D. Serrano-Molina; D. González-Rodríguez (7558-7565).
Modern supramolecular chemistry relies on the combination of diverse analytical techniques that can provide complementary information on complex self-assembly landscapes. Among them, resonance energy transfer, monitored by fluorescence emission spectroscopy, arises as a sensitive and convenient phenomenon to report binding intermolecular interactions. The use of molecular probes labelled with suitable complementary energy-transfer pairs can provide valuable information about the thermodynamics, kinetics and self-sorting characteristics of a particular self-assembled system. The objective of this work is to generate a set of nucleoside FRET probes that can be reliably employed to prove and analyse quantitatively H-bonding interactions between complementary Watson–Crick pairs. We first describe the preparation of a set of lipophilic nucleosides that are linked to a π-conjugated functional fragment. The bases include guanosine and 2-aminoadenosine as purine heterocycles, and cytidine and uridine as complementary pyrimidine bases. The π-conjugated moiety comprises either a short phenylene-ethynylene oligomer, a bithiophene, or a BODIPY dye. We then demonstrate that the last two chromophores constitute an energy donor–acceptor couple and that donor emission quenching can be related to the ratio of molecules bound to the complementary acceptor pair. Hence, fluorescence spectroscopy in combination with resonance energy transfer, is shown here to be a useful tool to study and quantify the association and self-sorting events between complementary and non-complementary nucleosides in apolar aromatic solvents, where the binding strength is considerably high, and sensitive techniques that employ low concentrations are demanded.
18O2 labeling experiments illuminate the oxidation of ent-kaurene in bacterial gibberellin biosynthesis by Raimund Nagel; Reuben J. Peters (7566-7571).
Bacteria can produce gibberellin plant hormones. While the bacterial biosynthetic pathway is similar to that of plants, the individual enzymes are very distantly related and arose via convergent evolution. The cytochromes P450 (CYPs) that catalyze the multi-step oxidation of the alkane precursor ent-kaurene (1) to ent-kauren-19-oic acid (5), are called ent-kaurene oxidases (KOs), and in plants are from the CYP701 family, and share less than 19% amino acid sequence identity with those from bacteria, which are from the phylogenetically distinct CYP117 family. Here the reaction series catalyzed by CYP117 was examined by 18O2 labeling experiments, the results indicate successive hydroxylation of 1 to ent-kauren-19-ol (2) and then ent-kauren-19,19-diol (3) and most likely an intervening dehydration to ent-kauren-19-al (4) prior to the concluding hydroxylation to 5. Accordingly, the bacterial and plant KOs converged on catalysis of the same series of reactions, despite their independent evolutionary origin.
Intramolecular hydrogen bonding in conformationally semi-rigid α-acylmethane derivatives: a theoretical NMR study by Antonio J. Mota; Jürgen Neuhold; Martina Drescher; Sébastien Lemouzy; Leticia González; Nuno Maulide (7572-7579).
Conformational mobility is a core property of organic compounds, and conformational analysis has become a pervasive tool for synthetic design. In this work, we present experimental and computational (employing Density Functional Theory) evidence for unusual intramolecular hydrogen bonding interactions in a series of α-acylmethane derivatives, as well as a discussion of the consequences thereof for their NMR spectroscopic properties.
1,5-Electrocyclization of conjugated azomethine ylides derived from 3-formyl chromene and N-alkyl amino acids/esters by E. Pravardhan Reddy; A. Sumankumar; B. Sridhar; Y. Hemasri; Y. Jayaprakash Rao; B. V. Subba Reddy (7580-7583).
A novel strategy has been developed for the synthesis of chromeno[3,4-b]pyrrol-4(3H)-one and substituted pyrrole derivatives through 1,5-electrocyclization of conjugated azomethine ylides. This is the first example of the preparation of highly substituted pyrrole derivatives from chromene-3-carboxaldehydes (non-enolizable aldehydes) and N-alkyl amino acids/esters. This method is simple and applicable to a diverse range of substrates.
Electronic effects on a one-pot aromatization cascade involving alkynyl-Prins cyclization, Friedel–Crafts alkylation and dehydration to tricyclic benzo[f]isochromenes by Robert J. Hinkle; Yuzhou Chen; Colleen P. Nofi; Shane E. Lewis (7584-7593).
A three-step domino reaction between 1-aryl-3-hexyne-2,6-diol derivatives and aldehydes is used to construct tricyclic 1,4-dihydro-2H-benzo[f]isochromenes. The cascade is initiated by BF3·OEt2 and involves alkynyl-Prins cyclization, Friedel–Crafts alkenylation, and dehydration/aromatization to create a new, central aromatic ring and eliminate 2 equiv. of water. Electron-donating substituents on the aryl ring of the 1-aryl-3-hexyne-2,6-diols significantly increase overall yields as do electron-rich aldehyde reaction partners. For 2,4-disubstituted 2H-benzo[f]isochromene products, diastereoselectivities in the alkynyl-Prins reaction are ∼1.4 : 1 in favor of the cis-diastereomer. The stereochemistry of one cis-product was verified by X-ray crystallographic analysis and a second structure was also verified by X-ray analysis.
Cu(ii)-Mediated keto C(sp3)–H bond α-acyloxylation of N,N-dialkylamides with aromatic carboxylic acids by Wenjing Li; Changzhen Yin; Xiao Yang; Hailong Liu; Xueli Zheng; Maolin Yuan; Ruixiang Li; Haiyan Fu; Hua Chen (7594-7599).
The selective oxidative coupling of aromatic carboxylic acids with the C(sp3)–H bond adjacent to the keto group of alkylamides has been developed by employing a low cost copper source. This provides an efficient approach for synthesis of O-benzoylglycolamides. The protocol displayed good functional group tolerance. A broad range of benzoic acids directly coupled with alkylamides to afford a variety of O-benzoylglycolamides in moderate to good yields. In addition, a reasonable radical mechanism was proposed based on EPR experiments.
Oxidative C–H functionalization of N-carbamoyl 1,2-dihydroquinolines by Ziqiang Liu; Lei Chen; Jing Li; Ke Liu; Jiaqi Zhao; Mengmeng Xu; Lei Feng; Ren-zhong Wan; Wei Li; Lei Liu (7600-7606).
A modular and efficient method for the synthesis of α-substituted 1,2-dihydroquinolines is described. Under mild metal-free conditions, readily available N-carbamoyl 1,2-dihydroquinolines undergo oxidative C–H alkynylation, alkenylation, and allylation with a range of potassium trifluoroborates using TEMPO oxoammonium salt as an oxidant.
Synthetic approach to tailored physical associations in peptide-polyurea/polyurethane hybrids by L. E. Matolyak; J. K. Keum; K. M. Van de Voorde; L. T. J. Korley (7607-7617).
Nature has achieved diverse functionality via hierarchical organization driven by physical interactions such as hydrogen bonding. Synthetically, polymer–peptide hybrids have been utilized to achieve these architectural arrangements and obtain diverse mechanical properties, stimuli responsiveness, and bioactivity. Here, we explore the impact of peptide ordering and soft/hard phase interactions in PEG-based non-chain extended and chain extended peptidic polyurea (PU) and polyurea/polyurethane (PUU) hybrids towards tunable mechanics. Increasing the peptide content of poly(ε-carbobenzyloxy-l-lysine) (PZLY) revealed an increase in α-helical formation and modulation in amine/ether hydrogen bonding, suggesting enhanced intermolecular hydrogen bonding between peptide segments and soft/hard blocks. A balance of phase mixing and microphase segregation was observed depending on competitive hydrogen bonding and the hybrid architecture. This phase behaviour strongly modulated the mechanical response, particularly modulus and extensibility. We anticipate that this solid-state, synthetic framework will expand the reach of our peptide hybrids into biointerfacing materials, including scaffolds and responsive actuators via peptide selection.
Controlling the photochemical reaction of an azastilbene derivative in water using a water-soluble pillararene by Danyu Xia; Pi Wang; Bingbing Shi (7618-7622).
Photochemistry plays an important role in our lives. It has also been a common tool in the laboratory to construct complicated systems from small molecules. Supramolecular chemistry provides an opportunity to solve some of the problems in controlling photochemical reactions via non-covalent interactions. By using confining media and weak interactions between the medium and the reactant molecule, the excited state behavior of molecules has been successfully manipulated. Pillararenes, a new class of macrocyclic hosts, have rarely been used in the field of photochemical investigations, such as the controlling of photo-induced reactions. Herein, we explore a synthetic macrocyclic host, a water-soluble pillararene, as a controlling tool to manipulate the photo-induced reactions (hydration) in water. A host–guest system in water based on a water-soluble pillararene and an azastilbene derivative, (E)-4,4′-dimethyl-4,4′-diazoniastilbene diiodide, has been constructed. Then this water-soluble pillararene was successfully employed to control the photohydration of the azastilbene derivative in water as a “protective agent”.
Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4) by Mykhaylo S. Frasinyuk; Wen Zhang; Przemyslaw Wyrebek; Tianxin Yu; Xuehe Xu; Vitaliy M. Sviripa; Svitlana P. Bondarenko; Yanqi Xie; Huy X. Ngo; Andrew J. Morris; James L. Mohler; Michael V. Fiandalo; David S. Watt; Chunming Liu (7623-7629).
Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.
The effect of comb architecture on complex coacervation by Brandon M. Johnston; Cameron W. Johnston; Rachel A. Letteri; Tyler K. Lytle; Charles E. Sing; Todd Emrick; Sarah L. Perry (7630-7642).
Complex coacervation is a widely utilized technique for effecting phase separation, though predictive understanding of molecular-level details remains underdeveloped. Here, we couple coarse-grained Monte Carlo simulations with experimental efforts using a polypeptide-based model system to investigate how a comb-like architecture affects complex coacervation and coacervate stability. Specifically, the phase separation behavior of linear polycation-linear polyanion pairs was compared to that of comb polycation-linear polyanion and comb polycation-comb polyanion pairs. The comb architecture was found to mitigate cooperative interactions between oppositely charged polymers, as no discernible phase separation was observed for comb-comb pairs and complex coacervation of linear-linear pairs yielded stable coacervates at higher salt concentration than linear-comb pairs. This behavior was attributed to differences in counterion release by linear vs. comb polymers during polyeletrolyte complexation. Additionally, the comb polycation formed coacervates with both stereoregular poly(l-glutamate) and racemic poly(d,l-glutamate), whereas the linear polycation formed coacervates only with the racemic polyanion. In contrast, solid precipitates were obtained from mixtures of stereoregular poly(l-lysine) and poly(l-glutamate). Moreover, the formation of coacervates from cationic comb polymers incorporating up to ∼90% pendant zwitterionic groups demonstrated the potential for inclusion of comonomers to modulate the hydrophilicity and/or other properties of a coacervate-forming polymer. These results provide the first detailed investigation into the role of polymer architecture on complex coacervation using a chemically and architecturally well-defined model system, and highlight the need for additional research on this topic.
Synthesis of 2-aminoBODIPYs by palladium catalysed amination by Rua B. Alnoman; Patrycja Stachelek; Julian G. Knight; Anthony Harriman; Paul G. Waddell (7643-7653).
Palladium catalysed coupling of the 2-iodoBODIPY 3 with a range of anilines and a primary alkylamine succeeds in generating the corresponding 2-aminoBODIPYs. These 2-aminoBODIPY derivatives are non-emissive and quantum chemical calculations and electrochemistry are consistent with charge transfer from the amine substituent. Attenuation of this charge transfer pathway by conversion of the 1,2-phenylenediamine derivative 9 into the corresponding benzimidazolone 10 restores the fluorescence and has been used as the basis for a fluorescence sensor for phosgene.
Copper-catalysed difluoroalkylation of aromatic aldehydes via a decarboxylation/aldol reaction by Jin-Wei Yuan; Shuai-Nan Liu; Wen-Peng Mai (7654-7659).
A copper-catalysed tandem decarboxylation/aldol reaction of simple aromatic aldehydes with 2,2-difluoro-3-oxo-3-arylpropanoic acid has been developed under mild conditions. This method provides a new route for the direct one-pot synthesis of difluorinated aldols in moderate to good yields from simple substrates.
Polymeric mannosides prevent DC-SIGN-mediated cell-infection by cytomegalovirus by S. Brument; C. Cheneau; Y. Brissonnet; D. Deniaud; F. Halary; S. G. Gouin (7660-7671).
Human cytomegalovirus (HCMV) is a beta-herpesvirus with a high prevalence in the population. HCMV is asymptomatic for immunocompetent adults but is a leading cause of morbidity for new born and immunocompromised patients. It was recently shown that the envelope glycoprotein B (gB) of HCMV interacts with the Dendritic Cell-Specific ICAM-3 Grabbing Non integrin (DC-SIGN) to infect the host. In this work we developed a set of DC-SIGN blockers based on mono-, di-, tetra and polyvalent mannosides. The multivalent mannosides were designed to interact with the carbohydrate recognition domains of DC-SIGN in a chelate or bind and recapture process, and represent the first chemical antiadhesives of HCMV reported so far. Polymeric dextrans coated with triazolylheptylmannoside (THM) ligands were highly potent, blocking the gB and DC-SIGN interaction at nanomolar concentrations. The compounds were further assessed for their ability to prevent the DC-SIGN mediated HCMV infection of dendritic cells. A dextran polymer coated with an average of 902 THM ligands showed an outstanding effect in blocking the HCMV trans-infection with IC50 values down to the picomolar range (nanomolar when expressed in THM concentration). Each THM moiety on the polymer surpassed the antiadhesive effect of the methylmannoside reference by more than four orders of magnitude. The compound proved non-cytotoxic at the high concentration of 2 mM and therefore represents an interesting antiadhesive candidate against HCMV and potentially against other virus hijacking dendritic cells to infect the host.
Synthesis of the fungus metabolite cladosin C by David Linder; Rainer Schobert (7672-7677).
Cladosin C is one of the few known enaminotetramic acids, isolated from extracts of the deep sea fungus Cladosporium sphaerospermum. It was synthesised in ten steps and 14% overall yield by a late-stage amination of the corresponding 3-acyltetramic acid. This was obtained by a Dieckmann condensation of an N-β-ketoacylaminoester derived from dehydrovalinate and the thioester-terminated side chain containing the stereogenic centre which stemmed from poly-(R)-3-hydroxybutyrate.
Visible-light-induced tandem cyclization of 2-alkynylanilines with disulfides: a convenient method for accessing benzothiophenes under transition-metal-free and photocatalyst-free conditions by Xiaoyu Xie; Pinhua Li; Qing Shi; Lei Wang (7678-7684).
A simple and efficient strategy for the preparation of benzothiophenes via visible-light-induced cyclization of 2-alkynylanilines with disulfides was developed. The reaction afforded the desired products in good yields at room temperature under transition-metal-free and photocatalyst-free conditions.
Amidinoquinoxaline N-oxides: spin trapping of O- and C-centered radicals by Nadia Gruber; Liliana R. Orelli; Roberto Cipolletti; Pierluigi Stipa (7685-7695).
Amidinoquinoxaline N-oxides represent a novel family of heterocyclic spin traps. In this work, their ability to trap O- and C-centered radicals was tested using selected derivatives with different structural modifications. All the studied nitrones were able to trap radicals forming persistent spin adducts, also in the case of OH and OOH radicals which are of wide biological interest as examples of ROS. The stability of the adducts was mainly attributed to the wide delocalization of the unpaired electron over the whole quinoxaline moiety. The nitroxide spectral parameters (hfccs and g-factors) were analyzed and the results were supported by DFT calculations. The N-19 hfccs and g-factors were characteristic of each aminoxyl and could aid in the identification of the trapped radical. The enhanced stability of the OH adducts under the employed reaction conditions could be ascribed to their possible stabilization by IHBs with two different acceptors: the N–O˙ moiety or the amidine functionality. DFT calculations indicate that the preferred IHB is strongly conditioned by the amidine ring size. While five membered homologues show a clear preference for the IHB with the N–O˙ group, in six membered derivatives this stabilizing interaction is preferentially established with the amidine nitrogen as an IHB acceptor.
Regioselective oxidative cross-coupling of benzo[d]imidazo[2,1-b]thiazoles with styrenes: a novel route to C3-dicarbonylation by Siddiq Pasha Shaik; Faria Sultana; A. Ravikumar; Satish Sunkari; Abdullah Alarifi; Ahmed Kamal (7696-7704).
A novel I2 promoted, highly efficient metal-free and peroxide-free greener domino protocol for the C3-dicarbonylation of benzo[d]imidazo[2,1-b]thiazoles (IBTs) with styrenes has been developed via oxidative cleavage of the C(sp2)–H bond, followed by C3-nucleophilic attack of IBT and oxidation. Interestingly, under these conditions 2-(benzo[d]imidazo[2,1-b]thiazol-2-yl)aniline gave the benzo[4′,5′]thiazolo[2′,3′:2,3]imidazo[4,5-c]quinoline derivative via oxidative cleavage of the C(sp2)–H bond, followed by Pictet–Spengler cyclization and aromatization. This method offers the advantages of broad substrate scope, ecofriendly feature and high atom economy apart from higher yields.
Stereodivergent Mannich reaction of bis(trimethylsilyl)ketene acetals with N-tert-butanesulfinyl imines by Lewis acid or Lewis base activation, a one-pot protocol to obtain chiral β-amino acids by Margarita Cantú-Reyes; Isabel Alvarado-Beltrán; Ricardo Ballinas-Indilí; Cecilio Álvarez-Toledano; Marcos Hernández-Rodríguez (7705-7709).
We report a one-pot synthesis of chiral β2,2,3-amino acids by the Mannich addition of bistrimethylsilyl ketene acetals to N-tert-butanesulfinyl imines followed by the removal of the chiral auxiliary. The synthesis and isolation of pure β-amino acid hydrochlorides were conducted under mild conditions, without strong bases and this method is operationally simple. The stereoselective reaction was promoted by two different activation methods that lead to different stereoisomers: (1) Lewis Acid (LA) catalysis with boron trifluoride diethyl etherate and (2) Lewis Base (LB) catalysis with tetrabutylammonium difluorotriphenylsilicate. The reaction presented good diastereoselectivity with LB activation and moderate to good dr with LA catalysis. The exceptions in both protocols were imines with electron donating groups in the aromatic ring.
Tandem radical cyclization to construct poly-brominated 2-oxindoles by Fengjuan Chen; Yajun Wang; Shijun Zhao; Wei Jiang; Congde Huo (7710-7714).
Catalytic amounts of TBHP (15 mol%) promoted tribromomethylation of activated alkenes has been developed. This method provided a metal-free aerobic way to construct tribromomethylated 2-oxindoles from the reaction of readily available N-arylacrylamides with CBr4via a proposed tandem radical cyclization process. Air is used as an efficient terminal oxidant in this transformation. The formation of 1,1-dibromoolefin derivatives was also realized at higher temperature under neat conditions.
Back cover (7715-7716).