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European Journal of Organic Chemistry - Herausgeber: Wiley
Die Zeitschrift publiziert Artikel aus dem gesamten Spektrum der synthetischen Organischen, Bioorganischen und physikalisch-organischen Chemie.
A convenient and efficient synthesis of 4-halo-2,5-dihydro-1,2-oxaphosphole 2-oxides through CuX2-mediated direct halocyclization of diethyl 1,2-allenylphosphonates was developed. The yields range from moderate to excellent. The efficiency of axial-to-central chirality transfer has also been studied. Further Suzuki cross-coupling of the resulting vinylic chlorides with dicyclohexyl(2,4,6-trimethoxyphenyl)phosphane (LB-Phos) as the ligand, was established.CuX2-mediated direct halocyclization of diethyl 1,2-allenylphosphonates was developed to afford 4-halo-2,5-dihydro-1,2-oxaphosphole 2-oxides. The efficiency of axial-to-central chirality transfer and subsequent Suzuki cross-coupling of the resultingvinylic chlorides with dicyclohexyl(2,4,6-trimethoxyphenyl)phosphane (LB-Phos) as the ligand were also investigated.
The intermolecular carbon–carbon bond formation between two alkenes also known as 1,2-hydrovinylation reaction can be realised with different transition metal catalysts. The application of styrene derivatives, norbornenes and other alkenes in asymmetric catalysis with a variety of chiral ligands leads to ?-chiral alkene products in an atom-economic transformation. Accordingly, the 1,2-hydrovinylation is one of just a few asymmetric transformations which produce stereogenic centres in the absence of polarised functional groups. The 1,4-hydrovinylation of terminal alkenes and 1,3-dienes can be controlled by the electronic nature of the alkene starting material for the selective formation of linear or branched 1,4-dienes. These adducts can be used for the synthesis of 1,3- as well as 1,4-dicarbonyl derivatives upon ozonolysis of suitable intermediates. As an extension of the 1,4-hydrovinylation reaction a cobalt-catalysed 1,4-hydrobutadienylation reaction is reported where two different 1,3-dienes react selectively for the formation of 1,3,6-trienes.The reaction of two alkenes to form a single product in a transition-metal-catalysed 1,2-hydrovinylation reaction generates a new stereogenic centre. Several applications utilising different combinations of starting materials and different catalysts are discussed. Also, the progress in transition-metal-catalysed 1,4-hydrovinylation reactions of alkenes with 1,3-dienes for the synthesis of 1,4-dienes is described. Recent applications for the synthesis of complex products enlarge the scope of the hydrovinylation reactions considerably.
An unprecedented oxidative cleavage of benzo[c]heterocycles using m-CPBA is reported. The reaction of 1,3-diaryl benzo[c]heterocycles with m-CPBA (meta-chloroperoxybenzoic acid) at room temperature for 5 min led to the formation of 1,2-diaroylbenzenes in good to excellent yields.An efficient procedure for the preparation of a variety of unsymmetrical 1,2-diaroylbenzenes was achieved at room temperature through a m-CPBA-mediated oxidative cleavage of benzo[c]furan analogs. The oxidative ring-opening reaction with benzo[c]thiophene and benzo[c]selenophene analogs was also successful.
Two silylated Pd–NHC complexes were immobilized on hybrid silicas by sol-gel cocondensation with tetraethyl orthosilicate (TEOS) and performed well as recyclable catalysts towards the Heck, Suzuki, and Sonogashira coupling reactions. Remarkable conversion and recyclability were achieved in the Suzuki reaction with a challenging aryl chloride. No side products and no undesired homocoupling were observed in Suzuki or Heck reactions, which facilitates the final purification step for the cross-coupling products. High turnover numbers and turnover frequencies were found for copper- and phosphane-free Sonogashira reaction between p-bromoacetophenone and phenylacetylene.New hybrid silica materials derived from NHC-palladium complexes have been prepared by a sol-gel process and efficiently applied as recyclable catalysts in C–C coupling reactions.
An efficient, organocatalytic enantioselective addition of cyclic diketones with ?,?-unsaturated ?-keto esters has been developed that affords products in high yields (up to 95?%) and excellent enantioselectivity (up to >99?%?ee) under mild conditions with a low catalyst loading (2.5 mol-%). The unsaturated ?-keto esters are effectively coordinated and activated through hydrogen bonds with the squaramides and proved to be excellent hydrogen-bond acceptors in this asymmetric organocatalytic reaction. This reaction provides valuable and easy access to chiral Michael adducts, which are important moieties in the skeletons of biological and pharmaceutical molecules.The Michael addition of cyclic diketones to ?,?-unsaturated ?-keto esters catalyzed by bifunctional squaramide-derived chiral catalysts to afford adducts in high yields (up to 95?%) and excellent enantioselectivities (up to 99?%?ee) under mild conditions is reported. The reaction affords chiral Michael adducts, which are important moieties in the skeletons of biological and pharmaceutical molecules.
The heterocyclization reactions of CF2-containing alkynylphosphonates with 2-aminobenzonitriles to give 2,3-difunctionalized 4-aminoquinolines were investigated. The influence of the R1 and R2 substituents and CF2X groups on the synthetic efficiency and specificity is also disclosed.The syntheses of various CF2-containing (4-aminoquinolin-3-yl)phosphonates have been reported. The reaction proceeded well by using K2CO3 as the basic mediator in refluxing toluene as the solvent.
The perylenequinones are a class of natural products characterized by a pentacyclic conjugated chromophore giving rise to photoactivity. Potentially useful light-activated biological activity, targeting protein kinase C (PKC), has been identified for several of the natural products. Recently discovered new members of this compound class, as well as several related phenanthro-perylenequinones, are reviewed. Natural product modifications that improve biological profiles are outlined, as well as avenues for the total synthesis of analogs not available from the natural product series. An overview of structure/function relationships is provided.Perylenequinones are a class of natural products characterized by a pentacyclic conjugated chromophore giving rise to photoactivity. Their structural complexity and light-induced biological activity have resulted in extensive study of these compounds. This review focuses on recent isolates in this class, total synthesis work, semisynthetic analogs, and biological activity studies.
The synthesis and X-ray structure of a new and readily available exTTF derivative (6) bearing a methyltriphenylphosphonium bromide moiety as a new building block for the construction of electroactive molecules is reported. The phosphonium salt 6, which was prepared in one step from 2-hydroxymethyl-exTTF as a stable yellow solid in 84?% yield, efficiently undergoes Wittig olefination reactions with a variety of aldehydes to predominantly form the E isomer. Electronic spectra and cyclic voltammetry of the novel compounds reveal the electronic communication between the electroactive units.The synthesis and X-ray structure of a new and readily available exTTF derivative bearing a methyltriphenylphosphonium bromide moiety as a new building block for the construction of electroactive molecules is described.
An efficient and rapid procedure for the N-alkyl enamination from thioketones to push–pull (E/Z)-enamine derivatives is reported. The starting thioketone 2 was obtained by regioselective thionation of 3-benzoylpyrrolo[2,3-b]quinoxalin-2-one (1) with Lawesson's reagent (LR). 1H NMR and X-ray crystal structure analyses of 1-aryl-3-(alkylaminophenylmethylidene)pyrrolo[2,3-b]quinoxalin-2-ones 3–6 confirmed that the E diastereoisomers predominated. Interconversion of the isolated E form of 3b and 4a into the Z configuration and their E/Z equilibria in [D6]DMSO were studied by temperature-dependent 1H NMR spectroscopy. The photophysical properties of compounds 1–6 are also reported. We found that the non-fluorescent compounds 3a–6a are chemosensors for the zinc ion. Fluorescent titrations of these sensors with zinc(II) acetate showed that compound 6a has the best working range of zinc concentrations with Kd = 3.77 00?±?0.51 ?M.An efficient N-alkyl enamination is reported as a convenient method for the insertion of metal-ion receptor units into a fluorescent indicator. New E/Z push–pull olefins have been characterised. The interconversion of the E into the Z forms and their equilibrium in [D6]DMSO were studied. Addition of zinc ions to the non-fluorescent free bases leads to fluorescent emission of the probes.
Herein, we describe the total syntheses of three bioactive pyrones isolated from Polygala sabulosa (i.e., 1, 4, and 7) and eight isolated from Piper methysticum (i.e., 8–10, 13, 15, and 18–20) using the Heck–Matsuda arylation as the key strategy. The evaluation of this methodology by employing different arenediazonium tetrafluoroborates revealed that the Heck arylation was more efficient when the olefin undergoing arylation possessed the vinyl-2-pyrone structural unit instead of the vinyl dihydro-2-pyrone moiety. The Heck–Matsuda arylation of many of the examined olefins proceeded in a practical manner with total regio- and stereocontrol.The Heck–Matsuda reaction was applied to the syntheses of three bioactive pyrones isolated from Polygala sabulosa, eight kavalactones isolated from Piper methysticum, and several kavalactone analogues.
2-Vinyl- and 2-(?-styryl)quinazolin-4-ones have been synthesized by intramolecular gold-catalyzed hydroamination and palladium-catalyzed carboamination of anthranilic allenamides, easily prepared by prototropic isomerization of the corresponding propargylamides. These procedures, which lead to N-Boc-protected quinazolinones, represent a more flexible alternative to the reported palladium-catalyzedamination of anthranilic allylamides, achievable only from N-tosylallylamides.Intramolecular transition-metal-catalyzed reactions of allenamides have been proven to be useful tools for accessing 2-vinyl- and 2-(?-styryl)quinazolin-4-ones. The two types of products were obtained by simple switching of the catalytic system, namely, gold-catalyzed hydroamination and palladium-catalyzed carboamination furnished 2-vinyl- and 2-(?-styryl)-substituted quinazolinones, respectively.
Aryl and hetaroaryl imidazole-1-sulfonates are efficiently arylated and alkenylated with aryl- and alkenylboronic acids and potassium trifluoroborates by using 0.5 mol-% palladacycles 1 or Pd(OAc)2 at 110 °C under aqueous and phosphane-free conditions. Reactions can be performed by using conventional or microwave heating, leading to biaryls, stilbenes, and alkenylarenes in good to high yields, and high regio- and diastereoselectivities. The optimized methodology allows in situ phenol sulfonylation and one-pot Suzuki arylation or alkenylation as well as orthogonal functionalization of halogen-containing aryl imidazolesulfonates.The title sulfonates are cross-coupled in high yields with aryl- and alkenylboronic acids and potassium trifluoroborates byusing oxime–palladacycles in water under microwave irradiation. One-pot phenol sulfonylation and Suzuki coupling as well as allows orthogonal functionalization of bifunctionalized aryl derivatives are allowed.
A facile and efficient synthesis of new fused pyrazoles through the Pd(OAc)2-mediated heteroarylation of heteroarene C–H bonds in Morita–Baylis–Hillman derivatives of 4-iodopyrazolecarbaldehydes is described.The facile and efficient synthesis of annulated pyrazoles through the Pd(OAc)2-mediated heteroarylation of heteroarene C–H bonds in substrates derived from the Morita–Baylis–Hillman reaction adducts of 4-iodopyrazolecarbaldehydes is described.
A DFT study has been performed to understand the [4+2] annulation reaction between ?-methylallenoate (2) and benzylidenemalononitrile (3), catalyzed by P(NMe2)3 (1). For the reaction channel to produce cyclohexene 4a as the predominated product, the catalytic cycle can be characterized by three stages: in situ generation of the 1,3-dipole IM2 between 1 and 2 (stage I); the addition of 3 to IM2 giving six-membered-ring intermediate IM8 (stage II); and catalyst 1 liberation from IM8 to produce 4a (stage III). For stage II, the pathway through direct [4+2] addition, followed by [1,3]-H transfer, enabled by the alkene carbon bearing nitrile groups, is feasible, but less favorable than the [3+2] addition pathway followed by water-aided [1,3]-H transfer. The pathway leading to the regioisomer of 4a (i.e., 4b) is substantially less favorable, which accounts for the exclusive regioselectivity (4a/4b = 100:0) of the reaction. The [4+2] annulations are different from the conventional [3+2] cycloadditions of allenoates and activated alkenes. For the latter, a trace of water was demonstrated to be critical, even though the reactions are carried out in so-called “anhydrous” solvents, because water is the only available hydrogen transfer mediator. In other words, the traditional [3+2] cycloadditions would not occur if the solvent were absolutely free of water. In contrast, [4+2] annulations can take place, even though water is completely absent, because the carbon (CCN of alkene 3) bearing the nitrile groups can serve as the hydrogen transfer mediator. The substitution effects of alkenes on the addition step of alkenes to IM2 have been further investigated.This DFT study reveals that the water-aided [3+2] addition and direct [4+2] addition mechanisms are both feasible for the titled [4+2] annulations. Unlike typical [3+2] annulations, which require water as hydrogen transfer mediator, [4+2] annulation can occur without additional mediator because the carbon bearing nitrile groups can act as the hydrogen transfer mediator.
Fluoride recognition by molecular receptors is attracting much interest in the scientific community and a variety of approaches are used to achieve recognition with high affinity and selectivity. Most of the synthetic systems reported have been extensively studied in organic solvents by using tetrabutylammonium fluoride (TBAF) as the source of fluoride. In many cases, titration behaviors are observed that cannot be ascribed to a classical 1:1 binding isotherm. By using UV/Vis, 19F NMR, and 1H NMR spectroscopy we have been able to highlight that the equilibrium between the fluoride and the corresponding bihalide ion, HF2–, which is inevitably generated in situ due to trace amounts of water, can be at the origin of this singular behavior. Our results highlight that when undertaking titrations with fluoride in DMSO, the data can be affected by the fluoride–bihalide equilibrium and that the latter species can even be the dominating species at low TBAF concentrations.The titration behavior for fluoride binding in DMSO can often not be ascribed to a classical 1:1 binding isotherm. The culprit can be water, which leads to the generation of other species that can interact with the molecular receptor. The plethora of equilibria to be considered makes the quantitative evaluation of fluoride binding extremely perilous.
Quaternary onium salts of halides can be efficiently converted into the corresponding quaternary onium salts of various anions [NO3–, BF4–, PF6–, CF3SO3–, CH3SO3–, ClO4–, p-CH3C6H4SO3–, CF3CO2–, 2,4-(NO2)2C6H3O–] by treating the onium halide with trimethyl phosphate under neat condition in the presence of an equivalent amount of conjugate acid of the desired anion.An efficient and scalable method for the conversion of quaternary onium halides into the corresponding salts of various anions [NO3–, BF4–, PF6–, CF3SO3–, CH3SO3–, ClO4–, pTsO–, CF3CO2–, 2,4-(NO2)2C6H3O–] is disclosed.
The cover picture shows an example of diastereoselective aldehyde/amine/alkyne coupling catalyzed by copper nanoparticles supported on titania under solvent-free conditions. The background picture depicts a panoramic view from Cerro Campanario (1052 m) in Bariloche (Río Negro, Argentina). This is one of the most beautiful and fascinating views in the region including: the East Perito Moreno's lake (aldehyde), West Perito Moreno's lake (amine), Trebol's pool (alkyne), Nahuel Huapi's lake (background), Llao Llao's peninsula and hotel, and the surrounding hills (López and Capilla in the foreground). Details are discussed in the article by F. Alonso et al. on p. 3093 ff.
The synthesis and characterization of four generations of palladium nanoparticle-cored Fréchet-type dendrimers (Pd-Gn) possessing direct palladium–carbon bonds are reported. These core–shell materials have been synthesized by the simultaneous reduction of different generation diazodendrons and PdII in an organic medium. The resulting organic–inorganic hybrid materials were characterized by IR, NMR and UV/Vis spectroscopic techniques. The formation of nearly spherical particles of 2–4 nm diameter was confirmed by TEM studies. The efficiency of one member of this series, Pd-G1, in catalysing important C–C bond-forming reactions such as Suzuki, Stille and Hiyama coupling reactions was investigated. The results clearly show that Pd-G1 can efficiently catalyse the cross-coupling of arylboronic acids, aryl stannanes and organosilicon compounds with differently substituted aryl halides in addition to efficiently catalysing hydrogenation reactions. The catalyst exhibited good recovery and recyclability in Suzuki coupling reactions. The study suggests that a single catalyst capable of catalysing several reactions can be designed.Palladium nanoparticle-cored dendrimers synthesized by the reduction of PdII in the presence of diazodendrons find use as efficient catalysts for different cross-coupling reactions with good recyclability.
Flash vacuum pyrolysis of 3,3,5,5-tetramethyl-1,2,4-trithiolane 1-oxide performed at 700 °C yields the 1-oxatrisulfan-3-yl radical (HOSS·) along with disulfur monoxide (S2O) and diisopropyl sulfide, which were isolated in argon matrices at 10 K. Upon irradiation with UV light, the 1-oxatrisulfan-3-yl radical undergoes isomerization to the 1-oxatrisulfan-1-yl radical (HSSO·). Both radicals were identified by comparison of their computed and experimental IR and UV/Vis spectra. In addition, density functional theory (DFT) computations offer a plausible explanation of the most likely reaction mechanism, suggesting that the initial step is a 1,3-H shift with simultaneous ring opening. A 1-oxatrisulfane derivative formed thereby undergoes fragmentations via a radical and a competitive concerted pathway leading to the observed final products. The same mechanism also governs the thermal fragmentation of di-tert-butyl disulfide S-oxide. Its pyrolysis at 700 °C affords an analogous set of products, including the 1-oxatrisulfan-3-yl radical (HOSS·) as the key intermediate.3,3,5,5-Tetramethyl-1,2,4-trithiolane 1-oxide was pyrolyzed in vacuo (FVP) yielding the 1-oxotrisulfan-1-yl radical, which was isolated in an Ar matrix at 10 K and subsequently characterized by spectroscopic methods (IR and UV/Vis). The same radical was obtained after vacuum pyrolysis of di-tert-butyl disulfide S-oxide.
The synthesis and characterization of several C3v-symmetrically extended tribenzotriquinacenes (TBTQs) bearing six benzylic C1-tentacular functional groups at the arene periphery were reported. A new C3v-symmetrical hexakis(chloromethyl)-substituted TBTQ derivative was used as the key intermediate, and other derivatives were synthesized with high efficiency by either sixfold nucleophilic substitution reactions with phenols or sixfold Friedel–Crafts alkylation reactions with various arenes.A new tribenzotriquinacene-based sixfold benzyl chloride bearing three n-propyl residues at the outer bridgehead positions was synthesized and found to be a versatile key intermediate for tentacular extensions of the C3v-symmetrical TBTQ framework by using efficient multiple Friedel–Crafts and etherification reactions.
5-Benzyl-3-phenyl-2-thioxoimidazolidin-4-one underwent thermal dehydrogenation to afford 5-benzylidene-2-thioxoimidaxolidin-4-one under microwave and flash vacuum pyrolysis conditions. A high predominance of the Z-isomer over the E-isomer of the imidazolidinone product was achieved. By using DFT and NBO calculations, the mechanism of the dehydrogenation and the selectivity were also explored.In this article we report the dehydrogenation reaction of a benzylthioxoimidazolidinone derivative by using two unconventional and solvent-free methodologies: flash vacuum pyrolysis and microwave-induced pyrolysis. DFT calculations were performed to understand the dehydrogenation mechanism and to explain the high selectivity achieved towards the formation of the Z-isomer.
The hydroarylation of styrenes with various arene(heteroarene) compounds using H-?-zeolite as a green and recyclable heterogeneous catalyst under mild reaction conditions has been developed. The catalyst showed versatility and high selectivity (up to 100?%) of desired 1,1-diarylalkanes in cyclohexane as solvent under the conditions studied. The catalyst could be reactivated by simple treatment with mineral acid at room temperature for better catalytic activity.Hydroarylation of styrenes with variousarene(heteroarene) compounds using H-?-zeolite as a green, heterogeneous and reusable catalyst under mild conditions is reported.
The successful development of planar-chiral bis-silanols 3a–d and their application as asymmetric organocatalysts in hetero-Diels–Alder (HDA) reactions is described. All precursors were easily prepared by addition of commerically available silyl electrophiles to a dilithiated [2.2]paracyclophane derivative followed by silane oxidations. The analogous bis-carbinols 7a–c have been prepared by addition of suitable Grignard reagents to bis-methoxycarbonyl derivative 6. Both racemic as well as enantiopure planar-chiral bis-silanols and bis-carbinols were obtained in good yields. The catalytic activities of the bis-silanols were analyzed by monitoring HDA reactions between Rawal's diene and aldehydes by in situ IR spectroscopy and comparing the resulting data with those obtained in catalyses with the corresponding bis-carbinol derivatives. The results show for the first time that planar-chiral bis-silanols with hydrogen-bonding capabilities can be applied as asymmetric organocatalysts leading to enantiomerically enriched products.Enantiopure, planar-chiral [2.2]paracyclophane-based bis-silanols and their carbon diol analogs were synthesized and used as hydrogen-bond-donating organocatalysts in a hetero-Diels–Alder reaction with Rawal's diene.
The solid-phase synthesis of 5?-O-[N-(acyl)sulfamoyl]adenosine derivatives is described. The use of a Rink amide polystyrene solid support together with an appropriately protected ribo-purine starting material allowed for the development of a highly reliable and practical route for the solid-phase synthesis of 5?-O-[N-(acyl)sulfamoyl]adenosines. The developed procedure enables the efficient parallel synthesis of the target compounds in high yields. These compounds are non-hydrolysable isosteres of acyl-adenylates, which play an important role in a range of different metabolic pathways such as ribosomal and non-ribosomal peptide synthesis, fatty acid oxidation or enzyme regulation; some adenylate-forming enzymes are potential drug targets.A novel and straightforward solid-phase protocol for the parallel synthesis of 5?-O-[N-(acyl)sulfamoyl]adenosines has been developed. The synthetic protocol enables the possibility of variation of the acyl group attached to the sulfamoyl moiety. Variation of the acyl group provides compounds useful for studies of various biological activities.
Chemical investigation of the ethyl acetate extract of Corynespora cassiicola, isolated from leaf tissues of the Chinese mangrove medicinal plant Laguncularia racemosa, yielded four new secondary metabolites, including three decalactones, xestodecalactones D–F (1–3) as well as corynesidone C (4), in addition to four known compounds. The structures of the new compounds were determined on the basis of one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. Absolute configurations of the optically active compounds 1–3 were determined by TDDFT ECD calculations of their solution conformers, proving that they belong to the (11S) series of xestodecalactones, opposite to the (11R) configuration of the known xestodecalactones A–C. All compounds were tested against a panel of human protein kinases. Among the isolated compounds, two inhibited several kinases such as IGF1-R and VEGF-R2 with IC50 values mostly in the low micromolar range.Three new xestodecalactones D–F (1–3) and a new corynesidone C were isolated from Corynespora cassiicola. The structures were determined by 1D and 2D NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configurations of 1–3 were determined by TDDFT ECD calculations. All compounds were tested against a panel of human protein kinases.
Facile syntheses of 2H-chromenes or 9-functionalized phenanthrenes under mild conditions in moderate to good yields have been developed. They each involve annulations of arynes with ?,?-unsaturated compounds bearing different electron-withdrawing groups (EWGs). Depending on the natures of the different EWGs, the reactions proceed by different pathways: enals react with arynes through a tandem [2+2] cycloaddition/thermal electrocyclic ring-opening/6e-electrocyclization sequence to afford 2H-chromenes, whereas acyl-/ethoxycarbonyl-/cyano-substituted styrenes undergo Diels–Alder reactions with arynes followed by aromatization to afford 9-functionalized phenanthrenes. The scope, limitations, regioselectivities and mechanisms have been studied and are discussed in detail.Depending on the natures of different EWGs in ?,?-unsaturated compounds, the reactions between arynes and ?,?-unsaturated compounds proceed by different tandem pathways to afford either 2H-chromenes or 9-functionalized phenanthrenes in a selective manner, which is of potential pharmaceutical interest.
The synthesis, separation, and characterization of some substituted stereoisomeric dimethylene-bridged molecular clips bearing donor or acceptor groups at the tips of the naphthalene sidewalls and two acetoxy, hydroxy, or methoxy groups at the central benzene spacer unit are reported. The host–guest complex formation was studied for these substituted molecular clips as host molecules with 1,2,4,5-tetracyanobenzene (TCNB), N-methyl-p-(methoxycarbonyl)pyridinium iodide (Kosower's salt, KS), and N-methylnicotinamideiodide (NMNA) as guest molecules. The binding constants, Ka, and the complexation-induced 1H NMR shifts of the guest signals, ??max, obtained by NMR titration experiments, are compared with those reported for the parent diacetoxybenzene, hydroquinone, or dimethoxybenzene clips. The diacetoxybenzene clip, bearing donor pyrrolidinyl groups at the tips of both naphthalene sidewalls, forms the most stable complexes with TCNB and KS, overwhelming the corresponding complexes of the parent clip and the clips bearing one nitro or methoxycarbonyl group at the tip of one naphthalene sidewall. The clips bearing two acceptor groups (two nitro or methoxycarbonyl groups) at the tips of both naphthalene sidewalls do not form any complex with TCNB, KS, or NMNA within the limits of NMR detection. The large complexation-induced 1H NMR shifts of the guest signals provide good evidence that in each complex the guest molecule is clipped between the naphthalene sidewalls of the host molecule by attractive aromatic ?–? and CH–? interactions, as suggested by force-field calculations. This structural assignment of the complexes is further confirmed by a single-crystal structure of the KS complex of the mono-nitro-substituted clip, which resembles the complex structure of the parent clip with KS. The good correlation between the clip's electrostatic potential surface (EPS; calculated by DFT for the donor- or acceptor-substituted molecular clips) and the host–guest complex stability confirms the assumption that in chloroform solution the host–guest binding (resulting from attractive aromatic ?–? and CH–? interactions) is largely electrostatic in nature, whereas the EPS values do not correlate with the binding constants found in methanol solution, indicating that additional binding forces (resulting for example from solvophobic effects) contribute to the host–guest binding. The separated optically active diacetoxybenzene clips substituted by one or two methoxycarbonyl groups at the naphthalene sidewalls are a good starting point for future studies of chiral molecular recognition and organic catalysis.New donor/acceptor-substituted chiral molecular clips form host–guest complexes with 1,2,4,5-tetracyanobenzene (TCNB),N-methyl-p-(methoxycarbonyl)pyridiniumiodide (Kosower's salt), and N-methylnicotinamide iodide (NMNA) through charge-transfer and CH–? interactions.
An efficient one-step synthesis of 2-amino-5H-pyrimido[5,4-b]indoles through a copper-catalyzed cascade reaction between 3-haloindole-2-carbaldehydes and guanidine hydrochloride is described. In contrast, the base-mediated reactions of either 3-haloindole-2-carbaldehydes or substituted indole-2-carbaldehydes with substituted amidine hydrochlorides in DMSO result in the formation of 2-(1,3,5-triazin-2-yl)-1H-indole derivatives in one step in excellent yields. Studies toward exploring the utility of the method demonstrate that even substituted benzaldehydes undergo a similar reaction to efficiently yield 2,4,6-trisubstituted 1,3,5-triazines. A plausible mechanism for the formation of substituted 1,3,5-triazines identifies the role of DMSO as an oxidant during the reaction.The synthesis of 2-amino-5H-pyrimido[5,4-b]indoles from 3-haloindole-2-carbaldehyde and guanidine hydrochloride is described. In contrast, 3-haloindole-2-carbaldehydes or indole-2-carbaldehydes react with substituted amidine hydrochlorides to give 2-(1,3,5-triazin-2-yl)-1H-indole derivatives in excellent yields. The latter protocol was used to prepare 2,4,6-trisubstituted 1,3,5-triazines.
Eight configurational 1-deoxynojirimycin isomers have been synthesized starting from a chiral cyanohydrin as the common precursor. The cyanohydrin chiral pool building block is easily accessible in large quantities by using almond hydroxynitrile lyase as the chiral catalyst in condensing hydrogen cyanide and crotonaldehyde. Our work complements the large body of literature on the synthesis of 1-deoxynojirimycin derivatives with the distinguishing feature that eight stereoisomers of this important class of glycosidase inhibitors can be derived from a common precursor in an efficient manner.The orthogonally protected heterocyclic building blocks 6 and 7 have been prepared from cyanohydrin 2 in overall yields of 76?%. Compounds 6 and 7 were converted into eight different stereoisomers of 1-deoxynojirimycin in overall yields of 14–75?% in three to ten steps.
O-Polysaccharides (O-antigens) are highly diverse glycopolymers present on the cell surface of Gram-negative bacteria, including the human opportunistic pathogen Providencia alcalifaciens. They define serospecificity of strains and are used for the serotyping of bacteria. In this work, a phosphorylated O-polysaccharide was isolated from P. alcalifaciens O22 and analyzed by chemical methods, ESI-MS, and 1H, 13C, and 31P NMR spectroscopy. It was found to contain two unusual components, 2-acetamido-4-amino-2,4,6-trideoxy-D-galactose (D-FucNAc4N) and D-glyceramide 2-phosphate (D-GroAN-2-P), the latter being identified for the first time in bacterial polysaccharides. The structure of the trisaccharide repeating unit of the O-polysaccharide was established to be 4)-(D-GroAN-2-P-3-)--D-GalNAc-(14)--D-Gal-(13)--D-FucNAc4N-(1.The structure of the O-polysaccharide released from the lipopolysaccharide of P. alcalifaciens O22 by mild acid delipidation was elucidated by chemical methods, high-resolution NMR spectroscopy, and ESI-MS. The repeating unit includes D-glyceramide 2-phosphate, reported here for the first time as a component of bacterial polysaccharides.
Chemical-bonding analysis in coronene, isocoronene, and circumcoronene has been performed by using the Adaptive Natural Density Partitioning (AdNDP) method. This analysis revealed that coronene and isocoronene have two globally delocalized concentric ?-systems. Circumcoronene does not have globally delocalized ?-systems; instead, it has seven local sextets and can be represented by a single Clar structure. Thus, today there are a few known polycyclic aromatic hydrocarbons with two concentric ?-systems, but there are as yet no examples of such molecules with three or more concentric ?-systems. The results revealed by the AdNDP analysis are consistent with the results obtained by the current-density maps, NICS and NICSZZ indices as well as MCI, PDI, Iring and ? indices.Two concentric ?-systems in coronene and isocoronene and a Clar structure for circumcoronene have been revealed by the Adaptive Natural Density Partitioning Analysis.
TBSOTf-promoted C–C coupling of alkyl and trialkylsilyl nitronates with silyl ketene acetals yields functionalized nitroso acetals. This conversion may serve as a new simple procedure to reverse the conventional reactivity of aliphatic nitro compounds. Preliminary results on the hydrogenation of nitroso acetals into amino acids derivatives, as well as TFA-catalyzed transformations of nitroso acetals, are examined to prove the possible utility of this umpolung procedure.A very simple approach for umpolung of the conventional reactivity of nitroalkanes through their activation by silylation offers a convenient and efficient strategy for their C–C coupling with ?-nucleophiles. Both primary (8 examples) and secondary (4 examples) nitroalkanes may be involved in coupling with silyl ketene acetals (4 examples) to provide a concise route to substituted ?-amino acids.
The scope and stereoselectivity of the Michael addition of ester enolates to ?-benzylidene and ?-alkylidene ?-dicarbonyl compounds was studied. Most substrates reacted in good to excellent yields. Michael acceptors bearing carboxylic functionalities reacted directly in the ?-position, whereas aldol and Michael addition competed with unsaturated ketones. The diastereoselectivity of the process is dependent on the substitution pattern of the Michael acceptor and the geometry of the enolate. (Z)-Enolates add to unsaturated malonates or dibenzoylmethane derivatives with good anti-selectivity, whereas (E)-enolates afforded the syn-diastereomers predominately. Unsaturated nitriles and Meldrum's acid derivatives reacted with low diastereoselectivity. A stereochemical model is proposed that accounts for all experimental results and allows the stereochemical outcome to be predicted.Michael addition reactions of ester enolates with various unsaturated ?-dicarbonyl compounds are presented. The diastereoselectivity of the addition can be controlled by employing enolates with defined geometry.The scope and limitations of the methodology are discussed.
New enantiopure crown ethers containing either an ethyl diarylphosphinate moiety [(S,S)-4 to (S,S)-7] or a proton-ionizable diarylphosphinic acid unit [(S,S)-8 to (S,S)-11] have been synthesized. Electronic circular dichroism (ECD) studies on the complexation of these new enantiopure crown ethers with the enantiomers of ?-(1-naphthyl)ethylammonium perchlorate (1-NEA) and with ?-(2-naphthyl)ethylammonium perchlorate (2-NEA) were also carried out. These studies showed appreciable enantiomeric recognition with heterochiral [(S,S)-crown ether plus either (R)-1- or (R)-2-NEA] preference. Theoretical calculations found three significant intermolecular hydrogen bonds in the complexes of (S,S)-9. Furthermore, preference for heterochiral complexes was also observed, in good agreement with ECD results. Complex formation constants were determined by NMR titration for four selected crown ether/NEA pairs.Enantiopure crown ethers containing either an ethyl phosphinate [(S,S)-4 to (S,S)-7] or a phosphinic acid moiety [(S,S)-8 to (S,S)-11] were synthesized and complexation with the enantiomers of 1- and 2-NEA was studied. Calculations showed three important hydrogen bonds between (S,S)-9 and each enantiomer of 1-NEA and 2-NEA. Appreciable enantiomeric recognition and heterochiral preference were found.
Both enantiomers of biologically and pharmaceutically interesting benzofuran-, benzothiophen-, and phenylfuran-based 1-heteroarylethanamines were prepared at close to theoretical yields by using Candida antarctica lipase B (Novozym 435) catalyzed (R)-selective N-acylation with isopropyl butanoate (enantiomeric ratio E > 200). The use of N-methyl-2-pyrrolidinone (NMP) as a cosolvent (1:30) in isopropyl butanoate solved the problem of low solubility of the compounds. Instability of the heterocyclic ring systems against traditional acid- and base-catalyzed hydrolysis was solved by using Candida antarctica lipase A as a commercial CAL-A-CLEA preparation for deprotection of the N-acylated (R) enantiomers in water. The slow, highly enantioselective (E > 200) hydrolyses of racemic butanamides was also observed in the presence of Novozym 435.Both enantiomers of seven 1-heteroarylethanamines were prepared by starting from the ketones. Enantiopurity was introduced by Candida antarctica lipase B catalyzed (R)-selective N-acylation. Low solubility issues were solved by the use of N-methylpyrrolidine as a cosolvent. (R)-Butanamides were deprotected by Candida antarctica lipase A catalyzed hydrolysis in water, to yield the (R)-amines.
6,6?-Bis(methylaminosulfonyl)-7,7?-dihydroxy-8,8?-biquinolyl (3) catalyzes (5–10 mol-%) the addition of trimethylsilyl cyanide to aldehydes (aryl, alkyl, and ?,?-unsaturated; 42–92?% yields), ketones (aryl alkyl, dialkyl; 22–82?% yields), and N-benzylaldimines (14–78?% yields) in toluene (0 °C or room temp.) to give the expected cyanohydrin and Strecker adducts following desilylation. Among a series of closely related compounds lacking any one of their defining structural features, bis-sulfonamide 3 and its N,N?-dimethyl derivative are exceptional in catalyzing the silylcyanation of benzaldehyde in the absence of all other additives. Hammett analysis of the competitive silylcyanation of para-substituted benzaldehydes catalyzed by 3 showed a linear free-energy relationship (R2 = 0.928) with a modest positive reaction constant (? = +1.52). X-ray diffraction analysis of (±)-3 indicated a cisoid biaryl conformation and the existence of an intramolecular hydrogen bond between C7?–OH and C7–O. Resolution of (±)-3 was achieved by HPLC separation of its tetravalerate derivative on a chiral stationary phase. The absolute configurations of the optical isomers of 3 were assigned by correlation of the ECD spectra with those of related biquinolyls of known configuration. The silylcyanation of aldehydes catalyzed by (–)-(aR)-3 leads to cyanohydrins with a preference for the (S)-configured product with an ee of <10?%. The organocatalytic action of 3 is ascribed to hydrogen bonding and Brønsted acid catalysis effects that are dependent on its acidifying sulfonamide groups, general base capability, and interannular proximity effects made possible by the biaryl structure.6,6?-Bis(methylaminosulfonyl)-7,7?-dihydroxy-8,8?-biquinolyl catalyzes the addition of trimethylsilyl cyanide to aldehydes, ketones, and N-benzylaldimines to give the expected cyanohydrin and Strecker adducts following desilylation. Related compounds lacking any one of the defining structural features of the biquinolyl failed to promote the same reaction in the absence of additives.
?-Helices are ubiquitous structural elements of proteins and are important in molecular recognition. Small molecules mimicking ?-helices have proven to be valuable biophysical probes or modulators of protein-protein interactions. Here, we present modeling studies and the modular solid-phase synthesis of teroxazole derivatives as a new class of ?-helix mimetics. The synthesis is compatible with a variety of functional groups and should thus be generally applicable for generating diversely substituted oligo-oxazole scaffolds. The teroxazole scaffold is predicted to be polar and to project peptidomimetic side chains at positions i, i+3, and i+6 of an ?-helix, which complements projection patterns of existing helix mimetics. The scaffold retains sufficient conformational flexibility to conform to induced-fit models of protein-protein interaction inhibition.A teroxazole scaffold, designed to be a helical peptide mimetic, has been prepared by modular solid-phase synthesis. This method for synthesizing diversely substituted oligo-oxazole scaffolds is versatile. The teroxazole scaffold is hydrophilic and mimics side chains i, i+3, and i+6, which covers a broader region on the ?-helix surface than previous ?-helix mimetics.
Morita–Baylis–Hillman derivatives have been extensively investigated as intermediates in the preparation of important classes of compounds. However, there are intrinsic limitations regarding the structure of the Michael electrophile acceptors, the aldehydes, and the catalysts. Therefore, this transformation has several drawbacks, including, for example, its long reaction times. Herein we present a simple, general, fast, and high-yielding protocol for the one-pot synthesis of Morita–Baylis–Hillman derivatives. Our approach is driven by a lithium selenolate Michael/aldol operation with concomitant O-functionalization/selenoxide elimination cascade sequences.Here we describe a one-pot, fast, and high-yielding methodology for the synthesis of different Morita–Baylis–Hillman derivatives by a four-component cascade reaction. The cascade is based on a Michael/aldol/O-functionalization/selenoxide elimination sequence. This protocol completely avoids the manipulation of selenium species with an unpleasant odor.
Sulfur and nitrogen half-mustard compounds lose their aggressive properties when the chlorine atom is replaced by a carbonate moiety. The anchimeric effect of the novel mustard carbonate analogues is investigated. The reaction follows first-order kinetics, does not need any base, and occurs with –OH, –NH and acidic –CH nucleophiles. Most of these molecules are unexplored and might provide a novel strategy for the preparation of compounds previously not easily accessible.The synthesis and the chemical reactivity of sulfur and nitrogen half-mustard carbonate analogues are reported. The replacement of the chlorine atom by a carbonate moiety results in harmless compounds, which – maintaining the same chemical behaviour – give access to intermediates and building blocks so far only poorly exploited.
Fosmidomycin (1a) and FR-90098 are potent inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate (MEP) pathway responsible for the biosynthesis of isoprenoids. This paper describes the synthesis of four types of targets bearing a phosphanyl-phosphonic acid motif as the common core for the inhibition of DXR. In these structures, the hydroxamic acid was replaced by various chelators based on a phosphinic acid linked to different functional groups capable of forming five- or six-membered chelating rings.Fosmidomycin (1a) and FR-90098 are potent inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR). The replacement of the hydroxamic acid by functionalized phosphinic acids led to four types of targets which could act as analogues of fosmidomycin.
An efficient direct method for di-, tri- and tetraformylation of thiacalix[4]arenes substituted on the para positions is described. Di- and triformylated thiacalix[4]arenes were obtained by formylation of partially propyl- or benzoyl-substituted thiacalix[4]arenes. Complete para-formylation was successfully achieved by formylation and dealkylation of tetraisopropoxythiacalix[4]arene conformers in one step. This experimental procedure is a simpler synthesis for completely formylated thiacalix[4]arene than the indirect method reported previously from brominated thiacalix[4]arene.Di- and triformylated thiacalix[4]arenes substituted on the para positions have been synthesized by formylation of partially propyl- or benzoyl-substituted thiacalix[4]arenes. The formylation of tetraisopropoxythiacalix[4]arene conformers gave the completely dealkylated tetraformylthiacalix[4]arene derivative. This result differs from the formylation of propoxythiacalix[4]arene.
A highly selective method for the alkoxycarboxylation and acylation of primary alcohols of pyranose derivatives is described. The reaction is high yielding and proceeds under mild conditions with 0.15–1 mol-% Sc(OTf)3 used in combination with anhydrides or pyrocarbonates at 40–50 °C. Selectivities observed for alkoxycarboxylation of unprotected pyranose derivatives are > 95?%, and this constitutes a significant advantage over existing methods. Mechanistic implications, including the role of steric demand and metal–heteroatom coordination are also discussed.A novel Sc-catalyzed alkoxycarboxylation and esterification reaction of unprotectedpyranose substrates is described. This method gives nearly complete selectivity compared with existing methods and avoids known problems with polycarboxylation/acylation. A preliminary mechanistic model is proposed.
With the extensive use of two-photon fluorescence microscopy (2PFM) in the biomedical field, the need for development of fluorescent probes with improved two-photon fluorescence (2PF) properties has triggered extensive studies in the synthesis of new probes that undergo efficient two-photon absorption (2PA). In order to provide a more comprehensive comparison of fluorophores for 2PF bioimaging, a figure of merit (FM) was developed by normalizing the 2PA action cross-section, a commonly used parameter for characterizing bioimaging 2PF probes, by the photodecomposition quantum yield. Another important aspect of developing 2PA fluorophores is hydrophilicity. Although hydrophilic fluorophores are generally preferred in 2PFM bioimaging, hydrophobic fluorophores are typically easier to synthesize and purify, and have been used successfully in 2PFM bioimaging. The methodologies of dispersing hydrophobic fluorophores into aqueous media, such as in a DMSO/water mixture, micelles, silica nanoparticles, or forming polymer nanoparticles, are reviewed. The design and synthesis of hydrophilic 2PA fluorophores, achieved by introducing polyethylene glycol (PEG), anionic acid groups, cationic ammonium salt, and PAMAM dendrimers, is presented. Introduction of specificity to target certain biomarkers via labeling of antibodies, DNA, smallbioactive molecules, and peptides, and for the sensing of sepcific cations and pH, is also reviewed.In this microreview, photophysical property criteria for the development of two-photon fluorescent probes are discussed. The methodologies of dispersing hydrophobic fluorophores into aqueous media and various approaches for the synthesis of hydrophilic fluorophores are presented. Efforts concerning target specificity towards selected biomarkers along with cation and pH sensing is also reviewed.
Organic reactions involving radical cation and radical anion intermediates are synthetically powerful umpolung processes that enable electronically mismatched couplings between pairs of electron-rich or pairs of electron-poor organic fragments. Nevertheless, the adoption of these reactions as synthetic methods has been relatively slow in comparison with that of reactions involving more conventional reactive intermediates such as carbanions, carbocations, and neutral radicals. This Microreview provides a brief survey of radical ion chemistry and highlights the use of transition metal photocatalysis as a convenient means to investigate radical-ion-mediated transformations.Radical ion chemistry is an underappreciated field of synthetic organic chemistry. This Microreview provides a brief survey of the unique reactivities of radical cations and radical anions and argues that photoredox catalysis is a convenient method for the generation of these reactive intermediates.
The enzymes of the non-mevalonate pathway for the isoprenoid biosynthesis are promising targets for the development of selective drugs for the treatment of important infectious diseases. This pathway is used by plants, many eubacteria, and apicomplexan protozoa, including major human pathogens such as Plasmodium falciparum and Mycobacterium tuberculosis, but not by humans who use the mevalonate pathway. In this work, we report on the design, synthesis, and biological evaluation of new ligands for the E. coli enzyme IspE. The focus of the study lies in the analysis of the ribose sub-pocket of the CDP-ME binding site. Therefore, we synthesized cytosine- and 2-aminopyridine-based inhibitors with various substituents targeting this sub-pocket at the enzyme active site. As cytosines display unexpectedly low solubilities in aqueous solution, special efforts were made to increase the water solubility of some compounds while maintaining the good binding affinities measured in earlier studies. In vitro studies showed IC50 values in the low micromolar to submicromolar range against E. coli IspE.We report the design, synthesis, and biological evaluation of new cytosine- and 2-aminopyridine-based ligands to explore the molecular recognition properties of the ribose sub-pocket of the substrate-binding site in the IspE protein of Escherichia coli, a model enzyme for P. falciparum IspE.
Novel one-pot syntheses of N-glycooxazolines (N at C-1), N-glycoaminooxazolines, and N-glycothiazolines have been developed. Thus, the reaction of tri-O-benzyl-D-glucal or tri-O-benzyl-D-galactal with aryl amides, heteroaryl amides, thioamides, and substituted ureas in the presence of N-iodosuccinimide (NIS) in dry propionitrile at 45 °C afforded the cyclized products in good yields. When tris(O-tert-butyldimethylsilyl)-D-glucal was employed, the 2-deoxy-2-iodoglycosylamide was isolated instead. Treatment of this newly formed glycosylamide with an anhydrous base afforded the O-glycooxazoline (O at C-1) in high to moderate yields. Product outcomes and the overall stereoselectivity of the reactions were found to be highly dependent on the nature of the sugar protecting group, the nature of the substituent on the amide, and the reaction temperature.A novel one-pot synthesis of N-glycooxazolines, N-glycothiazolines, and N-glycoaminooxazolines has been developed based on the frameworks of the natural products Allosamidin and Trehazolin. Access to these constructs was possible by the addition of heteroaryl amides, thiobenzamide, and substituted ureas to glycals in the presence of N-iodosuccinimide and propionitrile at high temperatures.
Enantiopure 3,6-dihydro-2H-1,2-oxazines were prepared by [3+3] cyclisations starting from lithiated methoxyallene and the L-erythrose-derived nitrones 1? and 3. The role of the side-chain protective group, which steers the highly selective formation of either anti- or syn-configured products, was demonstrated. A hydroboration/oxidation protocol smoothly converted 1,2-oxazine derivative syn-5 into secondary alcohol 6. After deprotection, polyhydroxylated tetrahydro-2H-1,2-oxazine 11, which can be regarded as an azasugar, was isolated. Analogous treatment of 1,2-oxazine anti-5 with the borane not only provided the expected secondary alcohol 7, but it also induced reduction of the C=C bond and ring opening. Treatment of syn-5 and anti-2 with hydrochloric acid in methanol induced deprotections and cyclisations leading to bicyclic tetrahydro-2H-1,2-oxazine derivatives. The second ring can be either a furan or a pyran ring. In the syn series, furan derivative 12 was formed exclusively, and its hydrogenolysis led to enantiopure aminofuran derivative 14. Acid-promoted rearrangement of unprotected anti-2 led to a mixture of bicyclic compounds with furan or pyran rings fused to the 1,2-oxazine core. However, when TBDPS-protected compound 20 was used it cleanly led to 1,2-oxazine 21 with a fused furan ring and then to aminofuran 22. Alternatively, the N–O bond in unprotected anti-2 was chemoselectively reduced with samarium diiodide, efficiently generating highly functionalized allylic alcohol 23. Acid-promoted cyclisation and deprotection furnished furan derivative 24. Mechanistic suggestions to explain the different outcomes of the acid-induced transformations are provided. Overall, it is demonstrated that the stereodivergent addition of lithiated alkoxyallenes to L-erythrose-derived nitrones allow flexible access to a series of enantiopure amino polyols, including aminofuran derivatives.Depending on the protection of the starting L-erythrose-derived nitrone, the addition of lithiated methoxyallene leads to the formation either of anti- or of syn-configured 1,2-oxazine derivatives. Subsequent hydroboration also proceeds with excellent stereoselectivity. The high synthetic value is demonstrated by conversion of the resulting intermediates into amino polyols.
The simple and practical syntheses of chiral guanidine organocatalysts and their evaluation in the asymmetric Michael addition reaction of malonates and ?-keto esters with nitro-olefins is reported. These organocatalysts are the first of their kind based on a tetrahydroisoquinoline framework. In addition, a microwave-assisted procedure for introducing the guanidine unit onto amino amide derivatives is reported. The chiral products were obtained with quantitative chemical efficiency (up to 99?% yield) and excellent enantioselectivity (up to 97?%?ee).The synthesis of chiral guanidine organocatalysts based on a tetrahydroisoquinoline framework and their evaluation in asymmetric Michael additions of malonates and ?-keto esters with nitro-olefins is reported. A microwave-assisted procedure for introducing the guanidine unit onto amino amide derivatives is also reported. The chiral products were obtained in up to 99?% yield with up to 97?%?ee.
Reaction of phenylpropynehydrazide with dimethylmalonyl chloride furnished the corresponding 4,4-dimethyl-1-(3-phenylprop-2-ynoyl)pyrazolidine-3,5-dione, which upon thermolysis underwent a 6-endo-dig cyclization to a pyrazolo[5,1-b][1,3]oxazine. The corresponding reaction of arylpropynehydrazides with monosubstituted malonyl chlorides furnished pyrazolo[5,1-b][1,3]oxazine-7-ones via intermediates that could not be isolated.The reaction of arylpropynehydrazides with monosubstituted malonyl chlorides leading to pyrazolo[5,1-b][1,3]oxazines is reported. This method can also be extended to the synthesis of pyrazolidine-3,5-dione, which subsequently can be converted by thermolysis into a pyrazolo[5,1-b][1,3]oxazine.
A straightforward synthesis of novel chiral polysiloxane-based metal stationary phases immobilized through a propylenoxy linker (Chirasil-Metal-OC3) to the polymeric backbone is presented. Synthesis was accomplished in six steps with high overall yields starting from commercially available, enantiopure (+)-(1S)-camphorsulfonic acid. Two different approaches towards Chirasil-Metal phases featuring either a propylenoxy or propylenthio linker used for immobilization through hydrosilylation are presented. Furthermore, a new protocol for the fluoroacylation, which is one of the key steps in the synthesis of (1R)-3-(perfluoroalkanoyl)camphorate metal complexes, was developed to improve the isolation and overall yield. The immobilization of (1R,4S)-10-(allyloxy)-3-(heptafluorobutanoyl)camphor – 10-(allyloxy)-hfbc – onto polysiloxanes as well as the incorporation of nickel(II), oxovanadium(IV), europium(III), and lanthanum(III) was characterized by FT ATR IR and NMR spectroscopy. Overall, seven different Chirasil-Metal-OC3 polymers with different separation properties were prepared by metal incorporation and variation of the amount of immobilized (1R,4S)-10-(allyloxy)-3-(heptafluorobutanoyl)camphor (10-allyloxy-hfbc: 3.5, 10.2, and 20.0?%). Their performance in enantioselective complexation gas chromatography was systematically studied and excellent enantioselectivity was found for Chirasil-Nickel-OC3. Separation of 29 small-sized compounds, encompassing, among others, epoxides, substituted alkenes and alkynes as well as alcohols and amides, was achieved with high separation factors ?. The synthetic strategy, enantiomer separations and thermal stability (up to 160 °C) demonstrates the versatility of the newly derived Chirasil-Metal-OC3 phases.A novel synthetic approach to camphor-based chemically bonded Chirasil-Metal-OC3 [Ni, Eu, La, V(O)] stationary phases and thir application in enantioselective complexation GC is presented. Immobilization and metal incorporation was studied with a range of selector concentrations using NMR and IR spectroscopy. Overall, 29 compounds with different functionalities were separated with ?-values up to 1.66.
We found that nitrogen-containing Lewis base mediated [4+2] annulation of but-3-yn-2-one with activated ketones could proceed efficiently to give the corresponding 2,3-dihydropyran-4-ones in moderate to good yields under mild conditions. The substrate scope has been carefully examined. Moreover, a plausible reaction mechanism for the [4+2] annulation of but-3-yn-2-one with activated ketones mediated by DABCO has been proposed on the basis of previous literature and our own investigations.We found that nitrogen-containing Lewis base mediated [4+2] annulations of but-3-yn-2-one with activated ketones could proceed efficiently to give the corresponding 2,3-dihydropyran-4-ones in moderate to good yields under mild conditions. The substrate scope has been carefully examined. A plausible reaction mechanism for the [4+2] annulation mediated by DABCO has been proposed.
New asymmetric total syntheses of (–)-dichotomines A–D (1–4) starting from L-tryptophan methyl ester and 2,3-O-isopropylidene-D-glyceraldehyde are described. The absolute configuration of the stereogenic center of (–)-dichotomine A (1) was reconfirmed as (S), on the basis of the X-ray crystallographic analysis of the conjugate (i.e., 17) of its methyl ester (i.e., 16) with (S)-N-tosylproline, whereas the absolute configurations of the stereogenic centers of (–)-dichotomines B–D (2–4) were revised as (R).New asymmetric total syntheses of (–)-dichotomines A–D (1–4) starting from L-tryptophan methyl ester and 2,3-O-isopropylidene-D-glyceraldehyde are described. The absolute configuration of the stereogenic center of (–)-dichotomine A (1) was reconfirmed as (S), whereas the absolute configurations of the stereogenic centers of (–)-dichotomines B–D (2–4) were revised as (R).
The photochemistry of 3-iodo-2,5,6-trifluoropyridyl azide (6c), matrix-isolated in argon, was investigated by IR and EPR spectroscopy. The primary photoproduct is 3-iodo-2,5,6-trifluoropyridylnitrene (7c) in its triplet ground state. Further irradiation produced very low yields of nitrene radical 3c, which shows a characteristic EPR spectrum. The yield of 3c, however, was too low for IR detection. Instead, azirinyl radical 11, formed from 3c by ring closure, could clearly be identified in the IR spectra. Other products observed were azirine 8c? and the ketenimine 9c?, which are formed in a photostationary equilibrium together with nitrine 7c.The combination of an aryl radical with an arylnitrene results in new motives for the construction of organic high-spin molecules. Photolysis of 3-iodo-2,5,6-trifluoropyridyl azide under the conditions of matrix isolation results in the formation of a nitrene radical with a quartet ground state. The electronic structure of this nitrene radical is described best as a ?,?,?-triradical. The nitrene radical is stable at cryogenic temperatures but, upon irradiation, rearranges to a thermodynamically more stable azirinyl radical.
Ru-catalyzed cycloisomerization of a 1,3-diene and the alkene of an N-dienyl-2-vinylaniline substrate proceeded smoothly, leading to a 3-exomethylene-2-vinylindole derivative in good yield. This useful synthon was successfully applied to the total synthesis of (±)-cinchonaminone.Ru-catalyzed cycloisomerization of a 1,3-diene and the alkene of an N-dienyl-2-vinylaniline substrate proceeded smoothly, leading to a 3-exomethylene-2-vinylindole derivative in good yield. This useful synthon was successfully applied to the total synthesis of (±)-cinchonaminone.
(R)- and (S)-4,4?-diaminomethyl-BINAP were prepared in three steps from enantiomerically pure BINAPO in a global yield of 52?%. A regioselective bromination of BINAPO with NBS in HMimPF6 gave the desired 4,4?-dibromo-BINAPO in quantitative yield, and the recyclability of the ionic liquid was demonstrated. Copper cyanide cyanation of 4,4?-dibromo-BINAPO gave the 4,4?-dicyano-BINAPO in 70?% yield. Both enantiomers were characterized by NMR spectroscopy and HPLC analysis, and the structures were confirmed by X-ray crystallography. The cyano and phosphane oxide groups of the resulting 4,4?-dicyano-BINAPO were reduced in one step to the corresponding 4,4?-diaminomethyl-BINAP by using tetramethyldisiloxane/Ti(OiPr)4 in 75?% yield.Previous synthesis of (R)- and (S)-4,4?-diaminomethyl-BINAP was effective, but the method presented several drawbacks including long reaction times and the use of a large excess amount of a harmful reagent. We have developed an improved and safer synthetic route starting from optically active BINAPO.
Palladium(II)-catalyzed ortho-olefination of arylaldehyde O-methyloximes by using O-methyloxime as a directing group gave 2-alkenylarylaldehyde O-methyloximes in moderate to good yields. After various reaction parameters (catalyst, oxidant, solvent, and reaction temperature) were examined, the optimal conditions for the reaction were identified. 2-Alkenylarylaldehydes could be obtained conveniently by hydrolysis of the coupling products. The kinetic isotope effect (kH/kD) for the C–H bond activation was provided, and the possible mechanism of the reaction was proposed.2-Alkenylarylaldehyde O-methyloximes were obtained through palladium(II)-catalyzed ortho-olefination of arylaldehyde O-methyloximes by using O-methyloxime as a directing group in moderate to good yields. Hydrolysis of the coupling products conveniently gave 2-alkenylarylaldehydes.
Metallated porphyrin tweezers have demonstrated a remarkable ability to function as reporters of absolute stereochemistry for a number of different classes of organic molecules. Flexibility in binding, however, can result in an ensemble of different Exciton Coupled Circular Dichroism (ECCD) active conformations that could lead to variable results. Linker flexibility was found to be a key determinant of binding conformation. Experimental results indicate that a balance between linker flexibility and rigidity could yield an optimum porphyrin tweezer that stabilizes a common conformation for all bound chiral guests. This leads to a more simplified approach to absolute stereochemical determination of asymmetry for small organic molecules. This was demonstrated by the use of a C3-linked zincated porphyrin tweezer that yields a common conformational preference for a variety of ?-chiral carboxylic acids derivatized with a diamine carrier.Metallated porphyrin tweezer systems are used as reporters of absolute stereochemistry. They bind to chiral guest molecules and adopt a specific helical arrangement that is observable via exciton coupled circular dichoroism. Conformational flexibility of the linker that joins the two porphyrins of a tweezer stabilizes a common conformation, as shown for a variety of ?-chiral carboxylic acids.
The three-component reactions of N-benzylbenzimidazolium salts, isatins, and malononitrile or ethyl cyanoacetate showed very interesting molecular diversity depending on the structures of the benzimidazolium salts. The reactions of N-benzyl-N?-p-nitrobenzylbenzimidazolium salts gave a series of zwitterionic salts in good yields. Under similar reaction conditions the reactions of N-benzyl-N?-phenacylbenzimidazolium salts resulted in the unexpected products with opening of the imidazole ring.The three-component reactions of N-benzylbenzimidazolium salts, isatins, and malononitrile or ethyl cyanoacetate showed very interesting molecular diversity depending on the structures of the benzimidazolium salts: zwitterionic or ring-opened products were obtained.
A new class of dirhodium(II) tetraamidinates derived from 2-(sulfonylimino)pyrrolidines has been prepared through ligand substitution by using dirhodium(II) acetate, in which (3,1) geometric isomers are formed predominantly. Among these complexes, (3,1)-Rh2(Msip)4, exhibits good catalytic performance in benzylic oxidation. In the presence of (3,1)-Rh2(Msip)4 a variety of benzylic derivatives, including strongly electron-deficient arylalkanes such as 1-ethyl-4-nitrobenzene, are readily oxidized in water by the inexpensive oxidant T-HYDRO® (70 wt.-% aqueous tert-butyl hydroperoxide).The synthesis of dirhodium(II) tetraamidinates derived from 2-(sulfonylimino)pyrrolidines and their use in the catalytic benzylic oxidation are described. A variety of benzylic derivatives, including strongly electron-deficient arylalkanes such as 1-ethyl-4-nitrobenzene, can be readily oxidized by T-HYDRO® in the presence of 1.0 mol-% (3,1)-Rh2(Msip)4 in water under mild reaction conditions.
The functionalized NHC obtained from salt 2 is a good ligand for palladium in the Heck–Matsuda reaction of arenediazonium salts and different alkenes. The reaction is performed with low catalyst loading (0.5–1 mol-% of Pd) and in the absence of a base for acrylates. The protocol is also useful for the preparation of cinnamide derivatives. Compound U-77863 has been prepared successfully in good isolated yield. Cyclohexene was found to be an appropriate substrate for the reaction, giving the corresponding 1-arylcyclohexene as a single regioisomer under the studied reaction conditions. The optimal parameters of the reaction were studied by employing a design of experiments approach. Thus, the use of a small set of reactions allows the trends of the different factors to be studied. This study revealed that the best catalytic system is formed by combination of Pd(OAc)2 and salt 2 in a 1:2 ratio. This catalytic system produces better results without the use of a base.A hydroxy-functionalized NHC in combination with a palladium source allows the Heck–Matsuda reaction to be carried out between different arenediazonium salts and various alkenes (i.e., acrylates, acrylamide, styrene, and cyclohexene) The optimal conditions to perform the reaction were determined by a design of experiments study.
Highly substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized through successive cyclization and Suzuki–Miyaura cross-coupling reactions. The palladium-catalyzed coupling reaction was optimized and a wide range of boronic acids was used to evaluate the scope and limitations of the methodology. The final compounds were obtained in fair to very good yields and high compatibility with various chemical functions or (hetero)cycles was observed.The synthesis of 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles obtained through the cyclization of 2-amino-5-bromo[1,3,4]thiadiazole and several ?-halo ketones followed by Suzuki–Miyaura cross-coupling with a variety of boronic acids was developed. The products were obtained in fair to very good yields.
In the present study, 6,12-diphenyldibenzo[b,f][1,5]diazocine, which X-ray diffraction measurements have now shown to possess a tub-shaped, eight-membered central ring, has been treated with sodium or lithium metal at 25 °C in THF, in an attempt to form the planar, Hückel-aromatic dianion by the addition of two electrons to the central diazocine. Hydrolysis of such an aromatic dianion should have led to the isomeric 5,12- or 5,6-dihydro derivative of the original diazocine. In actuality, the only product obtained quantitatively upon hydrolytic workup was the interesting quadricyclic transannular reduction product, 4b,9b-diphenyl-4b,5,9b,10-tetrahydroindolo[3,2-b]indole, whose 3D structure has now been confirmed by X-ray crystallography and 13C NMR spectroscopy. Preferential SET transannular reduction of the diazocine to yield the quadricyclic indolo[3,2-b]indole dianion, rather than the planar, Hückel-aromatic anion, is ascribed to the transannular electronic stabilization operative in the tub-shaped diazocine radical-anion. The quantitative generation of the indolo[3,2-b]indole dianion can be employed for the oxidative dimerization of the organic groups in benzylic lithium reagents. Thus treating one equivalent of the diazocine with two equivalents of benzyllithium, benzhydryllithium, or trityllithium yields quantitatively bibenzyl, 1,1,2,2-tetraphenylethane, or (4-benzhydrylphenyl)triphenylmethane, respectively. This oxidative dimerization is potentially of practical preparative scope, since the hydrolysis byproduct, the indolo[3,2-b]indole, is conveniently reconverted into the starting diazocine reagent by oxidation with chromium trioxide in acetic acid. The formation of the indolo[3,2-b]indole as a byproduct in the carbometalation of the diazocine by various RLi and Grignard reagents offers a clue as to the SET mechanism of carbometalation.6,12-Diphenyldibenzo[b,f][1,5]diazocine readily undergoes transannular SET reductions with sodium, lithium, or even benzylic lithium or magnesium reagents to yield, upon hydrolysis, 4b,9b-diphenyl-4b,5,9b,10-tetrahydroindolo[3,2-b]indole. This diazocine can thereby serve as a mechanistic probe for SET processes and as a reagent for the oxidative dimerization of benzylic organometallics.
The generation of (?6-aryne)chromium complexes as reactive intermediates was investigated in two ways. Although earlier attempts directed towards triflate eliminations from a variety of tricarbonyl(phenyl triflate)chromium complexes had failed, more electron-rich phenyl triflate complexes were considered. This was accomplished either by substitution with two methoxy groups in the arene ligand or by replacement of one of the three carbonyl ligands of the tricarbonylchromium complex with triphenylphosphane. However, the attempted elimination still did not take place; in spite of the increased electron densities in the aromatic ligands, anionic thia-Fries rearrangements were observed in high yields at –78 °C. As an alternative, elimination of lithium fluoride was tested. Tricarbonyl(2-lithiofluorobenzene)chromium(0) was generated by tin/lithium exchange. After hydrolytic workup, tricarbonyl(fluorobenzene)chromium was obtained as the main product, indicating that the lithiation step had been successful. A dimeric side product provided evidence for the intermediacy of (benzyne)tricarbonylchromium.Electron-rich (phenyl triflate)chromium complexes show an unexpectedly high propensity for anionic thia-Fries rearrangements, which take place at –78 °C with very high yields. Unlike in the case of the uncomplexed ligands, no aryne formation was observed.
New series of 2?,3?-dideoxy-2?-fluoro-3?-(hydroxyimino)-, -3?-(methoxyimino)- and -3?-(hydroxyamino)pyrimidine nucleosides were synthesized. Structural assignments of the former two derivatives, which were obtained as inseparable mixtures of (E) and (Z) isomers, were based upon 1H and 19F NMR spectroscopic analysis. In particular, we observed striking differences in 19F NMR spectra resulting from through-space N–F coupling for compounds having proximate nitrogen (oxime) and fluorine atoms with lone-pairs correctly oriented for overlapping. Antiviral and cytotoxic activities of the target nucleosides were evaluated; however, none of them showed any antiviral activity. Only 2?,3?-dideoxy-2?-fluoro-3?-(hydroxyamino)cytidine (19) showed moderate activity against the proliferation of murine leukemia cells (L1210).The title pyrimidine nucleosides were prepared from their respective 2?,3?-dideoxy-2?-fluoro parent nucleosides, and structural assignments were made based upon their 1H and 19F NMR spectra. Antiviral and antitumor activities were evaluated, but none of the target nucleosides showed antiviral properties, except for compound 19, which showed moderate cytotoxic activity.
The straightforward synthesis of new bicyclopropyl-substituted alkynes and 1,3-dienes and their application in cobalt-catalyzed Diels–Alder reactions are described. The cycloaddition processes generated the desired bicyclopropyl-substituted arene derivatives in moderate to good yields, depending on the steric congestion of the reaction partners. The regioselectivity of the cycloaddition was controlled by the ligand coordinated to the cobalt center. The cyclopropyl moiety remained unchanged over the course of the Diels–Alder reaction, indicating that no radical type intermediates were formed. Only in a single case did the DDQ oxidation of the primarily formed dihydroaromatic product lead to ring opening of a cyclopropyl subunit. In all of the other cases, cyclopropyl-modified arenes with various functionalities were obtained.The application of cyclopropyl-substituted alkynes and 1,3-dienes in cobalt-catalyzed Diels–Alder reactions led to various cyclopropyl-substituted arenes. In only one case, the ring-opened product was isolated. This shows that the cyclopropyl subunits were generally compatible with the conditions of the cobalt catalysis and of the subsequent DDQ oxidation of the dihydroaromatic intermediates.
An efficient N-selective alkylation of primary aromatic amines in molten quaternary ammonium salts, as the solvent, under relatively mild and base-free conditions is presented. On the basis of the Kamlet–Taft parameters and the nucleophilicity of the IL (ionic liquid) anions, the influence of the ionic liquid was evaluated. This protocol was validated on a larger multigram scale and with the syntheses of bioactive heterocycles (e.g., 1,4-benzothiazine and quinoxalines) and new efficient MALDI matrixes.A protocol for the selective N-alkylation of primary aromatic amines in tetraalkylammonium ionic liquids was developed. This approach complements existing strategies by broadening the scope with more challenging substrates (e.g., p-nitroaniline) and alkylating agents (chloroalkane).
Enantiopure ?-nitro alcohols are key chiral building blocks for the synthesis of bioactive pharmaceutical ingredients. The preparation of these target compounds in optically pure form has been the focus of much research and there has been an emergence of biocatalytic protocols in the past decade. For the first time, these biotransformations are the focus of this review. Herein, we describe two principal biocatalytic approaches to the Henry (nitroaldol) reaction. The first method is a direct enzyme-catalysed carbon–carbon bond formation resulting in either an enantio-enriched or enantiopure ?-nitro alcohol. The second approach describes the Henry reaction without stereocontrol followed by a biocatalytic resolution to yield the enantiopure ?-nitro alcohol.Enantiopure ?-nitro alcohols are key chiral pool intermediates for the synthesis of a wide array of bioactive molecules. Methods to gain access to these valuable synthons include organo-, transition metal- and bio-catalysis. In recent years biocatalytic methods have gained momentum in this area. This microreview details these advances, which principally include a direct enzyme-catalysed C–C bond formation or enzyme-mediated resolution of the products of the Henry reaction. This approach is reviewed in detail for the first time.
(E)-4-Aryl-1,1,1-trifluoro-3-tosylbut-3-en-2-one fluorinated building blocks were prepared through a two-step process. Treatment of these (E)-4-aryl-1,1,1-trifluoro-3-tosylbut-3-en-2-ones with arsonium bromides in the presence of Cs2CO3 in CH2Cl2 at reflux resulted in highly stereoselective ring closure to provide 4-tosyl-5-trifluoromethyl-trans-2,3-dihydrofurans in good to excellent yields.(E)-4-Aryl-1,1,1-trifluoro-3-tosylbut-3-en-2-ones were prepared through a two-step process and used as fluorinated building blocks in the stereoselective preparation of a series of 4-tosyl-5-trifluoromethyl-trans-2,3-dihydrofuran derivatives with the assistance of arsonium ylides.
Mannopyranose-derived methyl 1,2-orthoacetates (R = Me) and -benzoates (R = Ph) can function as glycosyl donors – upon BF3·Et2O activation in CH2Cl2 – in glycosylation reactions with monosaccharide acceptors to afford disaccharides in good yields. In the process, glycosylation is preferred to acid-catalyzed rearrangement leading to methyl mannopyranosides. Methyl 1,2-orthoesters can be also used in regioselective glycosylation protocols with monosaccharide diols, in which they display good regioselectivity.Methyl 1,2-orthoesters are useful glycosyl donors upon acid activation with boron trifluoride etherate. They react smoothly with monosaccharide alcohols or diols, leading to disaccharides in good to excellent yields. When monosaccharide diols are used as glycosyl acceptors, good regioselectivity in the glycosyl coupling is observed.
Cyclodextrins are important building blocks in organic chemistry. This review deals with the role of click chemistry in this family of cyclic oligosaccharides, focusing on the different areas of chemistry, including chromatography, biological applications, the elaboration of superstructures, and metal detection, that benefit from this reaction. In this paper, attention is given to organic modifications by using functionalizations such as azidation and propargylation and to click chemistry grafting onto the two faces of cyclodextrins. Research papers where cyclodextrins are not directly involved in a click chemistry reaction are not considered.A summary of chemical advances in the fields of chromatography, biological applications, the elaboration of superstructures, and metal detection is given when cyclodextrins meet the copper-catalyzed azide–alkyne cycloaddition reaction.
The transition-metal-catalyzed cyclization of alkynals viaoxametallacycle intermediates is a useful method for thestereoselective synthesis of cyclic allylic alcohol derivatives. The reductive cyclization reactions are catalyzed by titanium and nickel complexes using organosilanes, organoboranes, and organozincs as reducing agents. The alkylative, arylative, and alkenylative cyclization reactions are catalyzed by nickel complexes using organozincs and alkenylzirconiums. On the other hand, the recently developed rhodium-catalyzed reductive cyclization reactions of alkynals allow using dihydrogen as a reducing agent without the use of organometalloid and organometallic reagents. Furthermore, very recently, the rhodium-catalyzed acylative cyclization reactions of alkynals were accomplished by using aldehydes and acyl phosphonates as acylating reagents. Importantly, the use of the rhodium catalysts realized the enantioselective cyclization reactions of alkynals with excellent levels of enantioselection.The transition-metal-catalyzed cyclization of alkynals via metallacycle intermediates is a highly efficient method for the stereoselective synthesis of carbocycles and heterocycles. This microreview summarizes the development of the transition-metal-catalyzed cyclization reactions of alkynals via oxametallacycle intermediates.
Isocyanide-based multicomponent reactions (IMCRs) can be considered one of the breakthrough reaction classes of the last century. Moreover, asymmetric IMCRs have recently developed into powerful reactions for the versatile synthesis of highly complex molecules. The progress made in the development of stereoselective Passerini and Ugi reactions has led to the advancement of catalytic asymmetric IMCRs. This review gives an overview of recent advances in the field of asymmetric IMCRs with a focus on stereoselective ?-additions of isocyanides. In addition, the use of convertible isocyanides in stereoselective cascade IMCRs is covered and future opportunities and potential applications of (asymmetric) IMCRs are briefly discussed.This review discusses the use of various isocyanides (regular, chiral, and convertible) in asymmetric multicomponent reactions. In particular, stereoselective Ugi and Passerini reactions are highlighted, as well as their applications in modular sequential reactions and natural product synthesis.
Copper nanoparticles (mainly as Cu2O) on titania have been shown to catalyze the multicomponent synthesis of propargylamines from aldehydes, amines, and alkynes (A3 coupling) effectively at 70 °C under solvent-free conditions. Both aromatic and aliphatic aldehydes and alkynes have been combined with secondary amines to provide a wide range of propargylamines in moderate to excellent yields. Two examples of ketone/amine/alkyne (KA2) coupling are also included. The catalyst is easy to prepare, reusable at a low copper loading (0.5 mol-%), and exhibits higher catalytic activity than some commercially available copper sources. Some mechanistic aspects of the reaction have also been examined, which have unveiled the participation of copper(I) acetylides in a heterogeneous process.A3 coupling catalyzed by ultrafine copper nanoparticles on titania under solvent-free conditions is described. Some examples of KA2 coupling are also reported. The catalyst is reusable and exhibited better performance than commercially available copper catalysts. The participation of copper(I) acetylides in a heterogeneous process has been demonstrated.
The need for precise and flexible synthetic methodology to underpin modern research in chemical biology and materials science has fuelled a resurgence of interest in Huisgen 1,3-dipolar cycloaddition chemistry. Of late, the in vogue chemistry for the assembly of complex biological molecules and specialist materials has been the copper-catalysed azide alkyne cycloaddition (CuAAC) reaction. However, in certain circumstances aversion to the copper catalyst flaws this approach and alternatives have been sought. Click chemistry has developed beyond the original triazole-forming trick and azides are no longer the only dipoles pursued as click cycloaddition partners. This article reviews some of the complications of the CuAAC reaction and evaluates the potential of nitrile oxide/alkyne cycloaddition (NOAC) as a covalent conjugation tool. With a focus on applications in nucleic acid chemistry and materials science it presents the case for a prominent position for nitrile oxides in the catalyst-free bioconjugation toolbox.A lofty position will be reserved for nitrile oxide/alkyne cycloadditions amongst the valuable, catalyst-free, bioorthogonal “click” protocols. The future looks bright for the application of NOAC chemistry to contemporary problems in chemical biology and materials science.
Posted on 13 March 2012 | 2:53 pm
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