Et3SiH + KOtBu provide multiple reactive intermediates that compete in the reactions and rearrangements of benzylnitriles and indolenines

The combination of potassium tert-butoxide and triethylsilane is unusual because it generates multiple different types of reactive intermediates simultaneously that provide access to (i) silyl radical reactions, (ii) hydrogen atom transfer reactions to closed shell molecules and to radicals, (iii) electron transfer reductions and (iv) hydride ion chemistry, giving scope for unprecedented outcomes. Until now, reactions with this reagent pair have generally been explained by reference to one of the intermediates, but we now highlight the interplay and competition between them

Bridge functionalisation of bicyclo[1.1.1]pentane derivatives

"Escaping from flatland", by increasing the saturation level and three-dimensionality of drug-like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert-butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well-documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This minireview aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years

New reductive rearrangement of N-Arylindoles triggered by the Grubbs-Stoltz reagent Et3SiH/KOtBu

N-Arylindoles are transformed into dihydroacridines in a new type of rearrangement, through heating with triethylsilane and potassium tert-butoxide. Studies indicate that the pathway involves (i) the formation of indole radical anions followed by fragmentation of the indole C2-N bond, and (ii) a ring-closing reaction that follows a potassium-ion dependent hydrogen atom transfer step. Unexpected behaviors of ‘radical-trap’ substrates prove very helpful in framing the proposed mechanis

The NSAID glafenine rescues class 2 CFTR mutants via cyclooxygenase 2 inhibition of the arachidonic acid pathway

Most cases of cystic fibrosis (CF) are caused by class 2 mutations in the cystic fibrosis transmembrane regulator (CFTR). These proteins preserve some channel function but are retained in the endoplasmic reticulum (ER). Partial rescue of the most common CFTR class 2 mutant, F508del-CFTR, has been achieved through the development of pharmacological chaperones (Tezacaftor and Elexacaftor) that bind CFTR directly. However, it is not clear whether these drugs will rescue all class 2 CFTR mutants to a medically relevant level. We have previously shown that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen can correct F508del-CFTR trafficking. Here, we utilized RNAi and pharmacological inhibitors to determine the mechanism of action of the NSAID glafenine. Using cellular thermal stability assays (CETSAs), we show that it is a proteostasis modulator. Using medicinal chemistry, we identified a derivative with a fourfold increase in CFTR corrector potency. Furthermore, we show that these novel arachidonic acid pathway inhibitors can rescue difficult-to-correct class 2 mutants, such as G85E-CFTR > 13%, that of non-CF cells in well-differentiated HBE cells. Thus, the results suggest that targeting the arachidonic acid pathway may be a profitable way of developing correctors of certain previously hard-to-correct class 2 CFTR mutations

Behavioral responses of terrestrial mammals to COVID-19 lockdowns

DATA AND MATERIALS AVAILABILITY : The full dataset used in the final analyses (33) and associated code (34) are available at Dryad. A subset of the spatial coordinate datasets is available at Zenodo (35). Certain datasets of spatial coordinates will be available only through requests made to the authors due to conservation and Indigenous sovereignty concerns (see table S1 for more information on data use restrictions and contact information for data requests). These sensitive data will be made available upon request to qualified researchers for research purposes, provided that the data use will not threaten the study populations, such as by distribution or publication of the coordinates or detailed maps. Some datasets, such as those overseen by government agencies, have additional legal restrictions on data sharing, and researchers may need to formally apply for data access. Collaborations with data holders are generally encouraged, and in cases where data are held by Indigenous groups or institutions from regions that are under-represented in the global science community, collaboration may be required to ensure inclusion.COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals’ 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.The Radboud Excellence Initiative, the German Federal Ministry of Education and Research, the National Science Foundation, Serbian Ministry of Education, Science and Technological Development, Dutch Research Council NWO program “Advanced Instrumentation for Wildlife Protection”, Fondation Segré, RZSS, IPE, Greensboro Science Center, Houston Zoo, Jacksonville Zoo and Gardens, Nashville Zoo, Naples Zoo, Reid Park Zoo, Miller Park, WWF, ZCOG, Zoo Miami, Zoo Miami Foundation, Beauval Nature, Greenville Zoo, Riverbanks zoo and garden, SAC Zoo, La Passarelle Conservation, Parc Animalier d’Auvergne, Disney Conservation Fund, Fresno Chaffee zoo, Play for nature, North Florida Wildlife Center, Abilene Zoo, a Liber Ero Fellowship, the Fish and Wildlife Compensation Program, Habitat Conservation Trust Foundation, Teck Coal, and the Grand Teton Association. The collection of Norwegian moose data was funded by the Norwegian Environment Agency, the German Ministry of Education and Research via the SPACES II project ORYCS, the Wyoming Game and Fish Department, Wyoming Game and Fish Commission, Bureau of Land Management, Muley Fanatic Foundation (including Southwest, Kemmerer, Upper Green, and Blue Ridge Chapters), Boone and Crockett Club, Wyoming Wildlife and Natural Resources Trust, Knobloch Family Foundation, Wyoming Animal Damage Management Board, Wyoming Governor’s Big Game License Coalition, Bowhunters of Wyoming, Wyoming Outfitters and Guides Association, Pope and Young Club, US Forest Service, US Fish and Wildlife Service, the Rocky Mountain Elk Foundation, Wyoming Wild Sheep Foundation, Wild Sheep Foundation, Wyoming Wildlife/Livestock Disease Research Partnership, the US National Science Foundation [IOS-1656642 and IOS-1656527, the Spanish Ministry of Economy, Industry and Competitiveness, and by a GRUPIN research grant from the Regional Government of Asturias, Sigrid Rausing Trust, Batubay Özkan, Barbara Watkins, NSERC Discovery Grant, the Federal Aid in Wildlife Restoration act under Pittman-Robertson project, the State University of New York, College of Environmental Science and Forestry, the Ministry of Education, Youth and Sport of the Czech Republic, the Ministry of Agriculture of the Czech Republic, Rufford Foundation, an American Society of Mammalogists African Graduate Student Research Fund, the German Science Foundation, the Israeli Science Foundation, the BSF-NSF, the Ministry of Agriculture, Forestry and Food and Slovenian Research Agency (CRP V1-1626), the Aage V. Jensen Naturfond (project: Kronvildt - viden, værdier og værktøjer), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy, National Centre for Research and Development in Poland, the Slovenian Research Agency, the David Shepherd Wildlife Foundation, Disney Conservation Fund, Whitley Fund for Nature, Acton Family Giving, Zoo Basel, Columbus, Bioparc de Doué-la-Fontaine, Zoo Dresden, Zoo Idaho, Kolmården Zoo, Korkeasaari Zoo, La Passarelle, Zoo New England, Tierpark Berlin, Tulsa Zoo, the Ministry of Environment and Tourism, Government of Mongolia, the Mongolian Academy of Sciences, the Federal Aid in Wildlife Restoration act and the Illinois Department of Natural Resources, the National Science Foundation, Parks Canada, Natural Sciences and Engineering Research Council, Alberta Environment and Parks, Rocky Mountain Elk Foundation, Safari Club International and Alberta Conservation Association, the Consejo Nacional de Ciencias y Tecnología (CONACYT) of Paraguay, the Norwegian Environment Agency and the Swedish Environmental Protection Agency, EU funded Interreg SI-HR 410 Carnivora Dinarica project, Paklenica and Plitvice Lakes National Parks, UK Wolf Conservation Trust, EURONATUR and Bernd Thies Foundation, the Messerli Foundation in Switzerland and WWF Germany, the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions, NASA Ecological Forecasting Program, the Ecotone Telemetry company, the French National Research Agency, LANDTHIRST, grant REPOS awarded by the i-Site MUSE thanks to the “Investissements d’avenir” program, the ANR Mov-It project, the USDA Hatch Act Formula Funding, the Fondation Segre and North American and European Zoos listed at http://www.giantanteater.org/, the Utah Division of Wildlife Resources, the Yellowstone Forever and the National Park Service, Missouri Department of Conservation, Federal Aid in Wildlife Restoration Grant, and State University of New York, various donors to the Botswana Predator Conservation Program, data from collared caribou in the Northwest Territories were made available through funds from the Department of Environment and Natural Resources, Government of the Northwest Territories. The European Research Council Horizon2020, the British Ecological Society, the Paul Jones Family Trust, and the Lord Kelvin Adam Smith fund, the Tanzania Wildlife Research Institute and Tanzania National Parks. The Eastern Shoshone and Northern Arapahoe Fish and Game Department and the Wyoming State Veterinary Laboratory, the Alaska Department of Fish and Game, Kodiak Brown Bear Trust, Rocky Mountain Elk Foundation, Koniag Native Corporation, Old Harbor Native Corporation, Afognak Native Corporation, Ouzinkie Native Corporation, Natives of Kodiak Native Corporation and the State University of New York, College of Environmental Science and Forestry, and the Slovenia Hunters Association and Slovenia Forest Service. F.C. was partly supported by the Resident Visiting Researcher Fellowship, IMéRA/Aix-Marseille Université, Marseille. This work was partially funded by the Center of Advanced Systems Understanding (CASUS), which is financed by Germany’s Federal Ministry of Education and Research (BMBF) and by the Saxon Ministry for Science, Culture and Tourism (SMWK) with tax funds on the basis of the budget approved by the Saxon State Parliament. This article is a contribution of the COVID-19 Bio-Logging Initiative, which is funded in part by the Gordon and Betty Moore Foundation (GBMF9881) and the National Geographic Society.https://www.science.org/journal/sciencehj2023Mammal Research InstituteZoology and Entomolog

Studies towards the nucleophilic dearomatisation of electron-deficient heteroaromatics and hydrogen borrowing reactions of methanol

Introduction – Dearomatisation of Heteroaromatic Compounds The introduction provides a survey of dearomatisation reaction of heteroaromatics, with a particular focus on pyridines/pyridinium salts and furans. The mechanism, scope, and limitations of various approaches are covered, along with the goals of this project. Results and Discussion – Dearomatisation of Electron-Deficient Heteroaromatics This chapter initially explores the asymmetric addition of organometallic nucleophiles to pyridinium salts bearing a chiral counterion. Unfortunately, this approach ultimately proved unsuccessful, due to low observed enantioselectivities, and the low solubility of such salts. The second part of this chapter concerns the attempted asymmetric addition of dicarbonyl nucleophiles to electron-deficient furans, under conditions of chiral phase-transfer catalysts, affording bicyclic products in moderate enantioselectivity. Various alternative routes were also explored for the dearomatisation of furans and benzenoid systems. Introduction – Hydrogen Borrowing Alkylation Reactions with Alcohols The introduction surveys the range of methods available for the alkylation of various nucleophiles with alcohols under transition metal-catalysed conditions. Related methodologies are also explored, along with methods for the dehydrogenation of methanol. Results and Discussion - Rhodium-catalysed Methylation of Ketones Using Methanol This chapter describes the development of a novel ketone α-methylation using methanol. The development of reaction conditions is explored, followed by expansion of the substrate scope, including limitations of the methylation reaction. Mechanistic investigations support a methanol oxidation, aldol reaction/elimination, conjugate reduction pathway. Investigations into the role of O2 in the methylation reaction proved inconclusive. The utility of the reaction was also expanded via one-pot dialkylation reactions (work by Di Shen), Baeyer-Villiger oxidation of the products, and an attempted asymmetric transfer-hydrogenation. Results and Discussion - Interrupted Hydrogen Borrowing Reactions of Methanol This chapter looks to intercept intermediates from the α-methylation reaction. The selective methylenation of ketones is described, and a range of nucleophiles are screened for further functionalisation of ketones. Finally, a number of nucleophiles, including nitroalkanes, amines, peroxides and boronic acids are applied to one pot methylenation/conjugate addition protocols, affording complex products after two steps in one reaction vessel. Experimental Full experimental procedures and spectroscopic characterisation of compounds are provided.This thesis is not currently available in OR

Introduction to synthetic electrochemistry: new tricks for an old discipline

Guest Editors Kevin Lam, Shelley D. Minteer and Darren L. Poole introduce the Organic & Biomolecular Chemistry themed issue on synthetic electrochemistry