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Here, we describe a protocol for the metal-free, photo-induced borylation of unactivated C(sp 3 )-H bonds distal to an O -oxalate hydroxamic ester functionality. The methodology requires only substrate and bis(catecholato)diboron under light irradiation to effect the desired transformation. A range of linear and cyclic tertiary and secondary borylation products are obtained in good yields and high site-selectivity enabling the late-stage C(sp 3 )-H borylation of natural product derivatives and drug-like compounds., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Herein, we describe a formal dehydrogenative cross coupling of heterocycles with unactivated aliphatic amines. The resulting transformation enables the direct alkylation of common heterocycles by merging N-F-directed 1,5-HAT with Minisci chemistry, leading to predictable site selectivity. The reaction provides a direct route for the transformation of simple alkyl amines to value-added products under mild reaction conditions, making this an attractive option for C(sp 3 )-H heteroarylation.

Herein, we describe an iron-catalyzed benzylic C-H borylation reaction. The reaction targets primary and secondary C(sp 3 )-H bonds to deliver high-value boronic esters under mild conditions with short (7-8 min) reaction times. Functional groups are well tolerated, and complete site selectivity is observed in the presence of multiple benzylic C-H bonds.

Herein, we describe the nickel-catalyzed reductive arylation of remote C(sp 3 )-H bonds with aryl electrophiles. The reaction targets secondary and tertiary C(sp 3 )-H bonds to deliver all-carbon quaternary centers. The success of this method relies on a novel amidyl radical precursor that tolerates reducing conditions, namely O -oxalate hydroxamic acid esters.

The use of biochar as a soil amendment in forest ecosystems can be beneficial in the restoration of degraded soils. Forest insects such as the Douglas-fir tussock moth, Orgyia pseudotsugata (McDonnough) (Lepidoptera: Erebidae), may be exposed to biochar when the material is applied. Two experiments were conducted using biochar either (1) applied to the surface of the diet at three rates (0, 5, and 10 mg) or (2) incorporated into synthetic diet at four rates (0, 10, 20, and 40% volume/volume). The objective of both experiments was to determine if biochar on the surface or incorporated into a synthetic diet affected development and survival of O. pseudotsugata larvae. In both experiments, there was a significant decrease in estimated time to larval mortality in all biochar treatments compared to untreated controls. In the surface-applied biochar experiment, there was a significant difference in larval weight gain at day 12 between the control and 10 mg biochar treatments. In the experiment with biochar incorporated into the diet, mean larval weight at day 12 was highest in the low (10%) biochar treatment compared to all other treatments, although weight gain was only significantly different between the low- and high-concentration (40%) biochar treatments. Our results suggest that larvae, feeding on a low amount of biochar in the synthetic diet, may respond by engaging in compensatory feeding behavior. Fewer surviving larvae in the biochar treatment groups may contribute to the lack of significance found in the comparison of weight gain at day 24 in each experiment.

A straightforward method for the undirected trifluoromethylation of unactivated methylene units was developed. The reaction proceeds in aqueous acetonitrile with Grushin's reagent, bpyCu(CF 3 ) 3 , under broad-spectrum white-light irradiation. The trifluoromethylation tolerates a wide range of functional groups including ketones, esters, nitriles, amides, alcohols, and carboxylic acids. The C-H cleavage step is performed via intermolecular H atom abstraction, and the selectivities across a range of methylene units are reported. Mechanistic studies offer a general reaction coordinate for the overall transformation.

The site-selective trifluoromethylation of aliphatic systems remains an important challenge. This work describes a light-driven, copper-mediated trifluoromethylation of O -alkyl thiocarbonates. The reaction provides broad functional group tolerance (e.g., alkyne, alkene, phenol, free alcohol, electron-rich and -deficient arenes), thereby offering orthogonality and practicality for trifluoromethylation. A radical organometallic mechanism is proposed.

Research over the last 15 yr has shown widespread pheromone parsimony within the coleopteran family Cerambycidae, with a number of highly conserved pheromone motifs, often shared within and across subfamilies, tribes, and genera. Our goals were to increase our understanding of the evolution of volatile pheromones within the Cerambycidae, their role in reproductive isolation and to identify pheromones for use in the development of lures for monitoring cerambycids. Over 3 yr, we tested 12 compounds known to be cerambycid pheromones as possible attractants at sites across Idaho. This study focused on species within the cerambycine genus Phymatodes (Tribe: Callidiini). We also collected and analyzed headspace volatiles of captured Phymatodes dimidiatus (Kirby). Our results demonstrate that (R)-2-methylbutan-1-ol is a male-produced volatile pheromone for P. dimidiatus. These results are consistent with prior research suggesting that (R)-2-methylbutan-1-ol and (R)-3-hydroxyhexan-2-one, individually or in a blend of both compounds, commonly serve as pheromones for Phymatodes spp. We captured Phymatodes starting in mid-May, continuing through mid-August. Our data indicate that flight periods of Phymatodes spp. in Idaho overlap. These species may be utilizing various mechanisms to ensure reproductive isolation, such as the production of different volatile pheromones, minor components, and/or proportions of components, utilizing different host species and/or host volatiles, differing daily activity periods, and/or occupying different heights in the tree canopy. Our results contribute to the basic understanding of the chemical and behavioral ecology of the Cerambycidae and can be applied to the development of pheromone lures for monitoring of economically important or endangered species., (© The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Copper, an earth-abundant metal, has reemerged as a viable alternative to the versatile Pd-catalyzed C-N coupling. Coupling sterically hindered reaction partners, however, remains challenging. Herein, we disclose the discovery and development of a pyrrole-ol ligand to facilitate the coupling of ortho -substituted aryl iodides with sterically hindered amines. The ligand was discovered through a library screening approach and highlights the value of mining heteroatom-rich pharmaceutical libraries for useful ligand motifs. Further evaluation revealed that this ligand is uniquely effective in these challenging transformations. The reaction enables the coupling of sterically hindered primary and secondary amines, anilines, and amides with broad functional group tolerance., Competing Interests: The authors declare the following competing financial interest(s): E.C.S., M.C.H., T.S.F., and S.S. are AbbVie employees and may own AbbVie stocks. A.J.N. and V.S.C. were employees of AbbVie and may own AbbVie stocks. A.J.N. is currently an employee of Dow Chemicals. V.S.C. is currently an employee of Seattle Genetics. A.M. is a postdoctoral associate, and S.P.C. is an Associate Professor at Indiana University and have no conflicts of interest to disclose. The authors wish to acknowledge Dr. Seble Wagaw and Dr. DavidM. Barnes for helpful discussions. S.W. and D.M.B. are AbbVie employees and may own AbbVie stocks.

Introduction: A common criticism of the peer-review process is the often disparate nature of reviewer recommendations when a decision is rendered which belies the supposed uniformity of the process. The purpose of this investigation was to examine level of agreement between reviewers for Foot & Ankle International (FAI) and analyze variables which may have influenced agreement in order to better understand the peer-review process., Methods: Approval to conduct this investigation was obtained from the Executive Board and Editor in Chief of FAI. All manuscripts submitted to FAI during the calendar year 2016 which underwent formal peer-review were included in the analysis. For each reviewed manuscript, demographic data was collected regarding specific reviewer and manuscript characteristics in a de-identified manner., Results: 442 manuscripts underwent formal blinded peer-review by two independent reviewers during the study period. Only 199 manuscripts (45%) had a decision rendered in which both reviewers agreed on the same initial recommendation. There were no differences in demographic characteristics between the group of reviewers who agreed as compared to those who disagreed on the initial round of peer review. A similar number of indexed peer-reviewed publications between reviewers correlated with increased levels of agreement., Conclusions: During the study period, there was 45% initial agreement between reviewers for FAI when assessing the same manuscript. Aside from research productivity, no other reviewer-specific variables examined in this investigation were found to correlate with agreement. Specific recommendations and changes may be considered to increase the efficiency and effectiveness of the peer-review process., (Copyright © 2019 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Site-selective fluorination of aliphatic C-H bonds remains synthetically challenging. While directed C-H fluorination represents the most promising approach, the limited work conducted to date has enabled just a few functional groups as the arbiters of direction. Leveraging insights gained from both computations and experimentation, we enabled the use of the ubiquitous amine functional group as a handle for the directed C-H fluorination of Csp 3 -H bonds. By converting primary amines to adamantoyl-based fluoroamides, site-selective C-H fluorination proceeds under the influence of a simple iron catalyst in 20 minutes. Computational studies revealed a unique reaction coordinate for the catalytic process and offer an explanation for the high site selectivity., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

A direct and versatile copper-catalyzed trifluoromethylthiolation and trifluoromethylselenation of primary, secondary, and tertiary aliphatic C-H bonds was developed. The reaction provides direct access to molecules containing these emerging moieties in the presence of a wide range of common functional groups and in complex molecular environments.

Substoichiometric iron mediates the thioetherification of unactivated aliphatic C-H bonds directed by resident silylperoxides. Upon exposure to a catalytic amount of iron(II) triflate, TIPS-protected peroxides bearing primary, secondary, and tertiary C-H sites undergo chemoselective thioetherification of remote C-H bonds with diaryl disulfides. The reaction demonstrates a broad substrate scope and functional group tolerance without the use of any noble metal additives. Mechanistic experiments suggest that the reaction proceeds through 1,5-H atom abstraction by a hydroxyl radical generated with iron.

Rapid assembly of saturated nitrogen heterocycles-the synthetically more challenging variants of their aromatic relatives-can expedite the synthesis of biologically relevant molecules. Starting from a benzylic alcohol tethered to an unactivated alkene, an iron-catalyzed tandem alcohol substitution and hydroamination provides access to tetrahydroisoquinolines in a single synthetic step. Using a mild iron-based catalyst, the combination of these operations forms two carbon-nitrogen bonds and provides a unique annulation strategy to access this valuable core.

Modifying the electronic properties of olefins is the quintessential approach to tuning alkene reactivity. In this context, the exploration of trifluoromethyl groups as divergent electronic modifiers has not been considered. In this work, we describe a copper-mediated 1,2-(bis)trifluoromethylation of acetylenes to create E-hexafluorobutenes (E-HFBs) under blue light in a single step. The reaction proceeds with high yield and E/Z selectivity. Since the alkyne captures two trifluoromethyl groups from each molecule of bpyCu(CF 3 ) 3 , mechanistic studies were conducted to illuminate the role of the reactants. Interestingly, E-HFBs exhibit remarkable stability to standard olefin functionalization reactions in spite of the pendant trifluoromethyl groups. This finding has significant implications for medicine, agroscience, and materials., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Electrospray ionization (ESI) combined with ion mobility spectrometry (IMS) and mass spectrometry (MS) techniques is used to examine the Biginelli reaction in an ensemble of ions generated from droplets. We find evidence for rapid dihydropyrimidinone formation from condensation of ethyl acetoacetate, benzaldehyde, and urea on the very short timescales associated with the electrospray process (∼10 μs to ∼1.0 ms). Control bulk-solution reactions show no product formation even after several days. This implies that the in-droplet reaction rate is enhanced by an astonishing factor. Examination of the reaction conditions and characterization of the intermediates en route to product shows evidence for variations in the reaction mechanism. IMS separation shows that the Knoevenagel condensation intermediate from benzaldehyde and ethyl acetoacetate exists as both the cis - and trans -isomer, in a ∼5 to 1 ratio. We suggest that the dramatic acceleration arises because of increased reagent confinement as electrosprayed droplets shrink. The ability of IMS-MS to resolve intermediates (including isomers) provides a new means of understanding reaction pathways.

The hydrofunctionalization of alkenes, explored for over 100 years, offers the potential for a direct, atom-economical approach to value-added products. While thermodynamically favored, the kinetic barrier to such processes necessitates the use of catalysts to control selectivity and reactivity. Modern variants typically rely on noble metals that require different ligands for each class of hydrofunctionalization, thereby limiting generality. This Letter describes a general iron-based system that catalyzes the hydroamination and hydroetherification of simple unactivated olefins.

The direct, catalytic substitution of unactivated alcohols remains an undeveloped area of organic synthesis. Moreover, catalytic activation of this difficult electrophile with predictable stereo-outcomes presents an even more formidable challenge. Described herein is a simple iron-based catalyst system which provides the mild, direct conversion of secondary and tertiary alcohols to sulfonamides. Starting from enantioenriched alcohols, the intramolecular variant proceeds with stereoinversion to produce enantioenriched 2- and 2,2-subsituted pyrrolidines and indolines, without prior derivatization of the alcohol or solvolytic conditions., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C-H bonds with high selectivity for the least hindered hydrogen atom. The reaction provides monotrifluoromethylation and proceeds in an environmentally friendly acetone/water solvent system. The method can be used to install benzylic trifluoromethyl groups on highly functionalized drug molecules.

Many educational demonstrations of memory and recall employ word lists and number strings; items that lend themselves to semantic organization and "chunking." By applying taste recall to the adaptive memory paradigm, which evaluates memory from a survival-based evolutionary perspective, we have developed a simple, inexpensive exercise that defies mnemonic strategies. Most adaptive memory studies have evaluated recall of words encountered while imagining survival and non-survival scenarios. Here, we've left the lexical domain and hypothesized that taste memory, as measured by recognition, would be best when acquisition occurs under imagined threat of personal harm, namely poisoning. We tested participants individually while they evaluated eight teas in one of three conditions: in one, they evaluated the toxicity of the tea (survival condition), in a second, they considered the marketability of the tea and, in the third, they evaluated the bitterness of the tea. After a filler task, a surprise recognition task required the participants to taste and identify the eight original teas from a group of 16 that included eight novel teas. The survival condition led to better recognition than the bitterness condition but, surprisingly, it did not yield better recognition than the marketing condition. A second experiment employed a streamlined design more appropriate for classroom settings and failed to support the hypothesis that planning enhanced recognition in survival scenarios. This simple technique has, at least, revealed a robust levels-of-processing effect for taste recognition and invites students to consider the adaptive advantages of all forms of memory.

The Lepidoptera of North America Network, or LepNet, is a digitization effort recently launched to mobilize biodiversity data from 3 million specimens of butterflies and moths in United States natural history collections (http://www.lep-net.org/). LepNet was initially conceived as a North American effort but the project seeks collaborations with museums and other organizations worldwide. The overall goal is to transform Lepidoptera specimen data into readily available digital formats to foster global research in taxonomy, ecology and evolutionary biology.

Primary Objective: Repetition-lag memory training was developed to increase individuals' use of recollection as opposed to familiarity in recognition memory. The goals of this study were to examine the feasibility of repetition-lag training in patients with chronic stroke and to explore whether the training might show suggestions of transfer to non-trained tasks., Research Design: Quasi-experimental., Methods and Procedures: Patients (n = 17) took part in six repetition-lag training sessions and their gains on the training and non-trained tasks were compared to those of age-matched healthy controls (n = 30)., Main Outcomes and Results: All but two patients completed the training, indicating that the method is feasible with a wide range of patients with stroke. The amount patients gained on the training task was similar to that of healthy controls (that is, the Group × Time interactions were by-and-large not significant), suggesting that patients with stroke might benefit to the same degree as healthy adults from this training. Both groups showed some indication of transfer to the non-trained backward digit span task and visuospatial memory., Conclusions: These findings show that repetition-lag memory training is a possible approach with patients with stroke to enhance recollection. Further research on the method's efficacy and effectiveness is warranted.

This communication describes a mild, amide-directed fluorination of benzylic, allylic, and unactivated C-H bonds mediated by iron. Upon exposure to a catalytic amount of iron(II) triflate (Fe(OTf) 2 ), N-fluoro-2-methylbenzamides undergo chemoselective fluorine transfer to provide the corresponding fluorides in high yield. The reaction demonstrates broad substrate scope and functional group tolerance without the use of any noble metal additives. Mechanistic and computational experiments suggest that the reaction proceeds through short-lived radical intermediates with F-transfer mediated directly by iron.

The use of low-cost manganese(II) bromide (MnBr2) and tetramethylethylenediamine (TMEDA) catalyzes the cross coupling of (bis)pinacolatodiboron with a wide range of alkyl halides, demonstrating the first manganese-catalyzed coupling with alkyl electrophiles. This method allows access to primary, secondary, and tertiary boronic esters from the parent chlorides, which were previously inaccessible as coupling partners. The reaction proceeds in high yield with as little as 1000 ppm catalyst loading, while 5 mol % can provide high yields in as little as 30 min. Finally, radical-clock experiments revealed that at 0 °C direct borylation outcompetes alternative radical processes, thereby providing synthetically useful, temperature-controlled reaction outcomes.

Normal aging holds negative consequences for memory, in particular for the ability to recollect the precise details of an experience. With this in mind, Jennings and Jacoby (2003) developed a recollection training method using a single-probe recognition memory paradigm in which new items (i.e., foils) were repeated during the test phase at increasingly long intervals. In previous reports, this method has appeared to improve older adults' performance on several non-trained cognitive tasks. We aimed to further examine potential transfer effects of this training paradigm and to determine which cognitive functions might predict training gains. Fifty-one older adults were assigned to either recollection training (n = 30) or an active control condition (n = 21) for six sessions over 2 weeks. Afterward, the recollection training group showed a greatly enhanced ability to reject the repeated foils. Surprisingly, however, the training and the control groups improved to the same degree in recognition accuracy (d') on their respective training tasks. Further, despite the recollection group's significant improvement in rejecting the repeated foils, we observed little evidence of transfer to non-trained tasks (including a temporal source memory test). Younger age and higher baseline scores on a measure of global cognitive function (as measured by the Montreal Cognitive Assessment tool) and working memory (as measured by Digit Span Backward) predicted gains made by the recollection training group members.

The iron-catalyzed coupling of aryl sulfamates and tosylates with aryl Grignard reagents is reported for the first time. The methodology employs air-stable, low-cost FeF3·3H2O and the N-heterocyclic carbene ligand IPr·HCl as the preligand to form a long-lived catalyst upon treatment with aryl Grignards. The reaction provides a range of cross-coupled products in good-to-excellent yields. In contrast to previous reports with aryl chlorides, these reactions proceed with low levels of Grignard homocoupling regardless of the iron source.

Using 8-aminoquinoline-based aryl carboxamides, the direct ortho-alkylation can be achieved in high yields in the presence of an iron source, 1,2-bis(diphenylphosphino)ethane (dppe) and phenylmagnesium bromide. The reactions proceed without overalkylation and provide high levels of regioselectivity. The benzylation reactions can be performed in air with reagent-grade THF, while the alkylation works well with unactivated secondary bromides and iodides in 2-methyltetrahydrofuran. Moreover, the reactions only require 5-10 min.

The use of low-cost iron(III) acetoacetate (Fe(acac)3) and tetramethylethylenediamine (TMEDA) enables the direct cross-coupling of alkyl halides with bis(pinacolato)diboron. This approach allows for the borylation of activated or unactivated primary, secondary, and tertiary bromides. Moreover, even the borylation of benzylic or allylic chlorides, tosylates, and mesylates are possible. The reactions proceed under mild conditions at room temperature and show broad functional-group compatibility and "robustness" as measured by a modified Glorius robustness screen.

A simple, iron-based catalytic system allows for the inter- and intramolecular arylation of unactivated secondary alcohols. This transformation expands the substrate scope beyond the previously required activated alcohols and proceeds under mild reaction conditions, tolerating air and moisture. Furthermore, the use of an enantioenriched secondary alcohol provides an enantioenriched product for the intramolecular reaction, thereby offering a convenient approach to nonracemic products.

Background: Healthy, active ageing is strongly associated with good mental wellbeing which in turn helps to prevent mental illness. However, more investment has been made into research into interventions to prevent mental illness than into those designed to improve mental wellbeing. This applied research programme will provide high quality evidence for an intervention designed to improve and sustain mental wellbeing in older adults., Methods/design: This study was a multi-centre, pragmatic, two-arm, parallel group, individually randomised controlled trial to determine the population benefit of an occupational therapy based intervention for community living people aged 65 years or older. Participants (n = 268) will be identified in one city in the North of England and in North Wales through GP mail-outs, signposting by local authority, primary care staff and voluntary sector organisations and through community engagement. Participants will be randomised to one of two treatment arms: an intervention (Lifestyle Matters programme); or control (routine access to health and social care). All participants will be assessed at baseline, 6 and 24 months post-randomisation. The primary outcome, which is a person reported outcome, is the SF-36 Mental Health dimension at six months post randomisation. Secondary outcome measures have been selected to measure psychosocial, physical and mental health outcomes. They include other dimensions of the SF36, EQ-5D-3L, Brief Resilience Scale, General Perceived Self Efficacy Scale, PHQ-9, de Jong Gierveld Loneliness Scale, Health and Social Care Resource Use and the wellbeing question of the Integrated Household Survey 2011. A cost effectiveness analysis will investigate the incremental cost per Quality Adjusted Life Years (QALYs) of the Lifestyle Matters intervention compared with treatment as usual., Discussion: The questions being posed through this research are important given the increasing numbers of older people, pressure on the public purse and the associated need to support good health in the extended lifespan. The proposed trial will determine the clinical and cost effectiveness of the intervention delivered in a UK context. The results will support commissioners and providers with decisions about implementation., Trial Registration: Current Controlled Trials ISRCTN67209155.

A new route to trisubstituted olefins through a palladium-catalyzed alkyne insertion/reduction reaction with unactivated alkyl iodides is reported. The reaction proceeds under mild conditions and tolerates a range of functional groups and substitution patterns. Preliminary mechanistic inquiry suggests that the transformation may proceed through a hybrid radical/organometallic pathway.

Several theorists have described memory in Parkinson's disease (PD) as involving an amplification of the deficits seen in normal aging, and drawn parallels between PD and frontal lesion patients. Both normal aging and frontal lobe damage impair memory for the context in which one has encountered information (i.e., source memory). We thus sought to determine whether PD patients would show especially poor source memory. We assessed memory for perceptual (voice), spatial (location of loudspeaker), and temporal (list) source memory in 18 PD patients, 23 healthy older adults, and 35 young people. Although both the healthy aged and PD groups performed more poorly than the young on most of the memory tests, the PD patients failed to show significantly greater impairments than the healthy older adults. The PD patients did perform more poorly, however, on a measure of executive function (the Wisconsin Card Sorting Test [WCST]). We discuss potential reasons why PD had a surprisingly minimal effect on source memory in our study, and relate our data to broader theories of memory impairment in Parkinson's disease., (© 2013 The British Psychological Society.)

The Pd-catalyzed TBHP-mediated Wacker-type oxidation of internal alkenes is reported. The reaction uses 2-(4,5-dihydro-2-oxazolyl)quinoline (Quinox) as ligand and TBHP(aq) as oxidant to deliver single ketone constitutional isomer products in a predictable fashion from electronically biased olefins. This methodology is showcased through its application on an advanced intermediate in the total synthesis of the antimalarial drug artemisinin.

Background: The National School Health Policy guidelines (2002) stipulate that primary school learners should have their vision, speech, hearing, mental health, teeth, nutrition and development screened annually. In reality, especially in under-resourced areas such as the Eastern Cape, many learners with disabilities are not identified, with profound consequences for their ability to learn., Method: This article describes a cost-effective and community-empowering solution, Learner-to-Learner Visual Acuity Screening, whereby secondary school learners were trained to conduct basic visual acuity (VA) eye screening for foundation-phase learners., Results: Of a group of Grade R learners, 30% were identified as having impaired VA and referred for ophthalmic or optometric evaluation., Conclusions: This project created greater awareness among learners, parents and teachers regarding abnormal VA and increased interaction between secondary and primary school learners. This simple and cost-effective strategy could be easily and effectively replicated in other schools, helping to address the need for basic eye care.

The iron-catalyzed cross-coupling of aryl sulfamates and tosylates has been achieved with primary and secondary alkyl Grignards. This study of iron-catalyzed cross-coupling reactions also examines the isomerization and β-hydride elimination problems that are associated with the use of isopropyl nucleophiles. While a variety of iron sources were competent in the reaction, the use of FeF(3)•3H(2)O was critical to minimize nucleophile isomerization.

A palladium-catalyzed alkyne insertion/Suzuki reaction with unactivated alkyl iodides is described. Under the reaction conditions, selective migratory insertion of alkynes avoids β-hydride elimination and provides a facile synthesis of stereodefined, tetrasubstituted olefins. The transformation offers broad substrate scope for both the alkyl iodide and boron nucleophile. Mechanistic studies have revealed inversion of the stereocenter for the carbon bearing the iodide.

Malaria represents one of the most medically and economically debilitating diseases present in the world today. Fortunately, there exists a highly effective treatment based on the natural product artemisinin. Despite the development of several synthetic approaches to the natural product, a streamlined synthesis that utilizes low-cost chemical inputs has yet to materialize. Here we report an efficient, cost-effective approach to artemisinin. Key to the success of the strategy was the development of mild, complexity-building reaction cascades that allowed the use of readily available, affordable cyclohexenone as the key starting material.

The reduction of a palladium enolate prior to β-hydride elimination provides a unique reaction for the synthesis of the hydroazulene ring system. When combined with a transannular epoxide rearrangement cascade, the reductive-Heck reaction allows rapid entry to the oxo-bridged guaiane core of the englerins.

Voltage-gated sodium channels (VGSC) contribute to the initiation and propagation of action potentials within the nervous system. These channels are important targets for inhibition by several classes of drugs, including antiarrhythmics and local anesthetics. Structural and pharmacological studies have localized the binding of these drugs to a common site near the channel's intracellular pore region. Point mutations within this region disrupt local anesthetic inhibition of cardiac, CNS, and skeletal muscle VGSC subtypes. This study was designed to test whether a similar structural requirement for drug binding exists on the peripheral neuronal VGSC subtype; Na(v)1.7. In support of this hypothesis, an alanine substitution for phenylalanine at position 1737 (F1737A) in the pore lining S6 segment of domain IV in human Na(v)1.7 reduced both use- and state- dependent inhibition of the local anesthetics, lidocaine and tetracaine, by 8-21-fold. We also saw a 2-3-fold reduction in tonic inhibition with the F1737A mutant. The voltage dependence of both activation and inactivation were unaffected by the F1737A mutation, however, fast inactivation kinetics were impaired, such that a significant portion of inward current remained at the end of a 20-ms depolarization. These data suggest that F1737 forms a part of the high affinity binding of local anesthetics as well as mediating inactivation processes of neuronal Na(v)1.7 channels.

Measurements of δ(13)C in CO(2) have traditionally relied on samples stored in sealed vessels and subsequently analyzed using magnetic sector isotope ratio mass spectrometry (IRMS), an accurate but expensive and high-maintenance analytical method. Recent developments in optical spectroscopy have yielded instruments that can measure δ(13)CO(2) in continuous streams of air with precision and accuracy approaching those of IRMS, but at a fraction of the cost. However, continuous sampling is unsuited for certain applications, creating a need for conversion of these instruments for batch operation. Here, we present a flask (syringe) adaptor that allows the collection and storage of small aliquots (20-30 mL air) for injection into the cavity ring-down spectroscopy (CRDS) instrument. We demonstrate that the adaptor's precision is similar to that of traditional IRMS (standard deviation of 0.3‰ for 385 ppm CO(2) standard gas). In addition, the concentration precision (±0.3% of sample concentration) was higher for CRDS than for IRMS (±7% of sample concentration). Using the adaptor in conjunction with CRDS, we sampled soil chambers and found that soil-respired δ(13)C varied between two different locations in a piñon-juniper woodland. In a second experiment, we found no significant discrimination between the respiration of a small beetle (~5 mm) and its diet. Our work shows that the CRDS system is flexible enough to be used for the analysis of batch samples as well as for continuous sampling. This flexibility broadens the range of applications for which CRDS has the potential to replace magnetic sector IRMS., (Copyright © 2011 John Wiley & Sons, Ltd.)

A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 μM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics., (Copyright © 2011 Elsevier Ltd. All rights reserved.)