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新型糖氨基酸类化合物的合成研究
(2015)
Sugar amino acids (SAAs) are carbohydrate derivatives bearing both amino and carboxylic acid functional groups. SAAs represent an important class of multifunctional building blocks, which are amenable to serve as glycomimetics or peptidomimetics with well-defined structures and useful properties. Because SAAs exist in nature in many forms with various biological activities, recently, many unnatural SAAs, as the demand for finding new molecules to discover new drugs and new materials, have been designed and synthesized by a number of research groups. In this paper, we have developed a convenient method for the synthesis of novel SAAs gluco-7 and galacto-7 for the first time. The structure of gluco-7 was similar to the natural SAA glucosaminuronic acid that was a component of many typical bacterial cell walls and could be used for the preparation of type D flu vaccine; while galacto-7 was similar to the natural SAA galactosaminuronic acid that was one of bacterial Vi-antigen components of Escherichia coli. Starting from unexpensive and commercially available 3,4,6-tri-O-acetyl-D-glucal and 3,4,6-tri-O-acetyl-D-galactal, two novel SAAs gluco-7 and galacto-7 were achieved in the linear 6 steps with 34% overall yield and 19% overall yield, respectively. The key reactions included radical addition, decarboxylation, iodine generation reaction, azide reaction and reductive amination reaction. The crucial step was the synthesis of the target compound gluco-7 from gluco-6. By using method A, the target compound gluco-7 was obtained in 4 steps with 63% overall yield. To optimize the transformation from gluco-6 to gluco-7, method B was developed to generate gluco-7 by using one-pot reaction successfully with 76% yield only in one step. It proved that method B was superior to method A with shorter steps and higher yields. All the new compounds were characterized by IR, H-1 NMR, C-13 NMR and HRMS data. Study on the synthesis and biological evaluation of linear and cyclic oligomers derived from gluco-7 and galacto-7 are currently in progress.
An experimental and computational study on the impact of functional groups on the oxidation stability of higher acenes is presented. We synthesized anthracenes, tetracenes, and pentacenes with various substituents at the periphery, identified their photooxygenation products, and measured the kinetics. Furthermore, the products obtained from thermolysis and the kinetics of the thermolysis are investigated. Density functional theory is applied in order to predict reaction energies, frontier molecular orbital interactions, and radical stabilization energies. The combined results allow us to describe the mechanisms of the oxidations and the subsequent thermolysis. We found that the alkynyl group not only enhances the oxidation stability of acenes but also protects the resulting endoperoxides from thermal decomposition. Additionally, such substituents increase the regioselectivity of the photooxygenation of tetracenes and pentacenes. For the first time, we oxidized alkynylpentacenes by using chemically generated singlet oxygen (O-1(2)) without irradiation and identified a 6,13-endoperoxide as the sole regioisomer. The bimolecular rate constant of this oxidation amounts to only 1 X 10(5) s(-1) M-1. This unexpectedly slow reaction is a result of a physical deactivation of O-1(2). In contrast to unsubstituted or aryl-substituted acenes, photooxygenation of alkynyl-substituted acenes proceeds most likely by a concerted mechanism, while the thermolysis is well explained by the formation of radical intermediates. Our results should be important for the future design of oxidation stable acene-based semiconductors.
Carbohydrates carrying thiol groups at the C-2 position have been attached to gold nanoparticles (AuNPs) with stereocenters in close proximity to the surface for the first time. Their configurations can be clearly distinguished by the tendency of particle aggregation. AuNP surface plasmon resonance (SPR), X-ray photoelectron spectroscopy (XPS), and IR spectroscopy indicate that the thiocarbohydrates replace citrate molecules at different rates, causing aggregation and eventually precipitation. A quantitative formulation of this aggregation process shows that reactivities can vary by several magnitudes. Adsorption isotherms and kinetics also demonstrate that the number of thiocarbohydrates varies by a factor of two. Molecular mechanics force field (MMFF) calculations reveal their relative orientations. Based on these models, the different binding behavior can be ascribed to attractive van der Waals forces and hydrogen bonds. Such interactions occur either between the carbohydrate and AuNPs, by lateral intermolecular forces at the surface, or by interparticle attraction, in analogy to cell-surface carbohydrates of biological recognition systems. Aggregation of NPs therefore act as an indicator to differentiate between various carbohydrates with defined configurations.
The [4 + 2] cycloadditions of singlet oxygen to 9,10-diphenylanthracene (1) and the meta and para isomers of 9,10-dipyridylanthracene (2m/p) and 9,10-methoxyphenylanthracene (3m/p) have been studied by density functional calculations in the gas phase at the UB3LYP/6-31G* level and for the first time in solvents at the conductor-like polarizable continuum model (CPCM) UM062X/6-31G* level. The differences in calculated transition state (TS) energies derived from this method are in line with experimentally observed reactivity orders in solution. For the gas-phase reaction, the first TS of the stepwise pathway (TS1) has biradical character, and its energy lies below the energy of the TS of the concerted path (TSconc). In contrast, in the solvent acetonitrile, TS1 resembles a zwitterion and lies significantly higher than the TSconc. Thus, a concerted mechanism applies in solvents, and the energy gap between the TS of the two processes decreases with decreasing polarity. A change from a pyridyl against a methoxyphenyl substituent in the para position causes a maximal reduction of the activation barrier by approximately 1.7 kcal/mol, resulting in a fivefold increased reactivity.
Synthesis of Pyridylanthracenes and Their Reversible Reaction with Singlet Oxygen to Endoperoxides
(2017)
The ortho, meta, and para isomers of 9,10-dipyridylanthracene 1 have been synthesized and converted into their endoperoxides 1-O-2 upon oxidation with singlet oxygen. The kinetics of this reaction can be controlled by the substitution pattern and the solvent: in highly polar solvents, the meta isomer is the most reactive, whereas the ortho isomer is oxidized fastest in nonpolar solvents. Heating of the endoperoxides affords the parent anthracenes by release of singlet oxygen.
A convenient method for the synthesis of gamma-spirolactams in only three steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of chloroacetonitrile affords nitriles in moderate to good yields. Suitable precursors are methyl-substituted benzoic acids, naphthoic, and anthroic acid. Subsequent catalytic hydrogenation proceeds smoothly with PtO2 or Raney Ni as catalysts and lactams are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation at different pressures, affording products with 0, 1, or 2 double bonds. Overall, more than 15 new gamma-spirolactams have been synthesized in analytically pure form.
A convenient and general synthesis of 2-thiocarbohydrates via cerium ammonium nitrate oxidation of the thiocyanate ion is described. Radical addition to glycals proceeds with excellent regio- and good stereoselectivities in only one step, deprotection affords water-soluble 2-thio saccharides. Binding studies to Con A have been performed by isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR spectroscopy. The 2-thiomannose derivative binds even stronger to Con A than the natural substrate, offering opportunities for new lectin or enzyme inhibitors.
The esters of 4-hydroxy-cyclohexanone and a series of carboxylic acids R-COOH with R of different electronic and steric influence (R=Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, sec-Bu, t-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, and CBr3) were synthesized and the conformational equilibria studied by 1H and 13C NMR spectroscopy at 103 K and at 295 K, respectively. The geometry of optimized structures of the axial/equatorial chair conformers was computed at the ab initio MO and DFT levels of theory. Only one preferred conformation was obtained for the axial and the equatorial conformer as well. When comparing the conformational equilibria of the cyclohexanone esters with those of the corresponding cyclohexyl esters a certain polarity contribution of the cyclohexanone framework was revealed, which is independent of the substituent effects and increases the stability of the axial conformers by a constant amount.
The esters of 4-hydroxy-cyclohexanone and a series of carboxylic acids R-COOH with R of different electronic and steric influence (R=Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, sec-Bu, t-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, and CBr3) were synthesized and the conformational equilibria studied by H-1 and C-13 NMR spectroscopy at 103 K and at 295 K, respectively. The geometry of optimized structures of the axial 'equatorial chair conformers was computed at the ab initio MO and DFT levels of theory. Only one preferred conformation was obtained for the axial and the equatorial conformer as well. When comparing the conformational equilibria of the cyclohexanone esters with those of the corresponding cyclohexyl esters a certain polarity contribution of the cyclohexanone framework was revealed, which is independent of the substituent effects and increases the stability of the axial conformers by a constant amount.
para-Substituted benzoic acid esters of cyclohexanol, 1,4-dihydroxycyclohexane, 4-hydroxy-cyclohexanone and of the corresponding exo-methylene derivative were synthesized and the conformational equilibria of the cyclohexane skeleton studied by low temperature H-1 and C-13 NMR spectroscopy. The geometry optimized structures of the axial/equatorial chair conformers were computed at the DFT level of theory. Only one preferred conformation of the ester group was obtained for both the axial and the equatorial conformer, respectively. The content of the axial conformer increases with growing polarity of the 6-membered ring moiety; hereby, in addition, the effect of sp(2) hybridization/polarity of C(4)= O/C(4)= CH2 on the present conformational equilibria is critically evaluated. Another dynamic process could be studied, for the first time in this kind of compounds. (C) 2017 Elsevier Ltd. All rights reserved.
Sugar amino acids (SAAs), as biologically interesting structures bearing both amino and carboxylic acid functional groups represent an important class of multifunctional building blocks. In this study, we develop an easy access to novel SAAs in only three steps starting from nitro compounds in high yields in analytically pure form, easily available by ceric (IV) mediated radical additions. Such novel SAAs have been applied in the assembly of total nine carbopeptoids with the form of linear homo-and heterooligomers for the structural investigations employing circular dichroism (CD) spectroscopy, which suggest that the carbopeptoids emerge a well-extended, left (or right)-handed conformation similar to polyproline II (PPII) helices. NMR studies also clearly demonstrated the presence of ordered secondary structural elements. 2D-ROESY spectra were acquired to identify i+1NH <-> (C1H)-C-i, (C2H)-C-i correlations which support the conformational analysis of tetramers by CD spectroscopy. These findings provide interesting information of SAAs and their oligomers as potential scaffolds for discovering new drugs and materials.
In the search of new DNA groove binding agents a series of substituted 9,10-methylpyridiniumanthracenes have been synthesized and their interactions with DNA have been studied by UV/vis absorption, CD and fluorescence spectroscopy. A minor groove binding mode is confirmed by DNA melting studies, strong CD effects, the dependence of the binding affinity on ionic strength, and the differentiation between AT and GC base pairs. No binding occurs to GC sequences. Binding constants to calf thymus DNA (ct-DNA) and poly(dA:dT) in the range between 1 x 10(4) and 3 x 10(5) M-1 have been determined. The binding strength decreases with the size of substituents attached at the anthracene site. Variation of the substitution pattern of the charged groups shows that methyl groups in meta position cause slightly stronger binding than methyl groups in para position. In contrast, with these groups in ortho position, no binding interaction has been observed. The strongest binding is achieved with an expansion of the peripheral heterocycle from pyridine to quinoline. Molecular modeling reveals the pivotal role of the substitution pattern: Anthracenes with para and meta pyridines align along the minor grooves. On the other hand, the ortho derivative adopts no groove-alignment.
Bicyclic carbohydrate 1,2-lactones have been synthesized in only two steps and high yields by saponification and subsequent cyclization from known malonate addition products to glycals. The gluco-configured lactone serves as an important precursor for diversity-oriented syntheses. Thus, stereoselective opening of the lactone ring was realized with various nucleophiles in the presence of Sc(OTf)(3). This enabled the introduction of different substituents at the anomeric position, to afford a broad variety of 1-functionalized carbohydrates. On the other hand, stereoselective alpha-substitution of the gluco-configured lactone with different electrophiles and subsequent ring opening gives a collection of 2-functionalized saccharides. More than 30 products have been isolated in analytically pure form, and their configurations were unequivocally established by various NMR methods. Thus, carbohydrate 1,2-lactones are attractive precursors for the stereoselective synthesis of diverse saccharides.
Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates
(2021)
Stereoselective reactions of singlet oxygen are of current interest. Since enantioselective photooxygenations have not been realized efficiently, auxiliary control is an attractive alternative. However, the obtained peroxides are often too labile for isolation or further transformations into enantiomerically pure products. Herein, we describe the oxidation of naphthalenes by singlet oxygen, where the face selectivity is controlled by carbohydrates for the first time. The synthesis of the precursors is easily achieved starting from naphthoquinone and a protected glucose derivative in only two steps. Photooxygenations proceed smoothly at low temperature, and we detected the corresponding endoperoxides as sole products by NMR. They are labile and can thermally react back to the parent naphthalenes and singlet oxygen. However, we could isolate and characterize two enantiomerically pure peroxides, which are sufficiently stable at room temperature. An interesting influence of substituents on the stereoselectivities of the photooxygenations has been found, ranging from 51:49 to up to 91:9 dr (diastereomeric ratio). We explain this by a hindered rotation of the carbohydrate substituents, substantiated by a combination of NOESY measurements and theoretical calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide, which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form.
Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates
(2021)
Stereoselective reactions of singlet oxygen are of current interest. Since enantioselective photooxygenations have not been realized efficiently, auxiliary control is an attractive alternative. However, the obtained peroxides are often too labile for isolation or further transformations into enantiomerically pure products. Herein, we describe the oxidation of naphthalenes by singlet oxygen, where the face selectivity is controlled by carbohydrates for the first time. The synthesis of the precursors is easily achieved starting from naphthoquinone and a protected glucose derivative in only two steps. Photooxygenations proceed smoothly at low temperature, and we detected the corresponding endoperoxides as sole products by NMR. They are labile and can thermally react back to the parent naphthalenes and singlet oxygen. However, we could isolate and characterize two enantiomerically pure peroxides, which are sufficiently stable at room temperature. An interesting influence of substituents on the stereoselectivities of the photooxygenations has been found, ranging from 51:49 to up to 91:9 dr (diastereomeric ratio). We explain this by a hindered rotation of the carbohydrate substituents, substantiated by a combination of NOESY measurements and theoretical calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide, which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form.
A convenient synthesis of gamma-spirolactams in only two steps was developed. Birch reduction of benzoic acids and immediate alkylation with chloroacetonitrile afforded cyclohexadienes in high yields. The products could be isolated by crystallization on a large scale in analytically pure form. Subsequent hydrogenation with platinum(IV) oxide as the catalyst reduced the nitrile functionality and the double bonds in the same step with excellent stereoselectivity. The relative configurations were determined unequivocally by X-ray analyses. Direct cyclization of the intermediary formed amino acids afforded the desired gamma-spirolactams in excellent overall yields. The procedure is characterized by few steps, cheap reagents, and can be performed on a large scale, interesting for industrial processes.
Conformationally fixed carbohydrate analogues are promising small-molecule inhibitors for hydrolases like O-GlcNAcase (OGA); however, their synthesis usually requires many steps. Herein we describe cycloadditions of dichloroketene to various glycals and subsequent Beckmann rearrangements, which offer an easy and stereoselective entry to glycosamine derivatives in good yields. The reactions are applicable for hexoses, pentoses, and disaccharides, and transformations to the corresponding imidates proceed smoothly. First biological tests reveal that such imidates indeed inhibit human OGA.
A convenient synthesis of a racemic A-ring precursor of dihydroxyvitamin D-3 (calcitriol) is described. The key step involves the singlet oxygen ene reaction of the Lythgoe lactone, which proceeds with excellent regio- and good diastereoselectivities. Strong polar interactions are operative during the attack of O-1(2) to the double bond, which is important for the mechanism of such reactions
Terephthalic acid reacts with alkyl halides under Birch conditions to substituted 1,4-cyclohexadienes in high yields and good stereoselectivities. Electrophiles containing ester or nitrile groups undergo a surprising fragmentation under the reaction conditions. Subsequent treatment with chlorosulfonic acid proceeds by an interesting tandem decarbonylation/decarboxylation, affording 1,4-dialkylbenzenes in excellent regioselectivity. Thus our new method is superior to classical Friedel-Crafts alkylations.
Singlet oxygen can be released in the dark in nearly quantitative yield from endoperoxides of naphthalenes, anthracenes and pyridones as an alternative to its generation by photosensitization. Recently, new donor systems have been designed which operate at very low temperatures but which are prepared from their parent forms at acceptable rates. Enhancement of the reactivity of donors is conveniently achieved by the design of the substitution pattern or through the use of plasmonic heating of nanoparticle-bound donors. The most important aim of these donor molecules is to transfer singlet oxygen in a controlled and directed manner to a target. Low temperatures and the linking between donors and acceptors reduce the random walk of oxygen and may force an attack at the desired position. By using chiral donor systems, new stereocenters might be introduced into prochiral acceptors.
The generation of reactive singlet oxygen under mild conditions is of current interest in chemistry, biology, and medicine. We were able to release oxygen from dipyridylanthracene endoperoxides (EPOs) by using a simple chemical trigger at low temperature. Protonation and methylation of such EPOs strongly accelerated these reactions. Furthermore, the methyl pyridinium derivatives are water soluble and therefore serve as oxygen carriers in aqueous media. Methylation of the EPO of the ortho isomer affords the parent form directly without increasing the temperature under very mild conditions. This exceptional behavior is ascribed to the close contact between the nitrogen atom and the peroxo group. Singlet oxygen is released upon this reaction, and can be used to oxygenate an acceptor such as tetramethylethylene in the dark with no heating. Thus, a new chemical source of singlet oxygen has been found, which is triggered by a simple stimulus.
Regioselective synthesis of alkylarenes by two-step ipso-substitution of aromatic dicarboxylic acids
(2012)
A strategy for the regioselective alkylation of arenes was developed, starting from commercially available and inexpensive terephthalic acid or naphthalene-1,4-dicarboxylic acid. The method entails a formal ipso-substitution of the carboxylate groups by a sequence of reductive alkylation under Birch conditions and subsequent acid-mediated rearomatization with loss of carbon monoxide and carbon dioxide. More than 20 different arenes with various side-chains were synthesized. With naphthalene-1,4-dicarboxylic acid as starting material, we were able to control the degree of alkylation by choosing the appropriate electrophile in the Birch reduction. Thus, bisalkylated naphthalenes and naphthoic acids became available chemoselectively. All reactions afforded a single regioisomer exclusively in high yields. Overall, aromatic dicarboxylic acids are suitable substrates for a two-step ipso-substitution that allows the selective synthesis of alkylated benzenes and naphthalenes.
Arenes with various alkyl side-chains were synthesized in high yields and excellent regioselectivities. Starting from toluic and naphthoic acids, the carboxylate group was conveniently substituted by alkyl halides by Birch reduction and subsequent decarbonylation. The method is characterized by inexpensive starting materials and reagents, and methylation of arenes was realized. Besides simple alkyl substituents, the scope of arene functionalization was extended by benzyl, fluoro, amino, and ester groups. We were able to control the alkylation of 1-naphthoic acid during Birch reduction by the addition of tert-butanol. This allowed the regioselective synthesis of mono and bis-substituted naphthalenes from the same starting material.
The importance of carbohydrate chemistry in biological and medicinal chemistry has led to enormous developments in the synthesis of carbohydrate mimics. In this context, the synthesis of branched sugars in general and of 2-C-branched carbohydrates in particular, as well as the synthesis of 1,2-annulated sugars, have received immense attention. They serve not only as carbohydrate mimics in the form of stand-alone molecules, but also as useful intermediates in the synthesis of many natural products, their analogues, and glycosidase inhibitors. This microreview covers the recent synthetic efforts in this area and puts the subject matter into proper perspective for future developments.
C-branched carbohydrates are of current interest for glycochemistry, are widely found in nature and serve as important subunits in many antibiotics, bacterial polysaccharides and macrolides. Among C-functionalized saccharides, 2-C-branched carbohydrates represent challenging structures for synthetic chemists, since in contrast to C-glycosides they are not easily accessible from glycosyl bromides or other simple precursors. In this perspective we want to summarize recent approaches to 2-C-branched carbohydrates over the past fifteen years. The two main strategies are based on ring-opening of 1,2-cyclopropanated carbohydrates by various reagents, as well as radical additions to glycals and further transformations, developed in our group. Both methods are characterized by high stereoselectivities and good yields and give access to a broad variety of functionalized carbohydrate 2-C-analogs.
Carbohydrate radical stabilities in the 1- and 2-position have been determined by a radical clock approach, starting from cyclopropanated sugars with xanthates as precursors. Various hexoses and pentoses afforded 1-deoxy sugars as main products, indicating that anomeric radicals are more stable than radicals in the 2-position. An additional influence of the configurations on radical stabilities has been observed. Our results should be interesting for the understanding of 1,2-radical rearrangements in carbohydrate chemistry and offer an easy access to deoxy-vinyl sugars.
Quinoxalines XV : convenient synthesis and structural study of pyrazolo[1,5-alpha]quinoxalines
(2009)
A series of aryloxymethylquinoxaline oximes, hitherto unknown and synthesized from the corresponding aldehydes, afforded in only one step pyrazolo[1,5-;]quinoxalines in the presence of acetic anhydride at high temperatures. A formal [3,5]-sigmatropic rearrangement was proposed as the mechanistic rationale for this unprecedented transformation. Saponification with potassium hydroxide furnished the free phenol derivatives which were studied by NMR spectroscopy and accompanying theoretical DFT calculations, establishing intramolecular hydrogen bonding and the spatial magnetic properties. Additionally, mass spectrometric fragmentation was investigated by B/E-linked scans and collision-induced dissociation experiments. The fragmentation pattern devoted a new gas phase rearrangement process, which proved to be unique and characteristic for pyrazolo[1,5-;]quinoxalines.
Quinoxalines X : a new and convenient synthesis of 1H-Pyrazolo[3,4-b] quinoxalines (Flavazoles)
(2001)
Photodynamic therapy (PDT) is a mild but effective method to treat certain types of cancer upon irradiation with visible light. Here, three isomeric methylpyridinium alkynylanthracenes 1op were evaluated as sensitizers for PDT. Upon irradiation with blue or green light, all three compounds show the ability to initiate strand breaks of plasmid DNA. The mayor species responsible for cleavage is singlet oxygen (O-1(2)) as confirmed by scavenging reagents. Only isomers 1m and 1p can be incorporated into HeLa cells, whereas isomer 1o cannot permeate through the membrane. While isomer 1m targets the cell nucleus, isomer 1p assembles in the cellular cytoplasm and impacts the cellular integrity. This is in accordance with a moderate toxicity of 1p in the dark, whereas 1m exhibits no dark toxicity. Both isomers are suitable as PDT reagents, with a CC50 of 3 mu m and 75 nm, for 1p and 1m, respectively. Thus, derivative 1m, which can be easily synthesized, becomes an interesting candidate for cancer therapy.
The reaction of oxygen-substituted naphthalenes with singlet oxygen (O-1(2)) has been investigated, and labile endoperoxides have been isolated and characterized at -78 degrees C for the first time. Low-temperature kinetics by UV spectroscopy revealed that alkoxy and silyloxy substituents remarkably increase the rate of photooxygenations compared to 1,4-dimethylnaphthalene, whereas acyloxy-substituted acenes are inert towards O-1(2). The reactivities nicely correlate with HOMO energies and free activation energies, which we determined by density functional theory calculations. The lability of the isolated endoperoxides is due to their very fast back reaction to the corresponding naphthalenes even at -20 degrees C under release of O-1(2), making them to superior sources of this reactive species under very mild conditions. Finally, a carbohydrate-substituted naphthalene has been synthesized, which reacts reversibly with O-1(2) and might be applied for enantioselective oxidations in future work.
The photooxygenation of naphthalene to the corresponding endoperoxide (EPO) under various conditions is described. Substantial conversion is only observed at -10 degrees C and after more than two days, indicating that the [4+2] cycloaddition of singlet oxygen to this acene proceeds much more slowly than corresponding reactions of substituted naphthalenes, a rate constant of k = 5.4 +/- 0.3 M(-1)s(-1) was determined by competition kinetics. Another problem is the thermal lability and photochemical cleavage of the naphthalene EPO. We investigated the mechanism of this radical process depending on the light source and sensitizer in comparison to known cyclohexadiene EPO. Thus, bisepoxides and keto epoxides are formed after homolysis of the O-O bond by irradiation with sodium lamps or blue LEDs and subsequent cyclization. This process is accelerated by the sensitizers methylene blue and 9,10-dicyanoanthracene, indicating an electron transfer mechanism. Finally, the cleavage of the peroxidic bond is inhibited with red LEDs, and photooxygenation under such conditions affords 20 % EPO. Thus, we could demonstrate that contrary to literature statements singlet oxygen does indeed react with naphthalene.
Films of anthracene carboxylic acids were irradiated through photomasks and oxidized at the exposed regions by singlet oxygen upon sensitization. The efficiency of a photomask to protect the material underneath was investigated by optical and infrared spectroscopy. As the thickness of the film is reduced, the efficiency of the mask drops. This is explained by the migration of singlet oxygen at the solid-air interface, which in turn reacts at the masked area. For films with a thickness of < 15 nm, the efficiency of the mask approaches zero: sufficient efficiency is achieved at thicknesses > 100 nm. From the investigations, it will become clear that the contrast between the irradiated and masked area of an image is affected by reduction of the film thickness. On the other hand, the resolution of an image, which relates to the minimum feature size of an image, is not dependent on the thickness of the film. The contributions of "inside" and "outside" reactions are examined separately, and it quantitative approximation of the spatial range of both modes of the oxygenation is given. We set tip an approximate relation between mask efficiency and experimental conditions comprising internal and external oxygen diffusion, film thickness, and mask dimensions. These results give it deeper insight into the limits of resolution and contrast in singlet oxygen lithography.
9,10-substituted anthracenes are known for their useful optical properties like fluorescence, which makes them frequently used probes in sensing applications. In this article, we investigate the fundamental photophysical properties of three pyridyl-substituted variants. The nitrogen atoms in the pyridinium six-membered rings are located in the ortho-, meta-, and para-positions in relation to the anthracene core. Absorption, fluorescence, and transient absorption measurements were carried out and were complemented by theoretical calculations. We monitored the photophysics of the anthracene derivatives in chloroform and water investigating the protonated as well as their nonprotonated forms. We found that the optical properties of the nonprotonated forms are strongly determined by the anthracene chromophore, with only small differences to other 9,10-substituted anthracenes, for example diphenyl anthracene. In contrast, protonation leads to a strong decrease in fluorescence intensity and lifetime. Transient absorption measurements and theoretical calculations revealed the formation of a charge-transfer state in the protonated chromophores, where electron density is shifted from the anthracene moiety toward the protonated pyridyl substituents. While the para- and ortho-derivatives' charge transfer is still moderately fluorescent, the meta-derivative is affected much stronger and shows nearly no fluorescence. This nitrogen-atom-position-dependent sensitivity to hydronium activity makes a combination of these fluorophores very attractive for pH-sensing applications covering a broadened pH range.
Herein we demonstrate how the photoreaction between anthracenes and singlet oxygen (O-1(2)) is employed for applications either as photoswitch or as photoresist. Thin Films of the diaryl-alkyl anthracene 1 and the analogous oligomeric species 2 were it-radiated under photomasks to generate pattern structures composed of 1/1-O-2 and 2/2-O-2. Kelvin probe force microscopy (KPFM) provided a powerful and nondestructive method to image the pattern information. The following studies based on AFM, KPFM and contact angle measurements unfold that the two species 1 and 2 underwent different progressions after the imaging step. Degrading is observed for the monomeric compound 1 and the pattern eventually becomes recognizable in topography. In the oxidized state (1-O-2) the monomeric species remains physically stable. In consequence, the unreacted portion is removable and the remaining oxygenated form 1-O-2 is sufficiently stable to protect in underlying substrate (e.g., silver) from etching. Thus, the system 1/1-O-2 operates as photoresist. Oil the other hand, both states of the oligomier 2 remain stable. The Film is stable up to temperatures > 120 degrees C required to erase the pattern within acceptable time by cycloreversion. Anthracene 2 therefore acts as erasable and rewritable photochromic switch. The different behavior between 1 and 2 is explained by phase transitions which cause crystallization and finally ablation. Such transitions affect only the monomeric system 1/1-O-2 and not the oligomeric system 2/2-O-2. In conclusion, we designed two very similar materials based on diarylanthracenes, which can act either as a photoresist or as a rewritable photochrornic switch.
The conformational equilibrium of the axial/equatorial conformers of 4-methylene-cyclohexyl pivalate is studied by dynamic NMR spectroscopy in a methylene chloride/freon mixture. At 153K, the ring interconversion gets slow on the nuclear magnetic resonance timescale, the conformational equilibrium (-G degrees) can be examined, and the barrier to ring interconversion (G(#)) can be determined. The structural influence of sp(2) hybridization on both G degrees and G(#) of the cyclohexyl moiety can be quantified.
Singlet oxygen donors are of current interest for medical applications, but suffer from a short half-life leading to low singlet oxygen yields and problems with storage. We have synthesized more than 25new singlet oxygen donors based on differently substituted naphthalenes in only a few steps. The influence of functional groups on the reaction rate of the photooxygenations, thermolysis, half-life, and singlet oxygen yield has been thoroughly studied. We determined various thermodynamic data and compared them with density functional calculations. Interestingly, remarkable stabilities of functional groups during the photooxygenations and stabilizing effects for some endoperoxides during the thermolysis have been found. Furthermore, we give evidence for a partly concerted and partly stepwise thermolysis mechanism leading to singlet and triplet oxygen, respectively. Our results might be interesting for dark oxygenations and future applications in medicine.
Two different approaches. with an unsaturated carbohydrate as a radical acceptor and a carbohydrate derived aldehyde as a radical precursor, led to key intermediates in the synthesis of 3-deoxy-D-oct-2-ulosonic acids (KDO). Manganese(III) acetate and cerium(IV) ammonium nitrate were the reagents of choice for the oxidative generation of radicals, whereas samarium(II) iodide was employed for reductive couplings. Both strategies were realized by using easily available starting materials, with acetic acid as C-2 and ethyl acrylate as C-3 building blocks, respectively
An acyclic alkene derived from a carbohydrate is employed as a substrate for manganese-mediated radical reactions for the first time. The addition of malonate is interesting for the mechanism of such reactions, whereas acetic acid as radical precursor affords lactones in excellent yield. The main diastereomer was easily separated and represents a key intermediate in the synthesis of KDO
Gold(III) bromide is a suitable catalyst for the stereoselective cyclization of 2-C-malonyl carbohydrates to the anomeric center under retention of one ester group. Reopening of the lactones with alcohols in the presence of TMSOTf affords allyl, propargyl and benzyl glycosides with high alpha-selectivity.
The intramolecular transfer of energy (FRET) and electrons (Dexter) are of great interest for the scientific community and are well-understood. In contrast, the intramolecular transfer of singlet oxygen (O-1(2)), a reactive and short-lived oxygen species, has until now been unknown. This process would be very interesting because O-1(2) plays an important role in photodynamic therapy (PDT). Herein, we present the first successful intramolecular transfer of O-1(2) from a donor to acceptor. Also, we found a dependence of conformation and temperature comparable with those of FRET. We provide several pieces of evidence for the intramolecular character of this transfer, including competition experiments. Our studies should be interesting not only from the theoretical and mechanistic point of view but also for the design of new O-1(2) donors and applications in PDT.
Intermediates in the formation and thermolysis of peroxides from oxidations with singlet oxygen
(2014)
Herein we describe the recent mechanistic understandings of the singlet oxygen ene reaction to give hydroperoxides and the [4+2] cycloaddition affording endoperoxides. Both experimental findings and theoretical work conclude in the formation of intermediates structurally similar to perepoxides during the ene reaction. Such intermediates mainly control the regio- and stereoselectivities of this reaction class. For the [4+2] cycloaddition, both a synchronous concerted reaction (benzene, naphthalenes) and a stepwise reaction with a non-symmetric zwitterionic intermediate (larger acenes) have been found. The thermolysis of endoperoxides derived from acenes proceeds stepwise for anthracenes, but in a concerted manner for less stable adducts such as naphthalene.
The decomposition of anthracene endoperoxides has been investigated under various conditions. Thermolyses proceed via radical intermediates and afford anthracenes and rearrangement products, depending on the substitution pattern. Interestingly, not only the O-O but also the C-O bond can be cleaved homolytically. Under basic conditions fragmentations take place, affording anthraquinone, and reactive oxygen species. This mechanism explains the often observed decomposition of endoperoxides during work-up. Finally, an acid-catalyzed cleavage has been observed under release of hydrogen peroxide. The results should be interesting for the mechanistic understanding of peroxide decomposition and the endoperoxides might serve as mild sources of reactive oxygen species for future applications. Copyright (C) 2016 John Wiley & Sons, Ltd.
Influence of functional groups on the ene reaction of singlet oxygen with 1,4-cyclohexadienes
(2021)
The photooxygenation of 1,4-cyclohexadienes has been studied with a special focus on regio- and stereoselectivities. In all examples, only the methyl-substituted double bond undergoes an ene reaction with singlet oxygen, to afford hydroperoxides in moderate to good yields. We explain the high regioselectivities by a "large-group effect" of the adjacent quaternary stereocenter. Nitriles decrease the reactivity of singlet oxygen, presumably by quenching, but can stabilize proposed per-epoxide intermediates by polar interactions resulting in different stereoselectivities. Spiro lactams and lactones show an interesting effect on regio- and stereoselectivities of the ene reactions. Thus, singlet oxygen attacks the double bond preferentially anti to the carbonyl group, affording only one regioisomeric hydroperoxide. If the reaction occurs from the opposite face, the other regioisomer is exclusively formed by severe electrostatic repulsion in a perepoxide intermediate. We explain this unusual behavior by the fixed geometry of spiro compounds and call it a "spiro effect" in singlet oxygen ene reactions.
The aliphatic anthracene compound 1 and the oligomeric anthracene 2 were synthesized. Thin films of 1 and 2 mixed with the sensitizers tetraphenylporphyrin (TPP) and methylene blue (MB) were irradiated with visible light in air. Upon formation of singlet oxygen, the anthracene units were converted quantitatively to the corresponding endoperoxides. Heating of the irradiated samples afforded the parent anthracenes with high yields. Here, we demonstrate that the kinetics and reversibility of this reaction strongly depend on the microenvironment of the anthracene groups in the two compounds. The photooxidation of thin films of I is accompanied by interesting changes in the morphology of the film and allows the first application of 1 as a nondestructive negative-tone photo-resist for lithography and as an oxidizing ink. The morphology of 2 remained unchanged after photooxidation as a result of the stabilizing oligomer backbone. This stabilizing effect significantly improves the photochromic performance of 2. The reversibility of the photooxidation is very high (> 90%) for oligomeric films of 2 after several cycles of irradiation and beating. Decomposition of the anthracene and a loss of the activity of the sensitizer diminish slightly the performance of the monomeric species.
2-C-branched methyl glycosides react with various alcohols under gold catalysis to transglycosylated products. The method is applicable for the convenient synthesis of disaccharides. Without nucleophile a selective anomerization occurs, giving first access to alpha-configured 2-C-nitromethyl glycosides. The results are interesting for the mechanism of gold-catalyzed glycosidations.
Seven enzymes have been screened for the cleavage of aryl acetates. Phenyl and naphthyl acetates react with lipases and esterases, whereas the sterically demanding anthracene acetate gave a conversion only with porcine liver esterase and esterase 2 from Bacillus subtilis (BS2). These two enzymes have been employed on a preparative (0.5 mmol) scale and afforded cleavage products in 91 and 94% yields, even for anthracene acetate. Thus, this method is superior to chemical cleavage with catalytic amounts of sodium methoxide (Zemplen conditions), which gave only low conversions. Finally, regioselectivity has been achieved with an anthracene bisacetate, in which an ethyl group controls the cleavage of the first acetate. This indicates that steric interactions play a crucial role in the enzymatic cleavage of aryl acetates, which might be interesting for future applications or the development of enzyme inhibitors.
Editorial
(2017)
There is an ongoing interest in O-1(2) sensitizers, whose activity is selectively controlled by their interaction with DNA. To this end, we synthesized three isomeric pyridinium alkynylanthracenes 2 o-p and a water-soluble trapping reagent for O-1(2). In water and in the absence of DNA, these dyes show a poor efficiency to sensitize the photooxygenation of the trapping reagent as they decompose due to electron transfer processes. In contrast, in the presence of DNA O-1(2) is generated from the excited DNA-bound ligand. The interactions of 2 o-p with DNA were investigated by thermal DNA melting studies, UV/vis and fluorescence spectroscopy, and linear and circular dichroism spectroscopy. Our studies revealed an intercalative binding with an orientation of the long pyridyl-alkynyl axis parallel to the main axis of the DNA base pairs. In the presence of poly(dA : dT), all three isomers show an enhanced formation of singlet oxygen, as indicated by the reaction of the latter with the trapping reagent. With green light irradiation of isomer 2 o in poly(dA : dT), the conversion rate of the trapping reagent is enhanced by a factor >10. The formation of O-1(2) was confirmed by control experiments under anaerobic conditions, in deuterated solvents, or by addition of O-1(2) quenchers. When bound to poly(dG : dC), the opposite effect was observed only for isomers 2 o and 2 m, namely the trapping reagent reacted significantly slower. Overall, we showed that pyridinium alkynylanthracenes are very useful intercalators, that exhibit an enhanced photochemical O-1(2) generation in the DNA-bound state.
The title compounds, 2-azaspiro[4.5]deca-1-one, C₉H₁₅NO, (1a), cis-8-methyl-2-azaspiro[4.5]deca-1-one, C₁₀H₁₇NO, (1b), and trans-8-methyl-2-azaspiro[4.5]deca-1-one, C₁₀H₁₇NO, (1c), were synthesized from benzoic acids 2 in only 3 steps in high yields. Crystallization from n-hexane afforded single crystals, suitable for X-ray diffraction. Thus, the configurations, conformations, and interesting crystal packing effects have been determined unequivocally. The bicyclic skeleton consists of a lactam ring, attached by a spiro junction to a cyclohexane ring. The lactam ring adopts an envelope conformation and the cyclohexane ring has a chair conformation. The main difference between compound 1b and compound 1c is the position of the carbonyl group on the 2-pyrrolidine ring with respect to the methyl group on the 8-position of the cyclohexane ring, which is cis (1b) or trans (1c). A remarkable feature of all three compounds is the existence of a mirror plane within the molecule. Given that all compounds crystallize in centrosymmetric space groups, the packing always contains interesting enantiomer-like pairs. Finally, the structures are stabilized by intermolecular N–H···O hydrogen bonds.
The title compounds, 2-azaspiro[4.5]deca-1-one, C₉H₁₅NO, (1a), cis-8-methyl-2-azaspiro[4.5]deca-1-one, C₁₀H₁₇NO, (1b), and trans-8-methyl-2-azaspiro[4.5]deca-1-one, C₁₀H₁₇NO, (1c), were synthesized from benzoic acids 2 in only 3 steps in high yields. Crystallization from n-hexane afforded single crystals, suitable for X-ray diffraction. Thus, the configurations, conformations, and interesting crystal packing effects have been determined unequivocally. The bicyclic skeleton consists of a lactam ring, attached by a spiro junction to a cyclohexane ring. The lactam ring adopts an envelope conformation and the cyclohexane ring has a chair conformation. The main difference between compound 1b and compound 1c is the position of the carbonyl group on the 2-pyrrolidine ring with respect to the methyl group on the 8-position of the cyclohexane ring, which is cis (1b) or trans (1c). A remarkable feature of all three compounds is the existence of a mirror plane within the molecule. Given that all compounds crystallize in centrosymmetric space groups, the packing always contains interesting enantiomer-like pairs. Finally, the structures are stabilized by intermolecular N–H···O hydrogen bonds.
The title compounds, [(1R,3R,4R,5R,6S)-4,5-bis(acetyloxy)-7-oxo-2-oxabicyclo-
[4.2.0]octan-3-yl]methyl acetate, C14H18O8, (I), [(1S,4R,5S,6R)-5-acetyloxy-7-
hydroxyimino-2-oxobicyclo[4.2.0]octan-4-yl acetate, C11H15NO6, (II), and
[(3aR,5R,6R,7R,7aS)-6,7-bis(acetyloxy)-2-oxooctahydropyrano[3,2-b]pyrrol-5-
yl]methyl acetate, C14H19NO8, (III), are stable bicyclic carbohydrate derivatives.
They can easily be synthesized in a few steps from commercially available
glycals. As a result of the ring strain from the four-membered rings in (I) and
(II), the conformations of the carbohydrates deviate strongly from the ideal
chair form. Compound (II) occurs in the boat form. In the five-membered
lactam (III), on the other hand, the carbohydrate adopts an almost ideal chair
conformation. As a result of the distortion of the sugar rings, the configurations
of the three bicyclic carbohydrate derivatives could not be determined from
their NMR coupling constants. From our three crystal structure determinations,
we were able to establish for the first time the absolute configurations of all new
stereocenters of the carbohydrate rings.
The title compounds, [(1R,3R,4R,5R,6S)-4,5-bis(acetyloxy)-7-oxo-2-oxabicyclo[4.2.0]octan-3-yl]methyl acetate, C14H18O8, (I), [(1S,4R,5S,6R)-5-acetyloxy-7-hydroxyimino-2-oxobicyclo[4.2.0]octan-4-yl acetate, C11H15NO6, (II), and [(3aR,5R,6R,7R,7aS)-6,7-bis(acetyloxy)-2-oxooctahydropyrano[3,2-b]pyrrol-5-yl]methyl acetate, C14H19NO8, (III), are stable bicyclic carbohydrate derivatives. They can easily be synthesized in a few steps from commercially available glycals. As a result of the ring strain from the four-membered rings in (I) and (II), the conformations of the carbohydrates deviate strongly from the ideal chair form. Compound (II) occurs in the boat form. In the five-membered lactam (III), on the other hand, the carbohydrate adopts an almost ideal chair conformation. As a result of the distortion of the sugar rings, the configurations of the three bicyclic carbohydrate derivatives could not be determined from their NMR coupling constants. From our three crystal structure determinations, we were able to establish for the first time the absolute configurations of all new stereocenters of the carbohydrate rings.
The title compounds, [(1R,3R,4R,5R,6S)-4,5-bis(acetyloxy)-7-oxo-2-oxabicyclo-[4.2.0]octan-3-yl]methyl acetate, C14H18O8, (I), [(1S,4R,5S,6R)-5-acetyloxy-7-hydroxyimino-2-oxobicyclo[4.2.0] octan-4-yl acetate, C11H15NO6, (II), and [(3aR, 5R, 6R, 7R, 7aS)-6,7-bis(acetyloxy)-2-oxooctahydropyrano[3,2-b]pyrrol-5-yl] methyl acetate, C14H19NO8, (III), are stable bicyclic carbohydrate derivatives. They can easily be synthesized in a few steps from commercially available glycals. As a result of the ring strain from the four-membered rings in (I) and (II), the conformations of the carbohydrates deviate strongly from the ideal chair form. Compound (II) occurs in the boat form. In the five-membered lactam (III), on the other hand, the carbohydrate adopts an almost ideal chair conformation. As a result of the distortion of the sugar rings, the configurations of the three bicyclic carbohydrate derivatives could not be determined from their NMR coupling constants. From our three crystal structure determinations, we were able to establish for the first time the absolute configurations of all new stereocenters of the carbohydrate rings.
Closed and re-opened for business: C-2 branched carbohydrates 1 cyclize under conditions of decarboxylation to the hitherto unknown carbohydrate 1,2-lactones 2 in high yields. The gluco isomer can be opened at the anomeric position with various nuceophiles in the presence of Sc(OTf)3, which allows the stereoselective synthesis of 1-functionalized glucose derivatives 3. Thus, 1,2-bis-C-branched saccharides become available in only a few steps starting from glycals.
Phosphorus meets carbohydrates: Dimethyl phosphite reacts with ceric(IV) ammonium nitrate (CAN) to give phosphonyl radicals that add to glycals 1. The derivatives 2 were isolated in high yields and during a subsequent Horner-Emmons reaction underwent an interesting elimination to give 3,6-dihydro-2H-pyrans 3. The short sequence with simple precursors is applicable to the transformation of hexoses, pentoses, and disaccharides. Bn=benzyl.
A convenient method for the synthesis of γ-spirolactones in only 2–3 steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of ethylene oxide affords hydroxy acids, which undergo direct lactonization during work-up. Suitable precursors are methyl-substituted benzoic acids, naphthoic, and dicarboxylic acids. Subsequent hydrogenation proceeds smoothly with Pd/C as catalyst and saturated γ-spirolactones are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation with Raney nickel or Wilkinson's catalyst to obtain products with 1 double bond. Overall, more than 30 new γ-spirolactones have been synthesized in analytically pure form.
Catalytic amounts of a weak base are sufficient to induce the decomposition of anthracene endoperoxides to anthraquinone. The mechanism has been elucidated by isolation of intermediates in combination with DFT calculations. The whole process is suitable for the convenient generation of hydrogen peroxide under very mild conditions.
Catalytic amounts of a weak base are sufficient to induce the decomposition of anthracene endoperoxides to anthraquinone. The mechanism has been elucidated by isolation of intermediates in combination with DFT calculations. The whole process is suitable for the convenient generation of hydrogen peroxide under very mild conditions.
Catalytic amounts of a weak base are sufficient to induce the decomposition of anthracene endoperoxides to anthraquinone. The mechanism has been elucidated by isolation of intermediates in combination with DFT calculations. The whole process is suitable for the convenient generation of hydrogen peroxide under very mild conditions.
Barton esters have been introduced into the side chain of carbohydrates with high yields in only a few steps from easily available glycals. Their radical reactions afford 2-C-methyl and 2-C-bromomethyl hexoses, pentoses and disaccharides in good yields in analytically pure form. Since the Barton esters have been synthesized by an oxidative radical addition and their transformations by reductive radical processes, our results demonstrate the power of such reactions in carbohydrate chemistry.
Awards
(2013)
The photooxygenation of homochiral cyclohexene ketals, which are easily available from 2-cyclohexenone and L-tartrates, affords hydroperoxides and after reduction the corresponding allylic alcohols in good yields and high regioselectivities. This can be rationalized by electronic repulsions in a perepoxide intermediate and provides evidence for unfavorable 1,3 diaxial interactions with a dioxolane oxygen atom. Only low stereoselectivities were observed, due to the flexibility of the cyclohexene ring. However, the diastereomers could be separated and after cleavage of the auxiliary, 4-hydroxy-2-cyclohexen-1-one was isolated in enantiomerically pure form, which can serve as a building block for natural product synthesis.
Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells.
Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity.
The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogP(OW) larger than 3.5 and a polar surface area smaller than 100 angstrom(2).
The most effective compounds (IC50 in LtP < 2 mu M) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP.
Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group.
However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania.
The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models.
Radical reactions have found many applications in carbohydrate chemistry, especially in the construction of carbon–carbon bonds. The formation of carbon–heteroatom bonds has been less intensively studied. This mini-review will summarize the efforts to add heteroatom radicals to unsaturated carbohydrates like endo-glycals. Starting from early examples, developed more than 50 years ago, the importance of such reactions for carbohydrate chemistry and recent applications will be discussed. After a short introduction, the mini-review is divided in sub-chapters according to the heteroatoms halogen, nitrogen, phosphorus, and sulfur. The mechanisms of radical generation by chemical or photochemical processes and the subsequent reactions of the radicals at the 1-position will be discussed. This mini-review cannot cover all aspects of heteroatom-centered radicals in carbohydrate chemistry, but should provide an overview of the various strategies and future perspectives
Radical reactions have found many applications in carbohydrate chemistry, especially in the construction of carbon–carbon bonds. The formation of carbon–heteroatom bonds has been less intensively studied. This mini-review will summarize the efforts to add heteroatom radicals to unsaturated carbohydrates like endo-glycals. Starting from early examples, developed more than 50 years ago, the importance of such reactions for carbohydrate chemistry and recent applications will be discussed. After a short introduction, the mini-review is divided in sub-chapters according to the heteroatoms halogen, nitrogen, phosphorus, and sulfur. The mechanisms of radical generation by chemical or photochemical processes and the subsequent reactions of the radicals at the 1-position will be discussed. This mini-review cannot cover all aspects of heteroatom-centered radicals in carbohydrate chemistry, but should provide an overview of the various strategies and future perspectives
Activation of anthracene endoperoxides in leishmania and impairment of mitochondrial functions
(2018)
Leishmaniasis is a vector-borne disease caused by protozoal Leishmania. Because of resistance development against current drugs, new antileishmanial compounds are urgently needed. Endoperoxides (EPs) are successfully used in malaria therapy, and experimental evidence of their potential against leishmaniasis exists. Anthracene endoperoxides (AcEPs) have so far been only technically used and not explored for their leishmanicidal potential. This study verified the in vitro efficiency and mechanism of AcEPs against both Leishmania promastigotes and axenic amastigotes (L. tarentolae and L. donovani) as well as their toxicity in J774 macrophages. Additionally, the kinetics and radical products of AcEPs’ reaction with iron, the formation of radicals by AcEPs in Leishmania, as well as the resulting impairment of parasite mitochondrial functions were studied. Using electron paramagnetic resonance combined with spin trapping, photometry, and fluorescence-based oximetry, AcEPs were demonstrated to (i) show antileishmanial activity in vitro at IC50 values in a low micromolar range, (ii) exhibit host cell toxicity in J774 macrophages, (iii) react rapidly with iron (II) resulting in the formation of oxygen- and carbon-centered radicals, (iv) produce carbon-centered radicals which could secondarily trigger superoxide radical formation in Leishmania, and (v) impair mitochondrial functions in Leishmania during parasite killing. Overall, the data of different AcEPs demonstrate that their structures besides the peroxo bridge strongly influence their activity and mechanism of their antileishmanial action.
A series of 9,10-diarylanthracenes with various substituents at the ortho positions have been synthesised by palladium-catalysed cross-coupling reactions. Such compounds exhibit interesting physical properties and can be applied as molecular switches. Despite the high steric demand of the substituents, products were formed in moderate-to-good yields. In some cases, microwave conditions further improved yields. Bis-coupling afforded two isomers (syn and anti) that do not interconvert at room temperature. These products were easily separated and their relative stereochemistries were unequivocally assigned by NMR spectroscopy and X-ray analysis. The syn and anti isomers exhibit different physical properties (e.g., melting points and solubilities) and interconversion by rotation around the aryl-aryl axis commences at <100 °C for fluoro-substituted diarylanthracenes and at >300 °C for alkyl- or alkoxy-substituted diarylanthracenes. The reactions with singlet oxygen were studied separately and revealed different reactivities and reaction pathways. The yields and reactivities depend on the size and electronic nature of the substituents. The anti isomers form the same 9,10-endoperoxides as the syn species, occasionally accompanied by unexpected 1,4-endoperoxides as byproducts. Thermolysis of the endoperoxides exclusively yielded the syn isomers. The interesting rotation around the aryl-aryl axis allows the application of 9,10-diarylanthracenes as molecular switches, which are triggered by light and air under mild conditions. Finally, the oxygenation and thermolysis sequence provides a simple, synthetic access to a single stereoisomer (syn) from an unselective coupling step.