Electrochemical Synthesis of Isoxazolines: Method and Mechanism.

An electrochemical method for the green and practical synthesis of a broad range of substituted isoxazoline cores is presented. Both aryl and more challenging alkyl aldoximes are converted to the desired isoxazoline in an electrochemically enabled regio- and diastereoselective reaction with electron-deficient alkenes. Additionally, in-situ reaction monitoring methods compatible with electrochemistry equipment have been developed in order to probe the reaction pathway. Supporting analyses from kinetic (time-course) modelling and density functional theory support a stepwise, radical-mediated mechanism, and discounts hypothesised involvement of closed shell [3+2] cycloaddition pathways.

Stereoselective Remote Functionalization via Palladium-Catalyzed Redox-Relay Heck Methodologies.

Exploration of novel, three-dimensional chemical space is of growing interest in the drug discovery community and with this comes the challenge for synthetic chemists to devise new stereoselective methods to introduce chirality in a rapid and efficient manner. This Minireview provides a timely summary of the development of palladium-catalyzed asymmetric redox-relay Heck-type processes. These reactions represent an important class of transformation for the selective introduction of remote stereocenters, and have risen to prominence over the past decade. Within this Minireview, the vast scope of these transformations will be showcased, alongside applications to pharmaceutically relevant chiral building blocks and drug substances. To complement this overview, a mechanistic summary and discussion of the current limitations of the transformation are presented, followed by an outlook on future areas of investigation.

Evaluation of a web-based virtual nursing intervention to support self-management among adults with epilepsy: A mixed-methods study.

OBJECTIVE: A web-based intervention was developed to support epilepsy self-management. A mixed methods study was undertaken to evaluate the intervention's extent of utilization, acceptability and preliminary effects, and to assess user perception of it. METHODS: First, a pilot parallel-group randomized controlled trial was conducted with a convenience sample of 75 adult with epilepsy who had Internet access allocated on a 1:1 ratio into an experimental group that received the intervention (experimental group (EG), n = 37) and a control group invited to consult epilepsy-related websites (control group (CG), n = 38). Self-management, knowledge, and quality of life (QoL) outcomes were measured at baseline and one and three months later. Descriptive statistics of extent of utilization and acceptability were computed. Linear mixed models were conducted to assess change in outcomes over time and between groups. Subsequently, an exploratory qualitative study was carried out with 15 EG participants. Qualitative data were subjected to thematic analysis. RESULTS: Participants had a mean age of 40 years (range: 18-73), 45% were female, and mean time since diagnosis was 18 years (range: less than a year to 60 years). In the EG, 70% of the participants completed the intervention. Regarding acceptability, participants (n = 25) were satisfied overall (88%) and found content clear (92%) and the information reliable (100%). EG participants experienced greater improvement in QoL compared with CG participants, least-squares means (95% CI): 0.41 (0.06, 0.76). Three major themes emerged from the interviews (n = 15): intervention provides certain personal benefits; clinical content is of general interest but should be tailored; and intervention should target "new" patients early in the care trajectory. DISCUSSION: The web-based intervention shows promise in terms of usefulness in enhancing QoL, and user experience showed that it is acceptable and helpful. It could constitute a complementary service in support of existing services for people with epilepsy and their families.

Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of the Siliconate-Carbanion Dichotomy by Stopped-Flow NMR/IR.

The mechanism of CF3 transfer from R3SiCF3 (R = Me, Et, iPr) to ketones and aldehydes, initiated by M+X- (<0.004 to 10 mol %), has been investigated by analysis of kinetics (variable-ratio stopped-flow NMR and IR), 13C/2H KIEs, LFER, addition of ligands (18-c-6, crypt-222), and density functional theory calculations. The kinetics, reaction orders, and selectivity vary substantially with reagent (R3SiCF3) and initiator (M+X-). Traces of exogenous inhibitors present in the R3SiCF3 reagents, which vary substantially in proportion and identity between batches and suppliers, also affect the kinetics. Some reactions are complete in milliseconds, others take hours, and others stall before completion. Despite these differences, a general mechanism has been elucidated in which the product alkoxide and CF3- anion act as chain carriers in an anionic chain reaction. Silyl enol ether generation competes with 1,2-addition and involves protonation of CF3- by the α-C-H of the ketone and the OH of the enol. The overarching mechanism for trifluoromethylation by R3SiCF3, in which pentacoordinate siliconate intermediates are unable to directly transfer CF3- as a nucleophile or base, rationalizes why the turnover rate (per M+X- initiator) depends on the initial concentration (but not identity) of X-, the identity (but not concentration) of M+, the identity of the R3SiCF3 reagent, and the carbonyl/R3SiCF3 ratio. It also rationalizes which R3SiCF3 reagent effects the most rapid trifluoromethylation, for a specific M+X- initiator.

Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences.

Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium (3 H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

C-H Functionalisation for Hydrogen Isotope Exchange.

The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the physical and life sciences demand a range of methods for their installation in an array of molecular architectures. In this Review, we describe recent advances in synthetic C-H functionalisation for hydrogen isotope exchange.

Base-Catalyzed Aryl-B(OH)2 Protodeboronation Revisited: From Concerted Proton Transfer to Liberation of a Transient Aryl Anion.

Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as the mechanism for base-catalyzed protodeboronation of arylboronic acids. However, the study was limited to UV spectrophotometric analysis under acidic conditions, and the aqueous association constants (Ka) were estimated. By means of NMR, stopped-flow IR, and quenched-flow techniques, the kinetics of base-catalyzed protodeboronation of 30 different arylboronic acids has now been determined at pH > 13 in aqueous dioxane at 70 °C. Included in the study are all 20 isomers of C6HnF(5-n)B(OH)2 with half-lives spanning 9 orders of magnitude: <3 ms to 6.5 months. In combination with pH-rate profiles, pKa and ΔS⧧ values, kinetic isotope effects (2H, 10B, 13C), linear free-energy relationships, and density functional theory calculations, we have identified a mechanistic regime involving unimolecular heterolysis of the boronate competing with concerted ipso protonation/C-B cleavage. The relative Lewis acidities of arylboronic acids do not correlate with their protodeboronation rates, especially when ortho substituents are present. Notably, 3,5-dinitrophenylboronic acid is orders of magnitude more stable than tetra- and pentafluorophenylboronic acids but has a similar pKa.

Is the Pelvic Examination Still Crucial in Patients Presenting to the Emergency Department With Vaginal Bleeding or Abdominal Pain When an Intrauterine Pregnancy Is Identified on Ultrasonography? A Randomized Controlled Trial.

STUDY OBJECTIVE: We determine whether omitting the pelvic examination in emergency department (ED) evaluation of vaginal bleeding or lower abdominal pain in ultrasonographically confirmed early intrauterine pregnancy is equivalent to performing the examination. METHODS: We conducted a prospective, open-label, randomized, equivalence trial in pregnant patients presenting to the ED from February 2011 to November 2015. Patients were randomized to no pelvic examination versus pelvic examination. Inclusion criteria were aged 18 years or older, English speaking, vaginal bleeding or lower abdominal pain, positive ß-human chorionic gonadotropin result, and less than 16-week intrauterine pregnancy by ultrasonography. Thirty-day record review and follow-up call assessed for composite morbidity endpoints (unscheduled return, subsequent admission, emergency procedure, transfusion, infection, and alternate source of symptoms). Wilcoxon rank sum tests were used to assess patient satisfaction and throughput times. RESULTS: Only 202 (of a planned 720) patients were enrolled, despite extension of the study enrollment period. The composite morbidity outcome was experienced at similar rates in the intervention (no pelvic examination) and control (pelvic examination) groups (19.6% versus 22.0%; difference -2.4%; 90% confidence interval [CI] -11.8% to 7.1%). Patients in the intervention group were less likely to report feeling uncomfortable or very uncomfortable during the visit (11.2% versus 23.7%; difference -12.5; 95% CI -23.0% to -2.0%). CONCLUSION: Although there was only a small difference between the percentage of patients experiencing the composite morbidity endpoint in the 2 study groups (2.4%), the resulting 90% CI was too wide to conclude equivalence. This may have been due to insufficient power. Patients assigned to the pelvic examination group reported feeling uncomfortable more frequently.

Iridium-Catalyzed Formyl-Selective Deuteration of Aldehydes.

We report the first direct catalytic method for formyl-selective deuterium labeling of aromatic aldehydes under mild conditions, using an iridium-based catalyst designed to favor formyl over aromatic C-H activation. A good range of aromatic aldehydes is selectively labeled, and a one-pot labeling/olefination method is also described. Computational studies support kinetic product control over competing aromatic labeling and decarbonylation pathways.

Hydrogen isotope exchange with highly active iridium(I) NHC/phosphine complexes: a comparative counterion study.

Herein, we present a range of substrates that undergo hydrogen isotope exchange with an iridium(I) N-heterocyclic carbene/phosphine complex bearing the less coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate counterion and compare these with labelling using the equivalent, more established hexafluorophosphate complex. The changes in reactivity and selectivity of these complexes in a series of solvents are examined. Copyright © 2016 John Wiley & Sons, Ltd.

Iridium-Catalysed ortho-Directed Deuterium Labelling of Aromatic Esters--An Experimental and Theoretical Study on Directing Group Chemoselectivity.

Herein we report a combined experimental and theoretical study on the deuterium labelling of benzoate ester derivatives, utilizing our developed iridium N-heterocyclic carbene/phosphine catalysts. A range of benzoate esters were screened, including derivatives with electron-donating and -withdrawing groups in the para- position. The substrate scope, in terms of the alkoxy group, was studied and the nature of the catalyst counter-ion was shown to have a profound effect on the efficiency of isotope exchange. Finally, the observed chemoselectivity was rationalized by rate studies and theoretical calculations, and this insight was applied to the selective labelling of benzoate esters bearing a second directing group.

Anion effects to deliver enhanced iridium catalysts for hydrogen isotope exchange processes.

Synthesis of a series of iridium(I) complexes of the type [(COD)Ir(IMes)(PPh3)]X (X = BF4, OTf, and BArF) has been established. Application of these species in mild hydrogen isotope exchange processes revealed more efficient catalysis and, further, a wider solvent scope when employing larger, more weakly coordinating counterions.

An Account on BiVO4 as Photocatalytic Active Matter.

Photocatalytic materials are gaining popularity and research investment for developing light-driven micromotors. While most of the early work used highly stable TiO2 as a material to construct micromotors, mostly in combination with noble metals, other semiconductors offer a wider range of properties, including independence from high-energy UV light. This review focuses on our work with BiVO4 which has shown promise due to its small band gap and resulting ability to absorb blue light. Additionally, this salt's well-defined crystal structures lead to exploitable charge separation on different crystal facets, providing sufficient asymmetry to cause active propulsion. These properties have given rise to fascinating physical and chemical behaviors that show how rich and variable active matter can become. Here, we present the synthesis of different BiVO4 microparticles and their material properties that make them excellent candidates as active micromotors. A critical factor in understanding inherently asymmetric micromotors is knowledge of their flow fields. However, due to their small size and the need to use even smaller tracer particles to avoid perturbing the flow field, measuring flow fields at the microscale is a difficult task. We also present these first results, which allow us to demonstrate the correlation between chemical reactivity and the flow generated, leading to active motion. Due to the nontoxic nature of BiVO4, these visible-light-responsive microswimmers have been used to study the first steps toward applications, even in sensitive areas such as food technology. Although these initial tests are far from being realized, we have to face the fact that a single microswimmer will not be able to perform macroscale tasks. Therefore, we present the reader with the first simple studies of collective motion, hoping for many new contributions to the field. The one-step synthesis of BiVO4 clearly paves the way for studies requiring large numbers of particles. We predict that the combination of promising applications for a nontoxic material which is readily synthesized in large quantities will contribute pivotally to advance the field of active matter beyond the proof-of-concept stage.

Synthesis of 2,6-trans-Tetrahydropyrans Using a Palladium-Catalyzed Oxidative Heck Redox-Relay Strategy.

The C-aryl-tetrahydropyran motif is prevalent in nature in a number of natural products with biological activity; however, this challenging architecture still requires novel synthetic approaches. We demonstrate the application of a stereoselective Heck redox-relay strategy for the synthesis of functionalized 2,6-trans-tetrahydropyrans in excellent selectivity in a single step from an enantiopure dihydropyranyl alcohol, proceeding through a novel exo-cyclic migration. The strategy has also been applied to the total synthesis of a trans-epimer of the natural product centrolobine in excellent yield and stereoselectivity.

Application of neutral iridium(I) N-heterocyclic carbene complexes in ortho-directed hydrogen isotope exchange.

Bench-stable complexes of the type [Ir(COD)(NHC)Cl] (NHC = N-heterocyclic carbene) have been investigated within the field of hydrogen isotope exchange. By employing a sterically encumbered NHC within such complexes and catalyst loadings of only 5 mol%, moderate to high deuterium incorporations were achieved across a range of aromatic ketones and nitrogen-based heterocycles. The simple and synthetically accessible catalysts reported herein present alternatives to phosphine-based species and increase the available labelling systems with respect to established iridium-based isotope exchange methodologies.

Highlights from the 56th Bürgenstock Conference on Stereochemistry 2023.

Herein, we share an overview of the scientific highlights from speakers at the latest edition of the longstanding Bürgenstock Conference.

Computer vision as a new paradigm for monitoring of solution and solid phase peptide synthesis.

We report a strategy for the camera-enabled non-contact colourimetric reaction monitoring and optimisation of amide bond formation, mediated by coupling reagents. For amide bond formation in solution phase, investigation of reactions mediated by HATU, PyAOP, and DIC/Oxyma evidenced correlations between colour parameters extracted from video data and conversion to amide product measured by off-line HPLC analysis of concentration. These correlations, supported by mutual information analysis, were further investigated using video recordings of solid phase peptide synthesis (SPPS), co-analysed by off-line HPLC to track remaining unreacted substrate in solution. An optimisation method of coupling time in SPPS was derived from ΔE (a measurement of colour contrast), giving comparable isolated peptide yield and purity at 65-95% reduced overall reaction time. The same colour data enabled data-rich monitoring of reaction rate attenuation, consisted with computationally-derived measures of amino acid steric bulk. These findings provide a foundation for exploring the use of camera technology and computer vision towards automated and online mechanistic profiling of SPPS.

Teaching old presumptive tests new digital tricks with computer vision for forensic applications.

Presumptive (or 'spot') tests have served forensic scientists, law enforcement, and legal practitioners for over a hundred years. Yet, the intended design of such tests, enabling quick identification of drugs by-eye, also hides their full potential. Here, we report the development and application of time-resolved imaging methods of reactions attending spot tests for amphetamines, barbiturates, and benzodiazepines. Analysis of the reaction videos helps distinguish drugs within the same structural class that, by-eye, are judged to give the same qualitative spot test result. It is envisaged that application of these results will bridge the existing suite of field and lab-based confirmatory forensic tests, and support a broader range of colorimetric sensing technologies.

Computer vision for non-contact monitoring of catalyst degradation and product formation kinetics.

We report a computer vision strategy for the extraction and colorimetric analysis of catalyst degradation and product-formation kinetics from video footage. The degradation of palladium(ii) pre-catalyst systems to form 'Pd black' is investigated as a widely relevant case study for catalysis and materials chemistries. Beyond the study of catalysts in isolation, investigation of Pd-catalyzed Miyaura borylation reactions revealed informative correlations between colour parameters (most notably ΔE, a colour-agnostic measure of contrast change) and the concentration of product measured by off-line analysis (NMR and LC-MS). The breakdown of such correlations helped inform conditions under which reaction vessels were compromised by air ingress. These findings present opportunities to expand the toolbox of non-invasive analytical techniques, operationally cheaper and simpler to implement than common spectroscopic methods. The approach introduces the capability of analyzing the macroscopic 'bulk' for the study of reaction kinetics in complex mixtures, in complement to the more common study of microscopic and molecular specifics.

Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.