Enantioselective Synthesis of Heterocycles via Palladium Catalyzed Alkene Difunctionalization Reactions.

Enantiopure nitrogen and oxygen containing heterocycles are prominently displayed in a variety of important pharmaceuticals and biologically active products. As such accessing these scaffolds in an enantioselective and efficient manner is an interesting challenge. We envisioned that novel asymmetric carboamination and carboetherification reactions would be powerful methods to synthesize these enantiopure heterocycles, as you can generate a library of enantiopure compounds in a facile manner with this approach. While these enantioselective carboamination and carboetherification reactions are robust methods of accessing enantiopure heterocycles, at the onset of the work detailed in this thesis all of the efforts in this area were related to the formation of 5-membered rings bearing a single nitrogen heteroatom. As such, this thesis entails the development of new enantioselective carboamination and carboetherification reactions meant to address the above limitations. Chapter 2 details the development of an enantioselective carboamination reaction to access enantiopure imidazolidin-2-ones in up to 97:3 er. This work also shows how reaction conditions, namely the choice of aryl halide, use of water additive and substrate electronics, affect the final enantioselectivity observed in the products. Chapter 3 details the development of a general procedure to access tetrahydroquinolines, tetrahydroisoquinolines and tetrahydroquinoxalines all in > 95:5 er. Furthermore, these reactions in chapter 3 are rare transformations of this type that allow for the synthesis of quaternary centers in high enantioselectivity. Chapter 4 details the xiii development of a novel carboetherification reaction, and how using a modular TADDOL ligand scaffold allowed us to rationally design a ligand that afforded our desired products in >95:5 er. Lastly, Chapter 5 entails the initial results looking into the synthesis of enantiopure benzofused oxygen heterocycles.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113418/1/bahopki_1.pd

Development of Enantioselective Palladium‐Catalyzed Alkene Carboalkoxylation Reactions for the Synthesis of Tetrahydrofurans

The Pd‐catalyzed coupling of γ‐hydroxyalkenes with aryl bromides affords enantiomerically enriched 2‐(arylmethyl)tetrahydrofuran derivatives in good yield and up to 96:4 e.r. This transformation was achieved through the development of a new TADDOL/2‐arylcyclohexanol‐derived chiral phosphite ligand. The transformations are effective with an array of different aryl bromides, and can be used for the preparation of products bearing quaternary stereocenters.The construction of enantiomerically enriched tetrahydrofurans is accomplished by asymmetric Pd‐catalyzed cross‐coupling reactions between γ‐hydroxyalkenes and aryl bromides. Use of a palladium catalyst supported by a new TADDOL‐derived chiral phosphite ligand provides the tetrahydrofuran products in good yield with up to 96:4 e.r. (see scheme).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115961/1/anie_201506884_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115961/2/13390_ftp.pd

Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub.

Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation. TLR4/MD2 activation leads only to formation of TLR4/MD2 heterotetramers, but not oligomers, suggesting a stoichiometric mismatch between activated receptors and MyDDosomes. The strength of TLR4 signalling depends not only on the number and size of MyDDosomes formed but also how quickly these structures assemble. Activated TLR4, therefore, acts transiently nucleating assembly of MyDDosomes, a process that is uncoupled from receptor activation. These data explain how the oncogenic mutation of MyD88 (L265P) assembles MyDDosomes in the absence of receptor activation to cause constitutive activation of pro-survival NF-κB signalling

The social cognition of medical knowledge, with special reference to childhood epilepsy

This paper arose out of an engagement in medical communication courses at a Gulf university. It deploys a theoretical framework derived from a (critical) sociocognitive approach to discourse analysis in order to investigate three aspects of medical discourse relating to childhood epilepsy: the cognitive processes that are entailed in relating different types of medical knowledge to their communicative context; the types of medical knowledge that are constituted in the three different text types analysed; and the relationship between these different types of medical knowledge and the discursive features of each text type. The paper argues that there is a cognitive dimension to the human experience of understanding and talking about one specialized from of medical knowledge. It recommends that texts be studied in medical communication courses not just in terms of their discrete formal features but also critically, in terms of the knowledge which they produce, transmit and reproduce

Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH Randomized Clinical Trial

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191

Assessing Radiation Pressure as a Feedback Mechanism in Star-Forming Galaxies

Radiation pressure from the absorption and scattering of starlight by dust grains may be an important feedback mechanism in regulating star-forming galaxies. We compile data from the literature on star clusters, star-forming subregions, normal star-forming galaxies, and starbursts to assess the importance of radiation pressure on dust as a feedback mechanism, by comparing the luminosity and flux of these systems to their dust Eddington limit. This exercise motivates a novel interpretation of the Schmidt Law, the LIR-L'CO correlation, and the LIR-L'HCN correlation. In particular, the linear LIR-L'HCN correlation is a natural prediction of radiation pressure regulated star formation. Overall, we find that the Eddington limit sets a hard upper bound to the luminosity of any star-forming region. Importantly, however, many normal star-forming galaxies have luminosities significantly below the Eddington limit. We explore several explanations for this discrepancy, especially the role of "intermittency" in normal spirals - the tendency for only a small number of subregions within a galaxy to be actively forming stars at any moment because of the time-dependence of the feedback process and the luminosity evolution of the stellar population. If radiation pressure regulates star formation in dense gas, then the gas depletion timescale is 6 Myr, in good agreement with observations of the densest starbursts. Finally, we highlight the importance of observational uncertainties - namely, the dust-to-gas ratio and the CO-H2 and HCN-H2 conversion factors - that must be understood before a definitive assessment of radiation pressure as a feedback mechanism in star-forming galaxies.Comment: 12 pages, emulateapj, Accepted for publication in Ap

Paving the way for research findings: writers' rhetorical choices in education and applied linguistics

Notwithstanding the existence of previous investigations into how research results are presented in different academic disciplines, fewer studies have looked into how authors pave the way for their results, the interdisciplinary differences in ‘result pavements’, and the interconnections between their communicative functions and linguistic choices. Using the techniques of genre analysis, I have analyzed two corpora of research reports in applied linguistics and education in order to identify the possible ways in which experienced writers schematically pave the way for their findings. Using evidence based on authentic research articles, this study demonstrates how writers set the stage for their research results by (i) demonstrating their control of the structure and flow of result-related information, (ii) connecting past research with a current finding while furnishing pertinent background elements that lead the readership progressively to specific findings, (iii) regenerating readers’ interest in their initial research purposes, and (iv) deploying locatives to embed results in a ‘space-saving strategy’ aimed at presenting an abridged Results section. I have also analyzed interdisciplinary differences in the frequencies of these rhetorical steps and the range of intricate linguistic mechanisms employed by authors as communicative resources in each step to establish a smooth rhetorical transition that sets the stage for their research results

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented