Asymmetric Morita-Baylis-Hillmann reaction : catalyst development and mechanistic insights based on mass spectrometric back reaction screening

The aim of the research project described in chapter 2 of this thesis was to develop an efficient bifunctional phosphine catalyst that outperforms literature-known catalysts in the Morita-Baylis-Hillman reaction of methyl acrylate with aldehydes. For the evaluation of the chiral organocatalysts a mass spectrometric back reaction screening protocol of quasi-enantiomeric substrates was applied. Based on this technique, a multi-catalyst screening was developed which allowed the simultaneous determination of the intrinsic enantioselectivities of phosphines in a crude catalyst mixture. Finally, based on the data from the back reaction screening in hand together with kinetic measurements, the rate- and enantioselectivity-determining step in the catalytic cycle were identified. In chapter 3, the synthesis of new morpholine- and piperidine-based triazolium salts and their use as NHC catalysts for the asymmetric cross-benzoin reaction is discussed. In particular, the cross-benzoin reaction between benzaldehyde and hydrocinnamaldehyde was studied. The aim of this project was to design a catalyst that could produce the desired cross-benzoin product with high enantiomeric excess and chemoselectivity. Chapter 4 deals with the development of chiral NHC-phosphine ligands for the asymmetric iridium-catalyzed hydrogenation of different model substrates. This project was inspired by the previous work of Nanchen, a former member of the Pfaltz group. He synthesized a small library of different NHC-phosphine ligands for the hydrogenation of various substrates, however only moderate results in terms of reactivity and enantioselectivity were achieved. The aim of this project was to investigate NHC-based catalysts with conformationally more rigid structures

The impact of pharmacist-led medication reconciliation and interprofessional ward rounds on drug-related problems at hospital discharge

BACKGROUND During transitions of care, including hospital discharge, patients are at risk of drug-related problems (DRPs). AIM To investigate the impact of pharmacist-led services, specifically medication reconciliation at admission and/or interprofessional ward rounds on the number of DRPs at discharge. METHOD In this retrospective, single-center cohort study, we analyzed routinely collected data of patients discharged from internal medicine wards of a regional Swiss hospital that filled their discharge prescriptions in the hospital's community pharmacy between June 2016 and May 2019. Patients receiving one of the two or both pharmacist-led services (Study groups: Best Care = both services; MedRec = medication reconciliation at admission; Ward Round = interprofessional ward round), were compared to patients receiving standard care (Standard Care group). Standard care included medication history taken by a physician and regular ward rounds (physicians and nurses). At discharge, pharmacists reviewed discharge prescriptions filled at the hospital's community pharmacy and documented all DRPs. Multivariable Poisson regression analyzed the independent effects of medication reconciliation and interprofessional ward rounds as single or combined service on the frequency of DRPs. RESULTS Overall, 4545 patients with 6072 hospital stays were included in the analysis (Best Care n = 72 hospital stays, MedRec n = 232, Ward Round n = 1262, and Standard Care n = 4506). In 1352 stays (22.3%) one or more DRPs were detected at hospital discharge. The combination of the two pharmacist-led services was associated with statistically significantly less DRPs compared to standard care (relative risk: 0.33; 95% confidence interval: 0.16, 0.65). Pharmacist-led medication reconciliation alone showed a trend towards fewer DRPs (relative risk: 0.75; 95% confidence interval: 0.54, 1.03). CONCLUSION Our results support the implementation of pharmacist-led medication reconciliation at admission in combination with interprofessional ward rounds to reduce the number of DRPs at hospital discharge

Posttranslational, site-directed photochemical fluorine editing of protein sidechains to probe residue oxidation state via 19F-nuclear magnetic resonance

The fluorination of amino acid residues represents a near-isosteric alteration with the potential to report on biological pathways, yet the site-directed editing of carbon–hydrogen (C–H) bonds in complex biomolecules to carbon–fluorine (C–F) bonds is challenging, resulting in its limited exploitation. Here, we describe a protocol for the posttranslational and site-directed alteration of native γCH2 to γCF2 in protein sidechains. This alteration allows the installation of difluorinated sidechain analogs of proteinogenic amino acids, in both native and modified states. This chemical editing is robust, mild, fast and highly efficient, exploiting photochemical- and radical-mediated C–C bonds grafted onto easy-to-access cysteine-derived dehydroalanine-containing proteins as starting materials. The heteroaryl–sulfonyl reagent required for generating the key carbon-centered C• radicals that install the sidechain can be synthesized in two to six steps from commercially available precursors. This workflow allows the nonexpert to create fluorinated proteins within 24 h, starting from a corresponding purified cysteine-containing protein precursor, without the need for bespoke biological systems. As an example, we readily introduce three γCF2-containing methionines in all three progressive oxidation states (sulfide, sulfoxide and sulfone) as D-/L- forms into histone eH3.1 at site 4 (a relevant lysine to methionine oncomutation site), and each can be detected by 19F-nuclear magnetic resonance of the γCF2 group, as well as the two diastereomers of the sulfoxide, even when found in a complex protein mixture of all three. The site-directed editing of C–H→C–F enables the use of γCF2 as a highly sensitive, ‘zero-size-zero-background’ label in protein sidechains, which may be used to probe biological phenomena, protein structures and/or protein–ligand interactions by 19F-based detection methods

Detection and resolution of drug-related problems at hospital discharge focusing on information availability - a retrospective analysis

BACKGROUND Hospital stays are often associated with medication changes, which may lead to drug-related problems (DRPs). Medication reconciliation and medication reviews are strategies to detect and resolve DRPs. METHODS A descriptive cohort study was conducted using DRPs collected during routine pharmacist-led medication reconciliation and medication reviews in the hospital's community pharmacy at discharge (Zug Cantonal Hospital, Switzerland). In a simulation experiment, we retrospectively analysed the detection and resolution possibilities of these DRPs and their dependency on different information sources. RESULTS Overall, 6,087 prescriptions were filled in the hospital's community pharmacy (between June 2016 and May 2019). Among 1,352 prescriptions (with ≥ 1 documented DRP) a total of 1,876 DRPs were detected. The retrospective assessment showed that 1,115 DRPs could have been detected by performing simple medication reviews (based on the discharge prescription and the medication history), whereas in the remaining cases, additional clinical and/or patient-specific information would have been needed. In 944 (84.7 %) DRPs, which are detectable by simple medication reviews, the pharmacist would need to consult the prescriber for resolution. CONCLUSION The detection of DRPs is strongly influenced by the information available. These results support models with pre-discharge medication reconciliation and pharmacist-led medication review procedures enabling both comprehensive detection and facilitated resolution of DRPs