Site-Selective Cross-Coupling of Remote Chlorides Enabled by Electrostatically-Directed Palladium Catalysis

Control of site-selectivity in chemical reactions that occur remote from existing functionality remains a major challenge in synthetic chemistry. We describe a strategy that enables three of the most commonly used cross-coupling processes to occur with high site-selectivity on dichloroarenes which bear acidic functional groups. We have achieved this by repurposing an established sulfonylated phosphine ligand to exploit its inherent bifunctionality. Mechanistic studies suggest that the sulfonate group engages in attractive electrostatic interactions with the associated cation of deprotonated substrate, guiding cross-coupling to the chloride at the arene meta-position. This counterintuitive combination of anionic ligand and anionic substrate demonstrates an alternative design principle when considering applying non-covalent interactions to direct catalysis.We are grateful to AstraZeneca for PhD studentships through the AZ‐Cambridge PhD program (W.A.G. and R.P.), the Royal Society for a University Research Fellowship (R.J.P.), the EPSRC (EP/N005422/1) and the ERC (StG 757381)

Winter wren populations show adaptation to local climate

Most studies of evolutionary responses to climate change have focused on phenological responses to warming, and provide only weak evidence for evolutionary adaptation. This could be because phenological changes are more weakly linked to fitness than more direct mechanisms of climate change impacts, such as selective mortality during extreme weather events which have immediate fitness consequences for the individuals involved. Studies examining these other mechanisms may be more likely to show evidence for evolutionary adaptation. To test this, we quantify regional population responses of a small resident passerine (winter wren Troglodytes troglodytes) to a measure of winter severity (number of frost days). Annual population growth rate was consistently negatively correlated with this measure, but the point at which different populations achieved stability (λ = 1) varied across regions and was closely correlated with the historic average number of frost days, providing strong evidence for local adaptation. Despite this, regional variation in abundance remained negatively related to the regional mean number of winter frost days, potentially as a result of a time-lag in the rate of evolutionary response to climate change. As expected from Bergmann's rule, individual wrens were heavier in colder regions, suggesting that local adaptation may be mediated through body size. However, there was no evidence for selective mortality of small individuals in cold years, with annual variation in mean body size uncorrelated with the number of winter frost days, so the extent to which local adaptation occurs through changes in body size, or another mechanism remains uncertain

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Control of selectivity in palladium-catalysed cross-coupling reactions using a sulfonated phosphine ligand

Non-covalent interactions are routinely used by enzymes to control selectivity of chemical reactions during biosynthesis. This prevalence in nature has inspired chemists to adapt these interactions to control selectivity in small molecule catalysis. This thesis describes efforts towards utilising non-covalent interactions to influence site-selectivity and enantioselectivity during palladium-catalysed cross-coupling reactions – a category of transformations used widely by synthetic chemists for many purposes. This thesis focuses on members of the privileged dialkylbiarylphosphine ligand class, specifically sSPhos, which is the commercially available sulfonated variant of SPhos. The first part investigates the use of this ligand to impart site-selectivity in the cross-coupling of 3,4-dichloroarenes containing an acidic directing group. Selectivity was proposed to arise from an electrostatic interaction between the deprotonated substrate, the cation of the base and the anionic ligand. An intriguing characteristic of sSPhos is that it is a chiral molecule due to its desymmetrisation upon sulfonation. Resolution of the two enantiomers was achieved initially by preparative supercritical fluid chromatography in collaboration with AstraZeneca, and later by chemical resolution using a chiral auxiliary, work described in this thesis. The second half of this thesis evaluates the efficacy of this new chiral ligand in two classes of asymmetric Suzuki-Miyaura coupling: desymmetrisation, and formation of atropisomers. Desymmetrisation was investigated on protected benzyhydrylamines resulting in good to excellent enantioselectivities being observed. The formation of atropisomeric biaryls was investigated with a wide range of coupling partners, with moderate to good enantioselectivity observed for coupling partners containing polar functionality. Excellent enantioselectivity was observed for the synthesis of 2,2’-biphenols: a scaffold prevalent in natural products as well as in numerous privileged catalysts. Overall, this work demonstrates the utility of the privileged ligand sSPhos on controlling site- and enantio- selectivity in palladium-catalysed cross-coupling reactions using non-covalent interactions.AstraZeneca Funde

Collation of a century of soil invertebrate abundance data suggests long-term declines in earthworms but not tipulids.

Large-scale declines in terrestrial insects have been reported over much of Europe and across the world, however, population change assessments of other key invertebrate groups, such as soil invertebrates, have been largely neglected through a lack of available monitoring data. This study collates historic data from previously published studies to assess whether it is possible to infer previously undocumented long-term changes in soil invertebrate abundance. Earthworm and tipulid data were collated from over 100 studies across the UK, spanning almost 100 years. Analyses suggested long-term declines in earthworm abundance of between 1.6 to 2.1% per annum, equivalent to a 33% to 41% decline over 25 years. These appeared greatest in broadleaved woodlands and farmland habitats, and were greater in pasture than arable farmland. Significant differences in earthworm abundance between habitats varied between models but appeared to be highest in urban greenspaces and agricultural pasture. More limited data were available on tipulid abundance, which showed no significant change over time or variation between enclosed farmland and unenclosed habitats. Declines in earthworm populations could be contributing to overall declines in ecosystem function and biodiversity as they are vital for a range of ecosystem services and are keystone prey for many vertebrate species. If robust, our results identify a previously undetected biodiversity decline that would be a significant conservation and economic issue in the UK, and if replicated elsewhere, internationally. We highlight the need for long-term and large-scale soil invertebrate monitoring, which potentially could be carried out by citizen/community scientists

Collation of a century of soil invertebrate abundance data suggests long-term declines in earthworms but not tipulids.

Large-scale declines in terrestrial insects have been reported over much of Europe and across the world, however, population change assessments of other key invertebrate groups, such as soil invertebrates, have been largely neglected through a lack of available monitoring data. This study collates historic data from previously published studies to assess whether it is possible to infer previously undocumented long-term changes in soil invertebrate abundance. Earthworm and tipulid data were collated from over 100 studies across the UK, spanning almost 100 years. Analyses suggested long-term declines in earthworm abundance of between 1.6 to 2.1% per annum, equivalent to a 33% to 41% decline over 25 years. These appeared greatest in broadleaved woodlands and farmland habitats, and were greater in pasture than arable farmland. Significant differences in earthworm abundance between habitats varied between models but appeared to be highest in urban greenspaces and agricultural pasture. More limited data were available on tipulid abundance, which showed no significant change over time or variation between enclosed farmland and unenclosed habitats. Declines in earthworm populations could be contributing to overall declines in ecosystem function and biodiversity as they are vital for a range of ecosystem services and are keystone prey for many vertebrate species. If robust, our results identify a previously undetected biodiversity decline that would be a significant conservation and economic issue in the UK, and if replicated elsewhere, internationally. We highlight the need for long-term and large-scale soil invertebrate monitoring, which potentially could be carried out by citizen/community scientists

Collation of a century of soil invertebrate abundance data suggests long-term declines in earthworms but not tipulids.

Acknowledgements: We would like to acknowledge the help of UEA Master’s students Rhianna Wren, Evan Burdett, Abigail Hunns and Ashis Datta who assisted with the review and identification of relevant papers.Funder: BTO Donations and MembershipsFunder: Penchant FoundationFunder: Kenneth Trouth Gift in WillLarge-scale declines in terrestrial insects have been reported over much of Europe and across the world, however, population change assessments of other key invertebrate groups, such as soil invertebrates, have been largely neglected through a lack of available monitoring data. This study collates historic data from previously published studies to assess whether it is possible to infer previously undocumented long-term changes in soil invertebrate abundance. Earthworm and tipulid data were collated from over 100 studies across the UK, spanning almost 100 years. Analyses suggested long-term declines in earthworm abundance of between 1.6 to 2.1% per annum, equivalent to a 33% to 41% decline over 25 years. These appeared greatest in broadleaved woodlands and farmland habitats, and were greater in pasture than arable farmland. Significant differences in earthworm abundance between habitats varied between models but appeared to be highest in urban greenspaces and agricultural pasture. More limited data were available on tipulid abundance, which showed no significant change over time or variation between enclosed farmland and unenclosed habitats. Declines in earthworm populations could be contributing to overall declines in ecosystem function and biodiversity as they are vital for a range of ecosystem services and are keystone prey for many vertebrate species. If robust, our results identify a previously undetected biodiversity decline that would be a significant conservation and economic issue in the UK, and if replicated elsewhere, internationally. We highlight the need for long-term and large-scale soil invertebrate monitoring, which potentially could be carried out by citizen/community scientists

Wren BBS

Wren BBS datase

Wren biometrics

Wren biometric datase