Showing papers in "Beilstein Journal of Organic Chemistry in 2016"
TL;DR: An overview of computational methods used in different facets of drug discovery and highlight some of the recent successes is presented, both structure-based and ligand-based drug discovery methods are discussed.
Abstract: The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein-ligand docking, pharmacophore modeling and QSAR techniques are reviewed.
371 citations
TL;DR: An overview of NHC-catalysed benzoin reactions is presented and one of the earliest known carbon–carbon bond-forming reactions catalysed by NHCs is presented.
Abstract: N-Heterocyclic carbenes (NHCs) have emerged as a powerful class of organocatalysts that mediate a variety of organic transformations. The Benzoin reaction constitutes one of the earliest known carbon-carbon bond-forming reactions catalysed by NHCs. The rapid growth of NHC catalysis in general has resulted in the development of a variety of benzoin and benzoin-type reactions. An overview of such NHC-catalysed benzoin reactions is presented.
207 citations
TL;DR: This review is the first to collate and summarize main data on named and unnamed rearrangement reactions of peroxides.
Abstract: This review is the first to collate and summarize main data on named and unnamed rearrangement reactions of peroxides. It should be noted, that in the chemistry of peroxides two types of processes are considered under the term rearrangements. These are conventional rearrangements occurring with the retention of the molecular weight and transformations of one of the peroxide moieties after O-O-bond cleavage. Detailed information about the Baeyer-Villiger, Criegee, Hock, Kornblum-DeLaMare, Dakin, Elbs, Schenck, Smith, Wieland, and Story reactions is given. Unnamed rearrangements of organic peroxides and related processes are also analyzed. The rearrangements and related processes of important natural and synthetic peroxides are discussed separately.
136 citations
TL;DR: An overview about multicomponent reactions used for the synthesis of heterocyclic compounds bearing a phosphonate group on the ring is given.
Abstract: Multicomponent reactions (MCRs) are one of the most important processes for the preparation of highly functionalized organic compounds in modern synthetic chemistry. As shown in this review, they play an important role in organophosphorus chemistry where phosphorus reagents are used as substrates for the synthesis of a wide range of phosphorylated heterocycles. In this article, an overview about multicomponent reactions used for the synthesis of heterocyclic compounds bearing a phosphonate group on the ring is given.
123 citations
TL;DR: It is demonstrated that the exploration of specific microbial–host interactions, in combination with multidisciplinary dereplication processes, has emerged as a successful strategy to identify novel chemical entities and to shed light on the ecology and evolution of defensive associations.
Abstract: Here we review discoveries of secondary metabolites from microbes associated with insects. We mainly focus on natural products, where the ecological role has been at least partially elucidated, and/or the pharmaceutical properties evaluated, and on compounds with unique structural features. We demonstrate that the exploration of specific microbial–host interactions, in combination with multidisciplinary dereplication processes, has emerged as a successful strategy to identify novel chemical entities and to shed light on the ecology and evolution of defensive associations.
92 citations
TL;DR: The scope and limitations of an alternative to DMF derived from renewable sources (CyreneTM) in Sonogashira cross-coupling and Cacchi-type annulations are described.
Abstract: Pd-catalysed C-C bond formation is an essential tool within the pharmaceutical and agrochemical industries. Many of these reactions rely heavily on polar aprotic solvents; however, despite their utility, these solvents are incompatible with the drive towards more sustainable chemical synthesis. Herein, we describe the scope and limitations of an alternative to DMF derived from renewable sources (CyreneTM) in Sonogashira crosscoupling and Cacchi-type annulations.
72 citations
TL;DR: This review surveys the literature regarding the development of catalytic versions of the Wittig and aza-Wittig reactions with a presentation of the current state of the art regarding phosphine-catalyzed Wittig reactions.
Abstract: This review surveys the literature regarding the development of catalytic versions of the Wittig and aza-Wittig reactions. The first section summarizes how arsenic and tellurium-based catalytic Wittig-type reaction systems were developed first due to the relatively easy reduction of the oxides involved. This is followed by a presentation of the current state of the art regarding phosphine-catalyzed Wittig reactions. The second section covers the field of related catalytic aza-Wittig reactions that are catalyzed by both phosphine oxides and phosphines.
68 citations
TL;DR: This mini-review is to give a brief overview of α-pyrones and the mechanisms forming the basis of their natural synthesis, especially the chain interconnecting enzymes, showing homology to ketosynthases which catalyze Claisen-like condensation reactions.
Abstract: The α-pyrone moiety is a structural feature found in a huge variety of biologically active metabolites. In recent times new insights into additional biosynthetic mechanisms, yielding in such six-membered unsaturated ester ring residues have been obtained. The purpose of this mini-review is to give a brief overview of α-pyrones and the mechanisms forming the basis of their natural synthesis. Especially the chain interconnecting enzymes, showing homology to ketosynthases which catalyze Claisen-like condensation reactions, will be presented.
67 citations
TL;DR: The results from recent chemical investigations of this bacterial group are presented, the biosynthetic potential of these micropredators is compared with that of non-predatory bacteria and the link between predation and secondary metabolism is discussed.
Abstract: Bacteria, which prey on other microorganisms, are commonly found in the environment. While some of these organisms act as solitary hunters, others band together in large consortia before they attack their prey. Anecdotal reports suggest that bacteria practicing such a wolfpack strategy utilize antibiotics as predatory weapons. Consistent with this hypothesis, genome sequencing revealed that these micropredators possess impressive capacities for natural product biosynthesis. Here, we will present the results from recent chemical investigations of this bacterial group, compare the biosynthetic potential with that of non-predatory bacteria and discuss the link between predation and secondary metabolism.
64 citations
TL;DR: Evidence is shown that the encapsulation in CDs could be valuable for applications of carvacrol and thymol in food.
Abstract: Carvacrol and thymol have been widely studied for their ability to control food spoilage and to extend shelf-life of food products due to their antimicrobial and antioxidant activities. However, they suffer from poor aqueous solubility and pronounced flavoring ability that limit their application in food systems. These drawbacks could be surpassed by encapsulation in cyclodextrins (CDs). Applications of their inclusion complexes with CDs were reported without investigating the inclusion phenomenon in deep. In this study, inclusion complexes were characterized in terms of formation constants (K f), complexation efficiency (CE), CD:guest molar ratio and increase in bulk formulation by using an UV-visible competitive method, phase solubility studies as well as (1)H and DOSY (1)H NMR titration experiments. For the first time, a new algorithmic treatment that combines the chemical shifts and diffusion coefficients variations for all guest protons was applied to calculate K f. The position of the hydroxy group in carvacrol and thymol did not affect the stoichiometry of the inclusion complexes but led to a different binding stability with CDs. 2D ROESY NMR experiments were also performed to prove the encapsulation and illustrate the stable 3D conformation of the inclusion complexes. The structural investigation was accomplished with molecular modeling studies. Finally, the radical scavenging activity of carvacrol and thymol was evaluated by the ABTS radical scavenging assay. An improvement of this activity was observed upon encapsulation. Taken together, these results evidence that the encapsulation in CDs could be valuable for applications of carvacrol and thymol in food.
61 citations
TL;DR: This review describes unexpected dynamical behaviors of rearranging carbocations and the modern computational methods used to elucidate these aspects of reaction mechanisms.
Abstract: This review describes unexpected dynamical behaviors of rearranging carbocations and the modern computational methods used to elucidate these aspects of reaction mechanisms. Unique potential energy surface topologies associated with these rearrangements have been discovered in recent years that are not only of fundamental interest, but also provide insight into the way Nature manipulates chemical space to accomplish specific chemical transformations. Cautions for analyzing both experimental and theoretical data on carbocation rearrangements are included throughout.
TL;DR: In this review the synthesis of six-membered rings, that contain multiple chiral centers, either by a ring closing process or by a functionalization reaction on an already existing six- Membered ring, utilizing bifunctional (thio)ureas will be summarized.
Abstract: Organocatalysis, now running its second decade of life, is being considered one of the main tools a synthetic chemist has to perform asymmetric catalysis. In this review the synthesis of six-membered rings, that contain multiple chiral centers, either by a ring closing process or by a functionalization reaction on an already existing six-membered ring, utilizing bifunctional (thio)ureas will be summarized. Initially, the use of primary amine-thioureas as organocatalysts for the above transformation is being discussed, followed by the examples employing secondary amine-thioureas. Finally, the use of tertiary amine-thioureas and miscellaneous examples are presented.
TL;DR: In this review the addition of diverse protic and organometallic nucleophiles to electron-deficient alkenes followed by enantioselective protonation is summarized.
Abstract: The addition of nucleophiles to electron-deficient alkenes represents one of the more general and commonly used strategies for the convergent assembly of more complex structures from simple precursors. In this review the addition of diverse protic and organometallic nucleophiles to electron-deficient alkenes followed by enantioselective protonation is summarized. Reactions are first categorized by the type of electron-deficient alkene and then are further classified according to whether catalysis is achieved with chiral Lewis acids, organocatalysts, or transition metals.
TL;DR: The recent development of intermolecular C–H insertion in the application of C(sp3)–H bond functionalizations, especially for light alkanes, is reviewed and highlights the most recent accomplishments.
Abstract: The recent development of intermolecular C-H insertion in the application of C(sp(3))-H bond functionalizations, especially for light alkanes, is reviewed. The challenging problem of regioselectivity in C-H bond insertions has been tackled by the use of sterically bulky metal catalysts, such as metal porphyrins and silver(I) complexes. In some cases, high regioselectivity and enantioselectivity have been achieved in the C-H bond insertion of small alkanes. This review highlights the most recent accomplishments in this field.
TL;DR: The products obtained by incubation of farnesyl diphosphate (FPP) with six purified bacterial terpene cyclases were characterised by one- and two-dimensional NMR spectroscopic methods, allowing for a full structure elucidation.
Abstract: The products obtained by incubation of farnesyl diphosphate (FPP) with six purified bacterial terpene cyclases were characterised by one- and two-dimensional NMR spectroscopic methods, allowing for a full structure elucidation. The absolute configurations of four terpenes were determined based on their optical rotary powers. Incubation experiments with 13C-labelled isotopomers of FPP in buffers containing water or deuterium oxide allowed for detailed insights into the cyclisation mechanisms of the bacterial terpene cyclases.
TL;DR: This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muray mycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraysmycin biosynthesis.
Abstract: Muraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure-activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field.
TL;DR: This mini review highlights recent progress in developing and exploring new organic catalysts for electrophile activation through the formation of C–H hydrogen bonds and C–X halogen bonds.
Abstract: Hydrogen bond donor catalysis represents a rapidly growing subfield of organocatalysis. While traditional hydrogen bond donors containing N–H and O–H moieties have been effectively used for electrophile activation, activation based on other types of non-covalent interactions is less common. This mini review highlights recent progress in developing and exploring new organic catalysts for electrophile activation through the formation of C–H hydrogen bonds and C–X halogen bonds.
TL;DR: This review highlights the biosynthesis of heterocycles in polyketide natural products with a focus on oxygen and nitrogen-containingheterocycles with ring sizes between 3 and 6 atoms.
Abstract: This review highlights the biosynthesis of heterocycles in polyketide natural products with a focus on oxygen and nitrogen-containing heterocycles with ring sizes between 3 and 6 atoms. Heterocycles are abundant structural elements of natural products from all classes and they often contribute significantly to their biological activity. Progress in recent years has led to a much better understanding of their biosynthesis. In this context, plenty of novel enzymology has been discovered, suggesting that these pathways are an attractive target for future studies.
TL;DR: The methylene group of various substituted 2- and 4-benzylpyridines, benzyldiazines and benzyl(iso)quinolines was successfully oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant.
Abstract: The methylene group of various substituted 2- and 4-benzylpyridines, benzyldiazines and benzyl(iso)quinolines was successfully oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant. Application of the protocol in API synthesis is exemplified by the alternative synthesis of a precursor to the antimalarial drug Mefloquine. The oxidation method can also be used to prepare metabolites of APIs which is illustrated for the natural product papaverine. ICP-MS analysis of the purified reaction products revealed that the base metal impurity was well below the regulatory limit.
TL;DR: The general features and applications of CDs have been reviewed as well as their interactions with isolated biomolecules leading to the formation of inclusion or exclusion complexes and some potential medical applications are highlighted throughout several examples.
Abstract: In the field of host-guest chemistry, some of the most widely used hosts are probably cyclodextrins (CDs). As CDs are able to increase the water solubility of numerous drugs by inclusion into their hydrophobic cavity, they have been widespread used to develop numerous pharmaceutical formulations. Nevertheless, CDs are also able to interact with endogenous substances that originate from an organism, tissue or cell. These interactions can be useful for a vast array of topics including cholesterol manipulation, treatment of Alzheimer's disease, control of pathogens, etc. In addition, the use of natural CDs offers the great advantage of avoiding or reducing the use of common petroleum-sourced drugs. In this paper, the general features and applications of CDs have been reviewed as well as their interactions with isolated biomolecules leading to the formation of inclusion or exclusion complexes. Finally, some potential medical applications are highlighted throughout several examples.
TL;DR: The gold-catalyzed direct alkynylation of tryptophan in peptides using the hypervalent iodine reagent TIPS-EBX (1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one) proceeded in 50–78% yield under mild conditions and could be applied to peptides containing other nucleophilic and aromatic amino acids.
Abstract: The selective functionalization of peptides containing only natural amino acids is important for the modification of biomolecules. In particular, the installation of an alkyne as a useful handle for bioconjugation is highly attractive, but the use of a carbon linker is usually required. Herein, we report the gold-catalyzed direct alkynylation of tryptophan in peptides using the hypervalent iodine reagent TIPS-EBX (1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one). The reaction proceeded in 50-78% yield under mild conditions and could be applied to peptides containing other nucleophilic and aromatic amino acids, such as serine, phenylalanine or tyrosine.
TL;DR: This review aims to provide an overview about the catalytic asymmetric synthesis of biologically important 3-substituted 3-hydroxyoxindole-based further transformations and the construction of structurally novel scaffolds based on transition metal catalysis and organocatalysis.
Abstract: Oxindole scaffolds are prevalent in natural products and have been recognized as privileged substructures in new drug discovery Several oxindole-containing compounds have advanced into clinical trials for the treatment of different diseases Among these compounds, enantioenriched 3-hydroxyoxindole scaffolds also exist in natural products and have proven to possess promising biological activities A large number of catalytic asymmetric strategies toward the construction of 3-hydroxyoxindoles based on transition metal catalysis and organocatalysis have been reported in the last decades Additionally, 3-hydroxyoxindoles as versatile precursors have also been used in the total synthesis of natural products and for constructing structurally novel scaffolds In this review, we aim to provide an overview about the catalytic asymmetric synthesis of biologically important 3-substituted 3-hydroxyoxindoles and 3-hydroxyoxindole-based further transformations
TL;DR: The current mechanistic understanding of cyclisation reactions in Ribosomally synthesised and post-translationally modified peptides is discussed, and the current prospects for RiPP pathway discovery and characterisation are highlighted.
Abstract: Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a large class of natural products that are remarkably chemically diverse given an intrinsic requirement to be assembled from proteinogenic amino acids. The vast chemical space occupied by RiPPs means that they possess a wide variety of biological activities, and the class includes antibiotics, co-factors, signalling molecules, anticancer and anti-HIV compounds, and toxins. A considerable amount of RiPP chemical diversity is generated from cyclisation reactions, and the current mechanistic understanding of these reactions will be discussed here. These cyclisations involve a diverse array of chemical reactions, including 1,4-nucleophilic additions, [4 + 2] cycloadditions, ATP-dependent heterocyclisation to form thiazolines or oxazolines, and radical-mediated reactions between unactivated carbons. Future prospects for RiPP pathway discovery and characterisation will also be highlighted.
TL;DR: The peculiar reactivity of isosorbide and the non-toxic properties of DMC represent indeed a green match leading to several industrial appealing potential applications.
Abstract: In this review the reactivity of the bio-based platform compounds D-sorbitol and isosorbide with green reagents and solvent dimethyl carbonate (DMC) is reported Dehydration of D-sorbitol via DMC in the presence of catalytic amounts of base is an efficient and viable process for the preparation of the industrially relevant anhydro sugar isosorbide This procedure is "chlorine-free", one-pot, environmental friendly and high yielding The reactivity of isosorbide with DMC is equally interesting as it can lead to the formation of dicarboxymethyl isosorbide, a potential monomer for isosorbide-based polycarbonate, and dimethyl isosorbide, a high boiling green solvent The peculiar reactivity of isosorbide and the non-toxic properties of DMC represent indeed a green match leading to several industrial appealing potential applications
TL;DR: This review highlights the presence of enduracididine in natural products, its biosynthesis together with a review of analogues of endURacididine, illustrating the challenges encountered to date in the development of efficient synthetic routes to facilitate drug discovery efforts inspired by the discovery of teixobactin.
Abstract: Rising resistance to current clinical antibacterial agents is an imminent threat to global public health and highlights the demand for new lead compounds for drug discovery. One such potential lead compound, the peptide antibiotic teixobactin, was recently isolated from an uncultured bacterial source, and demonstrates remarkably high potency against a wide range of resistant pathogens without apparent development of resistance. A rare amino acid residue component of teixobactin, enduracididine, is only known to occur in a small number of natural products that also possess promising antibiotic activity. This review highlights the presence of enduracididine in natural products, its biosynthesis together with a review of analogues of enduracididine. Reported synthetic approaches to the cyclic guanidine structure of enduracididine are discussed, illustrating the challenges encountered to date in the development of efficient synthetic routes to facilitate drug discovery efforts inspired by the discovery of teixobactin.
TL;DR: The dramatic influence of the reaction media on the reaction rate and stereoselectivity of the process suggests that the intimate architecture of DESs deeply influences the reactivity of different species involved in the catalytic cycle.
Abstract: Different deep eutectic solvent (DES) mixtures were studied as reaction media for the continuous synthesis of enantiomerically enriched products by testing different experimental set-ups. L-Proline-catalysed cross-aldol reactions were efficiently performed in continuo, with high yield (99%), anti-stereoselectivity, and enantioselectivity (up to 97% ee). Moreover, using two different DES mixtures, the diastereoselectivity of the process could be tuned, thereby leading to the formation, under different experimental conditions, to both the syn- and the anti-isomer with very high enantioselectivity. The excess of cyclohexanone was recovered and reused, and the reaction could be run and the product isolated without the use of any organic solvent by a proper choice of DES components. The dramatic influence of the reaction media on the reaction rate and stereoselectivity of the process suggests that the intimate architecture of DESs deeply influences the reactivity of different species involved in the catalytic cycle.
TL;DR: An improved and greener protocol for the synthesis of benzimidazole derivatives, starting from o-phenylenediamine, with different aldehydes is reported, and it is found that the charge density on the oxygen of the carbonyl group has a significant impact on the reaction pathway.
Abstract: An improved and greener protocol for the synthesis of benzimidazole derivatives, starting from o-phenylenediamine, with different aldehydes is reported. Double-condensation products were selectively obtained when Er(OTf)3 was used as the catalyst in the presence of electron-rich aldehydes. Conversely, the formation of mono-condensation products was the preferred path in absence of this catalyst. One of the major advantages of these reactions was the formation of a single product, avoiding extensive isolation and purification of products, which is frequently associated with these reactions. Theoretical calculations helped to understand the different reactivity established for these reactions. Thus, we found that the charge density on the oxygen of the carbonyl group has a significant impact on the reaction pathway. For instance, electron-rich aldehydes better coordinate to the catalyst, which favours the addition of the amine group to the carbonyl group, therefore facilitating the formation of double-condensation products. Reactions with aliphatic or aromatic aldehydes were possible, without using organic solvents and in a one-pot procedure with short reaction time (2-5 min), affording single products in excellent yields (75-99%). This convenient and eco-friendly methodology offers numerous benefits with respect to other protocols reported for similar compounds.
TL;DR: In this study, a polymer, prepared by crosslinking cyclodextrin (CD) by means of a polycarboxylic acid, was used for the removal of pollutants from spiked solutions and discharge waters from the surface treatment industry.
Abstract: In this study, a polymer, prepared by crosslinking cyclodextrin (CD) by means of a polycarboxylic acid, was used for the removal of pollutants from spiked solutions and discharge waters from the surface treatment industry. In spiked solutions containing five metals, sixteen polycyclic aromatic hydrocarbons (PAH) and three alkylphenols (AP), the material exhibited high adsorption capacities: >99% of Co2+, Ni2+ and Zn2+ were removed, between 65 and 82% of the PAHs, as well as 69 to 90% of the APs. Due to the structure of the polymer and its specific characteristics, such as the presence of carboxylic groups and CD cavities, the adsorption mechanism involves four main interactions: ion exchange, electrostatic interactions and precipitation for metal removal, and inclusion complexes for organics removal. In industrial discharge waters, competition effects appeared, especially because of the presence of calcium at high concentrations, which competed with other pollutants for the adsorption sites of the adsorbent.
TL;DR: It is shown that cyclodextrin complexation may be used to design functional polymer materials with tailorable properties, especially for photo-, pH-, thermo- and redox-responsiveness and self-healing.
Abstract: The employment of cyclodextrin host–guest complexation to construct supramolecular assemblies with an emphasis on polymer networks is reviewed. The main driving force for this supramolecular assembly is host–guest complexation between cyclodextrin hosts and guest groups either of which may be discrete molecular species or substituents on a polymer backbone. The effects of such complexation on properties at the molecular and macroscopic levels are discussed. It is shown that cyclodextrin complexation may be used to design functional polymer materials with tailorable properties, especially for photo-, pH-, thermo- and redox-responsiveness and self-healing.
TL;DR: This review discusses marine-derived myxobacteria, which are particularly interesting due to their relatively recent discovery and due to the fact that their very existence was called into question.
Abstract: Myxobacteria are famous for their ability to produce most intriguing secondary metabolites. Till recently, only terrestrial myxobacteria were in the focus of research. In this review, however, we discuss marine-derived myxobacteria, which are particularly interesting due to their relatively recent discovery and due to the fact that their very existence was called into question. The to-date-explored members of these halophilic or halotolerant myxobacteria are all grouped into the suborder Nannocystineae. Few of them were chemically investigated revealing around 11 structural types belonging to the polyketide, non-ribosomal peptide, hybrids thereof or terpenoid class of secondary metabolites. A most unusual structural type is represented by salimabromide from Enhygromyxa salina. In silico analyses were carried out on the available genome sequences of four bacterial members of the Nannocystineae, revealing the biosynthetic potential of these bacteria.