Transamidation, or the conversion of one amide to another, is a long-standing challenge in organic synthesis. Although notable progress has been made in the transamidation of primary amides, the ...transamidation of secondary amides has remained underdeveloped, especially when considering aliphatic substrates. Herein, we report a two-step approach to achieve the transamidation of secondary aliphatic amides, which relies on non-precious metal catalysis. The method involves initial Boc-functionalization of secondary amide substrates to weaken the amide C-N bond. Subsequent treatment with a nickel catalyst, in the presence of an appropriate amine coupling partner, then delivers the net transamidated products. The transformation proceeds in synthetically useful yields across a range of substrates. A series of competition experiments delineate selectivity patterns that should influence future synthetic design. Moreover, the transamidation of Boc-activated secondary amide derivatives bearing epimerizable stereocenters underscores the mildness and synthetic utility of this methodology. This study provides the most general solution to the classic problem of secondary amide transamidation reported to date.
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IJS, KILJ, NUK, UL, UM, UPUK
The Suzuki-Miyaura coupling has become one of the most important and prevalent methods for the construction of C-C bonds. Although palladium catalysis has historically dominated the field, the use of ...nickel catalysis has become increasingly widespread because of its unique ability to cleave carbon-heteroatom bonds that are unreactive towards other transition metals. We report the first nickel-catalysed Suzuki-Miyaura coupling of amides, which proceeds by an uncommon cleavage of the amide C-N bond after N-tert-butoxycarbonyl activation. The methodology is mild, functional-group tolerant and can be strategically employed in sequential transition-metal-catalysed cross-coupling sequences to unite heterocyclic fragments. These studies demonstrate that amides, despite classically considered inert substrates, can be harnessed as synthons for use in reactions that form C-C bonds through cleavage of the C-N bond using non-precious metal catalysis.
A long-standing challenge in synthetic chemistry is the development of the transamidation reaction. This process, which involves the conversion of one amide to another, is typically plagued by ...unfavourable kinetic and thermodynamic factors. Although some advances have been made with regard to the transamidation of primary amide substrates, secondary amide transamidation has remained elusive. Here we present a simple two-step approach that allows for the elusive overall transformation to take place using non-precious metal catalysis. The methodology proceeds under exceptionally mild reaction conditions and is tolerant of amino-acid-derived nucleophiles. In addition to overcoming the classic problem of secondary amide transamidation, our studies expand the growing repertoire of new transformations mediated by base metal catalysis.
Background Foot orthoses are widely used in clinical practice to treat foot, lower limb and back pathology. As published information guiding the clinical use of foot orthoses is scarce, the aim of ...this study is to profile the review processes used by practicing podiatrists after issuing an orthotic device. Methods A cross-sectional observational study design formed the basis for a self-administered online questionnaire. The questionnaire was distributed through podiatry networks based in Australia. Results Two-hundred and thirty-eight practicing podiatrists participated in this study. Ninety-seven percent of respondents indicated that they would recommend a review appointment after the initial fitting of an orthotic device. Forty percent (n = 84) of respondents scheduled the first review appointment four weeks after the initial fitting, while 33% (n = 69) preferred a two-week review period. A second review consultation was standard practice for 32% (n = 68) or respondents, and were typically scheduled either two (23%, n = 12) or four (38%, n = 20) weeks after the initial review consultation. Annual review of orthotic devices was recommended by 64% (n = 123) of participants in the study, while 19% (n = 37) would suggest that yearly reviews were scheduled only if required. Conclusions Variation was identified in the orthotic review processes used by practicing podiatrists, although most respondents recommend a routine short-term review appointment for foot orthoses. It is not clear why practitioners adopt such varied approaches. In the absence of any clear evidence on this topic, it may be that the differing approaches to patient review reflect different philosophical perspectives regarding patient management.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In health, the glucose concentration of airway surface liquid (ASL) is 0.4 mM, about 12 times lower than the blood glucose concentration. Airway glucose homeostasis comprises a set of processes that ...actively maintain low ASL glucose concentration against the transepithelial gradient. Tight junctions between airway epithelial cells restrict paracellular glucose movement. Epithelial cellular glucose transport and metabolism removes glucose from ASL. Low ASL glucose concentrations make an important contribution to airway defense against infection, limiting bacterial growth by restricting nutrient availability. Both airway inflammation, which increases glucose permeability of tight junctions, and hyperglycemia, which increases the transepithelial glucose gradient, increase ASL glucose concentrations, with the greatest effect seen where they coexist. Elevated ASL glucose drives proliferation of bacteria able to use glucose as a carbon source, including Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacteria. Clinically, this appears to be important in driving exacerbations of chronic lung disease, especially in patients with comorbid diabetes mellitus. Drugs can restore airway glucose homeostasis by reducing the permeability of tight junctions (eg, metformin), increasing epithelial cell glucose transport (eg, β-agonists, insulin), and/or by lowering blood glucose (eg, dapagliflozin). In cell culture and animal models these reduce ASL glucose concentrations and limit bacterial growth, preventing infection. Observational studies in humans indicate that airway glucose homeostasis-modifying drugs could prevent chronic lung disease exacerbations if tested in randomized trials.
Recent studies have demonstrated that amides can be used in nickel‐catalyzed reactions that lead to cleavage of the amide C−N bond, with formation of a C−C or C−heteroatom bond. However, the general ...scope of these methodologies has been restricted to amides where the carbonyl is directly attached to an arene or heteroarene. We now report the nickel‐catalyzed esterification of amides derived from aliphatic carboxylic acids. The transformation requires only a slight excess of the alcohol nucleophile and is tolerant of heterocycles, substrates with epimerizable stereocenters, and sterically congested coupling partners. Moreover, a series of amide competition experiments establish selectivity principles that will aid future synthetic design. These studies overcome a critical limitation of current Ni‐catalyzed amide couplings and are expected to further stimulate the use of amides as synthetic building blocks in C−N bond cleavage processes.
Going aliphatic: In prior studies the nickel‐catalyzed activation of aromatic amides to forge C−C or C−heteroatom bonds through cleavage on the amide C−N bond has been developed. The first nickel‐catalyzed activation of amides derived from aliphatic carboxylic acids is now described, thus overcoming the key limitation associated with this class of reactions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To examine sleep patterns and sleep problems and their relationship with daytime functioning in adults with a diagnosis of an autism spectrum disorder and no comorbid intellectual disability ...(high-functioning autism spectrum disorder HFASD) compared to neurotypical (NT) adults.
Cross-sectional.
Home-based study.
36 adults with HFASD and 36 age-, intelligence quotient- and sex-matched NT adults.
Participants completed an online questionnaire battery including the Pittsburgh Sleep Quality Index (PSQI), a 14-d sleep wake diary and 14-d actigraphy data collection.
Adults with HFASD had significantly more general sleep disturbances and higher scores on the PSQI, longer sleep onset latencies (actigraphy), and poorer sleep efficiency (diary) and these results remained significant after accounting for the False Discovery Rate. Those adults with HFASD who did not have a comorbid diagnosis of anxiety/depression had significantly shorter total sleep time (diary and actigraphy) compared to NT adults. Compared to NT adults, the HFASD group self-reported significantly poorer refreshment scores upon waking in the morning and higher scores on the daytime dysfunction due to sleepiness subscale of the PSQI.
These findings support the notion that problems related to sleep, in particular insomnia, continue into adulthood in individuals with high-functioning autism spectrum disorder.
Amides are common functional groups that have been studied for more than a century. They are the key building blocks of proteins and are present in a broad range of other natural and synthetic ...compounds. Amides are known to be poor electrophiles, which is typically attributed to the resonance stability of the amide bond. Although amides can readily be cleaved by enzymes such as proteases, it is difficult to selectively break the carbon-nitrogen bond of an amide using synthetic chemistry. Here we demonstrate that amide carbon-nitrogen bonds can be activated and cleaved using nickel catalysts. We use this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. Our results provide a way to harness amide functional groups as synthetic building blocks and are expected to lead to the further use of amides in the construction of carbon-heteroatom or carbon-carbon bonds using non-precious-metal catalysis.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The human aptitude for imitation and social learning underpins our advanced cultural practices. While social learning is a valuable evolutionary survival strategy, blind copying does not necessarily ...facilitate survival. Copying from the majority allows individuals to make rapid judgments on the value of a trait, based on its frequency. This is known as the majority bias: an individual's tendency to copy the behavior elicited by the largest number of individuals in a population. An alternative approach is to follow those who are the most proficient. While there is evidence that children do show both processes, no study has directly pitted them against each other. To do this, in the current experiment 36 children aged between 4 and 5 years watched live actors demonstrate, as a group or individually, how to open novel puzzle boxes. Children exhibited a bias to the majority when group and individual methods were successful, but favored the individual if the group method was unsuccessful. Affiliating children with the unsuccessful majority group did not impact on this pattern.
Compares majority and proficiency biases in young children. Shows children will exhibit a majority bias, but not when it is inefficient, highlighting for the first time that children will copy to affiliate with a social group, though not if there is a cost to them doing so.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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