Expedient synthesis of 3-hydroxyisoquinolines and 2-hydroxy-1,4-naphthoquinones via one-pot aryne acyl-alkylation/condensation

A convenient method is disclosed for the synthesis of both 3-hydroxyisoquinolines and 2-hydroxy-1,4-naphthoquinones from b-ketoesters using a one-pot aryne acyl-alkylation/condensation procedure. When performed in conjunction with a one-step method for the synthesis of the b-ketoester substrates, this method provides a new route to these polyaromatic structures in only two steps from commercially available carboxylic acid starting materials. The utility of this approach is demonstrated in the synthesis of the atropisomeric P,N-ligand, QUINAP

Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation

Described in this report is the development of two unique methodologies exploiting the reactivity of arynes. Reaction of N-carbamoyl-functionalized enamine derivatives with benzyne affords substituted indolines. An orthogonal reactivity is uncovered when related enamine derivatives are modified as amides, such that isoquinolines are formed as the product of condensation with benzyne. This latter transformation is applied to a concise total synthesis of the opiate alkaloid papaverine

Benzannulated Bicycles by Three-Component Aryne Reactions

Triple crown: A pair of three-component coupling reactions between arynes, isocyanides, and either activated alkynes or phenyl esters generates unusual iminoindenones or phenoxy iminoisobenzofurans (see scheme), the latter of which may be advanced to o-ketobenzamides by performing direct hydrolysis. The synthetic utility of these compounds is demonstrated in a rapid preparation of substituted dibenzoketocaprolactams

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

© 2014 John Wiley & Sons Ltd. Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P  <  0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI]  = 11·6-106·4) and this was preserved in early-stage disease patients (P  <  0·0001, HR=19·3, 95% CI = 17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL

Teacher Performance Incentives and Student Outcomes

This paper reviews the evidence on the effectiveness of individual merit pay systems for teachers on student achievement, and it presents new empirical results based on a system established within a collective bargaining environment. While many merit pay systems have been established in school districts across the U.S., very little empirical evidence concerning their influence on student achievement exists. A natural experiment arose in a county in which one high school piloted a merit pay system that rewarded student retention and student evaluations of teachers while another comparable high school maintained a traditional compensation system. A difference-in-differences analysis implies that merit pay had no effect on grade point averages, reduced the percentage of students who dropped out of courses, reduced average daily attendance, and increased the percentage of students who failed. The outcomes illustrate the difficulty of instituting individual merit pay in schools. The goal was to increase student retention. A student was considered to be retained in a class if the student was present during a randomly selected day of the last week of classes. The system worked by this measure because the school experienced a significant reduction in course noncompleters. However it is not clear that this measure was correlated with student achievement or even average attendance, and indeed, neither of these outcomes were improved

Rapid and reversible impairment of episodic memory by a high-fat diet in mice.

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. This work was supported by an EASTBIO BBSRC PhD studentship to F.H.M., L.M.W., C.G., A.C.M., G.W.H. and F.M.C. are supported by Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS).Peer reviewedPublisher PD