DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally employed long (400–800 bp) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intra-species genetic variation. We report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterise four million SNPs and four hundred thousand structural variants, many of which are previously unknown. Our approach is effective for accurate, rapid and economical whole genome re-sequencing and many other biomedical applications.
The calculated (DFT, B3PW91) A(1) nu(CO) frequency in LNi(CO)(3) defines an electronic parameter that reliably predicts the relative donor powers of a wide variety of cationic, neutral, and negatively charged ligands. These calculated parameters correlate very well with the available Tolman and Lever parameters, and also with Hammett's sigma(m), where available. The method avoids any experimental limitations and, in particular, can be used for proposed ligands not yet experimentally available.
Air and thermally stable palladium(II) complexes of CNC and CCC bis-carbene pincer ligands have a twisted conformation and catalyze Heck olefination of activated aryl chlorides.
The synthesis and X-ray crystallographic characterization of a Pd complex (3) with a rigid C,N,C-tridentate pincer carbene ligand are described. At high temperatures (165 °C) it is an active and robust catalyst in the Heck reaction. Complex 3 gives some of the highest turnover numbers yet reported for coupling with aryl chlorides. Time dependence, reuse, and Heck reaction conditions are discussed for 3. Data with Fas base did not support Shaw's Heck mechanism. Suzuki and Sonogashira coupling reactions are also catalyzed by 3. The palladium carbene complex 5, containing an analogous C,N-bidentate ligand, is compared to 3 in terms of stability, catalytic activity, and reaction profile in the Heck reaction.
X-ray crystallographic analysis of red crystals formed on mixing octacarbonyldicobalt(0) and BINAP, combined with NMR evidence obtained from a catalytic asymmetric Pauson-Khand reaction, suggests that this complex is a precatalyst to this reaction and leads to a new hypothesis for the role of axially chiral diphosphanes in the catalytic asymmetric Pauson-Khand reaction.The Pauson-Khand reaction (PKR), the [2 + 2 + 1] cyclocarbonylation of an alkyne and an alkene to form a cyclopentenone, is of considerable synthetic interest not only because cyclopentenones are useful building blocks for more elaborate structures but also because they are important biologically active compounds in their own right. For example, the cyclopentenone prostanoids have recently started to attract much interest, and this area of research is now providing promising candidates for, inter alia, antiinflammatory and antiviral pharmaceuticals. 1 While most applications of the PKR to date have used stoichiometric amounts of cobalt, there are now several catalytic versions of the reaction available that use a range of metals. 2 Initial exploratory attempts to introduce asymmetry into the reaction using titanium, 3 rhodium, 4 and iridium 5 catalysts have been encouraging, providing good enantioselectivities and turnover numbers.The feasibility of an asymmetric cobalt-catalyzed PKR has been demonstrated. 6 Using octacarbonyldicobalt(0) (20 mol %) as the cobalt source, a range of chiral diphosphanes (20 mol %) were tested on standard intramolecular substrates. While very modest enantioselectivities were observed for DIOP, DuPHOS, and planar chiral ferrocene diphosphanes, high selectivities were observed with the axially chiral ligand BINAP. For example, cyclocarbonylation of enyne 1a (eq 1) gave the product cyclopentenone 2a in 53% yield and 90% ee in 14 h. It was proposed that the phosphorus atoms of the BINAP ligand bridge the two cobalt atoms, while cyclopentenone formation occurs with participation of both cobalt centers 6 according to the generally accepted Pauson-Khand mechanism. 7 As a result of our interest in the cobalt-catalyzed PKR, 8 we initiated a study of its asymmetric version. After detailing our modified conditions for the cobaltcatalyzed asymmetric PKR based on axially chiral diphosphanes, we wish to report herein (a) the isolation of a hexacarbonyldicobalt(0) complex in which BINAP binds to just one of the two cobalts and (b) evidence that suggests that this complex is a precatalyst to asymmetric catalytic PKRs.We initially examined the cyclocarbonylation of enyne 1a in the presence of (S)-BINAP. Optimization of this reaction led to the use of 3.75 mol % of Co 4 (CO) 12 as the cobalt source, 9 which in our hands proved more robust and reliable than Co 2 (CO) 8 , together with 7.5 mol % of (S)-BINAP. After Co 4 (CO) 12 and (S)-BINAP were premixed, operating at 75°C under 1.05 atm of carbon monoxide for 5 h gave a 70% yield of cyclopentenone 2a and 89% ee (Table 1, entry 1). A survey of five other diphosphanes (Table 1, entries ...
Methods are discussed for rapid screening of soluble and polymer-bound homogeneous catalysts for activity. A polymer-bound phosphine library is synthesized, and a modular tridentate pincer CNC bis-carbene Pd complex is described. The possibility of C-bound His in metalloenzymes is raised.Homogeneous catalysis has much to offer Green Chemistry. By allowing reactions to occur at lower temperature and pressure, energy is saved. By enhancing selectivity, waste is avoided. Waste can even be essentially eliminated if catalysis allows atom-economic processes to be used. These are reactions like eq. 1 in which all the atoms of the reagents are incorporated into the product [1,2]. This particular rhodium-catalyzed reaction-the Monsanto Process-is a commercially important route to acetic acid [3]. In contrast, much conventional industrial chemistry still goes via reactions that produce stoichiometric amounts of inorganic salts or tainted water as byproducts. MeOH + CO = MeCOOH(1)For each new application, new homogeneous catalysts may well need to be identified and optimized, then understood mechanistically. Mechanization and computerization, now becoming more readily available and efficient, can help with all these goals. Combinatorial chemistry [4][5][6][7], together with rapid catalyst screening [8,9], has potential value in identification and optimization. The latest methods of computational and theoretical chemistry can give very valuable mechanistic information in ruling out otherwise plausible pathways and predicting structural information for transient species and transition states [10]. Here, we naturally discuss only the title topic, although by doing so we do not intend to detract from the importance of mechanistic understanding.The principles of combinatorial chemistry have been covered in several recent monographs and reviews [11][12][13][14][15][16]. In summary, the concept involves creating a large number of chemically distinct species-called a library-in a controlled way. This library is then assayed by a suitable rapid screening protocol to see if a desired response is elicited. The library members showing a good response, termed "hits", are then analyzed to determine the chemical structure responsible for the desired response.The field has its intellectual roots in an understanding of how the immune system works and in Merrifield's [17] approach to polypeptide synthesis. The immune system has the task of tagging foreign biomolecules to label them for attack. To do this, it creates a library of polypeptides of variable structure, then senses when one of these peptides by chance binds strongly to a foreign target, such as the surface of an invading bacterium, for example. The successful immune system peptide is then synthesized on a large scale to carry out its defense role in the body.
N-Heterocyclic carbene derivatives of dicobalt octacarbonyl have been synthesized for the first time and tested in the Pauson−Khand reaction. Two complexes with both NHC and PPh3 ligands represent the only examples of structurally characterized dicobalt hexacarbonyl complexes with two different non-CO ligands.
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