New systems for catalytic asymmetric epoxidation

This thesis describes the catalytic asymmetric epoxidation of olefins mediated by oxaziridinium salts. The introduction highlights some of the most successful methods for preparing chiral oxiranes and hints at the synthetic utility of this versatile molecule. The second chapter is dedicated to our efforts to synthesize chiral iminium salts as catalysts for asymmetric epoxidation. The first part of this chapter describes previous Page group findings and leads on to the current author's efforts in this area. Initial results from modified amino acids, cyclo-condensed to form dihydroisoquinolinium salts, showed that an aromatic unit at C4 of our catalysts was vital for asymmetric induction. Following this, several catalysts substituted at the 4-position of the aromatic functionality were tested, and found to be effective mediators for asymmetric epoxidation. Triphenylethylene was epoxidized with up to 71% ee when using oxone as the stochieometric oxidant. [Continues.

A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles

A mild, high yielding approach to C-3 hydroxylated oxindoles using catalytic quantities of tetrabutylammonium fluoride and air as the stoicheiometric oxidant is reported over a wide range of substitution patterns

Continuous flow ozonolysis using atmospheric plasma

Ozonolysis is widely used in organic synthesis to obtain aldehydes and ketones from alkenes, a process of great interest, for example, for the pharmaceutical industry. This reaction is more environmentally accepted than other alternative oxidations and it has good atom efficiency. Ozonolysis, however, has an important drawback; the ozonides generated as intermediates in the process are unstable and pose a risk of explosion. To minimize this risk, continuous flow processing can be used, as this eliminates the accumulation of large amounts of hazardous intermediates, thereby offering an alternative to batch processing that greatly enhances the control and safety of the ozonolysis process.1,2 Here we report on the results obtained with an air plasma-driven continuous-flow ozonolysis system. (... continues

Snow Cover and Precipitation Impacts on Dry Season Streamflow in the Lower Mekong Basin

Climate change impacts on dry season streamflow in the Mekong River are relatively understudied, despite the fact that water availability during this time is critically important for agricultural and ecological systems. Analyses of two gauging stations (Vientiane and Kratie) in the Lower Mekong Basin (LMB) show significant positive correlations between dry season (March through May, MAM) discharge and upper basin snow cover and local precipitation. Using snow cover, precipitation, and upstream discharge as predictors, we develop skillful regression models for MAM streamflow at Vientiane and Kratie, and force these models with output from a suite of general circulation model (GCM) experiments for the twentieth and twenty-first centuries. The GCM simulations predict divergent trends in snow cover (decreasing) and precipitation (increasing) over the twenty-first century, driving overall negligible long-term trends in dry season streamflow. Our study demonstrates how future changes in dry season streamflow in the LMB will depend on changes in snow cover and precipitation, factors that will need to be considered when assessing the full basin response to other climatic and non-climatic drivers

Kinetic Resolution in Asymmetric Epoxidation using Iminium Salt Catalysis

The first reported examples of kinetic resolution in epoxidation reactions using iminium salt catalysis are described, providing up to 99% ee in the epoxidation of racemic cis-chromenes

The incidence and risk factors for new onset atrial fibrillation in the PROSPER study

Aims Atrial fibrillation/flutter (AF) is the most common arrhythmia in older people. It associates with reduced exercise capacity, increased risk of stroke, and mortality. We aimed to determine retrospectively whether pravastatin reduces the incidence of AF and whether any electrocardiographic measures or clinical conditions might be risk factors for its development. Methods and results The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was a randomized, double-blind controlled trial that recruited 5804 individuals aged 70-82 years with a history of, or risk factors for, vascular disease. A total of 2891 were allocated to pravastatin and 2913 to placebo; mean follow-up was 3.2 years. Electrocardiograms (ECGs), which were recorded at baseline, annually thereafter, and at run-out, were processed by computer and reviewed manually. In all, 264 of 2912 (9.1%) of the placebo group and 283 of 2888 (9.8%) of the pravastatin-treated group developed AF [hazard ratio 1.08 (0.92,1.28), P = 0.35)]. Multivariate analysis showed that PR and QTc intervals, age, left ventricular hypertrophy, and ST-T abnormalities were related to development of AF after adjustment for many variables including alcohol consumption, which itself was univariately predictive of developing AF. Previous myocardial infarction on the ECG was not a risk factor. A history of vascular disease was strongly linked with developing AF but not diabetes and hypertension. Conclusion Pravastatin does not reduce the incidence of AF in older people at risk of vascular disease, at least in the short-medium term. Risk factors for AF include older age, prolongation of PR or QTc intervals, left ventricular hypertrophy, and ST-T abnormalities on the EC

Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that presents clinicians with a diagnostic challenge. The use of natriuretic peptides to exclude a diagnosis of HFpEF has been proposed. We sought to compare HFpEF patients with N-terminal pro-brain natriuretic peptide (NT-proBNP) level above and below the proposed cut-off. Methods Stable patients (n = 30) with left ventricular (LV) ejection fraction ≥ 50% were eligible if they had a diagnosis of HF according to the European Society of Cardiology diagnostic criteria. Characteristics of patients with NT-proBNP below (≤125 pg/mL) and above (\u3e125 pg/mL) the diagnostic criterion were compared. Results There were 19 (66%) women with median age 54 years. Half were African American (16, 53%), and most were obese. There were no significant differences in clinical characteristics or medication use between groups. LV end-diastolic volume index was greater in high NT-proBNP patients (P = 0.03). Left atrial volume index, E/e\u27 ratio, and E/e\u27 ratio at peak exercise were not significantly different between NT-proBNP groups. Peak oxygen consumption (VO2), VO2 at ventilatory threshold, and ventilatory efficiency measures were impaired in all patients and were not significantly different between high and low NT-proBNP patients. Conclusions NT-proBNP was below the proposed diagnostic cut-off point of 125 pg/mL in half of this obese study cohort. Cardiac diastolic dysfunction and cardiorespiratory fitness were not significantly different between high and low NT-proBNP patients. These data indicate that excluding the diagnosis of HFpEF based solely on NT-proBNP levels should be discouraged

Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2)

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of con-firmed HF cases in the United States. However, there are no highly effective evidence-basedtreatments currently available for these patients. Inflammation correlates positively withadverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, hasbeen implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clini-cal trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 ran-domized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespi-ratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation inpatients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpointswill be placebo-corrected interval changes in peak oxygen consumption and ventilatory effi-ciency at week 12. In addition, secondary and exploratory analyses will investigate the effectsof IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function,quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinicaltrial will add to the growing body of evidence on the role of inflammation in cardiovascular dis-ease, specifically focusing on patients with HFpEF

"Copper-in-charcoal" revisited: delineating the nature of the copper species and its role in catalysis

"Copper-in-charcoal" has been shown to be a versatile catalytic source of supported copper for a variety of important synthetic transformations, as well as in other fields such as energy. We herein report the characterization of this material and the implications that its preparation has on catalysis, thus providing a greater understanding of the scope and limitations of this catalyst system. (Chemical Equation Presented)

Paleoclimate histories improve access and sustainability in index insurance programs

Proxy-based climate reconstructions can extend instrumental records by hundreds of years, providing a wealth of climate information at high temporal resolution. To date, however, their usefulness for informing climate risk and variability in policy and social applications has been understudied. Here, we apply tree-ring based reconstructions of drought for the last 700 years in a climate index insurance framework to show that additional information from long climate reconstructions significantly improves our understanding of the underlying climate distributions and variability. We further show that this added information can be used to better characterize risk to insurance providers, in many cases providing meaningful reductions in long-term contract costs to farmers in stand-alone policies. The impact of uncertainty on insurance premiums can also be reduced when insurers diversify portfolios, and the availability of long-term climate information from tree rings across a broad geographic range provides an opportunity to characterize spatial correlation in climate risk across geographic regions. Our results are robust to the range of climate variability experienced over the last 400 years and in model simulations of the twenty-first century, even within the context of changing baselines due to low frequency variability and secular climate trends. These results demonstrate the utility of longer-term climate histories in index insurance applications. Furthermore, they make the case from a climate-variability perspective for the continued importance of such approaches to improving the instrumental climate record, even into a non-stationary climate future