Alkaloid inspired spirocyclic oxindoles from 1,3-dipolar cycloaddition of pyridinium ylides

Cycloaddition reactions between pyridinium ylides and 3-alkenyl oxindoles that proceed in high yield and with very good regio- and diastereoselectivity are reported. The resulting cycloadducts have the same stereochemistry of biologically active oxindole alkaloids, such as strychnofoline

High Yielding Continuous-Flow Synthesis of Norketamine

A new continuous-flow process is presented for synthesis of the pharmaceutical intermediate norketamine (5). Our approach has been to take the well-established and industrially applied batch synthetic route to this promising antidepressant precursor and convert it to a telescoped multi-stage continuous-flow platform. This involves the α-bromination of a ketone, an imination/rearrangement sequence with liquid ammonia, and a thermally induced α-iminol rearrangement. Our approach is high yielding and provides several processing advantages including the reduction of many of the hazards conventionally associated with this route, particularly in the handling of liquid bromine, hydrogen bromide gas, and liquid ammonia. Each of these presents serious operational challenges in a batch process at scale

Variation in centre-specific survival in patients starting renal replacement therapy in England is explained by enhanced comorbidity information from hospitalization data

Background Unadjusted survival on renal replacement therapy (RRT) varies widely from centre to centre in England. Until now, missing data on case mix have made it impossible to determine whether this variation reflects genuine differences in the quality of care. Data linkage has the capacity to reduce missing data. Methods Modelling of survival using Cox proportional hazards of data returned to the UK Renal Registry on patients starting RRT for established renal failure in England. Data on ethnicity, socioeconomic status and comorbidity were obtained by linkage to the Hospital Episode Statistics database, using data from hospitalizations prior to starting RRT. Results Patients with missing data were reduced from 61 to 4%. The prevalence of comorbid conditions was remarkably similar across centres. When centre-specific survival was compared after adjustment solely for age, survival was below the 95% limit for 6 of 46 centres. The addition of variables into the multivariable model altered the number of centres that appeared to be ‘outliers’ with worse than expected survival as follows: ethnic origin four outliers, socioeconomic status eight outliers and year of the start of RRT four outliers. The addition of a combination of 16 comorbid conditions present at the start of RRT reduced the number of centres with worse than expected survival to one. Conclusions Linked data between a national registry and hospital admission dramatically reduced missing data, and allowed us to show that nearly all the variation between English renal centres in 3-year survival on RRT was explained by demographic factors and by comorbidity

A novel 1,3-dipolar cycloaddition strategy towards securinine and virosecurinine

This thesis describes the development of a novel synthetic route towards the Securinega alkaloids, securinine 1 and virosecurinine 2. The key reaction in this innovative approach is the l,3-dipolar cycloaddition between pyridinium stabilised ylides 169 and γ,δ-unsaturated butenolides 142, to form spirocyclic dihydropyridines 168 as single diastereoisomers. The Introduction chapter introduces the Securinega alkaloids and describes previous syntheses of securinine 1. This section also reports on developments in the field of l,3-dipolar cycloaddition chemistry, with particular emphasis on the cycloadditions of pyridinium stabilised ylides 169. Cycloadditions of γ,δ -unsaturated butenolides 142 with azomethine and other ylides are also described. The Results and Discussion section describes investigations which were conducted towards the total synthesis of securinine 1 and virosecurinine 2. A number of routes to γ,δ -unsaturated butenolides 191 were evaluated and are discussed. The optimum route was found to be a three step procedure from propargyl alcohols 193, via Johnson-Claisen rearrangement to 13- allenic esters, which were hydrolysed and then cyclised under transition metal catalysis. γ,δ -unsaturated butenolides 191 were then employed in l,3-dipolar cycloaddition reactions with pyridinium stabilised ylides 169. Dihydropyridines 168 formed in the cycloaddition step were found to be unstable and as such, strategies for the stabilisation of these compounds are discussed. Reduction afforded stable intermediates 229 prompting investigation to deliver intermediates that could be used to carry out the remaining cyclisation required for the synthesis of tetracyclic structures. Attempts at a variety of such ring closing reactions are described, the most advanced intermediates being committed to an intramolecular Heck reaction. Finally, expansion of the scope of the key cycloaddition reaction is described and opportunities for further developments are discussed. The Experimental section describes all procedures which were used to synthesise compounds disclosed in this thesis. Full spectroscopic data and characterisation is also provided. The Appendices include some relevant XRD, NMR and MS data for clarity.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Understanding the impact of academic difficulties among medical students: a scoping review

Background Many medical students may encounter a range of academic and personal challenges during their course of study, but very little is known about their experiences. Our aim was to review the literature to inform future scholarship and to inform policy change. Methods A scoping review was conducted searching PubMed, MEDLINE, EMBASE, PsycInfo, British Education Index, Web of Science and ERIC for English language primary research with no date limits. This retrieved 822 papers of which eight met the requirements for inclusion in the review. Data were independently reviewed by two researchers and underwent thematic analysis by the research team. Results Three major themes emerged. Theme 1: ‘Identity preservation’ addressed students' aim to preserve their sense of self in the face of academic difficulty and their tendency to seek support. This connected the apprehension many students expressed about their educational institutions to Theme 2: ‘The dual role of the medical school’—medical schools are required to support struggling students but are predominantly seen as a punitive structure acting as the gatekeeper to a successful career in medicine. Students' apprehension and attempts to protect their identities within this complex landscape often resulted in ‘maladaptive coping strategies’ (Theme 3). Conclusion Understanding and exploring the academic challenges faced by medical students through their own experiences highlight the need for the development of more individualised remediation strategies. Educators may need to do more to bridge the gap between students and institutions. There is a need to build trust and to work with students to enhance their sense of self and remediate approaches to engagement with learning, rather than focusing efforts on success in assessments and progression

Water based scale-up of CPO-27 synthesis for nitric oxide delivery

The authors thank Scottish Enterprise for funding for the scale up work (POC13). We gratefully acknowledge the EPSRC (EP/K025112/1) and the Royal society for the Brian Mercer Award for Innovation (MI120033).The applicability of water-based reflux and room temperature synthesis processes for the production of CPO-27 MOFs, suitable for NO delivery applications, is investigated. NO adsorption, storage and release performance of products obtained under reflux conditions are comparable to those of equivalent samples synthesised from traditional solvothermal methods at small scale. Products obtained from room temperature processes show lower NO release capability, although the quantities that are released are still more than adequate for biomedical applications. Results also reveal differences for the first time in NO uptake, storage and release depending on whether Zn, Ni or Mg is employed. The results indicate that while the crystallinity of CPO-27 (Zn) and CPO-27 (Mg) is not affected by moving to lower temperature methods, the crystallinity of CPO-27 (Ni) is reduced. Particle morphology and size is also affected. The low temperature processes are successfully demonstrated at 20L and 100L scale and the main problems encountered during scale-up are outlined. The 100L scale is in itself an appropriate production scale for some niche biomedical products. Indeed, results indicate that this synthesis approach is suitable for commercial production of MOFs for this application field. We also confirm that BET surface area from nitrogen adsorption at 77 K is not a good indicator for successful adsorption of NO.Publisher PDFPeer reviewe

Water based scale-up of CPO-27 synthesis for nitric oxide delivery

The applicability of water-based reflux and room temperature synthesis processes for the production of CPO-27 MOFs, suitable for NO delivery applications, is investigated. NO adsorption, storage and release performance of products obtained under reflux conditions are comparable to those of equivalent samples synthesised from traditional solvothermal methods at small scale. Products obtained from room temperature processes show lower NO release capability, although the quantities that are released are still more than adequate for biomedical applications. Results also reveal differences for the first time in NO uptake, storage and release depending on whether Zn, Ni or Mg is employed. The results indicate that while the crystallinity of CPO-27 (Zn) and CPO-27 (Mg) is not affected by moving to lower temperature methods, the crystallinity of CPO-27 (Ni) is reduced. Particle morphology and size is also affected. The low temperature processes are successfully demonstrated at 20L and 100L scale and the main problems encountered during scale-up are outlined. The 100L scale is in itself an appropriate production scale for some niche biomedical products. Indeed, results indicate that this synthesis approach is suitable for commercial production of MOFs for this application field. We also confirm that BET surface area from nitrogen adsorption at 77 K is not a good indicator for successful adsorption of NO