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RAND's evaluation of Jordan's Emergency Education Response Programme for Syrian refugee children identified significant successes and longer-term challenges. Key recommendations related to developing medium-term thinking and targeting gendered needs.

The alarming epidemic of obesity and physical inactivity at paediatric age urges societies to rise to the challenge of ensuring an active lifestyle. As one response to this, business enterprises are increasingly engaged in promoting sport and physical activity (PA) initiatives within the frame of corporate social responsibility (CSR). However, comparative analyses among industry sectors of CSR strategies for PA promotion with a particular focus on children are still lacking. This study aimed to explore (i) what are the CSR strategies for PA promotion adopted in different industry sectors and (ii) whether corporate engagement in promoting PA for children is supportive of children's rights to play and be physically active. Corporate pledges pertaining to CSR initiatives to promote PA were analysed. The hypothesis was that companies from different sectors employ different CSR strategies and that companies with a higher profile as regard to public health concerns for children tend to legitimate their action by adopting a compensatory strategy. Results show that the issue of PA promotion is largely represented within CSR commitments. CSR strategies for PA promotion vary across industry sectors and the adoption of a compensatory strategy for rising childhood obesity allows only a limited exploitation of the potential of CSR commitments for the provision of children's rights to play and be physically active. Actors within the fields of public health ethics, human rights and CSR should be considered complementary to develop mainstreaming strategies and improve monitoring systems of PA promotion in children.

Pharmacogenetics involves genetic testing of individual patients to guide drug treatment. Proponents argue that pharmacogenetics will achieve major gains in drug safety and efficacy, and revolutionise marketing. Pharmacogenetics also raises several policy concerns, including the need for sound information for clinical decision-making on drug-genetic test combinations. Currently, the pharmacogenetics science base and the rate of emergence of clinical applications are uncertain. Most commentary on pharmacogenetics focuses on new compounds, yet older drugs cause most adverse events. Test regulation in the USA appears fundamentally different from Europe, where evidence of safety or efficacy may not be required. Genetics research is needed as part of postmarketing surveillance systems. In routine clinical practice, computer-based health records with relevant decision support systems will also be needed. Without health policy action, pharmacogenetics could produce a new generation of poorly evaluated tests and drugs, with medicine becoming significantly less evidence-based, leading to rising costs, patient hazard and exclusions of drug-related ‘genetic minorities’ from evaluated treatments.

Twenty-four chiral dihydrofurocoumarin derivatives and structurally related compounds were separated using super/subcritical fluid chromatography (SFC) on three macrocyclic glycopeptide chiral stationary phases (CSPs). All the dihydrofurocoumarin derivatives could be resolved on at least one of the macrocyclic glycopeptide CSPs, and the Chirobiotic T column showed the best enantioselectivity for 21 of the dihydrofurocoumarins studied. The Chirobiotic TAG and Chirobiotic R CSPs separated similar numbers of chiral dihydrofurocoumarin derivatives (16 on Chirobiotic TAG and 15 on Chirobiotic R), but the Chirobiotic TAG column baseline resolved more samples than the Chirobiotic R column under similar experimental conditions. All separations were done isocratically with an outlet pressure regulated at 100 bar, a column temperature of 31 °C, and a flow rate of 3.0 mL min-1. Various amounts of methanol ranging from 2 to 25% (v/v) were added to the supercritical carbon dioxide in order to optimize the enantiomeric separations. All of the separations were completed in less than 15 min, and 81% of the separations were done in less than 10 min. The separation speed is one of the main advantages of SFC.

This article defines the public audit function and identifies pressures changing Value for Money (VFM) auditing in the public sector in the UK. These pressures have prompted a range of innovations in how organizations such as the National Audit Office carry out their evaluations. Related to these pressures is the rise of formal futures within the public sector. The implications of this thinking for VFM public auditing are examined. It is argued that, although conventional VFM auditing remains appropriate for much of the public sector, there are a growing number of public sector activities requiring a different approach. Such approaches include scenario planning. These not only present methodological problems for auditors but also raise important issues about the role of audit more generally. Finally, although these new tools may be helpful in many respects, it is suggested that they may increase the tension between anchoring parliamentary accountability in some statements of fact and contributing to improvements in the quality of public services.

David Melzer1†, Ron L Zimmern2, Don E Detmer3 & Tom Ling4 †Author for correspondence 1Director, Epidemiology for Policy Group, Department of Public Health and Primary Care, University of Cambridge, UK Tel : +44 (0)1223 330332 Fax: +44 (0)1223 330330 E-mail: dm214@medschl. cam.ac.uk 2Director, Public Health Genetics Unit, Cambridge, UK 3Gillings Professor of Health Management, Judge Institute of Management Studies, University of Cambridge, UK, and Professor Emeritus and Professor of Medical Education, University of Virginia, USA 4Professor of Public Policy, Anglia Polytechnic University, Cambridge, UK ‘Making good policy in the context of substantial uncertainty over the science base for pharmacogenetics will be challenging but clearly must be done.’

The Department for International Development (DfID) commissioned RAND Europe to conduct a Mid Term Review of the Strategic Impact Evaluation Fund, run by the World Bank.

Research summary describing our evaluation of the assessment process for submissions to the impact element of the Research Excellence Framework 2014 by UK universities, to explore strengths, weaknesses and implications for future similar exercises.

A set of 42 chiral compounds containing stereogenic sulfur was prepared. There were 31 chiral sulfoxide compounds, three tosylated sulfilimines and eight sulfinate esters. The separations were done using five different macrocyclic glycopeptide chiral stationary phases (CSPs), namely ristocetin A, teicoplanin, teicoplanin aglycone (TAG), vancomycin and vancomycin aglycone (VAG) and seven eluents, three normal-phase mobile phases, two reversed phases and two polar organic mobile phases. Altogether the macrocyclic glycopeptide CSPs were able to separate the whole set of the 34 sulfoxide enantiomers and tosylated derivatives. Five of the eight sulfinate esters were also separated. The teicoplanin and TAG CSPs were the most effective CSPs able to resolve 35 and 33 of the 42 compounds. The three other CSPs each were able to resolve more than 27 compounds. The normal-phase mode was the most effective followed by the reversed-phase mode with methanol-water mobile phases. Few of these compounds could be separated in the polar organic mode with 100% methanol mobile phases. Acetonitrile was also not a good solvent for the resolution of enantiomers of sulfur-containing compounds, neither in the reversed-phase nor in the polar organic mode. The structure of the chiral molecules was compared to the enantioselectivity factors obtained with the teicoplanin and TAG CSP. It is shown that the polarity, volume and shape of the sulfoxide substituents influence the solute enantioselectivity factor. Changing the oxidation state of the sulfur atom from sulfoxides to sulfinate esters is detrimental to the compound's enantioselectivity. The enantiomeric retention order on the teicoplanin and TAG CSPs was very consistent: the (S)-(1)-sulfoxide enantiomer was always the less retained enantiomer. In contrast, the (R)-(2)-enantiomer was less retained by the ristocetin A, vancomycin and vancomycin aglycone columns, showing the complementarity of these CSPs. The macrocyclic glycopeptide CSPs provided broad selectivity and effective separations of chiral sulfoxides. © 2002 Elsevier Science B.V. All rights reserved.

In the UK, joined–up government (JUG) was a central part of the first Blair government’s programme for public sector reform. It remains a pivotal, if more muted, feature of the second term. We will identify the range of disparate activities that have been branded as ‘joined up’. We then look at the variety of official guidance coming from the centre of government to highlight the overlapping and competing strategies that underpinned the implementation of joined–up government. Various competing strategies have been advocated and implemented at any one time. Therefore the situation was more fluid and more contested than might be inferred from the use of the homogenizing term ‘joined–up government’. We conclude by briefly considering what this implies for our understanding of intra–state relationships, of the relationships between public agencies and civil society, and the relationship between JUG and the politics of the Third Way.

In the summer of 1998 the National Health Service (NHS) Confederation in the UK used the opportunity provided by the celebrations marking the 50th anniversary of the NHS to engage in an exercise designed to stimulate thinking about the future of health services in Britain. A key part of this involved the creation of two possible future environments of the NHS. These became known as “the Madingley Scenarios”. In this article, the context of this work is briefly outlined before describing the main drivers that are shaping this environment (technology and information, new power structures, the changing relat ion ship with the living environment, and the effect of social and cultural change). The scenarios themselves are then outlined followed by some reflections on the value of this work in healthcare and beyond.

Background Governments can intervene to change health-related behaviours using various measures but are sensitive to public attitudes towards such interventions. This review describes public attitudes towards a range of policy interventions aimed at changing tobacco and alcohol use, diet, and physical activity, and the extent to which these attitudes vary with characteristics of (a) the targeted behaviour (b) the intervention and (c) the respondents. Methods We searched electronic databases and conducted a narrative synthesis of empirical studies that reported public attitudes in Europe, North America, Australia and New Zealand towards interventions relating to tobacco, alcohol, diet and physical activity. Two hundred studies met the inclusion criteria. Results Over half the studies (105/200, 53%) were conducted in North America, with the most common interventions relating to tobacco control (110/200, 55%), followed by alcohol (42/200, 21%), diet-related interventions (18/200, 9%), interventions targeting both diet and physical activity (18/200, 9%), and physical activity alone (3/200, 2%). Most studies used survey-based methods (160/200, 80%), and only ten used experimental designs. Acceptability varied as a function of: (a) the targeted behaviour, with more support observed for smoking-related interventions; (b) the type of intervention, with less intrusive interventions, those already implemented, and those targeting children and young people attracting most support; and (c) the characteristics of respondents, with support being highest in those not engaging in the targeted behaviour, and with women and older respondents being more likely to endorse more restrictive measures. Conclusions Public acceptability of government interventions to change behaviour is greatest for the least intrusive interventions, which are often the least effective, and for interventions targeting the behaviour of others, rather than the respondent him or herself. Experimental studies are needed to assess how the presentation of the problem and the benefits of intervention might increase acceptability for those interventions which are more effective but currently less acceptable.

[Reaction: see text] Six chiral ionic liquids were prepared and evaluated as "chiral induction solvents" in which two different dibenzobicyclo[2.2.2]octatrienes were photoisomerized to chiral products. Enantiomeric excesses from 3 to 12% were obtained from the photochemical di-pi-methane rearrangement. Results indicate that the chiral induction derives from an ion pairing interaction of the deprotonated diacids with the ionic liquid cation. This is the first report on chiral induction via a chiral IL for an irreversible, unimolecular photochemical isomerization.

Introduction Chronic obstructive pulmonary disease (COPD) is a chronic life-limiting condition with high symptom-burden and carer-burden. National guidance on end of life care calls for quality care for patients with any condition, yet we rely on frameworks developed for cancer with its largely predictable trajectory. Aim To develop evidence-based recommendations to inform a new framework to improve care and support of patients living with advanced COPD and their informal carers. Methods The Living with Breathlessness Study was a multiple-component, population-based, mixed-method longitudinal, multiple-perspective research programme to identify new evidence on health and social care needs and preferences of patients with advanced COPD and their carers. It followed more than 500 patients and carers for up to 18-months through interview and survey methods. Qualitative data on barriers and facilitators to meeting needs were collected from clinicians. Programme-wide evidence was synthesised to identify recommendations. Stakeholder views were then collected through a workshop and online survey. Results Six inter-related recommendations emerged, linked by the concept of proactive person-centred care: (1) Stop the continual focus on the challenge of prognosis and unpredictability of trajectories as barriers to meeting needs, (2) Change targets to incentivise person-centred care within existing services, (3) Enable identification and response to patient support needs (through evidence-based tools and approaches), (4) Identify and support patients’ informal carers (through evidence-based tools and approaches), (5) Identify and respond to psychological morbidity in patients and informal carers identify and respond to psychological morbidity, (6) Change societal attitudes and understandings of COPD, breathlessness, palliative care and informal carer support. The recommendations are underpinned by action points to enable delivery. The recommendations garnered significant support from stakeholders, with caution regarding ease of implementation which varied by recommendation. Conclusion These six inter-related recommendations, and supporting action points, could inform a new framework for care and support in advanced COPD likely to have resonance for those living with other advanced non-malignant long term conditions, and for clinicians striving to support them.

Introduction COPD is a progressive condition with high symptom burden. Advanced COPD management should relieve symptoms, optimise daily functioning and reduce carer burden. Our knowledge of clinician barriers and facilitators to meeting the needs of these patients and their informal carers is limited. Aim To identify modifiable barriers to meeting care and support needs of patients with advanced COPD and their carers. Methods Purposively-sampled clinicians nominated by a population-based cohort of patients with advanced COPD participating in the Living with Breathlessness Study, took part in Longitudinal qualitative interviews on barriers and facilitators to meeting needs, and analysed using a Framework approach. Identified barriers were reviewed and recommendations to overcome them presented to stakeholders via workshop and online survey methods. Results Identification and assessment of patient need, and barriers and facilitators to doing so, were largely driven by organisational and medical agendas, rather than person-centred care models. There was little evidence of clinician engagement with patients’ informal carers. There was a mismatch between clinicians’ perceptions of changes in patient need during the 18-month study duration and those of patients and carers. Clinicians felt unprepared for end-of-life care discussions and found patient readiness for these conversations difficult to assess. Clinician-identified patient, organisational and professional facilitators included trust, time and accessibility. Conclusion Actioning recommendations such as stopping focusing on the challenge of prognostication as a barrier to meeting need, changing targets to incentivise person-centred care and identifying and supporting carers could improve care and support of patients and carers living with advanced COPD. This report is independent research supported by the National Institute for Health Research (Career Development Fellowship, CDF-2012-05-218). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

Introduction: In 2009, the English Department of Health appointed 16 integrated care pilots which aimed to provide better integrated care. We report the quantitative results from a multi-method evaluation of six of the demonstration projects which used risk profiling tools to identify older people at risk of emergency hospital admission, combined with intensive case management for people identified as at risk. The interventions focused mainly on delivery system redesign and improved clinical information systems, two key elements of Wagner's Chronic Care Model.Methods: Questionnaires to staff and patients. Difference-in-differences analysis of secondary care utilisation using data on 3,646 patients and 17,311 matched controls, and changes in overall secondary care utilisation.Results: Most staff thought that care for their patients had improved. More patients reported having a care plan but they found it significantly harder to see a doctor or nurse of their choice and felt less involved in decisions about their care. Case management interventions were associated with a 9% increase in emergency admissions. We found some evidence of imbalance between cases and controls which could have biased this estimate, but simulations of the possible effect of unobserved confounders showed that it was very unlikely that the sites achieved their goal of reducing emergency admissions. However, we found significant reductions of 21% and 22% in elective admissions and outpatient attendance in the six months following an intervention, and overall inpatient and outpatient costs were significantly reduced by 9% during this period. Area level analyses of whole practice populations suggested that overall outpatient attendances were significantly reduced by 5% two years after the start of the case management schemes.Conclusion: Case management may result in improvements in some aspects of care and has the potential to reduce secondary care costs. However, to improve patient experience, case management approaches need to be introduced in a way which respects patients' wishes, for example the ability to see a familiar doctor or nurse.

Background. In 2008, the English Department of Health appointed 16 'Integrated Care Pilots' which used a range of approaches to provide better integrated care. We report qualitative analyses from a three year multi-method evaluation to identify barriers and facilitators to successful integration of care. Theory and methods. Data were analysed from transcripts of 213 in-depth staff interviews, and from semi-structured questionnaires (the 'Living Document') completed by staff in pilot sites at six points over a two-year period. Emerging findings were therefore built from 'bottom up' and grounded in the data. However, we were then interested in how these findings compared and contrasted with more generic analyses. Therefore after our analyses were complete we then systematically compared and contrasted the findings with the analysis of barriers and facilitators to quality improvement identified in a systematic review by Kaplan et al (2010) and the analysis of more micro-level shapers of behaviour found in Normalisation Process Theory (May et al 2007). Neither of these approaches claims to be full blown theories but both claim to provide mid-range theoretical arguments which may be used to structure existing data and which can be undercut or reinforced by new data.Results and discussion. Many barriers and facilitators to integrating care are those of any large scale organisational change. These include issues relating to leadership, organisational culture, information technology, physician involvement, and availability of resources. However, activities which appear particularly important for delivering integrated care include personal relationships between leaders in different organisations, the scale of planned activities, governance and finance arrangements, support for staff in new roles, and organisational and staff stability. We illustrate our analyses with a 'routemap' which identifies questions that providers may wish to consider when planning interventions to improve the integration of care.

Background The National Institute for Health Research (NIHR) was established in 2006 with the aim of creating an applied health research system embedded within the English National Health Service (NHS). NIHR sought to implement an approach for monitoring its performance that effectively linked early indicators of performance with longer-term research impacts. We attempted to develop and apply a conceptual framework for defining appropriate key performance indicators for NIHR. Method Following a review of relevant literature, a conceptual framework for defining performance indicators for NIHR was developed, based on a hybridisation of the logic model and balanced scorecard approaches. This framework was validated through interviews with key NIHR stakeholders and a pilot in one division of NIHR, before being refined and applied more widely. Indicators were then selected and aggregated to create a basket of indicators aligned to NIHR's strategic goals, which could be reported to NIHR's leadership team on a quarterly basis via an oversight dashboard. Results Senior health research system managers and practitioners endorsed the conceptual framework developed and reported satisfaction with the breadth and balance of indicators selected for reporting. Conclusions The use of the hybrid conceptual framework provides a pragmatic approach to defining performance indicators that are aligned to the strategic aims of a health research system. The particular strength of this framework is its capacity to provide an empirical link, over time, between upstream activities of a health research system and its long-term strategic objectives.

Background: In response to concerns that the needs of the aging population for well-integrated care were increasing, the English National Health Service (NHS) appointed 16 Integrated Care Pilots following a national competition. The pilots have a range of aims including development of new organisational structures to support integration, changes in staff roles, reducing unscheduled emergency hospital admissions, reduced length of hospital stay, increasing patient satisfaction, and reducing cost. This paper describes the evaluation of the initiative which has been commissioned.Study design and data collection methods: A mixed methods approach has been adopted including interviews with staff and patients, non-participant observation of meetings, structured written feedback from sites, questionnaires to patients and staff, and analysis of routinely collected hospital utilisation data for patients/service users. The qualitative analysis aims to identify the approaches taken to integration by the sites, the benefits which result, the context in which benefits have resulted, and the mechanisms by which they occur.Methods of analysis: The quantitative analysis adopts a 'difference in differences' approach comparing health care utilisation before and after the intervention with risk-matched controls. The qualitative data analysis adopts a 'theory of change' approach in which we triangulate data from the quantitative analysis with qualitative data in order to describe causal effects (what happens when an independent variable changes) and causal mechanisms (what connects causes to their effects). An economic analysis will identify what incremental resources are required to make integration succeed and how they can be combined efficiently to produce better outcomes for patients.Conclusion: This evaluation will produce a portfolio of evidence aimed at strengthening the evidence base for integrated care, and in particular identifying the context in which interventions are likely to be effective. These data will support a series of evaluation judgements aimed at reducing uncertainties about the role of integrated care in improving the efficient and effective delivery of healthcare.

In 2004 a UK charity, The Health Foundation, established the 'Engaging with Quality Initiative' to explore and evaluate the benefits of engaging clinicians in quality improvement in healthcare. Eight projects run by professional bodies or specialist societies were commissioned in various areas of acute care. A developmental approach to the initiative was adopted, accompanied by a two level evaluation: eight project self-evaluations and a related external evaluation. This paper describes how the protocol for the external evaluation was developed. The challenges faced included large variation between and within the projects (in approach, scope and context, and in understanding of quality improvement), the need to support the project teams in their self-evaluations while retaining a necessary objectivity, and the difficulty of evaluating the moving target created by the developmental approach adopted in the initiative. An initial period to develop the evaluation protocol proved invaluable in helping us to explore these issues.

The clinical utility of newly identified genetic variants associated with common diseases needs evaluation

This study was to assess the impact of an initiative promoting independent living for disabled people, developed by the English disability charity Papworth Trust.

Hallsworth and Ling present an overview of the achievements of the European Union Platform on Diet, Physical Activity and Health in 2006. The Platform brings together stakeholders from across Europe, all of whom are undertaking actions to improve the health of European citizens. The report presents the Platform’s achievements by summarising information contained in 121 monitoring forms that were provided by members of the Platform.

Uncertainty for policy makers is not new but the pressure to make decisions under conditions of uncertainty is perhaps greater than ever. The arrival of new scientific developments such as pharmacogenetics offers potentially great benefits (as well as significant risks). They have passionate supporters as well as doubters. The evidence is often extensive but unclear and policy makers may find themselves under pressure to make decisions before they feel that the evidence is compelling. The UK is particularly well placed to play a leading role in the development of pharmacogenetics and is equally well placed to derive the benefits to both health and wealth that could flow from this. However, the uncertainties threaten to overwhelm the capacity of policy makers to act effectively. The uncertainties are both about the context within which the science and delivery of pharmacogenetics is being developed and about the interests that could be served. This paper maps these uncertainties and concludes with some suggestions, drawing on deliberative democracy and futures thinking, as to how policy makers might manage the tensions and dilemmas they face by moving from an unstable, emergent policy arena to a more stable one.

HPLC enantiomeric separations of a wide variety of racemic analytes was evaluated using chiral stationary phases (CSPs) based on the macrocyclic glycopeptides teicoplanin (T), teicoplanin aglycone (TAG), and methylated teicoplanin aglycone (Me-TAG) in two different mobile phase modes, i.e., the RP mode and the polar organic (PO) mode. Comparison of the enantiomeric separations using Chirobiotic T, Chirobiotic TAG, and the methylated form of TAG were conducted in order to gain a better understanding of the roles of the polar functional groups on the CSP. Substantial effects due to the cleavage of saccharides and/or methylation on chiral separations were observed in both separation modes. Improved separation efficiencies for many acidic analytes were obtained by methylating the H-bonding groups of TAG. These groups were believed to be a contributing factor to band broadening on TAG due to their negative effect on mass transfer between the stationary phase and mobile phase. Ionic/dipolar interactions between the carboxylate group of the analytes and the amine groups on T, TAG, or Me-TAG are important for chiral discrimination. Therefore, analytes possessing a carboxyl group are good candidates for successful separations on these CSPs. Hydrophobic interactions are important for enantiomeric separations in the RP mode where the H-bonding interactions between analytes and the chiral selectors are relatively weak. Me-TAG offers higher hydrophobicity, which can accentuate the interactions of analytes with hydrophobic moieties, but these interactions are not necessarily stereoselective. In the PO mobile phase, electrostatic/dipolar interactions between polar functional groups are the dominating interactions in chiral recognition. Another important factor is steric fit, which could be changed with every modification of the T structure. Therefore, substantial changes of enantioseparations were obtained within this studied group of CSPs. The PO mode was shown to be the most powerful mobile phase mode for enantiomeric separations on T-based stationary phases, mainly due to the improved efficiency. Methylation of the TAG proved to be a very useful tool for investigating the chiral recognition mechanism for this group of chiral selectors.

We report the first separation of the enantiomers of hypericin. Their steady-state optical spectra and ultrafast primary photoprocesses are investigated in chiral environments. Within experimental error, there is no difference between the two enantiomers in any of the systems considered. This is consistent with the emerging picture that the rich and extended absorption spectrum of hypericin is not a result of ground-state heterogeneity. It is also consistent with the observation that the spectra and photophysics of hypericin are generally insensitive to environments in which it does not aggregate.

A set of 28 racemic dihydrofurocoumarins in which the stereogenic center is located in the furan ring have been synthesized. Currently no effective asymmetric synthesis of this class of compounds exists, although their enantiomers are produced biologically by certain plants. Their diverse medicinal properties are being investigated in several laboratories. The enantioselective separation of these dihydrofurocoumarins by three native and six derivatized cyclodextrins has been evaluated in the reversed-phase mode, the polar organic mode, and normal-phase mode. The hydroxypropyl-beta-cyclodextrin is the most effective chiral stationary phase (CSP) at separating the dihydrofurocoumarins into enantiomers, showing some enantioselectivity for 22 dihydrofurocoumarins, and baseline resolving 16 of the 28 compounds in the reversed-phase mode. The acetyl-beta-cyclodextrin and 2,3-dimethyl-beta-cyclodextrin also showed enantioselectivity for a large number (18 and 17, respectively) of dihydrofurocoumarins in the reversed-phase mode. The native cyclodextrins are ineffective and the aromatic derivatized beta-cyclodextrins are only marginally effective at separating the furocoumarin enantiomers in the reversed-phase mode. The polar organic mode and the normal-phase mode have also been evaluated with these CSPs, but no enantioseparations were observed.

Enantiomer separations by HPLC using the macrocyclic glycopeptides teicoplanin (Chirobiotic T), teicoplanin aglycon (Chirobiotic TAG), and ristocetin A (Chirobiotic R) chiral stationary phases (CSP) have been achieved on a unique series of potentially biologically active racemic analogues of dihydrofurocoumarin. The macrocyclic glycopeptides have proven to be very selective for this class of compound. All of the 28 chiral analogues examined afforded baseline separation on at least one of the macrocyclic glycopeptide CSP. The teicoplanin CSP showed the broadest enantioselectivity with 24 of the compounds baseline separated. The TAG and the R CSP produced 23 and 14 baseline separations respectively. All three mobile phase modes, i.e. normal phase (NP), reversed phase (RP), and new polar organic modes (PO), have been evaluated. The NP mode proved to be most effective for the separation of chiral dihydrofurocoumarins on all CSP tested. In the reversed phase (RP) mode, all three CSP separated a similar number of compounds. It was observed that the structural characteristics of the analytes and steric effects are very important factors leading to chiral recognition. Hydrogen bonding was found to play a secondary role in chiral discrimination in the normal phase and polar organic modes. Hydrophobic interactions are important for chiral separation in the reversed-phase mode. Chromatographic retention data does not provide information on the absolute configuration of these chiral dihydrofurocoumarin derivatives. However, when coupled with circular dichroism using the exciton coupling chirality method, the enantiomer elution order and the absolute configuration of some chiral dihydrofurocoumarins were successfully determined.

A phenyl-substituted chiral dihydrofuroangelicin, 4-methyl-8-(2-E-phenylethenyl)-8,9-dihydro-2H-furo[2,3-h]-1-benzopyran-2-one, synthesized in racemic form, has been resolved by HPLC chiral separation, and its absolute configuration determined by the non-empirical exciton chirality method. The solution conformation has been investigated through NMR and molecular modeling methods: two minima found by molecular mechanics and DFT methods are in keeping with observed 1H–1H 3J coupling constants and NOE effects. The experimental CD spectrum for the second eluted enantiomer shows a positive couplet between 230 and 350 nm (amplitude A = + 15.7); by application of the exciton chirality method, the absolute configuration of this enantiomer at C8 is determined as (S). The experimental spectrum is in very good agreement with the one evaluated by means of DeVoe coupled-oscillator calculations, using the DFT calculated geometries.

The chiral recognition capabilities of three macrocyclic glycopeptide chiral selectors, namely teicoplanin (Chirobiotic T), its aglycone (Chirobiotic TAG) and ristocetin (Chirobiotic R), were evaluated with supercritical and subcritical fluid mobile phases. A set of 111 chiral compounds including heterocycles, analgesics (nonsteroidal antiinflamatory compounds), beta-blockers, sulfoxides, N-protected amino acids and native amino acids was separated on the three chiral stationary phases (CSPs). All separations were done with an outlet pressure regulated at 100 bar, 31 degrees C and at 4 ml/min. Various amounts of methanol ranging from 7 to 67% (v/v) were added to the carbon dioxide along with small amounts (0.1 to 0.5%, v/v) of triethylamine and/or trifluoroacetic acid. The Chirobiotic TAG CSP was the most effective closely followed by the Chirobiotic T column. Both columns were able to separate, partially or fully, 92% of the enantiomers of the compound set. The ristocetin chiral selector could partially or baseline resolve only 60% of the enantiomers tested. All separations were done in less than 15 min and 70% were done in less than 4 min. The speed of the separations is the main advantage of the use of SFC compared to normal-phase HPLC. In addition, SFC is advantageous for preparative separations with easy solute recovery and solvent disposal.

Coumarins are associated with a variety of pharmacological activities which have led to the synthesis of numerous derivatives. However, no general method for determination of the absolute configuration of chiral coumarins is known. This has now been achieved for a series of dihydrofuroangelicins bearing a variety of C-8 substituted double bonds, synthesized in the racemic form and resolved through enantioselective chromatography. A combined chemical/chiroptical protocol has been developed in which the C[double bond, length as m-dash]C double bonds are replaced with a styrenoid chromophore through either (i) cross metathesis, (ii) Heck reaction, or (iii) a combined method of cross metathesis and Heck reaction with about 1 mg sample under mild conditions. The coupling between the styrenoid and coumarin chromophores gives rise to clear-cut exciton coupled CD curves, suitable for assignments of absolute configurations. The solution conformation of the styrenoid derivatives is determined by NMR and DFT molecular modeling; the electronic structure of the 7-hydroxy coumarin chromophore is also clarified by semi-empirical and TDDFT methods. The conformation thus derived, in conjunction with quantitative DeVoe's coupled-oscillator CD calculation, establishes the absolute configurations of the coumarins. The theoretical study described herein justifies the straightforward approach of the current chemical/exciton chirality protocol to this type of dihydrofuroangelicins.