Two Metals Are Better Than One in the Gold Catalyzed Oxidative Heteroarylation of Alkenes

We present a detailed study of the mechanism for oxidative heteroarylation, based on DFT calculations and experimental observations. We propose binuclear Au(II)–Au(II) complexes to be key intermediates in the mechanism for gold catalyzed oxidative heteroarylation. The reaction is thought to proceed via a gold redox cycle involving initial oxidation of Au(I) to binuclear Au(II)–Au(II) complexes by Selectfluor, followed by heteroauration and reductive elimination. While it is tempting to invoke a transmetalation/reductive elimination mechanism similar to that proposed for other transition metal complexes, experimental and DFT studies suggest that the key C–C bond forming reaction occurs via a bimolecular reductive elimination process (devoid of transmetalation). In addition, the stereochemistry of the elimination step was determined experimentally to proceed with complete retention. Ligand and halide effects played an important role in the development and optimization of the catalyst; our data provides an explanation for the ligand effects observed experimentally, useful for future catalyst development. Cyclic voltammetry data is presented that supports redox synergy of the Au···Au aurophilic interaction. The monometallic reductive elimination from mononuclear Au(III) complexes is also studied from which we can predict a ~ 15 kcal/mol advantage for bimetallic reductive elimination

First Meeting of the joint IOC-ICES Study Group on Nutrient Standards (SGONS)

A meeting of the joint IOC-ICES Study Group on Nutrient Standards (SGONS) was held in Paris, France on 23-24 March 2010. It focused on the ongoing activities of the SGONS and plans for extended international collaborations to establish global comparability of the nutrient data from the world’s ocean. Thirty two scientists and experts from 11 countries and 2 delegates from IOC attended the meeting. The discussions followed the Terms of References of SGONS established in July 2009. Development of the reference materials for nutrients in seawater (RMNS) were also discussed in collaboration with the producers. The background and history of SGONS and an international nutrients scale system INSS and the progress with the production of RMNS materials and their current availability were reported. The production of RMNS and the latest status of the RMNS production facility, current status on the certification of RMNS for nitrate, nitrite, phosphate and silicate at the National Metrology Institute of Japan were also reported. The revised nutrients analysis manual which is being undertaken by the SGONS hopefully would be completed by 1 August 2010, and it will be published on line at the Go-Ship website. Results obtained with RMNS solutions used on the P6 reoccupation cruise in 2009-2010 by SIO (Scripps Institute of Oceanography, USA) showed that considerable improvement could be made in the internal comparability of the data by referencing it to the RMNS results and related good comparability with the previous P6 cruise in 2003 by JAMSTEC when RMNS were also used. The meeting strongly endorsed the idea of a ship board workshop in 2013/14 during which major groups would carry out a full inter-comparison of all procedures including analytical methods on board a research ship. The global stability test of RMNS by ten core laboratories of SGONS which started in 2009 will continue for more two years. It also was agreed to set up an international steering committee to plan the next inter-laboratory comparison study which will extend the study to about 70 laboratories working globally on deep sea hydrography. This will happen in early 2011. Future arrangements were considered for the collection of more batches of seawater for the preparation of RMNS waters suitable for use in all major water masses, and a list of candidate cruises in 2010/2011 was prepared. The related point of the extension of the use of RMNS for work in shelf sea water was also discussed, this followed on from discussions at the ICES Marine Chemistry Working Group (MCWG) meeting in 2010. The ICES MCWG considered that the use of suitable RMNS solutions would be valuable for improving the inter comparability of shelf sea data and be a valuable complement to work with the existing QUASIMEME proficiency testing scheme

Phosphoramidite Gold(I)-Catalyzed Diastereo- and Enantioselective Synthesis of 3,4-Substituted Pyrrolidines

In this article the utility of phosphoramidite ligands in enantioselective AuI catalysis was explored in the development of highly diastereo- and enantioselective AuI-catalyzed cycloadditions of allenenes. A Au^I-catalyzed synthesis of 3,4-disubstituted pyrrolidines and γ-lactams is described. This reaction proceeds through the enantioselective AuI-catalyzed cyclization of allenenes to form a carbocationic intermediate that is trapped by an exogenous nucleophile, resulting in the highly diastereoselective construction of three contiguous stereogenic centers. A computational study (DFT) was also performed to gain some insight into the underlying mechanisms of these cycloadditions. The utility of this new methodology was demonstrated through the formal synthesis of (−)-isocynometrine

Mechanistic Study of Gold(I)-Catalyzed Intermolecular Hydroamination of Allenes

The intermolecular hydroamination of allenes occurs readily with hydrazide nucleophiles, in the presence of 3-12% Ph_3PAuNTf_2. Mechanistic studies have been conducted to establish the resting state of the gold catalyst, the kinetic order of the reaction, the effect of ligand electronics on the overall rate, and the reversibility of the last steps in the catalytic cycle. We have found the overall reaction to be first order in gold and allene and zero order in nucleophile. Our studies suggest that the rate-limiting transition state for the reaction does not involve the nucleophile and that the active catalyst is monomeric in gold(I). Computational studies support an “outersphere” mechanism and predict that a two-step, no intermediate mechanism may be operative. In accord with this mechanistic proposal, the reaction can be accelerated with the use of more electron-deficient phosphine ligands on the gold(I) catalyst

Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy

INTRODUCTION AND OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is a genetically and phenotypically heterogeneous disease; there is still a large proportion of patients with no identified disease-causing mutation. Although the majority of mutations are found in the MYH7 and MYBPC3 genes, mutations in Z-disk-associated proteins have also been linked to HCM. METHODS: We assessed a small family with HCM based on family history, physical examination, 12-lead ECG, echocardiogram and magnetic resonance imaging. After exclusion of mutations in eleven HCM disease genes, we performed direct sequencing of the TCAP gene encoding the Z-disk protein titin-cap (also known as telethonin). RESULTS: We present a novel TCAP mutation in a small family affected by HCM. The identified p.C57W mutation showed a very low population frequency, as well as high conservation across species. All of the bioinformatic prediction tools used considered this mutation to be damaging/deleterious. Family members were screened for this new mutation and a co-segregation pattern was detected. Both affected members of this family presented with late-onset HCM, moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction and low risk of sudden cardiac death. CONCLUSIONS: We present evidence supporting the classification of the TCAP p.C57W mutation, encoding the Z-disk protein titin-cap/telethonin as a new likely pathogenic variant of hypertrophic cardiomyopathy, with a specific phenotype in the family under analysis

Expression of Subclinical Atherosclerosis for Different Cardiovascular Risk Factors in Young Populations

INTRODUCTION: Carotid intima-media thickness (cIMT) is considered an early marker for atherosclerosis, but there are few studies on the expression of this marker in younger populations. OBJECTIVES: To evaluate cIMT in younge patients (aged 30-50 years) and its expression according to cardiovascular risk factors. METHODS: We analyzed individuals admitted for an invasive cardiac procedure. Normal cIMT was defined as 1.50 mm. Lipid profile, anthropometric parameters, fasting blood glucose and estimated GFR were also determined. RESULTS: A total of 106 patients were included (59% male), with a mean age of 43 +/- 5 years, 36% with hypertension, 22% smokers, 32% with known hyperlipidemia, 16% with diabetes, 39% under statin therapy and 40% with metabolic syndrome (AHA/NHLBI definition). Mean cIMT was 0.69 +/- 0.26 mm, and was normal in 74% of the patients, thickened in 20% and with atherosclerotic plaques in 6%. cIMT correlated directly with age (r = 0.26, p = 0.007), log fasting glucose (r = 0.21, p = 0.04), and log triglycerides (r = 0.24, p = 0.017), and tended to correlate with the number of components of metabolic syndrome (r = 0.17, p = 0.08). However, on multivariate analysis, only age remained as an independent predictor (r = 0.29, p = 0.005). Diabetic patients had greater cIMT (0.81 +/- 0.22 vs. 0.67 +/- 0.26 mm, p = 0.039) and there was a trend for greater cIMT in those with metabolic syndrome (0.75 +/- 0.29 vs. 0.66 +/- 0.23 mm, p = 0.09). There were no differences for the other risk factors, A higher number of risk factors in a single patient showed a trend for increased cIMT (p = 0.083) CONCLUSIONS: Age is the only independent determinant of cIMT in a young population. Diabetic patients have greater cIMT and a trend was seen in those with metabolic syndrome, possibly influenced by its relation with diabetes, one of the components of the metabolic syndrome

Gold-Catalyzed Intramolecular Aminoarylation of Alkenes: C-C Bond Formation through Bimolecular Reductive Elimination

Gold-ilocks and the 3 mol % catalyst: Bimetallic gold bromides allow the room temperature aminoarylation of unactivated terminal olefins with aryl boronic acids using Selectfluor as an oxidant. A catalytic cycle involving gold(I)/gold(III) and a bimolecular reductive elimination for the key CC bond-forming step is proposed. dppm= bis(diphenylphosphanyl)methane

Quality control procedures and methods of the CARINA database

Data on the carbon and carbon relevant hydrographic and hydrochemical parameters from previously not publicly available cruises in the Arctic, Atlantic and Southern Ocean have been retrieved and merged to a new data base: CARINA (CARbon IN the Atlantic). These data have gone through rigorous quality control (QC) procedures to assure the highest possible quality and consistency. All CARINA data were subject to primary QC; a process in which data are studied in order to identify outliers and obvious errors. Additionally, secondary QC was performed for several of the measured parameters in the CARINA data base. Secondary QC is a process in which the data are objectively studied in order to quantify systematic differences in the reported values. This process involved crossover analysis, and as a second step the offsets derived from the crossover analysis were used to calculate corrections of the parameters measured on individual cruises using least square models. Significant biases found in the data have been corrected in the data products, i.e. three merged data files containing measured, calculated and interpolated data for each of the three regions (i.e. Arctic Mediterranean Seas, Atlantic, and Southern Ocean). Here we report on the technical details of the quality control and on tools that have been developed and used during the project, including procedures for crossover analysis and least square models. Furthermore, an interactive website for uploading of results, plots, comments etc. was developed and was of critical importance for the success of the project, this is also described here