Showing papers in "Organic and Biomolecular Chemistry in 2009"
TL;DR: An overview on the strategies to trigger biosynthetic pathways to yield "cryptic natural products" through external cues, co-cultivation and genomic approaches such as genome-mining, epigenetic remodeling, and engineered pathway activation are given.
Abstract: Natural products from microorganisms are a crucial source for novel therapeutics. Even so, it seems that many valuable compounds are overlooked when culturing microbes under standardized laboratory conditions. Many biosynthesis genes remain silent and such “cryptic” or “orphan” pathways are only activated under specific conditions. This report gives an overview on the strategies to trigger biosynthetic pathways to yield “cryptic natural products” through external cues, co-cultivation and genomic approaches such as genome-mining, epigenetic remodeling, and engineered pathway activation.
491 citations
TL;DR: A good correlation between the activation energy and the polar character of Diels-Alder reactions measured as the charge transfer at the transition state structure has been found and this electronic parameter controls the reaction rate to an even greater extent than other recognized structural features.
Abstract: A good correlation between the activation energy and the polar character of Diels–Alder reactions measured as the charge transfer at the transition state structure has been found. This electronic parameter controls the reaction rate to an even greater extent than other recognized structural features. The proposed polar mechanism, which is characterized by the electrophilic/nucleophilic interactions at the transition state structure, can be easily predicted by analyzing the electrophilicity/nucleophilicity indices defined within the conceptual density functional theory. Due to the significance of the polarity of the reaction, Diels–Alder reactions should be classified as non-polar (N), polar (P), and ionic (I).
416 citations
TL;DR: The optimal systems displaying the largest multivalency effects are discussed and a number of popular target proteins for multivalent binding/inhibition have been selected.
Abstract: Multivalent carbohydrates are currently produced in many forms ranging from dendrimers, polymers, micelles, vesicles, nanoparticles to functionalized nanotubes, in order to enhance the potency of the carbohydrates as ligands or inhibitors. Variations in valency range from systems containing two carbohydrate units to those containing more than 2000. In this perspective a number of popular target proteins for multivalent binding/inhibition have been selected. The optimal systems displaying the largest multivalency effects are discussed with respect to their mechanism of multivalent binding.
306 citations
TL;DR: As guidelines for peptoid folding are elucidated and the known biological activities are expanded, it is anticipated these connections will provide a pathway toward the de novo design of functional peptoids.
Abstract: Oligomers of N-substituted glycine, or peptoids, are versatile tools to probe biological processes and hold promise as therapeutic agents. An underlying theme in the majority of recent peptoid research is the connection between peptoid function and peptoid structure. For certain applications, well-folded peptoids are essential for activity, while unstructured peptoids appear to suffice, or even are superior, for other applications. Currently, these structure–function connections are largely made after the design, synthesis, and characterization process. However, as guidelines for peptoid folding are elucidated and the known biological activities are expanded, we anticipate these connections will provide a pathway toward the de novo design of functional peptoids. In this perspective, we review several of the peptoid structure–function relationships that have been delineated over the past five years.
257 citations
TL;DR: This perspective focuses on recent advances in the synthesis of these phosphorusole-based pi systems with representative examples that would give valuable guidelines for designing phosphole-containing opto-electrochemical materials.
Abstract: Phospholes are known to exhibit characteristic optical and electrochemical properties derived from the phosphorus-bridged 1,3-dienic π system. Particular interest has recently been paid to their π-conjugated derivatives, such as non-fused phospholes, dibenzo[b,d]phospholes, benzo[b]phospholes, benzo[c]phospholes and related compounds. This perspective focuses on recent advances in the synthesis of these phosphole-based π systems with representative examples that would give valuable guidelines for designing phosphole-containing opto-electrochemical materials.
251 citations
TL;DR: A magnetic nanoparticle-supported Pd catalyst was readily prepared from inexpensive starting materials and shown to catalyze various oxidation reactions with high turnover number (TON) and excellent selectivity.
Abstract: A magnetic nanoparticle-supported Pd catalyst was readily prepared from inexpensive starting materials and shown to catalyze various oxidation reactions with high turnover number (TON) and excellent selectivity. The ease of recovery using an external magnetic field, high activity, and the intrinsic stability of the catalyst make this protocol economic and sustainable.
243 citations
TL;DR: The enantioselective intramolecular aminative functionalization of unactivated alkenes and related π-systems is a straight-forward and atom economical strategy for the synthesis of chiral nitrogen heterocycles.
Abstract: The enantioselective intramolecular aminative functionalization of unactivated alkenes and related π-systems is a straight-forward and atom economical strategy for the synthesis of chiral nitrogen heterocycles. These reactions can be categorized as oxidatively neutral, such as alkene hydroamination, or as oxidative reactions, such as alkene difunctionalization, e.g. aminooxygenation and carboamination. This perspective reviews the current work in the field and explores mechanistic trends that are common among the different catalysts and reaction types.
233 citations
TL;DR: Recent advances in the Meyer-Schuster reaction are featured, including several demonstrated techniques for improving the scope, andStrengths and weaknesses of each technique are discussed, and outstanding problems that warrant further study are highlighted.
Abstract: The Meyer–Schuster rearrangement is the conversion of propargyl alcohols into α,β-unsaturated carbonyl compounds via a formal 1,3-hydroxyl shift and tautomerization. The major challenge associated with the Meyer–Schuster reaction is that of selectively promoting the desired rearrangement over the myriad other reaction pathways available to propargyl alcohols. This Perspective Article features recent advances in the Meyer–Schuster reaction, including several demonstrated techniques for improving the scope. Strengths and weaknesses of each technique are discussed, and outstanding problems that warrant further study are highlighted. The primary motivation for research and development of the Meyer–Schuster rearrangement is as a means of preparing α,β-unsaturated carbonyl compounds as part of a two-stage olefination strategy.
231 citations
TL;DR: The present emerging area deals with the recent advances in the use of pi-activated alcohols in the catalytic and stereoselective construction of benzylic stereocenters.
Abstract: The direct functionalization of aromatic compounds, via Friedel–Crafts alkylation reactions with alcohols, is one of the cornerstones in organic chemistry. The present emerging area deals with the recent advances in the use of π-activated alcohols in the catalytic and stereoselective construction of benzylic stereocenters.
208 citations
TL;DR: The synthesis, the chemical and photochemical reactivity, and the use of 1,2,4-oxadiazoles in materials and as bioactive compounds have been reviewed.
Abstract: The synthesis, the chemical and photochemical reactivity, and the use of 1,2,4-oxadiazoles in materials and as bioactive compounds have been reviewed. The material in this survey includes some historical background, general features, state-of-the-art applications together with a critical discussion about current limitations and suggestions for future developments.
190 citations
TL;DR: A new fungal metabolite, nygerone A (), featuring a unique 1-phenylpyridin-4(1H)-one core that had previously not been reported from any natural source, has been obtained from Aspergillus niger using a chemical epigenetics methodology.
Abstract: A new fungal metabolite, nygerone A (), featuring a unique 1-phenylpyridin-4(1H)-one core that had previously not been reported from any natural source, has been obtained from Aspergillus niger using a chemical epigenetics methodology.
TL;DR: This emerging area examines recent developments in the activation of strained rings, focusing on enantioselective reactions.
Abstract: Activation of otherwise inert bonds has significant potential in the design of efficient and synthetically useful transformations. While general catalytic carbon–carbon single bond activations are still in their infancy, this emerging area examines recent developments in the activation of strained rings, focusing on enantioselective reactions.
TL;DR: A rapid, high-throughput screening methodology has been developed for the determination of transaminase activity, and three techniques have been developed to drive transamination reactions toward complete conversion.
Abstract: A rapid, high-throughput screening methodology has been developed for the determination of transaminase activity. This pH based, colorimetric assay can also be used to scale reactions directly from 100 μL screening scale to 25 mL development scale. Additionally, three techniques have been developed to drive transamination reactions toward complete conversion. The first method uses lactate dehydrogenase to remove the inhibitory pyruvate keto acid by-product from the reaction and drive reaction equilibrium toward the desired amine. The second method is a single enzyme system, and uses a large excess of isopropylamine to drive the transamination. Method three requires only a catalytic amount of amine donor, as an amino acid dehydrogenase is employed to regenerate the amine donor in situ using ammonia. All three systems have been demonstrated for the production of optically pure methylbenzylamine from acetophenone. An enantiomeric excess of >99% was achieved for both the R- and S-methylbenzylamine products.
TL;DR: Ratiometric methods of analysis have been developed for the selective determination of lactate or citrate in microlitre samples of human serum, urine or prostate fluids following comparison of anion binding affinities for a family of nine luminescent europium(III) complexes.
Abstract: Ratiometric methods of analysis have been developed for the selective determination of lactate or citrate in microlitre samples of human serum, urine or prostate fluids following comparison of anion binding affinities for a family of nine luminescent europium(III) complexes.
TL;DR: A new catalyst for an old material: magnetite is a good catalyst for the selective N-alkylation of aromatic amines using benzylic alcohols as electrophiles and could discriminate between aromatic and aliphatic amines, as well as between Benzylic and alphatic alcohols.
Abstract: A new catalyst for an old material: magnetite is a good catalyst for the selective N-alkylation of aromatic amines using benzylic alcohols as electrophiles. The process could be repeated up to eight times without losing effectiveness. The catalyst recycling is very easy, using a simple magnet. The catalyst is selective and could discriminate between aromatic and aliphatic amines, as well as between benzylic and aliphatic alcohols, as the reactions only take place with aromatic amines and benzylic alcohols.
TL;DR: The different strategies followed for the preparation of chirally modified nanoparticles and their application in asymmetric catalysis are reviewed.
Abstract: Functionalized nanoparticles find increasing application as catalysts for enantioselective transformations. In this account the different strategies followed for the preparation of chirally modified nanoparticles and their application in asymmetric catalysis are reviewed.
TL;DR: The ethyl oxazole-4-carboxylate was directly and regioselectivelyAlkenylated, benzylated and alkylated with alkenyl-, benzyl-, allyl- and alKYl halides in the presence of catalytic amounts of palladium acetate with caesium carbonate using Buchwald's JohnPhos ligand.
Abstract: The ethyl oxazole-4-carboxylate was directly and regioselectively alkenylated, benzylated and alkylated with alkenyl-, benzyl-, allyl- and alkyl halides in the presence of catalytic amounts of palladium acetate with caesium carbonate using Buchwald's JohnPhos ligand.
TL;DR: Azides, nitrones, and azomethine ylides are the most appropriate 1,3-dipoles for the synthesis of privileged structures with the highest biological responses against viruses.
Abstract: In the present perspective the advances and real possibilities of 1,3-dipolar cycloadditions as key steps in the total synthesis of virus inhibitors are described. Azides, nitrones, and azomethine ylides are the most appropriate 1,3-dipoles for the synthesis of privileged structures with the highest biological responses against viruses.
TL;DR: Analysis of the photophysical parameters and intracellular imaging data indicates that porphyrin dimers are promising candidates for one-photon and two- photon excited PDT.
Abstract: We have investigated the photophysical properties and intracellular behaviour of a series of hydrophilic conjugated porphyrin dimers. All the dimers exhibit intense linear absorption at 650–800 nm and high singlet oxygen quantum yields (0.5–0.9 in methanol), as required for an efficient sensitiser for photodynamic therapy (PDT). They also exhibit fluorescence at 700–800 nm, with fluorescence quantum yields of up to 0.13 in methanol, and show extremely large two-photon absorption maxima of 8,000–17,000 GM in the near-IR. The dimers aggregate in aqueous solution, but aggregation is reduced by binding to bovine serum albumin (BSA), as manifested by an increase in fluorescence intensity and a sharpening in the emission bands. This process can be regarded as a model for the interaction with proteins under physiological conditions. Confocal fluorescence microscopy of live cells was used to monitor the rate of cellular uptake, intracellular localisation and photostability. Porphyrin dimers with positively charged substituents partition into cells more efficiently than the negatively charged dimers. The photostability of these dimers, in living cells, is significantly better than that of the clinical photosensitiser verteporfin. Analysis of the photophysical parameters and intracellular imaging data indicates that these dimers are promising candidates for one-photon and two-photon excited PDT.
TL;DR: The synthesis of a series of hydrophilic butadiyne-linked conjugated zinc porphyrin dimers, designed as photodynamic therapy (PDT) agents, which exhibit exceptionally high two-photon absorption cross sections and red-shifted linear absorption spectra making them ideal candidates for one- photon and two-Photon excited photodynamic Therapy.
Abstract: We report the synthesis of a series of hydrophilic butadiyne-linked conjugated zinc porphyrin dimers, designed as photodynamic therapy (PDT) agents. These porphyrin dimers exhibit exceptionally high two-photon absorption cross sections (delta(max) approximately 8,000-17,000 GM) and red-shifted linear absorption spectra (lambda(max) approximately 700-800 nm) making them ideal candidates for one-photon and two-photon excited photodynamic therapy. Four polar triethyleneglycol substituents are positioned along the sides of each dimer, but, on their own, these TEG chains do not confer sufficient solubility in aqueous physiological media for reproducible delivery into live cells. Charged cationic (methylpyridinium and trimethylammonium) and anionic (sulfonate and carboxylate) substituents have been appended to the meso-positions of porphyrin dimers using three synthetic strategies: 1) Suzuki coupling, 2) Sonogashira coupling, and 3) nucleophilic Senge arylation. Approaches 1 and 3 both allow attachment of aromatic substituents directly to the meso-positions of porphyrins. Approach 2 provides a route to hydrophilic porphyrin dimers with an ethyne link between the porphyrin and the polar aromatic substituent. The palladium-catalysed approaches 1 and 2 allow the synthesis of a broader range of meso-capped porphyrins, as many aryl halides are available. However the synthesis of the intermediate required for these routes necessitates a statistical reaction step, which decreases the overall yield. On the other hand, Senge-arylation provides highly regioselective nucleophilic aromatic substitution, and offers higher overall yield than the other routes. All these charged dimers exhibit good solubility in polar solvents (e.g. methanol) and aqueous solvent mixtures (aqueous DMSO or DMF).
TL;DR: This work characterized the activity and stereospecificity of four secondary alcohol dehydrogenases (sADHs) towards acetoin reduction and constructed synthetic pathways in E. coli to produce enantiomerically pure (R,R)-2, 3-butanediol (2,3-BDO) from glucose.
Abstract: We characterized the activity and stereospecificity of four secondary alcohol dehydrogenases (sADHs) towards acetoin reduction and constructed synthetic pathways in E coli to produce enantiomerically pure (R,R)-2,3-butanediol (2,3-BDO) from glucose with a titer of 61 g/L (enantio purity >99%), and yield of 031 g product/g glucose (62% of theoretical maximum)
TL;DR: The different families of calix[6]arene-based receptors presented here highlight the importance of having a flexible and polarized hydrophobic structure to accommodate the guest.
Abstract: The selective recognition of substrates or cofactors is a key feature of biological processes. It involves coordination bonds, hydrogen bonding, charge/charge and charge/dipole interactions. In this Perspective, we describe how the calix[6]arene core can be functionalized and shaped to act as a biomimetic molecular receptor. The strategy relies on the selective introduction of three amino arms on alternate phenolic positions. Upon metal ion binding or self-assembly via multiple ion-pairing and H-bonding, these amino arms are projected towards each other, thus closing the calixarene small rim. The resulting cone-shaped receptors act as molecular funnels displaying high affinities for a variety of neutral guests. Their hosting properties can be finely tuned by changing the small or the large rim or by allosteric effects. Induced-fit processes are also often observed as the cavity can expand for large guests or shrink for small ones. Hence, the different families of calix[6]arene-based receptors presented here highlight the importance of having a flexible and polarized hydrophobic structure to accommodate the guest.
TL;DR: Which transformations are particularly desirable, and the progress that has been made on developing methods for carrying out those transformations using copper, nickel or palladium catalysts, are described.
Abstract: Aryl halides are common synthetic targets themselves, and also highly versatile synthetic intermediates. Aryl chlorides are much more widely available and easier to synthesise than the other halide derivatives, so the development of effective methods for interconverting aryl halide derivatives would therefore be extremely useful. This article outlines which transformations are particularly desirable, and describes the progress that has been made on developing methods for carrying out those transformations using copper, nickel or palladium catalysts. The possible mechanisms of these reactions are discussed, with a view to identifying areas for future investigation.
TL;DR: The current study showed that 1-5 operated as photoinduced electron transfer (PET) sensors, as no significant changes were observed in their absorption spectra, while their fluorescence emissions were quenched upon recognition of ions such as AcO(-), H2PO4(-) and F(-), which demonstrates that bidirectional PET sensing occurs in such naphthalimide based anion sensors.
Abstract: The thiourea based 4-amino-1,8-naphthalimide molecules 1–5 were designed as fluorescent anion sensors and their photophysical properties investigated upon recognition of biologically relevant anions such as acetate, dihydrogen phosphate and fluoride in DMSO. Synthesised in a single step from their respective aniline precursors, 6–9, these molecules were designed on the fluorophore–spacer–receptor principle, where in the case of sensors 1–3 the thiourea anion recognition moieties were connected to the fluorophore via the 4-amino moiety, while sensors 4 and 5 had the thiourea moieties connected to the ‘imide’via a CH2 spacer. The current study showed that 1–5 operated as photoinduced electron transfer (PET) sensors, as no significant changes were observed in their absorption spectra, while their fluorescence emissions were quenched upon recognition of ions such as AcO−, H2PO4− and F−, which demonstrates that bidirectional PET sensing occurs in such naphthalimide based anion sensors.
TL;DR: A new "dual-mode" chromogenic and fluorescent turn-on probe for the selective sensing of biological thiols in MeOH-H(2)O cosolvent at physiological pH 7.40.
Abstract: A new “dual-mode” chromogenic and fluorescent turn-on probe (2) for the selective sensing of biological thiols is reported. In MeOH–H2O cosolvent at physiological pH 7.40 (MeOH–H2O = 3:7), biological thiols cleave the 2,4-dinitrobenzenesulfonyl group to release the chromo- and fluorophore merocyanine (3).
TL;DR: A general anion templation methodology for the construction of a variety of interpenetrated and interlocked molecular structures and shows favourable selective anion binding characteristics distinct from their separate components.
Abstract: The potential of interlocked host rotaxane and catenane structures as innovative optical and electrochemical sensors is highlighted. Interlocked structures can be engineered to bind specific guests within the topologically constrained three dimensional cavities created during their template-driven syntheses. This binding ability, when coupled to the signal transduction capabilities associated with appended reporter groups and their dynamic structures, make catenanes and rotaxanes highly promising candidates for the development of molecular sensors. With the ultimate challenge of fabricating highly selective anion sensing configurations, a three-staged strategy has been followed. First, we developed a general anion templation methodology for the construction of a variety of interpenetrated and interlocked molecular structures. [2]Rotaxanes and [2]catenanes synthesised using this novel protocol show, after template removal, favourable selective anion binding characteristics distinct from their separate components. At the second stage, the incorporation of redox- and photo-active groups into these interlocked frameworks converts them into electrochemical/optical molecular sensors. In the final third stage, the confinement of interlocked anion receptors at surfaces results in the fabrication of devices exhibiting highly selective binding and electrochemical and/or optical sensing behaviour.
TL;DR: The results demonstrate that multivalency can be used in some case to modulate both the affinity and the selectivity of glycosidase inhibition.
Abstract: A series of mono-, di- and tri-valent iminosugars based on oligoethylene scaffolds and N-substituted deoxynojirymicin epitopes have been synthesized by “click chemistry” to study the effect of multivalency on glycosidase inhibition. Biological evaluation evidenced differences in the inhibition trends as a function of the enzyme nature. The results demonstrate that multivalency can be used in some case to modulate both the affinity and the selectivity of glycosidase inhibition.
TL;DR: Chemoselective cross-coupling reactions were demonstrated for C-S bonds in the BODIPY dyes 1 and 4, and similar reactions were applied to make the two-dye cassette system 11.
Abstract: Chemoselective cross-coupling reactions were demonstrated for C–S bonds in the BODIPY dyes 1 and 4, and similar reactions were applied to make the two-dye cassette system 11
TL;DR: Two novel SF5 analogs of the antimalarial agent mefloquine were synthesized in 5 steps and 10-23% overall yields and found to have improved activity and selectivity against malaria parasites.
Abstract: Two novel SF5 analogs of the antimalarial agent mefloquine were synthesized in 5 steps and 10–23% overall yields and found to have improved activity and selectivity against malaria parasites. This work also represents the first report of SF5-substituted quinolines.
TL;DR: A highly effective decarboxylative cross-coupling reaction of cinnamic acid with aryl iodide catalyzed by the combination of palladium chloride and CyJohnPhos in the presence of Ag2CO3 as an additive proceeds efficiently with good functional-group tolerance.
Abstract: A highly effective decarboxylative cross-coupling reaction of cinnamic acid with aryl iodide catalyzed by the combination of palladium chloride and CyJohnPhos in the presence of Ag2CO3 as an additive is described. The desired carbon-carbon bond formation proceeds efficiently with good functional-group tolerance.