3.1. C-M and X-H as Nucleophiles 1806 3.2. C-H and X-M as Nucleophiles 1809 3.2.1. C-Halogen Bond Formations 1809 3.2.2. C-O Bond Formations 1812 3.3. C-H and X-H as Nucleophiles 1812 3.3.1. C-O Bond Formations 1812 3.3.2. C-N Bond Formations 1815 4. Oxidative X-X Bond Formations between Two Nucleophiles 1819 5. Conclusions 1819 Author Information 1819 Biographies 1819 Acknowledgment 1820 References 1820

Bond Formations between Two Nucleophiles: Transition Metal Catalyzed Oxidative Cross-Coupling Reactions

Recent Advances in Polyoxometalate-Catalyzed Reactions

Water is the lingua franca of life on our planet and is the solvent of choice for Nature to carry out her syntheses.1 In contrast, our methods of making complex organic molecules have taken us far away from the watery milieu of biosynthesis. Indeed, it is fair to say that most organic reactions commonly used both in academic laboratories and in industry fail in the presence of water or oxygen. As a direct consequence of our attempts to mimick Nature's way of making new chemical bonds, we learned to rely on highly reactive nucleophilic and electrophilic reagents to gain control of the chemical reactivity and to channel chemical reactions down a desired pathway. The requirement for the protection of all protic functional groups, such as alcohols and amines, is another corollary of our reliance on these energetic species. Nevertheless, chemical transformations in aqueous solvents are not new to organic chemists. On the contrary, they have attracted attention of scientists for many years: the first use of water for an organic reaction could be dated back to Wohler's synthesis of urea from ammonium cyanate.2 From a true organic synthesis perspective, the earliest example could be the synthesis of indigo by Baeyer and Drewsen in 1882 (Scheme 1).3 In their synthesis, a suspension of o-nitrobenzaldehyde 1 in aqueous acetone was treated with a solution of sodium hydroxide. The immediate formation of the characteristic blue color of indigo 2 ensued, and the product subsequently precipitated.



Scheme 1



Water possesses many unique physical and chemical properties: large temperature window in which it remains in the liquid state, extensive hydrogen bonding, high heat capacity, large dielectric constant, and optimum oxygen solubility to maintain aquatic life forms. These distinctive properties are the consequence of the unique structure of water.4,5 The structure and properties of water have been studied by scientists representing almost all fields of knowledge, and new theoretical models continue to emerge.6,7 Water is also known to enhance the rates and to affect the selectivity of a wide variety of organic reactions.8,9

In spite of these potential advantages, water is still not commonly used as a sole solvent for organic synthesis, at least in part because most organic compounds do not dissolve in water to a significant extent, and solubility is generally considered a prerequisite for reactivity: “corpora non agunt nisi soluta” (substances do not react unless dissolved). Consequently, in the many examples of “aqueous reactions” organic co-solvents are employed in order to increase the solubility of organic reactants in water.9,10 Alternatively, hydrophilicity of the reactants is increased by the introduction of polar functional groups, again to make the resulting compound at least partially water soluble.11 However, these manipulations tend to diminish and even negate the advantages of low cost, simplicity of reaction conditions, ease of workup, and product isolation that water has over traditional solvents. Therefore, the currently burgeoning field of organic synthesis in aqueous media encompasses a large family of reactions. The solubility of reacting species and products can range from complete to partial to practically none, so that reaction mixtures can be both homogeneous and heterogeneous. The amount of water can also range widely, from substoichiometric quantities to a large volume in which the reactants are suspended or dissolved. Several terms have been used in the literature to describe reactions in aqueous millieu. In water, in the presence of water, and on water are commonly found in the recent publications and are often used interchangeably to describe reactions that proceed under very different conditions.12,13 There is also a growing number of examples micellar catalysis in the presence of non-ionic surfactants, such as Triton X-100 and PTS (a tocopherol-based amphiphile).14-18

In this review, we attempt to survey organic transformations that benefit from being performed on water under the conditions defined by Sharpless and co-workers: when insoluble reactant(s) are stirred in aqueous emulsions or suspensions without the addition of any organic co-solvents. In many cases, it is impossible to ascertain whether the reaction is occuring in or on water, but as long as the reaction mixture remains heterogeneous and the overall process appears to benefit from it (either in terms of increased reaction rate or enhanced selectivity), it qualifies.

The ‘on water’ moniker reflects the defining attribute of these reactions: the lack of solubility of the reactant(s) in water. A considerable rate acceleration is often observed in reactions carried out under these conditions over those in organic solvents.19 Furthermore, in many cases a significant rate increase of on water reactions over reactions carried out neat indicates that rate acceleration is not merely a consequence of increased concentration of the reacting species. Naturally, the degree of on water acceleration varies between different reaction classes, and even when it is modest, there are other advantages to carrying out reactions in this manner. Firstly, water is an excellent heat sink due to its large heat capacity, making exothermic processes safer and more selective, especially when they are carried out on large scale. Secondly, reactions of water-insoluble substrates usually lead to the formation of water-insoluble products. In such cases, product isolation simply involves filtration of solid products (or phase separation in case of liquids). Finally, the growing list of examples wherein reactions performed on water are not only faster but also more selective (whether chemo-, regio-, or enantio-) underscores the significant potential for process intensification for reactions performed on water.

Although claims of the ecological advantages and “greenness” of water are almost invariably found in the opening paragraphs of reports describing aqueous reactions, they should be taken with a grain of salt. The low cost, relative abundance, and inherent safety of water notwithstanding, the environmental impact of a process is determined by many factors, such as the efficiency of the reaction in terms of atom economy,20 the nature of solvents used in the reaction workup, the residual concentration of regulated organic compounds and metal catalysts remaining in the aqueous waste, and the costs of its clean up or disposal.21,22 The mere finding that a process performs as well in water as it does in an organic solvent tells us little about its potential environmental impact.

The field of aqueous organic synthesis has been regularly and comprehensively reviewed.9,10,23-27 In addition, recent reviews focusing on microwave assisted organic synthesis in water,28 reactions in near-critical water,29 and biocatalysis in water30 have been published. Accordingly, these topics are not covered in the present review.

Organic Synthesis “On Water”

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities. Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

/pdf/natural-products-in-drug-discovery-advances-and-4axj6y2vp0.pdf

Natural products in drug discovery: advances and opportunities.

Microscopy and mass spectrometry (MS) are complementary techniques: The former provides spatiotemporal information in living cells, but only for a handful of recombinant proteins at a time, whereas the latter can detect thousands of endogenous proteins simultaneously, but only in lysed samples. Here, we introduce technology that combines these strengths by offering spatially and temporally resolved proteomic maps of endogenous proteins within living cells. Our method relies on a genetically targetable peroxidase enzyme that biotinylates nearby proteins, which are subsequently purified and identified by MS. We used this approach to identify 495 proteins within the human mitochondrial matrix, including 31 not previously linked to mitochondria. The labeling was exceptionally specific and distinguished between inner membrane proteins facing the matrix versus the intermembrane space (IMS). Several proteins previously thought to reside in the IMS or outer membrane, including protoporphyrinogen oxidase, were reassigned to the matrix by our proteomic data and confirmed by electron microscopy. The specificity of peroxidase-mediated proteomic mapping in live cells, combined with its ease of use, offers biologists a powerful tool for understanding the molecular composition of living cells.

Proteomic Mapping of Mitochondria in Living Cells via Spatially Restricted Enzymatic Tagging

It is difficult to imagine organic chemistry without organo-halogen compounds and the molecular halogens needed for their preparation. The halogens have very different reactivity, with iodine usually requiring some form of activation, while others are reactive and hazardous chemicals. To avoid their use, various modified reagents have been discovered (N-bromo- and N-chlorosuccinimide, Selectfluor..), but halogens are used to prepare these reagents and when they are used the atom economy is poor. A better approach, which is based on biomimetric research on oxidative halogenation in nature, consists of generating the halogenating reagent in situ under acidic conditions from a halide salt. The result of such a reaction has been halogenation with 100 % halogen atom economy. Suitable oxidants for the oxidation of halides are hydrogen peroxide and oxygen.

Oxidative Halogenation with "Green" Oxidants: Oxygen and Hydrogen Peroxide

http://www.sciencemadness.org/talk/files.php?pid=241870&aid=18016

Bromination of ketones with H2O2–HBr “on water”

The metabolic cofactor coenzyme A (CoA) gained renewed attention because of its roles in neurodegeneration, protein acetylation, autophagy and signal transduction. The long-standing dogma is that eukaryotic cells obtain CoA exclusively via the uptake of extracellular precursors, especially vitamin B5, which is intracellularly converted through five conserved enzymatic reactions into CoA. This study demonstrates an alternative mechanism that allows cells and organisms to adjust intracellular CoA levels by using exogenous CoA. Here CoA was hydrolyzed extracellularly by ectonucleotide pyrophosphatases to 4'-phosphopantetheine, a biologically stable molecule able to translocate through membranes via passive diffusion. Inside the cell, 4'-phosphopantetheine was enzymatically converted back to CoA by the bifunctional enzyme CoA synthase. Phenotypes induced by intracellular CoA deprivation were reversed when exogenous CoA was provided. Our findings answer long-standing questions in fundamental cell biology and have major implications for the understanding of CoA-related diseases and therapies.

Ajda Podgoršek

Papers

Oxidative Halogenation with "Green" Oxidants: Oxygen and Hydrogen Peroxide

Bromination of ketones with H2O2–HBr “on water”

Extracellular 4 '-phosphopantetheine is a source for intracellular coenzyme A synthesis

Visible light induced ‘on water’ benzylic bromination with N-bromosuccinimide

Oxidative Halogenierungen mit umweltschonenden Oxidationsmitteln: Sauerstoff und Wasserstoffperoxid